On the thermodynamics of plasticity during quasi-isentropic compression of metallic glass

Entropy production in quasi-isentropic compression (QIC) is critically important for understanding the properties of materials under extremeconditions. However, the origin and accurate quantification of entropy in this situation remain long-standing challenges. In this work, a framework is established for the quantification of entropy production and partition, and their relation to microstructural change in QIC. Cu50Zr50is taken as a model material, and its compression is simulated by molecular dynamics. On the basis of atomistic simulation-informed physicalproperties and free energy, the thermodynamic path is recovered, and the entropy production and its relation to microstructural change aresuccessfully quantified by the proposed framework. Contrary to intuition, entropy production during QIC of metallic glasses is relativelyinsensitive to the strain rate ˙γ when ˙γ ranges from 7.5 × 10^(8) to 2 × 10^(9)/s, which are values reachable in QIC experiments, with a magnitudeof the order of 10^(−2)kB/atom per GPa. However, when ˙γ is extremely high (>2 × 10^(9)/s), a notable increase in entropy production rate with˙γ is observed. The Taylor–Quinney factor is found to vary with strain but not with strain rate in the simulated regime. It is demonstrated thatentropy production is dominated by the configurational part, compared with the vibrational part. In the rate-insensitive regime, the increase inconfigurational entropy exhibits a linear relation to the Shannon-entropic quantification of microstructural change, and a stretched exponential relation to the Taylor–Quinney factor. The quantification of entropy is expected to provide thermodynamic insights into the fundamentalrelation between microstructure evolution and plastic dissipation.

Image Hiding with High Robustness Based on Dynamic Region Attention in the Wavelet Domain

Hidden capacity,concealment,security,and robustness are essential indicators of hiding algorithms.Currently,hiding algorithms tend to focus on algorithmic capacity,concealment,and security but often overlook the robustness of the algorithms.In practical applications,the container can suffer from damage caused by noise,cropping,and other attacks during transmission,resulting in challenging or even impossible complete recovery of the secret image.An image hiding algorithm based on dynamic region attention in the multi-scale wavelet domain is proposed to address this issue and enhance the robustness of hiding algorithms.In this proposed algorithm,a secret image of size 256×256 is first decomposed using an eight-level Haar wavelet transform.The wavelet transform generates one coefficient in the approximation component and twenty-four detail bands,which are then embedded into the carrier image via a hiding network.During the recovery process,the container image is divided into four non-overlapping parts,each employed to reconstruct a low-resolution secret image.These lowresolution secret images are combined using densemodules to obtain a high-quality secret image.The experimental results showed that even under destructive attacks on the container image,the proposed algorithm is successful in recovering a high-quality secret image,indicating that the algorithm exhibits a high degree of robustness against various attacks.The proposed algorithm effectively addresses the robustness issue by incorporating both spatial and channel attention mechanisms in the multi-scale wavelet domain,making it suitable for practical applications.In conclusion,the image hiding algorithm introduced in this study offers significant improvements in robustness compared to existing algorithms.Its ability to recover high-quality secret images even in the presence of destructive attacksmakes it an attractive option for various applications.Further research and experimentation can explore the algorithm’s performance under different scenarios and expand its potential applications.

Relaxation of Ne^(1+)1s^(0)2s^(2)2p^(6)np produced by resonant excitation of an ultraintense ultrafast x-ray pulse

The creation and relaxation of double K-hole states 1s^(0)2s^(2)2p^(6)np(n≥3)of Ne^(1+)in the interaction with ultraintense ultrafast x-ray pulses are theoretically investigated.The x-ray photon energies are selected so that x-rays first photoionize1s^(22)s^(22)p^(6) of a neon atom to create a single K-hole state of 1s2s^(22)p^(6) of Ne^(1+),which is further excited resonantly to double K-hole states of ls^(0)2s^(2)2p^(6)np(n≥3).A time-dependent rate equation is used to investigate the creation and relaxation processes of 1s^(0)2s^(2)2p^(6)np,where the primary microscopic atomic processes including photoexcitation,spontaneous radiation,photoionization and Auger decay are considered.The calculated Auger electron energy spectra are compared with recent experimental results,which shows good agreement.The relative intensity of Auger electrons is very sensitive to the photon energy and bandwidth of x-ray pulses,which could be used as a diagnostic tool for x-ray free electron laser and atom experiments.

