Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source fo...Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source for NPC survival,but the effects and underlying mechanisms of increased extracellular matrix(ECM)stiffness on NPC glycolysis remain unknown.In this study,hydrogels with different stiffness were established to mimic the mechanical environment of NPCs.Notably,increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis,and NPCs cultured on rigid substrates exhibited a reduction in glycolysis.展开更多
Changes in vascular stiffness are associated with the development and progression of many diseases, especially in cardiovascular disease. However, the effect of vascular stiffness on the endothelial cells (ECs) is not...Changes in vascular stiffness are associated with the development and progression of many diseases, especially in cardiovascular disease. However, the effect of vascular stiffness on the endothelial cells (ECs) is not fully understood. Therefore, this study aims to determine the gene expression changes of ECs cultured on the matrices with different stiffness (1 kPa and 40 kPa, respectively) by RNA-seq, thereby broadening the knowledge between mechanics and biology. We obtained 1775 differentially expressed genes (DEGs) by RNA-seq, with 450 up-regulated and 1325 down-regulated DEGs in ECs cultured on soft matrix (1 kPa) compared to those cultured on stiff matrix (40 kPa). After that, we performed a series of functional enrichment analyses based on DEGs and found that DEGs were enriched in many signaling pathways like adhesion junction. Furthermore, transcription factor (TF) target gene prediction analysis and protein-protein interaction (PPI) analysis were also conducted. We found that mechanotransduction signaling related TFs such as BRD4 are involved in. And in the PPI analysis, some genes encoding extracellular matrix proteins such as fibronectin 1 (FN1) were identified as the hub genes. In order to confirm the RNA-seq results, we performed real-time qPCR analysis on the genes of interest, including FN1, collagen α2 (IV) chain, matrix metalloproteinase-14 and integrin α5, and found that the expression levels of all these genes were down-regulated on soft matrix, suggesting that soft matrix caused by pathological conditions may directly attenuate vascular barrier function. This study offers the insights about the effects of physical stimulation on cells, paving a way for vascular tissue engineering, regenerative medicine, disease modeling and therapies.展开更多
The monocyte/macrophage infiltration plays critical roles in the development of atherosclerosis.Arterial stiffness is a cholesterol-independent risk factor for cardiovascular events.The regulation of arterial stiffnes...The monocyte/macrophage infiltration plays critical roles in the development of atherosclerosis.Arterial stiffness is a cholesterol-independent risk factor for cardiovascular events.The regulation of arterial stiffness on biomechanics of macrophages and its underlying mechanism remains unclear.We prepared polyacrylamide gels with low and high stiffness that corresponded to healthy and diseased blood vessels,respectively.We found that macrophages cultured on stiff matrix had increased rigidity and migration ability compared to those on soft matrix.An actin capping protein,tropomodulin1(Tmod1)was upregulated in macrophages by stiff matrix and in arteries with high stiffness.Further analyses showed that deficiency of Tmod1 in macrophages completely or partially prevented the changes in actin polymerization,cell adhesion and cell spreading induced by stiff matrix.Overexpression of Tmod1 in macrophages enhanced actin polymerization,cell adhesion and spreading on stiff matrix.Tmod1 was involved in the regulation of vinculin expression and formation of focal adhesion in macrophages on stiff matrix.Finally,the deficiency of Tmod1 in macrophages retarded the formation of atherosclerotic plaques in blood vessels with high matrix stiffness.The results suggest that Tmod1 was a key regulator in macrophage rigidity and migration on stiff substrate.The present work will help us to understand the biomechanical mechanisms for the development of atherosclerosis.展开更多
Human mesenchymal stem cells(hMSCs)have immense wound healing potential due to their immunomodulatory behavior.To control this behavior and reduce heterogeneity,researchers look to biomaterials,as matrix stiffness and...Human mesenchymal stem cells(hMSCs)have immense wound healing potential due to their immunomodulatory behavior.To control this behavior and reduce heterogeneity,researchers look to biomaterials,as matrix stiffness and viscoelasticity have been shown to control hMSC immunomodulation.However,the understanding of the effects of these biophysical cues on hMSC immunomodulation remains limited;a broad study investigating the potentially synergistic effects of matrix stiffness and viscoelasticity on hMSC immunomodulation is needed in order to support future work developing biomaterials for hMSC wound healing applications.We developed polyacrylamide(PAAm)gels with varying matrix stiffnesses with or without a viscoelastic element and explored the effects of these on hMSC-matrix interactions and immunomodulatory cytokine expression in both a normal growth media and an immunomodulatory growth media mimetic of a chronic,non-healing wound.Expression of IL-10,VEGF,and PGE2 were upregulated in immunomodulatory growth media over normal growth media,demonstrating the synergistic effects of biochemical signaling on hMSC immunomodulatory behavior.In addition,the addition of a viscoelastic element had both inhibitory and accentuating effects based on the cytokine and biochemical signaling in the cell culture media.Overall,this study provides a broad perspective on the immunomodulatory behavior of hMSCs due to stiffness and viscoelasticity.展开更多
This paper investigates the development and performance of a new higher-order geometric stiffness matrix that more closely approximates the theoretically derived stiffness coefficients.Factors that influence the accur...This paper investigates the development and performance of a new higher-order geometric stiffness matrix that more closely approximates the theoretically derived stiffness coefficients.Factors that influence the accuracy of the solution are studied using two columns,two braced frames,and one unbraced frame.Discussion is provided when the new geometric stiffness matrix can be used to improve the buckling load analysis results and when it may provide only nominal additional benefit.展开更多
