Dilated cardiomyopathy（DCM）is characterized by the dilated heart chambers and reduced systolic function in the absence of specific aetiology[1].Approximately one third of DCM cases are hereditary.In recent years,DCM...Dilated cardiomyopathy（DCM）is characterized by the dilated heart chambers and reduced systolic function in the absence of specific aetiology[1].Approximately one third of DCM cases are hereditary.In recent years,DCM concomitant with arrhythmias and sudden death resulting from gene mutation has been widely展开更多
Through advances in technology,the genetic basis of cancer has been investigated at the genomic level,and many fundamental questions have begun to be addressed.Among several key unresolved questions in cancer biology,...Through advances in technology,the genetic basis of cancer has been investigated at the genomic level,and many fundamental questions have begun to be addressed.Among several key unresolved questions in cancer biology,the molecular basis for the link between nuclear deformation and malignancy has not been determined.Another hallmark of human cancer is aneuploidy;however,the causes and consequences of aneuploidy are unanswered and are hotly contested topics.We found that nuclear lamina proteins lamin A/C are absent in a significant fraction(38%) of human breast cancer tissues.Even in lamin A/C-positive breast cancer,lamin A/C expression is heterogeneous or aberrant(such as non-nuclear distribution) in the population of tumor cells,as determined by immunohistology and immunofluorescence microscopy.In most breast cancer cell lines,a significant fraction of the lamin A/C-negative population was observed.To determine the consequences of the loss of lamin A/C,we suppressed their expression by shRNA in noncancerous primary breast epithelial cells.Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation,resembling that of cancer cells,as observed by immunofluorescence microscopy.The lamin A/C-suppressed breast epithelial cells developed aneuploidy as determined by both flow cytometry and fluorescence in situ hybridization.We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer aberrations in nuclear morphology and aneuploidy.展开更多
This paper proposes a higher-order shear deformation theory to predict the bending response of the laminated composite and sandwich plates with general lamination configurations.The proposed theory a priori satisfies ...This paper proposes a higher-order shear deformation theory to predict the bending response of the laminated composite and sandwich plates with general lamination configurations.The proposed theory a priori satisfies the continuity conditions of transverse shear stresses at interfaces.Moreover,the number of unknown variables is independent of the number of layers.The first derivatives of transverse displacements have been taken out from the inplane displacement fields,so that the C 0 shape functions are only required during its finite element implementation.Due to C 0 continuity requirements,the proposed model can be conveniently extended for implementation in commercial finite element codes.To verify the proposed theory,the fournode C 0 quadrilateral element is employed for the interpolation of all the displacement parameters defined at each nodal point on the composite plate.Numerical results show that following the proposed theory,simple C 0 finite elements could accurately predict the interlaminar stresses of laminated composite and sandwich plates directly from a constitutive equation,which has caused difficulty for the other global higher order theories.展开更多
Objective The apoptosis of vascular smooth muscle cells(VSMCs)influenced by abnormal cyclic stretch is crucial for vascular remodeling during hypertension.We explored that the causes of mechano-responsive lamin A/C ch...Objective The apoptosis of vascular smooth muscle cells(VSMCs)influenced by abnormal cyclic stretch is crucial for vascular remodeling during hypertension.We explored that the causes of mechano-responsive lamin A/C changingin aonormai cyclic stretcn and its roles in VSMC apoptosis.Methods and results Our previous vascular proteomics study revealed that LaminA/C is mechano-sensitive molecule.When VSMCs are subjected to cyclic stretch,the expression of LaminA/C is significantly changed which participates dysfunctions of VSMCs during hypertension.However,the molecular mechanism involved in regulation of LaminA/C expression and the role of LaminA/C in the VSMC apoptosis during cyclic stretch application are still unclear.In the present study,VSMCs were subjected to different amplitudes of cyclic steetch in vitro:5%cyclic stretch(physiological strain)or 15%cyclic stretch(pathological strain).The expression of 2 different selective cleavage isomers of LaminA/C,i.e.LaminA and LaminC,and the apoptosis of VSMCs were detected.The results showed that compared with 5%group,15%cyclic stretch significantly decreased the expression of LaminA and LaminC,and promoted the apoptosis of VSMCs.Using specific small interfering RNA(siRNA)transfection which targets on LMNA the encoding gene of LaminA/C,the expression of LaminA and LaminC in VSMCs was significantly decreased,and the apoptosis was significantly