The concave-wall jet characteristics in vertical cylinder separator with inlet baffle component

The concave-wall jet was formed in the vertical cylinder separator with inlet baffle component.The effect of curvature of radial baffle on the jet flow in the separator was investigated by the experiment of concentration and the numerical simulation of species transport.The results show that the concave-wall jet was confined within the narrow region near the concave-wall and the flow disturbance in the center of separator was weakened.The distribution of concentration and the flow region of wall jet depended on the curvature of radial baffle(K).Compared with the turbulent intensity of the plate baffle(K=0),that of concave baffle(K=2)reduced by 6.1%and the turbulent intensity of convex baffle(K=-2)increased by 13.5%.The best flow stability was obtained by the concave baffle because the baffle outlet was similar to convergent nozzle.The outlet convergent angle was between 0°and 19.5°when 0≤K≤2.The secondary vortices were caused by the tangential velocity irregularity on the cross-section of two axial baffles in the separator with convex baffle.The baffle with K≥0 was more suitable in separator inlet than that with K<0.

Lattice Thermal Conductivity of MgSiO_(3) Perovskite and Post-Perovskite under Lower Mantle Conditions Calculated by Deep Potential Molecular Dynamics

Lattice thermal conductivity(κlat)of MgSiO_(3) perovskite and post-perovskite is an important parameter for the thermal dynamics in the Earth.Here,we develop a deep potential of density functional theory quality under entire thermodynamic conditions in the lower mantle,and calculate theκlatby the Green-Kubo relation.Deep potential molecular dynamics captures full-order anharmonicity and considers ill-defined phonons in low-κlatmaterials ignored in the phonon gas model.Theκlatshows negative temperature dependence and positive linear pressure dependence.Interestingly,theκlatundergos an increase at the phase boundary from perovskite to post-perovskite.We demonstrate that,along the geotherm,theκlatincreases by 18.2% at the phase boundary.Our results would be helpful for evaluating Earth’s thermal dynamics and improving the Earth model.

Soft and Hard Tissue Changes Following Treatment of Class Ⅱ Division 1 Malocclusion with Twin-Block and Myofunctional Appliance: A Pilot Study

Background Many cases of ClassⅡdeformities have been reported to be treated with prefabricated appliances.The aim of this study was to distinguish the clinical effect of traditional custom-made appliances and prefabricated appliances in the treatment of ClassⅡdivision 1 malocclusion.Therefore,soft and hard tissue changes following treatment of ClassⅡdivision 1 malocclusion using the twin-block(TB)appliance was compared to that using the Myofunctional Research Company(MRC)appliance(K1+K2)combined with oral myofunctional treatment(OMT)(MRC+OMT).Methods The study included 22 children(6 boys and 16 girls aged 9–11 years)with ClassⅡdivision 1 malocclusion along with mandibular retrognathism with a 5–12 mm overjet,basic normal maxillary status,and stage 2 or 3 cervical vertebral maturation(CVM).Participants were randomly assigned into two groups,the TB group and the MRC+OMT group for 12 months.Standardized lateral cephalograms were used to assess skeletal,dental,and soft tissue changes from pre-to post-treatment.Independent t-tests were used to compare the initial and final cephalometric status and tissue changes between the groups.Results The TB and MRC+OMT groups resulted in different degrees of lateral changes;however,improvements of skeletal and soft tissue indices were significantly greater in the TB group than in the MRC+OMT group.Conclusion TB was more effective than MRC+OMT in treating children aged 9–11 years with ClassⅡdivision 1 malocclusion.However,further research using custom-made appliances with OMT is recommended,and further investigations are needed to confirm these findings.