Background:Despite integrin being highlighted as a stiffness-sensor molecule in matrix stiffness-driven angiogenesis,other stiffness-sensor molecules and their mechanosensory pathways related to angiogenesis in hepato...Background:Despite integrin being highlighted as a stiffness-sensor molecule in matrix stiffness-driven angiogenesis,other stiffness-sensor molecules and their mechanosensory pathways related to angiogenesis in hepatocellular carcinoma(HCC)remain obscure.Here,we explored the interplay between Piezo1 and integrinβ1 in the mechanosensory pathway and their effects on HCC angiogenesis to better understand matrix stiffness-induced angiogenesis.Methods:The role of Piezo1 in matrix stiffness-induced angiogenesis was investigated using orthotopic liver cancer SD rat models with high liver stiffness background,and its clinical significance was evaluated in human HCC tissues.Matrix stiffness-mediated Piezo1 upregulation and activation were assayed using an in vitro fibronectin(FN)-coated cell culture system with different stiffness,Western blotting and Ca^(2+)probe.The effects of shPiezo1-conditioned medium(CM)on angiogenesis were examined by tube formation assay,wound healing assay and angiogenesis array.The underlying mechanism by which Piezo1 participated in matrix stiffness-induced angiogenesis was analyzed by microRNA quantitative real-time polymerase chain reaction(qRT-PCR),matrix stiffness measurement,dual-luciferase reporter assay,ubiquitination assay and co-immunoprecipitation.Results:Increased matrix stiffness significantly upregulated Piezo1 expression at both cellular and tissue levels,and high expression of Piezo1 indicated an unfavorable prognosis.High matrix stiffness also noticeably enhanced the activation level of Piezo1,similar to its expression level.Piezo1 knockdown significantly suppressed tumor growth,angiogenesis,and lung metastasis of HCC rat models with high liver stiffness background.shPiezo1-CM from HCC cells attenuated tube formation and migration abilities of vascular endothelial cells remarkably,and analysis of differentially expressed pro-angiogenic factors revealed that Piezo1 promoted the expression and secretion of vascular endothelial growth factor(VEGF),CXC chemokine ligand 16(CXCL16)and insulin-like growth factor binding protein 2(IGFBP2).Matrix stiffness-caused Piezo1 upregulation/activation restrained hypoxia inducible factor-1α(HIF-1α)ubiquitination,subsequently enhanced the expression of downstream pro-angiogenic factors to accelerate HCC angiogenesis.Besides,collagen 1(COL1)-reinforced tissue stiffening resulted in more expression of Piezo1 via miR-625-5p.Conclusions:This study unravels a new mechanism by which the inte-grinβ1/Piezo1 activation/Ca2+influx/HIF-1αubiquitination/VEGF,CXCL16 and IGFBP2 pathway participates in matrix stiffness-driven HCC angiogenesis.Simultaneously,a positive feedback regulation loop as stiff matrix/integrinβ1/miR-625-5p/Piezo1 and COL1/stiffer matrix mediates matrix stiffness-caused Piezo1 upregulation.展开更多
Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotyp...Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotype to a proinflammatory phenotype, whereby the cell secretes chemotactic and inflammatory cytokines, e.g. MCP1 and IL6, to functionally regulate monocyte and macrophage infiltration during the development of various vascular diseases including arteriosclerosis. Here, by culturing vSMCs on polyacrylamide (PA) substrates with variable elastic moduli, we discovered a role of discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds collagens, in mediating the mechanical regulation of vSMC gene expression, phenotype, and proinflammatory responses. We found that ECM stiffness induced DDR1 phosphorylation, oligomerization, and endocytosis to repress the expression of DNA methyltransferase 1 (DNMT1), very likely in a collagen-independent manner. The DDR1-to-DNMT1 signaling was sequentially mediated by the extracellular signal-regulated kinases (ERKs) and p53 pathways. ECM stiffness primed vSMC to a proinflammatory phenotype and this regulation was diminished by DDR1 inhibition. In agreement with the in vitro findings, increased DDR1 phosphorylation was observed in human arterial stiffening. DDR1 inhibition in mouse attenuated the acute injury or adenine diet-induced vascular stiffening and inflammation. Furthermore, mouse vasculature with SMC-specific deletion of Dnmt1 exhibited proinflammatory and stiffening phenotypes. Our study demonstrates a role of SMC DDR1 in perceiving the mechanical microenvironments and down-regulating expression of DNMT1 to result in vascular pathologies and has potential implications for optimization of engineering artificial vascular grafts and vascular networks.展开更多
The biophysical factors of biomaterials such as their stiffness regulate stem cell differentiation.Energy metabolism has been revealed an essential role in stem cell lineage commitment.However,whether and how extracel...The biophysical factors of biomaterials such as their stiffness regulate stem cell differentiation.Energy metabolism has been revealed an essential role in stem cell lineage commitment.However,whether and how extracellular matrix(ECM)stiffness regulates energy metabolism to determine stem cell differentiation is less known.Here,the study reveals that stiff ECM promotes glycolysis,oxidative phosphorylation,and enhances antioxidant defense system during osteogenic differentiation in MSCs.Stiff ECM increases mitochondrial fusion by enhancing mitofusin 1 and 2 expression and inhibiting the dynamin-related protein 1 activity,which contributes to osteogenesis.Yes-associated protein(YAP)impacts glycolysis,glutamine metabolism,mitochondrial dynamics,and mitochondrial biosynthesis to regulate stiffness-mediated osteogenic differentiation.Furthermore,glycolysis in turn regulates YAP activity through the cytoskeletal tension-mediated deformation of nuclei.Overall,our findings suggest that YAP is an important mechanotransducer to integrate ECM mechanical cues and energy metabolic signaling to affect the fate of MSCs.This offers valuable guidance to improve the scaffold design for bone tissue engineering constructs.展开更多
