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Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis

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Bioactive Materials 2022年第11期7卷 406-424页

作者： Jin Wang Si-an Xie Ning Li Tao Zhang weijuan yao Hucheng Zhao Wei Pang Lili Han Jiayu Liu Jing Zhou Department of Physiology and Pathophysiology School of Basic Medical SciencesHemorheology CenterSchool of Basic Medical SciencesPeking UniversityBeijingPR China Key Laboratory of Molecular Cardiovascular Science Ministry of EducationBeijingPR China National Health Commission Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides Beijing Key Laboratory of Cardiovascular Receptors ResearchPeking UniversityBeijingPR China Department of Gastroenterology Beijing Friendship HospitalCapital Medical UniversityNational Clinical Research Center for Digestive DiseaseBeijing Digestive Disease CenterBeijing Key Laboratory for Precancerous Lesion of Digestive DiseaseBeijingPR China Center for Biomechanics and Bioengineering Key Laboratory of Microgravity(National Microgravity Laboratory)And Beijing Key Laboratory of Engineered Construction and MechanobiologyInstitute of MechanicsChinese Academy of SciencesBeijingPR China School of Engineering Sciences University of Chinese Academy of SciencesBeijingPR China Department of Vascular Surgery Peking University People’s HospitalBeijingPR China Institute of Biomechanics and Medical Engineering School of Aerospace EngineeringTsinghua UniversityBeijingPR China

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.

关键词： Matrix stiffness Inflammation DDR1 DNMT1 Mechanotransduction

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Interleukin-10 concentration-dependently impairs the biophysical characteristics and motility of mature dendritic cells

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医用生物力学 2013年第S1期28卷 89-90页

作者： Xiaoli Xu Hui Xue weijuan yao Zhu Zeng Department of Biotechnology School of Medical BioengineeringGuiyang Medical College Department of Biophysics Health Science CenterPeking University

Tumor microenvironment is composed of the tumor cells,stromal cells,microvascular tissue fluid,constitute small amount of infiltrating cells and cytokines.In recent years,more and more evidence that tumor microenvironment play an important role in tumorigenesis.Tumor cells,immune cells and other mesenchymal cells interact and create an immunosuppressive microenvironment through a variety of immunosuppressive factors which vascular endothelial growth factor（VEGF）,transformed growth factor-β1（TGF-β1）and interleukin-10（IL-10）),which suppress immunology functions and promote tumor cells to escape immune surveillance,ultimately leading to tumor growth and metastasis.Dendritic cells（DCs）,the most potent antigen presenting cell as now known,play a key role in the anti-tumor immune process.The pre-

关键词： Interleukin microvascular infiltrating immunology interleukin surveillance cytokines ultimately suppress mature

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Tmod1 Affects the Immune Functions and Biophysical Properties of Dendritic Cells Through TLR4 Signaling Pathway and Cytoskeleton Remodeling

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医用生物力学 2019年第A1期34卷 152-153页

作者： Xianmei Liu Xue Xia LAmy Sung weijuan yao Zhu Zeng School of Basic medical Sciences/School of Biology&Engineering Guizhou Medical UniversityGuiyang550025China School of Basic Medical Science Peking UniversityBeijing100022China Department of Bioengineering University of CaliforniaSan DiegoLa Jolla92122USA

Background Dendritic cells(DCs)are the most important antigen-presenting cells due to their professional and extremely efficient antigen-presenting function.The dynamics of cytoskeleton plays crucial regulated roles on DCs’immune functions and biophysical properties.Several evidences show that tumor-derived suppressive cytokines deteriorate DCs’immune functions through remodeling their F-actin cytoskeleton.But the underlying mechanism is still elusive.Tropomodulin1(Tmod1),a cytoskeleton-binding protein,regulates and stabilizes actin filaments lengths and cytoskeleton architecture,which involves in the regulations of the morphology,formation of neural dendrites and biophysical properties of cells.Our previous studies found that mature DCs(mDCs)had a higher expression of Tmod1 than immature DCs(imDCs). Therefore,it’s hypothesized that Tmod1 maybe involve in the modification of DCs’functions.Objective The aim of the study is to investigate the effects of Tmodl on the immune functions and biophysical properties of DCs and the underlying mechanisms in order to further understand the biological behaviors of DCs.Methods Bone marrow-derived cells were harvested from wild type(C57BL/6 J)mice and Tmod1 knockout mice(Tmod1 overexpressing transgenic(TOT)/Tmod1-/-)and differentiated to immature dendritic cells(imDCs)by rmGM-CSF and rmIL-4.imDCs were then matured by lipopolysaccharides(LPS)treatment.The expressions of the surface markers in DCs,including CD80,CD86,CD40,MHC-Ⅱand CCR7,were detected by flow cytometry,Western blot and qRT-PCR.The inflammation cytokines such as IL-6,IFN-γ,IFN-βand IL-10 were also detected by flow cytometry.The immune functions and the biophysical properties of DCs were compared between the wild type and Tmod1 knockout mice.The F-actin content and dendritic pseudopodia of these two kinds of DCs were detected by flow cytometry and laser scanning confocal microscope respectively.Finally,we detected the MyD88 dependent and independent signaling pathway to discover the molecular mechanisms.Results We fo