Balance between education and game-play— A case study of design and optimization of the mini-game book classification

Purpose： Based on our experience of designing and testing a computer-based game for teaching undergraduate students information literacy （IL） concepts and skills, this paper summarizes the basic strategies for striking a balance between education and entertainment for the designers of quality IL games. Design/methodology/approach： The project team recruited 10 college students to play the game and post-game group interviews revealed problems and optimization priorities. The optimized game was tested among 50 college students. Based on a comparison of testing results of the two versions of the game, basic strategies for designing quality 1L games were summarized. Findings： The following 5 basic strategies can effectively promote combination of education and entertainment： l） using adventure games to enhance gaming experience, 2） plotting an intriguing story to attract players, 3） motivating players to engage in game play with game components such as challenge, curiosity, fantasy and control, 4） presenting learning materials through game props, and 5） assigning players tasks to be completed with subject knowledge. Research limitations： The 5 basic strategies have been tested only in the development process of one game, and the book classification knowledge in the mini-game is limited to the 22 major categories of the Chinese Library Classification. Practical implications： University libraries may refer to our experience to design and utilize educational games to promote the IL education for college students. Originality value： Few empirical studies tested and summarized strategies for combining learning and fun in the design of IL games for university students. The 5 strategies, which are summarized in the process of design and optimization of the mini-game book classification, are valuable for other designers of IL games.

A comparative analysis of information literacy curriculum standards in the educational programs of high schools in China and in the United States

Our study aims to take a closer look at China's current information literacy(IL) program standards at secondary schools and to analyze their level of success and/or failures in a comparative way with those of the United States in terms of fulfilling their each other's mission-oriented mandates. Our research findings show that China's current IL standards of high schools contain a disproportionate emphasis on information technology(IT). Moreover, the stipulations of these IL standards are narrowly construed and without being solidly grounded on a broad and comprehensive educational perspective. We also suggest that there are two underlying causes for this set of unsound IL standards in China.Firstly, there is a lack of collaboration between two major competing forces engaged in the curricular development and research of IL in China: Those professionals in educational IT discipline vis-à-vis those in Library and Information Science. Secondly, library professionals have a very limited influence on major socio-cultural policies, even at their own institutions. As a result, this paper recommends the following three possible measures,which may help remedy this situation strategically: 1) Establishing a set of new IL curriculum standards based on an IL-centered educational perspective; 2) establishing a teacher-librarian's training program to promote school librarians' role in IL education; and 3) strengthening the research and development of an online IL education program and an accompanied evaluation mechanism.

Biphasical Force-Dependent CD40 L Ligation-Induced Activation of Integrin α5β1 under Flows

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.

Morphometric Studies of Human Coronary Artery Trees in Healthy and Disease

Objective According to the report from American Heart Association(AHA),cardiovascular diseases(CVDs)are the leading causes of death globally,and coronary artery disease(CAD),known as coronary atherosclerotic plaques,accounts for over 30%of cardiovascular diseases.Therefore,it is of great clinical significance to study the relationship between coronary bifurcations morphometrical feature change and coronary artery disease.Although coronary atherosclerosis has been extensively investigated,there is a lack of in-deep study on the differences in morphometric features between optimal and realistic geometry of coronary arterial trees.The purpose of the present paper is to determine the morphological changes in patients with CAD lesion compared with non-coronary artery disease(non-CAD)subjects.Methods Due to the difficulty of studying the coronary bifurcations in vivo,image-based in vitro anatomical 3D models have been widely used as a noninvasive method for morphometric measurement and clinical diagnosis of the coronary bifurcations.With the development of coronary computed tomography angiography(CTA)hardware and software technologies,the CTA imaging technique has been shown a promising application in the characterization,visualization,and identification of coronary artery disease in recent decades.The CTA images used to reconstruct three-dimensional(3D)coronary arterial trees are from Asia populations(Southern Chinese populations),including five cadavers without CAD lesion and 102 patients with CAD lesion.The best fit artery diameter was calculated as twice the average radius between the points in the centerlines and the points on the coronary arterial inner wall.The bifurcation angles between larger daughter artery and smaller daughter artery were determined by the intersection angle of their centerlines.Murray’s law was introduced to assess the deviation of the realistic vascular networks from its optimal state.Results Based on the morphometric analysis of coronary artery bifurcations in non-CAD subjects and patients with CAD lesion subjects,the most important finding is that morphological feature parameters of non-CAD subjects are closer to the optimal values than those of patients with CAD lesion.Moreover,by comparing the morphometric data between the left and right coronary arteries,the right coronary artery exhibits a structure closer to the optimal one in morphological feature than the left coronary artery.In addition,coronary arterial trees with CAD lesion have higher asymmetry and larger area expansion ratio(AER)than those of the coronary arterial trees without CAD lesion.Conclusions We morphologically found that the coronary arterial trees with CAD lesion and left are more likely to deviate from the optimal structure predicted by Murray’s law than those without CAD lesion and right.The degree to which coronary arterial system deviating from their optimal state may directly affect the incidence of coronary artery disease.This computer morpho-logical analysis strategy is illustrated to be effective in the distinguishing of the geometric differences between the healthy and diseased coronary arteries,and the analysis method may have a large potential in cardiovascular disease earlier diagnosis.