Cardiac fibroblast(CF)differentiation into myofibroblasts is a crucial cause of cardiac fibrosis,which increases in the extracellular matrix(ECM)stiffness.The increased stiffness further promotes CF differentiation an...Cardiac fibroblast(CF)differentiation into myofibroblasts is a crucial cause of cardiac fibrosis,which increases in the extracellular matrix(ECM)stiffness.The increased stiffness further promotes CF differentiation and fibrosis.However,the molecular mechanism is still unclear.We used bioinformatics analysis to find new candidates that regulate the genes involved in stiffnessinduced CF differentiation,and found that there were binding sites for the POU-domain transcription factor,POU2F1(also known as Oct-1),in the promoters of 50 differentially expressed genes(DEGs)in CFs on the stiffer substrate.Immunofluorescent staining and Western blotting revealed that pathological stiffness upregulated POU2F1 expression and increased CF differentiation on polyacrylamide hydrogel substrates and in mouse myocardial infarction tissue.A chromatin immunoprecipitation assay showed that POU2F1 bound to the promoters of fibrosis repressors IL1R2,CD69,and TGIF2.The expression of these fibrosis repressors was inhibited on pathological substrate stiffness.Knockdown of POU2F1 upregulated these repressors and attenuated CF differentiation on pathological substrate stiffness(35 kPa).Whereas,overexpression of POU2F1 downregulated these repressors and enhanced CF differentiation.In conclusion,pathological stiffness upregulates the transcription factor POU2F1 to promote CF differentiation by inhibiting fibrosis repressors.Our work elucidated the crosstalk between CF differentiation and the ECM and provided a potential target for cardiac fibrosis treatment.展开更多
A three-dimensional beam element is derived based on the principle of stationary total potential energy for geometrically nonlinear analysis of space frames. A new tangent stiffness matrix, which allows for high order...A three-dimensional beam element is derived based on the principle of stationary total potential energy for geometrically nonlinear analysis of space frames. A new tangent stiffness matrix, which allows for high order effects of element deformations, replaces the conventional incremental secant stiffness matrix. Two deformation stiffness matrices due to the variation of axial force and bending moments are included in the tangent stiffness. They are functions of element deformations and incorporate the coupling among axial, lateral and torsional deformations. A correction matrix is added to the tangent stiffness matrix to make displacement derivatives equivalent to the commutative rotational degrees of freedom. Numerical examples show that the proposed dement is accurate and efficient in predicting the nonlinear behavior, such as axial-torsional and flexural-torsional buckling, of space frames even when fewer elements are used to model a member.展开更多
Increased matrix stiffness is a common phenomenon in solid tumor tissue and is regulated by both tumor and mesenchymal cells.The increase in collagen and lysyl oxidase family proteins in the extracellular matrix leads...Increased matrix stiffness is a common phenomenon in solid tumor tissue and is regulated by both tumor and mesenchymal cells.The increase in collagen and lysyl oxidase family proteins in the extracellular matrix leads to deposition,contraction,and crosslinking of the stroma,promoting increased matrix stiffness in tumors.Matrix stiffness is critical to the progression of various solid tumors.As a mechanical factor in the tumor microenvi-ronment,matrix stiffness is involved in tumor progression,promoting biological processes such as tumor cell proliferation,invasion,metastasis,angiogenesis,drug resistance,and immune escape.Reducing tissue stiffness can slow down tumor progression.Therefore targeting matrix stiffness is a potential option for tumor therapy.This article reviews the detailed mechanisms of matrix stiffness in different malignant tumor phenotypes and potential tumor therapies targeting matrix stiffness.Understanding the role and mechanisms of matrix stiffness in tumors could provide theoretical insights into the treatment of tumors and assist in the clinical development of new drug therapies.展开更多
Dynamic stiffness matrix method is applied to compute vibration of hull girder in this paper. This method can not only simplify the computational model, but also get much higher frequencies and responses accurately. T...Dynamic stiffness matrix method is applied to compute vibration of hull girder in this paper. This method can not only simplify the computational model, but also get much higher frequencies and responses accurately. The analytical expressions of dynamic stiffness matrix of a Timoshenko beam for transverse vibration are presented in this paper. All effects of rotatory inertia and shear deformation are taken into account in the formulation. The resulting dynamic stiffness matrix combined with the Wittrick-Williams algorithm is used to compute natural frequencies and mode shapes of the 299,500 DWT VLCC, and then the vibrational responses are solved by the mode superposition method. The computational results are compared with those obtained from other approximate methods and experiment, and it indicates that the method is accurate and efficient.展开更多
Time-varying stiffness is one of the most important dynamic characteristics of rolling element bearings.The method of analyzing the elements in the bearing stiffness matrix is usually adopted to investigate the charac...Time-varying stiffness is one of the most important dynamic characteristics of rolling element bearings.The method of analyzing the elements in the bearing stiffness matrix is usually adopted to investigate the characteristics of bearing stiffness.Linear mapping structure of the bearing stiffness matrix is helpful to understand the varying compliance excitation and its influence on vibration transmission.In this study,a method to analyze the mapping structure of bearing stiffness matrix is proposed based on the singular value decomposition of block matrices in the stiffness matrix.Not only does this method have the advantages of coordinate transformation independence and unit independence,but also the analysis procedure involved is geometrically intuitive.The time-varying stiffness matrix of double-row tapered bearing is calculated and analyzed using the proposed method under two representative load cases.The principal stiffnesses and principal axes defined in the method together indicate the dominant and insignificant stiffness properties with the corresponding directions,and the vibration transmission properties are also revealed.Besides,the coupling behaviors between different shaft motions are found during the analysis of mapping structure.The mechanism of the generation of varying compliance excitation is also revealed.展开更多