increased.In order to study the molecular mechanism involved in cyclic stretch regulating the expression of LaminA/C,we focused on the microRNA(miR).Bioinformatics analysis showed that the 3’untranslated region(3’UTR)of LMNA has two potential binding sites to miR-124-3p.Double luciferase reported system revealed that both sites have binding abilities to miR-124-3p.Under static condition,miR-124-3p inhibitor significantly up-regulated the expression levels of LaminA and LaminC,while the miR-124-3p mimics significantly down-regulated them.RT-PCR results showed that 15%cyclic stretch significantly up-regulated the expression of miR-124-3p compared with 5%cyclic stretch.Furthermore,in order to study the role of changeed LaminA/C in VSMC apoptosis,LMNA-specific siRNA was transfected to repress the expression of LaminA/C in VSMCs,and Protein/DNA microarray was used to detecte the activity of transcription factors.The transcription factors whose activity were changed significantly(increase or decrease more than 2 times)were analyzed by cluster analysis and ingenurity pathway analysis(IPA).Six transcription factors associated with apoptosis were screened,in which TP53 was activated by the specific siRNA transfection and the other 5 were inavtived,including TP53,CREB1,MYC,STAT1/5/6 and JUN.Using abdominal aorta coarctation hypertensive model,the change of miR-124-3p in VSMCs was explored in vivo.A marked increase of miR-124-3p in thoracic aorta was revealed compared with the sham-operated controls,and in situ FISH revealed that this increase was mainly in the VSMCs.Conclusions The present study suggest that abnormally increased cyclic stretch(15%)up-regulates the expression of miR-124-3p in VSMCs,which subsequently targets on the 3’UTR of LMNA and decreases the expression of nuclear envelope protein LaminA/C;the repressed LaminA/C may play an important role in the apoptosis of VSMCs by regulating the activity of virious transcription factors,such as TP53,CREB1,MYC,STAT1/5/6 and JUN.The present study may provide a new insight into understanding the molecular mechanisms of vascular remodeling.展开更多
The purpose of this paper is to apply the theoretical model developed in References [1] 08D0C9EA79F9BACE118C8200AA004BA90B02000000080000000E0000005F005200650066003400310032003700320039003100350035000000 -[6] 08D0C9EA7...The purpose of this paper is to apply the theoretical model developed in References [1] 08D0C9EA79F9BACE118C8200AA004BA90B02000000080000000E0000005F005200650066003400310032003700320039003100350035000000 -[6] 08D0C9EA79F9BACE118C8200AA004BA90B02000000080000000E0000005F005200650066003400310032003700320039003100360030000000 in order to analyze the geometrically nonlinear free dynamic response of C-C-SS-SS rectangular CFRP symmetrically laminated plates so as to investigate the effect of nonlinearity on the nonlinear resonance frequencies, the nonlinear fundamental mode shape and associated bending stress patterns at large vibration amplitudes. Various values of the plate aspect ratio and the amplitude of vibrations will be considered, and useful numerical data also are provided.展开更多
基金the funds of "the Youth Fund of Nantong Health Bureau 2015",ID:WQ2015009
文摘Dilated cardiomyopathy（DCM）is characterized by the dilated heart chambers and reduced systolic function in the absence of specific aetiology[1].Approximately one third of DCM cases are hereditary.In recent years,DCM concomitant with arrhythmias and sudden death resulting from gene mutation has been widely
基金supported by funds from concept awards BC097189 and BC076832 from Department of Defense(USA)Grants R01CA095071,R01CA099471,and CA79716to Xiang-Xi Xu from NCI
文摘Through advances in technology,the genetic basis of cancer has been investigated at the genomic level,and many fundamental questions have begun to be addressed.Among several key unresolved questions in cancer biology,the molecular basis for the link between nuclear deformation and malignancy has not been determined.Another hallmark of human cancer is aneuploidy;however,the causes and consequences of aneuploidy are unanswered and are hotly contested topics.We found that nuclear lamina proteins lamin A/C are absent in a significant fraction(38%) of human breast cancer tissues.Even in lamin A/C-positive breast cancer,lamin A/C expression is heterogeneous or aberrant(such as non-nuclear distribution) in the population of tumor cells,as determined by immunohistology and immunofluorescence microscopy.In most breast cancer cell lines,a significant fraction of the lamin A/C-negative population was observed.To determine the consequences of the loss of lamin A/C,we suppressed their expression by shRNA in noncancerous primary breast epithelial cells.Down-regulation of lamin A/C in breast epithelial cells led to morphological deformation,resembling that of cancer cells,as observed by immunofluorescence microscopy.The lamin A/C-suppressed breast epithelial cells developed aneuploidy as determined by both flow cytometry and fluorescence in situ hybridization.We conclude that the loss of nuclear envelope structural proteins lamin A/C in breast cancer underlies the two hallmarks of cancer aberrations in nuclear morphology and aneuploidy.