Biphasic Force-Dependent CD40 L-CD40 Interaction

CD40 receptor and its ligand CD40 L are the members of TNFR and TNF family,respectively.CD40 is expressed on antigen-presenting cells(APC)as a monomer,and would be dimerized upon its oligomerization through binding to its ligand CD40 L.Such dimer formation was shown to be essential for some CD40 signaling events,including phosphoinositide-3 kinase(PI-3 K)activation,the subsequent B7-2 upregulation and the production of IL-8.CD40 L is primarily expressed on activated T cells and activated platelets,and acts as an important costimulatory molecule especially on T follicular helper cells.It is believed that CD40-CD40 L interaction deeply involved in many immune events for the host defense against pathogens and cancer.CD40-CD40 L interaction mediates intracellular signaling along different pathways,such as the canonical and noncanonical nuclear factorκB pathway,mitogen-activated protein kinases,phosphatidylinositol-3 kinase(PI3K)and the phospholipase Cy pathway,is necessary for successful adaptive immune responses mainly relevant to development of CD8+CTLs,and is deeply involved in cross-talks among T cell,B cell,tumor cell,platelet and etc.However,interaction of CD40 with platelet CD40 L would occur in hemodynamics environments,and the regulation of force on this interaction remain unclear.Besides polymerization of CD40,the hemodynamic environment could be believed to regulate interaction between CD40 and its ligand.To reveal the mechanical regulation mechanism of interaction between CD40 L and CD40,atomic force microscope(AFM)was used in the adhesion frequency assay for measuring two-dimensional(2D)kinetics of CD40 L with CD40(the monomer and its dimer)at zero-force and force-clamp assay for measuring single-bond lifetimes of CD40 L/CD40 complex in a range of forces at single-molecule level.AFM cantilever probes were functionalized by incubation with CD40 L in buffer,and soaked in phosphate-buffered saline(PBS)containing 1%bovine serum albumin(BSA)to block nonspecific binding.Polystyrene dishes were coated with CD40(the monomer and its dimer)and then filled with PBS containing 1%BSA.Our data showed that the adhesion frequency of CD40 L with CD40 monomer and its dimer was 0.10 and0. 15,respectively,showing a higher affinity of CD40 L to CD40 dimer rather than its monomer;the rupture force for CD40 L dissociating from CD40 monomer and its dimer was 23 and 31pN,respectively,demonstrating a higher mechanical strength of complex of CD40 L with CD40 dimer instead of monomer;and increasing tension will prolong first and then shorten the bond lifetime of CD40 L-CD40 complex with force threshold of about 1OpN,and dimerization of CD40 had significantly increased enhanced the bond lifetime of CD40 L-CD40 complex,showing a dimerization-enhanced affinity of CD40 to CD40 L and'Catch-Slip'bond mechanism of CD40 L-CD40 interaction.These results suggest that,through upregulating the binding affinity with CD40 L,the polymerization of CD40 stabilizes the linkers and thereby communication between cell and cell,so does the force being small than the force threshold Both CD40 polymerization-and'Catch bond'-induced enhancement of affinity of CD40 with CD40 L may be necessary for stable cross talks between two cells.This finding may be useful for understanding CD40/CD40 L-induced events importantly in physiological or pathological processes at molecular and cellular level.