Using Stricklin Melhod￣[5],we have this paper has derived the formulas for the ge-neration of non-linear element stiffness matrix of a triangle element when considering both the bending and the in-plane membrane forc...Using Stricklin Melhod￣[5],we have this paper has derived the formulas for the ge-neration of non-linear element stiffness matrix of a triangle element when considering both the bending and the in-plane membrane forces. A computer programme for the calculation of large deflection and inner forces of shallow shells is designed on theseformulas. The central deflection curve computed by this programme is compared with other pertaining results.展开更多
In this paper, we established a finite element (FEM) model to analyze the dynamic characteristics of arch bridges. In this model, the effects of adjustment to the length of a suspender on its geometry stiffness matrix...In this paper, we established a finite element (FEM) model to analyze the dynamic characteristics of arch bridges. In this model, the effects of adjustment to the length of a suspender on its geometry stiffness matrix are stressed. The FEM equations of mechanics characteristics, natural frequency and main mode are set up based on the first order matrix perturbation theory. Applicantion of the proposed model to analyze a real arch bridge proved the improvement in the simulation precision of dynamical characteristics of the arch bridge by considering the effects of suspender length variation.展开更多
Element stiffness equation is very important in structural analysis, and directly influences the accuracy of the results. At present, derivation method of element stiffness equation is relatively mature under ambient ...Element stiffness equation is very important in structural analysis, and directly influences the accuracy of the results. At present, derivation method of element stiffness equation is relatively mature under ambient temperature, and the elastic phrase of material stress-strain curve is generally adopted as physical equation in derivation. However, the material stress-strain relationship is very complicated at elevated temperature, and its form is not unique, which brings great difficulty to the derivation of element stiffness equation. Referring to the derivation method of element stiffness equation at ambient temperature, by using the continuous function of stress-strain-temperature at elevated temperature, and based on the principle of virtual work, the stiffness equation of space beam element and the formulas of stiffness matrix are derived in this paper, which provide basis for finite element analysis on structures at elevated temperature.展开更多
The dynamic deformation of harmonic vibration is used as the shape functions of the finite annular plate element, and sonic integration difficulties related to the Bessel's functions are solved in this paper. Then...The dynamic deformation of harmonic vibration is used as the shape functions of the finite annular plate element, and sonic integration difficulties related to the Bessel's functions are solved in this paper. Then the dynamic stiffness matrix of the finite annular plate element is established in closed form and checked by the direct stiffness method. The paper has given wide convcrage for decomposing the dynamic matrix into the power series of frequency square. By utilizing the axial symmetry of annular elements, the modes with different numbers of nodal diameters at s separately treated. Thus some terse and complete results are obtained as the foundation of structural characteristic analysis and dynamic response compulation.展开更多
In this paper, the expressions of both increment stiffness matrix and total quantum stiffness matrix in nonlinear analyses are derived in detail, and their relationship is discussed in mathematical meaningThe results ...In this paper, the expressions of both increment stiffness matrix and total quantum stiffness matrix in nonlinear analyses are derived in detail, and their relationship is discussed in mathematical meaningThe results given in our paper will be of great importance to the analyses of nonlinear numerical and nonlinear stability in finite element methods.展开更多
A new modification for the shear lag model is given and the expressions for the stiffness and yield Strength of short fiber metal matri×composite are derived. These expressions are then compared with our experime...A new modification for the shear lag model is given and the expressions for the stiffness and yield Strength of short fiber metal matri×composite are derived. These expressions are then compared with our experimental data in a SiCw/Al-Li T6 composite and the published experimental data on different SiCw/Al T6 composites and also compared with the previous shear lag models and the other theoretical models.展开更多
The standard formula for geometric stiffness matrix calculation, which is convenient for most engineering applications, is seen to be unsatisfactory for large strains because of poor accuracy, low convergence rate, an...The standard formula for geometric stiffness matrix calculation, which is convenient for most engineering applications, is seen to be unsatisfactory for large strains because of poor accuracy, low convergence rate, and stability. For very large compressions, the tangent stiffness in the direction of the compression can even become negative, which can be regarded as physical nonsense. So in many cases rubber materials exposed to great compression cannot be analyzed, or the analysis could lead to very poor convergence. Problems with the standard geometric stiffness matrix can even occur with a small strain in the case of plastic yielding, which eventuates even greater practical problems. The authors demonstrate that amore precisional approach would not lead to such strange and theoretically unjustified results. An improved formula that would eliminate the disadvantages mentioned above and leads to higher convergence rate and more robust computations is suggested in this paper. The new formula can be derived from the principle of virtual work using a modified Green-Lagrange strain tensor, or from equilibrium conditions where in the choice of a specific strain measure is not needed for the geometric stiffness derivation (which can also be used for derivation of geometric stiffness of a rigid truss member). The new formula has been verified in practice with many calculations and implemented in the RFEM and SCIA Engineer programs. The advantages of the new formula in comparison with the standard formula are shown using several examples.展开更多
基金supported by the National Nature Science Foundation of China(No.82002345 to J.D and 81902179 to L.S)the Gusu Talent Program(No.Qngg2022008 and GSWS2021027 to J.D)the Preliminary Research Project of the Second Affiliated Hospital of Soochow University(No.SDFEYBS1905 to J.D).
