As a key regulator of immune response,CD40 L is usually associated with chronic disease-related inflammation,autoimmune diseases and malignant diseases.Receptor recognition of platelet CD40 L is the initial event that...As a key regulator of immune response,CD40 L is usually associated with chronic disease-related inflammation,autoimmune diseases and malignant diseases.Receptor recognition of platelet CD40 L is the initial event that mediates platelet aggregation and leukocyte immune response.Unlike soluble CD40 L,the interaction between transmembrane platelet CD40 L and its receptors occurs within the cell junction surface,usually,in a physiological and pathological high blood flow shear stress environment.This two-dimensional reaction kinetics should be a mechano-chemical coupling process.In addition to its classical receptor CD40,CD40 L also binds to receptorα5β1,CD40 L can bind to the resting state of integrinα5β1,but the mechanical regulation mechanism of integrinα5β1 activation under fluid shear stress remains unclear.We assume that the force can promote CD40 L-inducedα5β1 activation.To check this hypothesis,we performed flow chamber experiment to investigate interaction of CD40 L andα5β1.In experiments,the bottom of the flow chamber is functionalized by a suitable concentration of CD40 L,and the fiber spheres of 6μm diameter was coated withα5β1.The selection of CD40 L concentration was based on the observation that as many tether events ofα5β1-coated spheres as possible were observed rather than stable adhesion events of these spheres.Theα5β1-coated sphere suspension was poured over the CD40 L-coated substrates in the flow chamber under different shear rates.A high-speed camera was used to observe and record tether events of fiber spheres at a rate of 100 frames per second.According to our affinity state transition model for integrin,the data were analyzed to obtain the rate of integrin activation and its mechanical regulation characteristics.Our results demonstrated that the interaction betweenα5β1 and CD40 L is biphasic force-dependent,showing mechano-chemical regulation mechanism of'Catch-slip bond'transition.The affinity jumping model was well fitted with the data obtained from flow chamber experiment at various wall shear stresses.We found that,CD40 L ligation-induced jumping ofα5β1 affinity state from low to medium(or high)one will occur within 0.5-1.0 second,resulting in prolonging of bond lifetimes.And,frequency distribution of the tether events number with tether lifetime under each force,exhibits obvious doublet peaks,one within 0.5-1 s and second within 1.5-2.5 s,indicating theα5β1 affinity state transform from low to high one.The probability distribution of the tether lifetime under different shear forces are not linear,and exists a turning point,which shows that the rate ofα5β1 dissociation from CD40 L is fast first,and then become slow,showing a force-induced conformation transformation of the integrinα5β1 from low affinity state to high affinity one.Our findings suggest that,the continuous force stimulation will quickly cause the affinity state change of integrinα5β1. The dissociation rate of theα5β1/CD40 L complex decreases first and then increases with wall shear stress,exhibiting a'Catch-slip bond'transformation of interaction betweenα5β1-CD40 L.This mechanical regulation mechanism exists in interaction of CD40 L not only toα5β1 at low affinity state but also to one at high affinity state.Our results should be useful in understanding the mechanical regulation mechanism of a5β1-CD40 L interaction-mediated cellular immune response and inflammatory processes.展开更多
通过彩色多普勒超声显像仪观测普萘洛尔与5-单硝酸异山梨醇酯(ISMN)联用对肝硬化门静脉血流动力学的影响。19例乙型肝炎后肝硬化患者并有内镜证实的食管静脉曲张。治疗组ISMN 20mg,每日2次,普萘洛尔10mg～20mg,每日3次;对照组为健康受...通过彩色多普勒超声显像仪观测普萘洛尔与5-单硝酸异山梨醇酯(ISMN)联用对肝硬化门静脉血流动力学的影响。19例乙型肝炎后肝硬化患者并有内镜证实的食管静脉曲张。治疗组ISMN 20mg,每日2次,普萘洛尔10mg～20mg,每日3次;对照组为健康受试者。采用同个体自身治疗前后对照研究。结果表明应用普萘洛尔与ISMN治疗1周后,Dpv、Vpv均显著性下降(P<0.01),Opv也显著性降低(711.76±515.52 vs 484.02±222.93)mL/min,P<0.01;Qsv显著性降低(558.07±354.62 vs 394.02±267.57)ml/min,P<0.01;但Qsmv的变化不明显(P>0.05)。治疗4周后也获得了同样的效果。普萘洛尔与ISMN联用可以降低Qpv和Qsv,具有预防上消化道出血的作用。展开更多
The internal turbulent flow in conical diffuser is a very complicated adverse pressure gradient flow.DLR k-ε turbulence model was adopted to study it.The every terms of the Laplace operator in DLR k-ε turbulence mod...The internal turbulent flow in conical diffuser is a very complicated adverse pressure gradient flow.DLR k-ε turbulence model was adopted to study it.The every terms of the Laplace operator in DLR k-ε turbulence model and pressure Poisson equation were discretized by upwind difference scheme.A new full implicit difference scheme of 5-point was constructed by using finite volume method and finite difference method.A large sparse matrix with five diagonals was formed and was stored by three arrays of one dimension in a compressed mode.General iterative methods do not work wel1 with large sparse matrix.With algebraic multigrid method(AMG),linear algebraic system of equations was solved and the precision was set at 10-6.The computation results were compared with the experimental results.The results show that the computation results have a good agreement with the experiment data.The precision of computational results and numerical simulation efficiency are greatly improved.展开更多