PSGL-1 Ligation-Induced Activation of Mac-1 under Flows

Inflammation and thrombosis usually occur together in many diseases,such as cardiovascular disease(CVD)and stroke,which remain to be the mostdetrimental human health killers.The crucial relevant cellular and molecular events include platelet-leukocyte interaction,platelet P-selectin secretion of activated platelet and activation of leukocyte integrin Mac-1(also known asαMβ2 or CD11b/CD18),which has binding site of platelet receptor glycoprotein lbα(GPlboα). Circulating leukocytes tethered to,rolled on and firmly adhered at the activated platelets on vascular wall,through interaction of platelet P-selectin with leukocyte P-selectin glycoprotein ligand-1(PSGL-1)and Mac-1 with GPlbα.We assume that there is a rapid signaling pathway in PSGL-1 ligation-induced activation of Mac-1,for forming a stable gap junction intracellular communication between platelet and leukocyte.To test this assumption,we observed the tethering events and calcium bursting of neutrophils on immobilized P-selectin only or plus GPlbαwith use of the parallel plate flow chamber(PPFC)technique and intracellular calcium ion detector Fluo-4 AM at various wall shear stresses,and examined the dynamic force spectrum for interaction of Mac-1 plus Mn2+and GPlbαby single-molecule atomic force microscopy(AFM).In the PPFC experiments,the intracellular calcium flux of firmly adhered neutrophils on immobilized P-selectin only or plus GPlbαwas observed in real timeby fluorescence microscopy,and the tether events of neutrophils was recorded by an inverted microscope and a high speed CMOS acquisition system in 1280 pixels×1024 pixels at 100 frames per second(fps). Captured images were analyzed by Image Pro Plus.Our results indicated that force triggered,enhanced and quickened the cytoplasmic calcium bursting of neutrophils.Calcium bursting may be induced first by interaction of the activated neutrophil Integrin Mac-1 and GPlbα,but not by P-selectin ligation to its ligand PSGL-1.Being triggered and speeded up by wall shear stress,the P-selectin-induced activation of Mac-1 in neutrophils was a previous events of calcium bursting,and occurred within one second.The tether lifetime of neutrophils on immobilized P-selectin only or plus GPlbαincreased first and then decreased with wall shear stress,and the wall shear stress threshold is 0.3 dyn/cm2 for P-selectin only but 0.25 dyn/cm2 for P-selectin plus GPlbα.It suggested a mechanical regulation mechanism of'Catch-slip bond'transition for Mac-1/GPlbαcomplex,like P-selectin/PSGL-1 complex.It was also demonstrated through the single-molecule AFM data,which showed that force regulated binding of activated Mac-1 to GPlbαthrough the Catch bond mechanism for tensile force small than 31.25 pN,being matched with the PPFC experimental data.The tether lifetime of neutrophils on immobilized P-selectin plus GPlbαwas more long than that on P-selectin only,showing the P-selectin-induced activation of Mac-1 on neutrophils was a rapid but local events under flows.In summary,force rapidly triggers and promotes the PSGL-1 ligation-induced activation of Mac-1 on neutrophils,leading to formation of stable intercellular communication between leukocytes and platelets.This finding should be useful in understanding of platelet-leukocytes interaction-mediated biological process in cellular inflammation responses and thrombus formation.