文摘Increased matrix stiffness of nucleus pulposus(NP)tissue is a main feature of intervertebral disc degeneration(IVDD)and affects various functions of nucleus pulposus cells(NPCs).Glycolysis is the main energy source for NPC survival,but the effects and underlying mechanisms of increased extracellular matrix(ECM)stiffness on NPC glycolysis remain unknown.In this study,hydrogels with different stiffness were established to mimic the mechanical environment of NPCs.Notably,increased matrix stiffness in degenerated NP tissues from IVDD patients was accompanied with impaired glycolysis,and NPCs cultured on rigid substrates exhibited a reduction in glycolysis.
文摘Changes in vascular stiffness are associated with the development and progression of many diseases, especially in cardiovascular disease. However, the effect of vascular stiffness on the endothelial cells (ECs) is not fully understood. Therefore, this study aims to determine the gene expression changes of ECs cultured on the matrices with different stiffness (1 kPa and 40 kPa, respectively) by RNA-seq, thereby broadening the knowledge between mechanics and biology. We obtained 1775 differentially expressed genes (DEGs) by RNA-seq, with 450 up-regulated and 1325 down-regulated DEGs in ECs cultured on soft matrix (1 kPa) compared to those cultured on stiff matrix (40 kPa). After that, we performed a series of functional enrichment analyses based on DEGs and found that DEGs were enriched in many signaling pathways like adhesion junction. Furthermore, transcription factor (TF) target gene prediction analysis and protein-protein interaction (PPI) analysis were also conducted. We found that mechanotransduction signaling related TFs such as BRD4 are involved in. And in the PPI analysis, some genes encoding extracellular matrix proteins such as fibronectin 1 (FN1) were identified as the hub genes. In order to confirm the RNA-seq results, we performed real-time qPCR analysis on the genes of interest, including FN1, collagen α2 (IV) chain, matrix metalloproteinase-14 and integrin α5, and found that the expression levels of all these genes were down-regulated on soft matrix, suggesting that soft matrix caused by pathological conditions may directly attenuate vascular barrier function. This study offers the insights about the effects of physical stimulation on cells, paving a way for vascular tissue engineering, regenerative medicine, disease modeling and therapies.
基金supported by National Natural Science Foundation of China(Nos.31570938,32171143,and 31771280 to W.Y.)Natural Science Foundation of Beijing(No.7232042 to X.W.).
文摘The monocyte/macrophage infiltration plays critical roles in the development of atherosclerosis.Arterial stiffness is a cholesterol-independent risk factor for cardiovascular events.The regulation of arterial stiffness on biomechanics of macrophages and its underlying mechanism remains unclear.We prepared polyacrylamide gels with low and high stiffness that corresponded to healthy and diseased blood vessels,respectively.We found that macrophages cultured on stiff matrix had increased rigidity and migration ability compared to those on soft matrix.An actin capping protein,tropomodulin1(Tmod1)was upregulated in macrophages by stiff matrix and in arteries with high stiffness.Further analyses showed that deficiency of Tmod1 in macrophages completely or partially prevented the changes in actin polymerization,cell adhesion and cell spreading induced by stiff matrix.Overexpression of Tmod1 in macrophages enhanced actin polymerization,cell adhesion and spreading on stiff matrix.Tmod1 was involved in the regulation of vinculin expression and formation of focal adhesion in macrophages on stiff matrix.Finally,the deficiency of Tmod1 in macrophages retarded the formation of atherosclerotic plaques in blood vessels with high matrix stiffness.The results suggest that Tmod1 was a key regulator in macrophage rigidity and migration on stiff substrate.The present work will help us to understand the biomechanical mechanisms for the development of atherosclerosis.
文摘Human mesenchymal stem cells(hMSCs)have immense wound healing potential due to their immunomodulatory behavior.To control this behavior and reduce heterogeneity,researchers look to biomaterials,as matrix stiffness and viscoelasticity have been shown to control hMSC immunomodulation.However,the understanding of the effects of these biophysical cues on hMSC immunomodulation remains limited;a broad study investigating the potentially synergistic effects of matrix stiffness and viscoelasticity on hMSC immunomodulation is needed in order to support future work developing biomaterials for hMSC wound healing applications.We developed polyacrylamide(PAAm)gels with varying matrix stiffnesses with or without a viscoelastic element and explored the effects of these on hMSC-matrix interactions and immunomodulatory cytokine expression in both a normal growth media and an immunomodulatory growth media mimetic of a chronic,non-healing wound.Expression of IL-10,VEGF,and PGE2 were upregulated in immunomodulatory growth media over normal growth media,demonstrating the synergistic effects of biochemical signaling on hMSC immunomodulatory behavior.In addition,the addition of a viscoelastic element had both inhibitory and accentuating effects based on the cytokine and biochemical signaling in the cell culture media.Overall,this study provides a broad perspective on the immunomodulatory behavior of hMSCs due to stiffness and viscoelasticity.