基金supported by the National Natural Science Foundation of China ( 116272109, 11432006)
文摘As a key regulator of immune response,CD40 L is usually associated with chronic disease-related inflammation,autoimmune diseases and malignant diseases.Receptor recognition of platelet CD40 L is the initial event that mediates platelet aggregation and leukocyte immune response.Unlike soluble CD40 L,the interaction between transmembrane platelet CD40 L and its receptors occurs within the cell junction surface,usually,in a physiological and pathological high blood flow shear stress environment.This two-dimensional reaction kinetics should be a mechano-chemical coupling process.In addition to its classical receptor CD40,CD40 L also binds to receptorα5β1,CD40 L can bind to the resting state of integrinα5β1,but the mechanical regulation mechanism of integrinα5β1 activation under fluid shear stress remains unclear.We assume that the force can promote CD40 L-inducedα5β1 activation.To check this hypothesis,we performed flow chamber experiment to investigate interaction of CD40 L andα5β1.In experiments,the bottom of the flow chamber is functionalized by a suitable concentration of CD40 L,and the fiber spheres of 6μm diameter was coated withα5β1.The selection of CD40 L concentration was based on the observation that as many tether events ofα5β1-coated spheres as possible were observed rather than stable adhesion events of these spheres.Theα5β1-coated sphere suspension was poured over the CD40 L-coated substrates in the flow chamber under different shear rates.A high-speed camera was used to observe and record tether events of fiber spheres at a rate of 100 frames per second.According to our affinity state transition model for integrin,the data were analyzed to obtain the rate of integrin activation and its mechanical regulation characteristics.Our results demonstrated that the interaction betweenα5β1 and CD40 L is biphasic force-dependent,showing mechano-chemical regulation mechanism of'Catch-slip bond'transition.The affinity jumping model was well fitted with the data obtained from flow chamber experiment at various wall shear stresses.We found that,CD40 L ligation-induced jumping ofα5β1 affinity state from low to medium(or high)one will occur within 0.5-1.0 second,resulting in prolonging of bond lifetimes.And,frequency distribution of the tether events number with tether lifetime under each force,exhibits obvious doublet peaks,one within 0.5-1 s and second within 1.5-2.5 s,indicating theα5β1 affinity state transform from low to high one.The probability distribution of the tether lifetime under different shear forces are not linear,and exists a turning point,which shows that the rate ofα5β1 dissociation from CD40 L is fast first,and then become slow,showing a force-induced conformation transformation of the integrinα5β1 from low affinity state to high affinity one.Our findings suggest that,the continuous force stimulation will quickly cause the affinity state change of integrinα5β1. The dissociation rate of theα5β1/CD40 L complex decreases first and then increases with wall shear stress,exhibiting a'Catch-slip bond'transformation of interaction betweenα5β1-CD40 L.This mechanical regulation mechanism exists in interaction of CD40 L not only toα5β1 at low affinity state but also to one at high affinity state.Our results should be useful in understanding the mechanical regulation mechanism of a5β1-CD40 L interaction-mediated cellular immune response and inflammatory processes.
文摘通过彩色多普勒超声显像仪观测普萘洛尔与5-单硝酸异山梨醇酯(ISMN)联用对肝硬化门静脉血流动力学的影响。19例乙型肝炎后肝硬化患者并有内镜证实的食管静脉曲张。治疗组ISMN 20mg,每日2次,普萘洛尔10mg～20mg,每日3次;对照组为健康受试者。采用同个体自身治疗前后对照研究。结果表明应用普萘洛尔与ISMN治疗1周后,Dpv、Vpv均显著性下降(P<0.01),Opv也显著性降低(711.76±515.52 vs 484.02±222.93)mL/min,P<0.01;Qsv显著性降低(558.07±354.62 vs 394.02±267.57)ml/min,P<0.01;但Qsmv的变化不明显(P>0.05)。治疗4周后也获得了同样的效果。普萘洛尔与ISMN联用可以降低Qpv和Qsv,具有预防上消化道出血的作用。
基金Projects(59375211,10771178,10676031) supported by the National Natural Science Foundation of ChinaProject(07A068) supported by the Key Project of Hunan Education CommissionProject(2005CB321702) supported by the National Key Basic Research Program of China
文摘The internal turbulent flow in conical diffuser is a very complicated adverse pressure gradient flow.DLR k-ε turbulence model was adopted to study it.The every terms of the Laplace operator in DLR k-ε turbulence model and pressure Poisson equation were discretized by upwind difference scheme.A new full implicit difference scheme of 5-point was constructed by using finite volume method and finite difference method.A large sparse matrix with five diagonals was formed and was stored by three arrays of one dimension in a compressed mode.General iterative methods do not work wel1 with large sparse matrix.With algebraic multigrid method(AMG),linear algebraic system of equations was solved and the precision was set at 10-6.The computation results were compared with the experimental results.The results show that the computation results have a good agreement with the experiment data.The precision of computational results and numerical simulation efficiency are greatly improved.