Mechano-Chemical Regulation of VWF-A Activity in Flow

Von Willebrand Factor(VWF),a multimeric plasma glycoprotein,is synthesized in endothelial cells and megakaryocytes.In adhesion and aggregation of circulating platelets towards to the sites of vascular injury,VWF captures and activates the circulating platelets through interaction with platelet GPlba.As a triplet complex of A1A2A3,the VWF-A domain is a closed conformation with a low affinity to GPlba,but mutations or pathological hemodynamic environment of high fluid shear stress can induce the closed A domain to become an extended one.However,the key events in the force-and/or mutation-induced activation of VWF-A under flows remains unclear.Therefore,with techniques of AFM and PPFC,we here examined transformation of conformation and function of VWF-A under various wall shear stresses,for understanding regulation of force on VWF-A activation.Interesting,AFM scanning imaging data showed that VWF-A molecules on substrate pretreated by perfusing distilled water at various wall shear stresses shortened first and then lengthened as increasing of the pre-loaded wall shear stress,and the threshold of the wall shear stress is about 100 dyn/cm2,demonstrating that increasing pre-loaded wall shear stress would make the treated-A1A2A3 conformation gradually transform from a loose spherical structure to a compact one first and then become an open or extended one.The adhesion frequency of GPlba-coated Polystyrene microspheres(3-μm radius)on the VWF-A-coated substrates decreased first and then increased with the preloaded wall shear stress,which has a same threshold mentioned above.These results suggested that,force-induced activation of VWF-A occurs just at high wall shear stresses(>100 dyn/cm2).The mechanical stability of the closed A1A2A3 conformation would be weakened by the gain of function(GOF)mutant R1 308 L of A1 and enhanced by the loss of function(LOF)mutant G1324S,as it should be.To further reveal the molecular mechanism of the force-induced enhancing or weakening of VWF-A activation,we performed AFM experiment to investigate interaction of A1(WT A1 and its two mutants,the GOF mutant R1 308 L and the LOF mutant G1324S)with A2 and A3,respectively.The adhesive frequency of A1 with A2was larger than that of A1 with A3,showing that A1 was in favor of A2 rather than A3.And,the lifetimes of A1-A2 and A1-A3bond were biphasic force-dependent,showing a'Catch-slip bond'transform in binding of A1 to A2 or A3.It suggested that under the low wall shear stresses,force could inhibit VWF activity through a catch bond mechanism,which enhanced the stability of the closed A1A2A3 conformation,but under high wall shear stresses,the force would enhance VWF activity through a slip bond mechanism,which promoted conformational transform of VWF-A from closed to extended one through reducing the stability of the closed A1A2A3 structure.Our results showed that the GOF mutant R1 308 L would down-regulate the binding affinity of A1 to A2,leading to a low barrier in opening of the closed VWF-A structure.In contrast,the LOF mutant G1324S would enhance the stability of the closed VWF-A conformation by up-regulating the binding affinity of A1 to A2,leading to inhibition of VWF activity.

Molecular Dynamic Simulation of Kindlin F3 Domain with Integrin β3-tail

Integrin activation,the transition from a low to a high affinity state,regulates the numerous cellular responses consequent to integrin engagement by extracellular matrix proteins.Kindlin proteins,play crucial roles in the integrin-signaling pathway by directly interacting with and activating integrins,which mediate the cell-extracellular matrix adhesion and signaling.As a widely distributed PTB domain protein and a major member of the kindlin family,kindlin2 interacts withβ3-tail,bridges talin-activated integrins to promote integrin aggregation,and enhances talin-induced integrin activation.Thus,kindlin2 is identified as a coactivator of integrins.Unlike talins,kindlin2 cannot directly alter the conformation of the integrin transmembrane helix and fail to activate integrin alone.Nevertheless,although it is widely accepted that kindlins and talins synergistically promote integrin activation,the underlying mechanism is unclear.Thus,the study of the force dissociation of the kindlin2/β3-tail complex and the conformation stabilization under different mechanical micro-environments should be of great significance for the further understanding of the structural basis of its synergistically activation of integrin.To reveal the molecular dynamics mechanism of interaction between kindlin2 andβ3-tail,we perform molecular dynamics(MD)simulations for this complex with different computing strategies interaction.In MD simulations,the available crystal structures of Kindlin-2/β3-tail complex(Protein Data Bank code 5XQ1)was downloaded from the PDB database.Two software packages,VMD for visualization and modeling and NAMD 2.13 for energy minimizations and MD simulations,were used here.The steadystate conformation of the complex was obtained from the equilibrium simulation.The dissociation event was observed by the constant velocity simulation,and the mechanical stability of the complex was observed by the constant force simulation.Our results showed that,during the equilibrium of the kindlin2-F3/β34ail complex,the residue MET612,LYS613 and TRP615 on the F3 domain of kindlin2 contributed to hydrogen-bonding with the corresponding residues onβ3 integrin.These bonds exhibit moderate or strong stability through steered molecular dynamics(SMD)simulation.During the constant velocity simulation,the complex exhibits a variety of unfolding pathways against tension applications,which are mainly distinguished by the disruption of hydrogen-bonds between the F3 domain a1/a2 helixes andβ1/β2 sheets.During the constant force simulation,the different phases of the composite force dissociation have different dissociation probabilities,which shows the biphasic force-dependent characteristics.And,the key residues in the pulling were recognized according not only to the number of interacting residue pairs,but also to their bond strength.Using molecular dynamics simulation,we showed the steady state of the kindlin2-F3/β3-tail complex under different tensile forces,and observe the dynamic process of molecular interaction.A possible underlying biophysical mechanism is that,the dissociation of Kindlin2-F3/β3-tail complex is biphasic force-dependent,and the conformations under different stretching states have different binding affinities.This study not only provides insights into the structural basis and mechanical regulation mechanisms of the kindlin/integrin interaction,in understanding in kindlin/integrin-related signaling in different cellular biological processes,but also provides new ideas for novel drug design and the treatment of related diseases.