文摘This paper investigates the development and performance of a new higher-order geometric stiffness matrix that more closely approximates the theoretically derived stiffness coefficients.Factors that influence the accuracy of the solution are studied using two columns,two braced frames,and one unbraced frame.Discussion is provided when the new geometric stiffness matrix can be used to improve the buckling load analysis results and when it may provide only nominal additional benefit.
基金ational Natural Science Foundation of China,Grant/Award Number:81972910。
文摘Background:Despite integrin being highlighted as a stiffness-sensor molecule in matrix stiffness-driven angiogenesis,other stiffness-sensor molecules and their mechanosensory pathways related to angiogenesis in hepatocellular carcinoma(HCC)remain obscure.Here,we explored the interplay between Piezo1 and integrinβ1 in the mechanosensory pathway and their effects on HCC angiogenesis to better understand matrix stiffness-induced angiogenesis.Methods:The role of Piezo1 in matrix stiffness-induced angiogenesis was investigated using orthotopic liver cancer SD rat models with high liver stiffness background,and its clinical significance was evaluated in human HCC tissues.Matrix stiffness-mediated Piezo1 upregulation and activation were assayed using an in vitro fibronectin(FN)-coated cell culture system with different stiffness,Western blotting and Ca^(2+)probe.The effects of shPiezo1-conditioned medium(CM)on angiogenesis were examined by tube formation assay,wound healing assay and angiogenesis array.The underlying mechanism by which Piezo1 participated in matrix stiffness-induced angiogenesis was analyzed by microRNA quantitative real-time polymerase chain reaction(qRT-PCR),matrix stiffness measurement,dual-luciferase reporter assay,ubiquitination assay and co-immunoprecipitation.Results:Increased matrix stiffness significantly upregulated Piezo1 expression at both cellular and tissue levels,and high expression of Piezo1 indicated an unfavorable prognosis.High matrix stiffness also noticeably enhanced the activation level of Piezo1,similar to its expression level.Piezo1 knockdown significantly suppressed tumor growth,angiogenesis,and lung metastasis of HCC rat models with high liver stiffness background.shPiezo1-CM from HCC cells attenuated tube formation and migration abilities of vascular endothelial cells remarkably,and analysis of differentially expressed pro-angiogenic factors revealed that Piezo1 promoted the expression and secretion of vascular endothelial growth factor(VEGF),CXC chemokine ligand 16(CXCL16)and insulin-like growth factor binding protein 2(IGFBP2).Matrix stiffness-caused Piezo1 upregulation/activation restrained hypoxia inducible factor-1α(HIF-1α)ubiquitination,subsequently enhanced the expression of downstream pro-angiogenic factors to accelerate HCC angiogenesis.Besides,collagen 1(COL1)-reinforced tissue stiffening resulted in more expression of Piezo1 via miR-625-5p.Conclusions:This study unravels a new mechanism by which the inte-grinβ1/Piezo1 activation/Ca2+influx/HIF-1αubiquitination/VEGF,CXCL16 and IGFBP2 pathway participates in matrix stiffness-driven HCC angiogenesis.Simultaneously,a positive feedback regulation loop as stiff matrix/integrinβ1/miR-625-5p/Piezo1 and COL1/stiffer matrix mediates matrix stiffness-caused Piezo1 upregulation.
基金This work was funded by the National Natural Science Foundation of the China(#91949112,#81974052,#81921001,#91939302,and#31870930)Peking University Health Science Center,the Plan for Strengthening the Basic Research(#BMU2020JC002).
文摘Vascular smooth muscle cell (vSMC) is highly plastic as its phenotype can change in response to mechanical cues inherent to the extracellular matrix (ECM). VSMC may be activated from its quiescent contractile phenotype to a proinflammatory phenotype, whereby the cell secretes chemotactic and inflammatory cytokines, e.g. MCP1 and IL6, to functionally regulate monocyte and macrophage infiltration during the development of various vascular diseases including arteriosclerosis. Here, by culturing vSMCs on polyacrylamide (PA) substrates with variable elastic moduli, we discovered a role of discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase that binds collagens, in mediating the mechanical regulation of vSMC gene expression, phenotype, and proinflammatory responses. We found that ECM stiffness induced DDR1 phosphorylation, oligomerization, and endocytosis to repress the expression of DNA methyltransferase 1 (DNMT1), very likely in a collagen-independent manner. The DDR1-to-DNMT1 signaling was sequentially mediated by the extracellular signal-regulated kinases (ERKs) and p53 pathways. ECM stiffness primed vSMC to a proinflammatory phenotype and this regulation was diminished by DDR1 inhibition. In agreement with the in vitro findings, increased DDR1 phosphorylation was observed in human arterial stiffening. DDR1 inhibition in mouse attenuated the acute injury or adenine diet-induced vascular stiffening and inflammation. Furthermore, mouse vasculature with SMC-specific deletion of Dnmt1 exhibited proinflammatory and stiffening phenotypes. Our study demonstrates a role of SMC DDR1 in perceiving the mechanical microenvironments and down-regulating expression of DNMT1 to result in vascular pathologies and has potential implications for optimization of engineering artificial vascular grafts and vascular networks.