基金supported by the National Natural Science Foundation of China (10802052,11072156)the Program for Liaoning Excellent Talents in University (LR201033)the Program for Science and Technology of Shenyang (F10-205-1-16)
文摘This paper proposes a higher-order shear deformation theory to predict the bending response of the laminated composite and sandwich plates with general lamination configurations.The proposed theory a priori satisfies the continuity conditions of transverse shear stresses at interfaces.Moreover,the number of unknown variables is independent of the number of layers.The first derivatives of transverse displacements have been taken out from the inplane displacement fields,so that the C 0 shape functions are only required during its finite element implementation.Due to C 0 continuity requirements,the proposed model can be conveniently extended for implementation in commercial finite element codes.To verify the proposed theory,the fournode C 0 quadrilateral element is employed for the interpolation of all the displacement parameters defined at each nodal point on the composite plate.Numerical results show that following the proposed theory,simple C 0 finite elements could accurately predict the interlaminar stresses of laminated composite and sandwich plates directly from a constitutive equation,which has caused difficulty for the other global higher order theories.
基金supported by grants from the National Natural Science Foundation of China( 11572199 and 11625209)
文摘Objective The apoptosis of vascular smooth muscle cells(VSMCs)influenced by abnormal cyclic stretch is crucial for vascular remodeling during hypertension.We explored that the causes of mechano-responsive lamin A/C changingin aonormai cyclic stretcn and its roles in VSMC apoptosis.Methods and results Our previous vascular proteomics study revealed that LaminA/C is mechano-sensitive molecule.When VSMCs are subjected to cyclic stretch,the expression of LaminA/C is significantly changed which participates dysfunctions of VSMCs during hypertension.However,the molecular mechanism involved in regulation of LaminA/C expression and the role of LaminA/C in the VSMC apoptosis during cyclic stretch application are still unclear.In the present study,VSMCs were subjected to different amplitudes of cyclic steetch in vitro:5%cyclic stretch(physiological strain)or 15%cyclic stretch(pathological strain).The expression of 2 different selective cleavage isomers of LaminA/C,i.e.LaminA and LaminC,and the apoptosis of VSMCs were detected.The results showed that compared with 5%group,15%cyclic stretch significantly decreased the expression of LaminA and LaminC,and promoted the apoptosis of VSMCs.Using specific small interfering RNA(siRNA)transfection which targets on LMNA the encoding gene of LaminA/C,the expression of LaminA and LaminC in VSMCs was significantly decreased,and the apoptosis was significantly increased.In order to study the molecular mechanism involved in cyclic stretch regulating the expression of LaminA/C,we focused on the microRNA(miR).Bioinformatics analysis showed that the 3’untranslated region(3’UTR)of LMNA has two potential binding sites to miR-124-3p.Double luciferase reported system revealed that both sites have binding abilities to miR-124-3p.Under static condition,miR-124-3p inhibitor significantly up-regulated the expression levels of LaminA and LaminC,while the miR-124-3p mimics significantly down-regulated them.RT-PCR results showed that 15%cyclic stretch significantly up-regulated the expression of miR-124-3p compared with 5%cyclic stretch.Furthermore,in order to study the role of changeed LaminA/C in VSMC apoptosis,LMNA-specific siRNA was transfected to repress the expression of LaminA/C in VSMCs,and Protein/DNA microarray was used to detecte the activity of transcription factors.The transcription factors whose activity were changed significantly(increase or decrease more than 2 times)were analyzed by cluster analysis and ingenurity pathway analysis(IPA).Six transcription factors associated with apoptosis were screened,in which TP53 was activated by the specific siRNA transfection and the other 5 were inavtived,including TP53,CREB1,MYC,STAT1/5/6 and JUN.Using abdominal aorta coarctation hypertensive model,the change of miR-124-3p in VSMCs was explored in vivo.A marked increase of miR-124-3p in thoracic aorta was revealed compared with the sham-operated controls,and in situ FISH revealed that this increase was mainly in the VSMCs.Conclusions The present study suggest that abnormally increased cyclic stretch(15%)up-regulates the expression of miR-124-3p in VSMCs,which subsequently targets on the 3’UTR of LMNA and decreases the expression of nuclear envelope protein LaminA/C;the repressed LaminA/C may play an important role in the apoptosis of VSMCs by regulating the activity of virious transcription factors,such as TP53,CREB1,MYC,STAT1/5/6 and JUN.The present study may provide a new insight into understanding the molecular mechanisms of vascular remodeling.
文摘The purpose of this paper is to apply the theoretical model developed in References [1] 08D0C9EA79F9BACE118C8200AA004BA90B02000000080000000E0000005F005200650066003400310032003700320039003100350035000000 -[6] 08D0C9EA79F9BACE118C8200AA004BA90B02000000080000000E0000005F005200650066003400310032003700320039003100360030000000 in order to analyze the geometrically nonlinear free dynamic response of C-C-SS-SS rectangular CFRP symmetrically laminated plates so as to investigate the effect of nonlinearity on the nonlinear resonance frequencies, the nonlinear fundamental mode shape and associated bending stress patterns at large vibration amplitudes. Various values of the plate aspect ratio and the amplitude of vibrations will be considered, and useful numerical data also are provided.