The Mechanical Stabilization and Multi-States of the Stretched VWF A2 Domain

At the vascular injury sites,the ultra-large (UL) multimeric von willebrand Factor (VWF) is released in response to physiological and pathophysiological stimuli,and mediates platelet adhesion,aggregation,and cross-linking to maintain hemostasis.This UL-VWF is specifically cleaved by ADAMTS13(A Disintegrin And Metalloprotease with a ThromboSpondintype-1 motif,member 13)to prevent microvascular thrombosis.Each VWF monomer consists of five types of repeat domains in the order of D1-D2-D’-D3-A1-A2-A3-D4-C1-C2-C3-C4-C5-C6-CK,in which the A2 domain contains the ADAMTS13cleavage site(Tyr1605-Met1606),exposure of which requires mechanical or chemical stimuli.Under flows,fluid shear stress regulates VWF degradation and size distribution through opening the A2 domain and exposing its cleavage site for ADAMTS13.VWF A2 domain contains a C-terminal vicinal disulfide bond,a calcium binding sites,and a flexibleα4-less-loop.These unique structure features together make A2 more sensitive to mechanical signal than other VWF A subdomains,i.e.A1 and A3 domains.It is believed that A2 is first bound with and then cleaved by ADAMTS13,together with force-induced conformation transformation.To reveal molecular basis of this two-step model of VWF hydrolyzation by ADAMTS13,we here examined stretch-induced unfolding processes of VWF A2 domain in more detail by Steered molecular dynamics(SMD)simulations,with the use of crystal structure of VWF A2(PDB ID 3GXB),and observed that there were multiple quasi-stable conformations of stretched A2 until itsβ4-strand and a3-helix were pulled away the central hydrophobic core and the cleavage sites were fully accessible to solvent.Our MD simulation data showed that,in unfolding,at first,the cleavage site residue Tyr1605 was exposed partially and binding sites for Spacer domain of ADAMTS13 were exposed to a high level whenα6-helix was separated from A2 body;then,withβ6-strand and a5-helix been pulled away,the binding sites for Cysrich domain of ADAMTS13 was exposed completely while the exposure degree of Tyr1605 was not improved;further,separation ofβ5-strand andα4-less-loop made Tyr1605 and Met1606 and the respective binding sites for ADAMTS13 Spacer domain,Cys-rich domain,and Disintegrin-like domain be fully exposed to reach the optimal catalytic state;lastly,withβ4-strand separation,the cleavage sites and binding sites all were overstretched,leading to mismatch of ADAMTS13 and A2 conformation especially in the binding sites.This conformational mismatch may cause reduction of ADAMTS13 hydrolysis efficiency.Furthermore,the data of SMD simulations under constant forces demonstrated that,the stretched A2 conformation had different quasi-stable states,which all had the better mechanical stability within simulation time of 100 ns;and the conformational transformation from one state to another must overcome their respective potential barriers.The hydrolysis efficiency should depend on each state of the stretched A2 conformation,because of the exclusive matched-degree of A2 and ADMATS13.This computer prediction on the mechanical stability and multi-states of stretched A2 provides a novel insight into the mechano-chemical regulation on cleavage of A2 by ADAMTS13.It would be helpful for design of related drug targeting the binding sites on A2 and exosites on ADAMTS13 for the treatment of patients with acquired TTP.

Vehicular Electronic Image Stabilization System Based on a Gasoline Model Car Platform

Noise,vibration and harshness(NVH)problems in vehicle engineering are always challenging in both traditional vehicles and intelligent vehicles.Although high accuracy manufacturing,modern structural roads and advanced suspension technology have already significantly reduced NVH problems and their impacts;off-road condition,obstacles and extreme operating condition could still trigger NVH problems unexpectedly.This paper proposes a vehicular electronic image stabilization(EIS)system to solve the vibration problem of the camera and ensure the environment perceptive function of vehicles.Firstly,feature point detection and matching based on an oriented FAST and rotated BRIEF(ORB)algorithm are implemented to match images in the process of EIS.Furthermore,a novel improved random sampling consensus algorithm(i-RANSAC)is proposed to eliminate mismatched feature points and increase the matching accuracy significantly.And an adaptive Kalman filter(AKF)is applied to improve the adaptability of the vehicular EIS.Finally,an experimental platform based on a gasoline model car was established to validate its performance.The experimental results show that the proposed EIS system can satisfy vehicular performance requirements even under off-road condition with obvious obstacles.