关键词： Tmod1 dendritic cells immune functions biophysical properties cytoskeleton

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The expressions of erythrocyte tropomodulin isoforms response to mechanical stresses

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医用生物力学 2013年第S1期28卷 127-127页

作者： weijuan yao Jian Song Xiaolan Zhang Lanping Amy Sung Hemorheology Center Department of Physiology and PathophysiologyPeking University Health Science Center Chengde Medical College Institute of Microbiology Chinese Academy of Sciences Department of Bioengineering University of California

Erythrocyte tropomodulin（E-Tmod）is a capping protein at the slow-growing end of the actin filaments and regulates the length of the junctional complex in the erythrocyte membrane skeleton[1].E-Tmod has two alternative promoters,PE0,and PE1,upstream of exons EO and E1,respectively.They drive the expression of two E-Tmod isoforms,E-Tmod41 and ETmod29,which play different yet coordinated roles in cytoskeleton reorganization[2].This study aimed at investigating the expessions of the two E-Tmod isoforms response to the mechanical stresses,i.e.,shear stress and hydrostatic pressure.A cone-plate flow system and a hydrostatic pressure device were developed.Murine erythroleukemia（MEL）cells were subjected

关键词： erythrocyte cytoskeleton reorganization hydrostatic upstream coordinated filaments aimed responsive length

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The role of tropomodulin1 in the migration inhibition of macrophage induced by oxLDL

The role of tropomodulin1 in the migration inhibition of mac...

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第十一届全国生物力学学术会议暨第十三届全国生物流变学学...

作者： weijuan yao Fang Ding Yuan Wu Xifu Wang Lide Xie L.Amy Sung Hemorheology Center Department of Physiology and PathophysiologyPeking University Health Science Center Chengde Medical College Emergency Department Beijing Anzhen HospitalCapital Medical University Department of Bioengineering University of California

Objective:The migration inhibition of macrophage is the core event in the development of atherosclerosis.But the mechanisms remain elusive.Oxidized low density lipoprotein(oxLDL)is one of the main factors that inhibit macrophage migration.The cytoskeletal proteins determine the deformability and migration of the cells.Tropomodulin1(Tmod1)is a cytoskeleton protein that caps the pointed end of actin filaments and plays an im-

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A novel topology with controllable wideband baseband impedance for power amplifiers

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Frontiers of Information Technology & Electronic Engineering 2024年第2期25卷 308-315页

作者： yao yao Zhijiang DAI Mingyu LI School of Intelligent Technology and Engineering Chongqing University of Science and TechnologyChongqing400065China School of Microelectronics and Communication Engineering Chongqing UniversityChongqing400065China

This paper presents a novel topology to control the baseband impedance of a power amplifier(PA)to avoid performance deterioration in concurrent dual-band mode.This topology can avoid pure resonance of capacitors and inductors LC,which leads to a high impedance at some frequency points.Consequently,it can be applied to transmitters that are excited by broadband signals.In particular,by adjusting the circuit parameters and increasing stages,the impedance of the key frequency bands can be flexibly controlled.A PA is designed to support this design idea.Its saturated output power is around 46.7 dBm,and the drain efficiency is>68.2%(1.8-2.3 GHz).Under concurrent two-tone excitation,the drain efficiency reaches around 40%even under 5.5 dB back-off power with the tone spacing from 10 MHz to 500 MHz.These results demonstrate that the proposed topology is capable of controlling wideband baseband impedance.

关键词： Baseband impedance Concurrent dual-band Power amplifier

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Physiological fluid flow-derived shear stress:a negative regulator for dendritic cells-induced immune response?

Physiological fluid flow-derived shear stress:a negative reg...

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第十届全国免疫学学术大会

作者： Cuifang Wu Rong Dong Zuquan Hu Jinhua Long Wenhui Hu Hui Yang Wei Qiu Chunlin Zhang weijuan yao Zhu Zeng Guizhou Medical University Health Science Center of Peking University

Objective:To study the response of dendritic cells(DCs)to shear stress.Methods:The DCs were exposed to different laminar flow shear stress for a given time course and their morphological characteristics,F-actin cytoskeleton and immune function were analyzed.Results:Shear stress could significantly remodel the morphological characteristics and F-actin cytoskeleton organizations of DCs.Simultaneously,the expression levels of some cell surface molecules were markedly downregulated by shear stress,including immune-associated molecules CD1a,CD11c,CD40,CD80,CD83,CD86,CCR7,CD205 and HLA-DR,and adhesion molecules CD18,CD11a,CD54,CD62P and CD106.The immune function of DCs was influenced by shear stress in magnitude and duration-dependent fashion,with these changes associated with some micro RNA and lnc RNA.Conclusion:The morphological characteristics and immune function of DCs could be impaired by shear stress.Thus,it can be inferred that shear stress may be a negative regulator for DCs-induced immune response,supporting the viewpoint of immuno-mechanobiology or mechanoimmunology.Our recent findings are significant for further understanding the biological behavior of DCs and for improving the clinical efficiency of DCs-based tumor vaccines.