基金supported by National Natural Science Foundation of China[grant numbers 32171310,11972067,U20A20390,11827803,12332019].
文摘The biophysical factors of biomaterials such as their stiffness regulate stem cell differentiation.Energy metabolism has been revealed an essential role in stem cell lineage commitment.However,whether and how extracellular matrix(ECM)stiffness regulates energy metabolism to determine stem cell differentiation is less known.Here,the study reveals that stiff ECM promotes glycolysis,oxidative phosphorylation,and enhances antioxidant defense system during osteogenic differentiation in MSCs.Stiff ECM increases mitochondrial fusion by enhancing mitofusin 1 and 2 expression and inhibiting the dynamin-related protein 1 activity,which contributes to osteogenesis.Yes-associated protein(YAP)impacts glycolysis,glutamine metabolism,mitochondrial dynamics,and mitochondrial biosynthesis to regulate stiffness-mediated osteogenic differentiation.Furthermore,glycolysis in turn regulates YAP activity through the cytoskeletal tension-mediated deformation of nuclei.Overall,our findings suggest that YAP is an important mechanotransducer to integrate ECM mechanical cues and energy metabolic signaling to affect the fate of MSCs.This offers valuable guidance to improve the scaffold design for bone tissue engineering constructs.
基金support of a grant from the National Natural Science Foundation of China(81530009 to Y.Y.Z.)a grant from the National Natural Science Foundation of China(81822003 and 81670205 to H.X.)a grant from Natural Science Foundation of Beijing Municipality(7191013 to E.D.D.).
文摘Cardiac fibroblast(CF)differentiation into myofibroblasts is a crucial cause of cardiac fibrosis,which increases in the extracellular matrix(ECM)stiffness.The increased stiffness further promotes CF differentiation and fibrosis.However,the molecular mechanism is still unclear.We used bioinformatics analysis to find new candidates that regulate the genes involved in stiffnessinduced CF differentiation,and found that there were binding sites for the POU-domain transcription factor,POU2F1(also known as Oct-1),in the promoters of 50 differentially expressed genes(DEGs)in CFs on the stiffer substrate.Immunofluorescent staining and Western blotting revealed that pathological stiffness upregulated POU2F1 expression and increased CF differentiation on polyacrylamide hydrogel substrates and in mouse myocardial infarction tissue.A chromatin immunoprecipitation assay showed that POU2F1 bound to the promoters of fibrosis repressors IL1R2,CD69,and TGIF2.The expression of these fibrosis repressors was inhibited on pathological substrate stiffness.Knockdown of POU2F1 upregulated these repressors and attenuated CF differentiation on pathological substrate stiffness(35 kPa).Whereas,overexpression of POU2F1 downregulated these repressors and enhanced CF differentiation.In conclusion,pathological stiffness upregulates the transcription factor POU2F1 to promote CF differentiation by inhibiting fibrosis repressors.Our work elucidated the crosstalk between CF differentiation and the ECM and provided a potential target for cardiac fibrosis treatment.
文摘A three-dimensional beam element is derived based on the principle of stationary total potential energy for geometrically nonlinear analysis of space frames. A new tangent stiffness matrix, which allows for high order effects of element deformations, replaces the conventional incremental secant stiffness matrix. Two deformation stiffness matrices due to the variation of axial force and bending moments are included in the tangent stiffness. They are functions of element deformations and incorporate the coupling among axial, lateral and torsional deformations. A correction matrix is added to the tangent stiffness matrix to make displacement derivatives equivalent to the commutative rotational degrees of freedom. Numerical examples show that the proposed dement is accurate and efficient in predicting the nonlinear behavior, such as axial-torsional and flexural-torsional buckling, of space frames even when fewer elements are used to model a member.
基金supported by grants from the National Natural Science Foundation of China(11832008)the Fundamental Research Funds for the Central Universities(2023CDJXY-051)the Open Foundation of Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors(2021B0303010151).
文摘Increased matrix stiffness is a common phenomenon in solid tumor tissue and is regulated by both tumor and mesenchymal cells.The increase in collagen and lysyl oxidase family proteins in the extracellular matrix leads to deposition,contraction,and crosslinking of the stroma,promoting increased matrix stiffness in tumors.Matrix stiffness is critical to the progression of various solid tumors.As a mechanical factor in the tumor microenvi-ronment,matrix stiffness is involved in tumor progression,promoting biological processes such as tumor cell proliferation,invasion,metastasis,angiogenesis,drug resistance,and immune escape.Reducing tissue stiffness can slow down tumor progression.Therefore targeting matrix stiffness is a potential option for tumor therapy.This article reviews the detailed mechanisms of matrix stiffness in different malignant tumor phenotypes and potential tumor therapies targeting matrix stiffness.Understanding the role and mechanisms of matrix stiffness in tumors could provide theoretical insights into the treatment of tumors and assist in the clinical development of new drug therapies.