Generation of Intense Sub-10 fs Pulses at 385 nm

We demonstrated the generation and characterization of 9.7 fs,180 J pulses centered at 385 nm via the frequency doubling of few-cycle near-infrared pulses.Both moderate conversion efficiency(9.5%)and broad phase matching bandwidth(20 nm)were achieved by shaping the spectra of the fundamental pulses.The strong intensity dependence of second-order harmonic generation and well controlled material dispersion ensured the inexistence of satellite pulses,which was confirmed by the self-diffraction frequency resolved optical gating measurement.

MiR-93-5p in BM-MSCs-derived exosomes amelio­rates renal fibrosis by affecting macrophage polar­ization

MiRNAs and macrophages play important roles in renal fibrosis.The exosomes secreted by bone marrow mesenchymal stem cells(BM-MSCs)can alleviate renal fibrosis.What is not clear,however,is whether a type of miRNAs in the BM-MSCs exosomes can alleviate renal fibrosis by modulating macrophage polarization.First,we take a high-throughput sequencing of miRNAs in exo­somes of BM-MSCs from chronic kidney disease(CKD)and normal people.Then we used the UUO mouse model and injected exosomes into the tail vein.The macrophages were stimulated with lipopolysaccharide(LPS).MSC-Exo or exosomes from BM-MSCs transfected with miR-93-5p inhibitor(Inhi-Exo)were added to the culture medium.The macrophages were transfected with miR-93-5p inhibitor or miR-93-5p mimic alone.The expression of miR-93-5p in exosomes of CKD patients was significantly decreased compared with normal people and in the LPS-stimulated macrophages and UUO mice kidneys.After stimulation with LPS,the macrophages polarized toward M1 subtype.MSC-Exo or miR-93-5p mimic promoted macrophages from M1 to M2 sub­type.Inhi-Exo or miR-93-5p inhibitor blocked the differentiation from M1 to M2 subtype.Significant fibrotic changes occurred in the kidneys of UUO mice,and M1 macrophages were significantly increased.After injecting exosomes into the tail vein of UUO mice,the degree of renal fibrosis was alleviated,the expression of miR-93-5p in the kidney was significantly increased,and the renal macrophages differentiated from M1 to M2 subtype.These results demonstrated that miR-93-5p in the exosomes derived from BM-MSCs can improve renal fibrosis by inducing macrophage differentiation from M1 to M2 subtype.

A Research on the Relationship between Intestinal Flora and Human Longevity

The exploration of human life and health is advancing with the changes of the times.With the growth of age,the occurrence of chronic diseases of human immunity and organ system is frequent,which has a serious impact on human health.Genes,environment and other random factors determine the outcome of longevity,and intestinal flora is considered to be a decisive factor affecting human health and longevity,mainly because of its huge impact on human immunity,growth and development.The study of the relationship between intestinal flora and longevity is beneficial to improve the health status of the elderly and improve the overall life level of human beings,which has great scientific research value.This review will review the role of intestinal flora in longevity.

广泛型牙周炎Ⅲ期C级口腔综合治疗1例

目的:本病例报道1例广泛型牙周炎Ⅲ期C级患者的多学科联合治疗及4年随访。诊治经过:52岁男性患者,进行牙周基础治疗、牙体根管治疗、正畸治疗及种植修复的联合治疗,并接受牙周维护治疗及4年长期随访。结果:经过4年的多学科联合治疗,患者牙周炎症处于静止期,全口咬合趋于协调稳定,缺失牙得到修复。结论:牙周基础治疗和维护治疗对于控制牙周炎症具有重要作用,牙周联合正畸和种植治疗使患者前牙的美观性和后牙的功能性均得到提高,其远期预后较好。