关键词： Dendritic cells Shear stress F-actin cytoskeleton Immune function

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New progress of small-molecule drugs in the treatment of inflammatory bowel disease

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Chinese Medical Journal 2024年第5期137卷 556-558页

作者： Dongying yao Zhihua Ran Department of Gastroenterology Zhou Pu Hospital affiliated to Shanghai University of Health&Medical SciencesShanghai 201318China

With the advent of small-molecule drugs,treatment of inflammatory bowel disease(IBD)has reached a new stage.In contrast to biologics,small-molecule drugs can be made into oral dosage forms with a short half-life and are suitable for administration 1–2 times a day.Small-molecule drugs work by inhibiting the transmission of key intracellular signaling pathways in the pathogenesis of ulcerative colitis(UC)and Crohn’s disease(CD)[Figure 1].They do not induce anti-drug antibodies in patients or lead to loss of response after treatment.

关键词： drugs treatment inflammatory

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Numerical investigation of non-uniform temperature fields for proppant and fluid phases in supercritical CO_(2)fracturing

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Particuology 2024年第7期90卷 149-163页

作者： Boyu Liu Jun yao Research Center of Multiphase Flow in Porous Media China University of Petroleum(East China)Qingdao 266000China

The non-uniform temperature distribution in supercritical CO_(2)(Sc-CO_(2))fracturing influences the density,viscosity,and volume expansion or shrinkage rate of Sc-CO_(2),impacting proppant migration.This study presents a coupled computational fluid dynamics-discrete element method and heat transfer model to examine the effects of proppant bed shape and the heat transfers of proppant-wall,proppant-fluid,and fluid-wall on the fluid and proppant temperature fields.The Sc-CO_(2)volume expansion is assessed under various temperature conditions by evaluating the volume-averaged Sc-CO_(2)density.Several factors,including proppant size,shape,thermal conductivity,concentration,temperature difference,and injection velocity,are carefully analyzed to elucidate their impacts.The findings elucidate the existence of four distinct zones in the fluid temperature field.Each zone exhibits different magnitudes of temperature change under diverse conditions and undergoes dynamic transformations with the development of the proppant bed.The fluid-wall heat transfer and the fluid temperatures in Zones C and D are significantly subject to the fluid injection velocity(governing the heating duration),the temperature difference between fluid and formation(impacting the magnitude of heat flux),and the proppant bed shape(controlling the effective heating area).Additionally,the proppant-wall and proppant-fluid heat transfers determine the temperatures of both the proppant bed and the fluid within Zone B,showing a strong correlation with proppant thermal conductivity,proppant size,injection velocity,and temperature difference.The proposed coupled model provides valuable insights into the temperature distributions and flow behaviors of temperature-dependent fracturing fluids and proppants.

关键词： CFD-DEM Heat transfer Compressible fluid CO_(2)sequestration Proppant transport

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Fresh-Keeping Decision and Coordination of Fresh Agricultural Product Supply Chain Considering Carbon Cap-and-Trade under Different Dominance

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Journal of Systems Science and Systems Engineering 2024年第1期33卷 30-51页

作者： Yang Yang Guanxin yao China Institute for Agricultural Equipment Industrial Development Jiangsu UniversityZhenjiang212013China Jiangsu Modern Logistics Research Base Yangzhou UniversityYangzhou225009China

In the context of low carbon,this paper discussed the impact of the carbon cap-and-trade policy on the fresh-keeping decision-making of two-echelon fresh agricultural product supply chains under different dominance,and designed cost-sharing contracts to coordinate the supply chain of fresh agricultural products dominated by suppliers and retailers respectively.The results showed that:dominance has no effect on the fresh-keeping decision and total revenue of fresh agricultural product supply chain,but it affects the internal income distribution,and dominance does not always bring more benefits;the implementation of carbon cap-and-trade reduces the fresh-keeping decision-making of fresh agricultural products supply chain and reduces the free-rider income of followers;the role of higher carbon trading price is twofold,which not only brings about the speculation of leading enterprises,but also promotes the application of low-carbon technologies;consumers’high preference for freshness,low-cost and high-efficiency low-carbon technology are all conducive to improving the fresh-keeping efforts and benefits of the supply chain;cost-sharing contracts can coordinate the supply chain of fresh agricultural products.

关键词： Dominant power carbon cap-and-trade policy fresh agricultural product supply chain fresh-keeping decision-making

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