文摘Dynamic stiffness matrix method is applied to compute vibration of hull girder in this paper. This method can not only simplify the computational model, but also get much higher frequencies and responses accurately. The analytical expressions of dynamic stiffness matrix of a Timoshenko beam for transverse vibration are presented in this paper. All effects of rotatory inertia and shear deformation are taken into account in the formulation. The resulting dynamic stiffness matrix combined with the Wittrick-Williams algorithm is used to compute natural frequencies and mode shapes of the 299,500 DWT VLCC, and then the vibrational responses are solved by the mode superposition method. The computational results are compared with those obtained from other approximate methods and experiment, and it indicates that the method is accurate and efficient.
基金the Joint Funds of the National Natural Science Foundation of China(Grant No.U1834202).
文摘Time-varying stiffness is one of the most important dynamic characteristics of rolling element bearings.The method of analyzing the elements in the bearing stiffness matrix is usually adopted to investigate the characteristics of bearing stiffness.Linear mapping structure of the bearing stiffness matrix is helpful to understand the varying compliance excitation and its influence on vibration transmission.In this study,a method to analyze the mapping structure of bearing stiffness matrix is proposed based on the singular value decomposition of block matrices in the stiffness matrix.Not only does this method have the advantages of coordinate transformation independence and unit independence,but also the analysis procedure involved is geometrically intuitive.The time-varying stiffness matrix of double-row tapered bearing is calculated and analyzed using the proposed method under two representative load cases.The principal stiffnesses and principal axes defined in the method together indicate the dominant and insignificant stiffness properties with the corresponding directions,and the vibration transmission properties are also revealed.Besides,the coupling behaviors between different shaft motions are found during the analysis of mapping structure.The mechanism of the generation of varying compliance excitation is also revealed.
文摘Using Stricklin Melhod￣[5],we have this paper has derived the formulas for the ge-neration of non-linear element stiffness matrix of a triangle element when considering both the bending and the in-plane membrane forces. A computer programme for the calculation of large deflection and inner forces of shallow shells is designed on theseformulas. The central deflection curve computed by this programme is compared with other pertaining results.
基金Supported by the Key Teacher Foundation of Chongqing University (No. 717411067)
文摘In this paper, we established a finite element (FEM) model to analyze the dynamic characteristics of arch bridges. In this model, the effects of adjustment to the length of a suspender on its geometry stiffness matrix are stressed. The FEM equations of mechanics characteristics, natural frequency and main mode are set up based on the first order matrix perturbation theory. Applicantion of the proposed model to analyze a real arch bridge proved the improvement in the simulation precision of dynamical characteristics of the arch bridge by considering the effects of suspender length variation.
基金the National Natural Science Foundation of China(No.50578093)
文摘Element stiffness equation is very important in structural analysis, and directly influences the accuracy of the results. At present, derivation method of element stiffness equation is relatively mature under ambient temperature, and the elastic phrase of material stress-strain curve is generally adopted as physical equation in derivation. However, the material stress-strain relationship is very complicated at elevated temperature, and its form is not unique, which brings great difficulty to the derivation of element stiffness equation. Referring to the derivation method of element stiffness equation at ambient temperature, by using the continuous function of stress-strain-temperature at elevated temperature, and based on the principle of virtual work, the stiffness equation of space beam element and the formulas of stiffness matrix are derived in this paper, which provide basis for finite element analysis on structures at elevated temperature.
文摘The dynamic deformation of harmonic vibration is used as the shape functions of the finite annular plate element, and sonic integration difficulties related to the Bessel's functions are solved in this paper. Then the dynamic stiffness matrix of the finite annular plate element is established in closed form and checked by the direct stiffness method. The paper has given wide convcrage for decomposing the dynamic matrix into the power series of frequency square. By utilizing the axial symmetry of annular elements, the modes with different numbers of nodal diameters at s separately treated. Thus some terse and complete results are obtained as the foundation of structural characteristic analysis and dynamic response compulation.
文摘In this paper, the expressions of both increment stiffness matrix and total quantum stiffness matrix in nonlinear analyses are derived in detail, and their relationship is discussed in mathematical meaningThe results given in our paper will be of great importance to the analyses of nonlinear numerical and nonlinear stability in finite element methods.
文摘A new modification for the shear lag model is given and the expressions for the stiffness and yield Strength of short fiber metal matri×composite are derived. These expressions are then compared with our experimental data in a SiCw/Al-Li T6 composite and the published experimental data on different SiCw/Al T6 composites and also compared with the previous shear lag models and the other theoretical models.
文摘The standard formula for geometric stiffness matrix calculation, which is convenient for most engineering applications, is seen to be unsatisfactory for large strains because of poor accuracy, low convergence rate, and stability. For very large compressions, the tangent stiffness in the direction of the compression can even become negative, which can be regarded as physical nonsense. So in many cases rubber materials exposed to great compression cannot be analyzed, or the analysis could lead to very poor convergence. Problems with the standard geometric stiffness matrix can even occur with a small strain in the case of plastic yielding, which eventuates even greater practical problems. The authors demonstrate that amore precisional approach would not lead to such strange and theoretically unjustified results. An improved formula that would eliminate the disadvantages mentioned above and leads to higher convergence rate and more robust computations is suggested in this paper. The new formula can be derived from the principle of virtual work using a modified Green-Lagrange strain tensor, or from equilibrium conditions where in the choice of a specific strain measure is not needed for the geometric stiffness derivation (which can also be used for derivation of geometric stiffness of a rigid truss member). The new formula has been verified in practice with many calculations and implemented in the RFEM and SCIA Engineer programs. The advantages of the new formula in comparison with the standard formula are shown using several examples.
