Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.

Microdynamic mechanical properties and fracture evolution mechanism of monzogabbro with a true triaxial multilevel disturbance method

The far-field microdynamic disturbance caused by the excavation of deep mineral resources and underground engineering can induce surrounding rock damage in high-stress conditions and even lead to disasters.However,the mechanical properties and damage/fracture evolution mechanisms of deep rock induced by microdynamic disturbance under three-dimensional stress states are unclear.Therefore,a true triaxial multilevel disturbance test method is proposed,which can completely simulate natural geostress,excavation stress redistribution(such as stress unloading,concentration and rotation),and subsequently the microdynamic disturbance triggering damaged rock failure.Based on a dynamic true triaxial test platform,true triaxial microdynamic disturbance tests under different frequency and amplitudes were carried out on monzogabbro.The results show that increasing amplitude or decreasing frequency diminishes the failure strength of monzogabbro.Deformation modulus gradually decreases during disturbance failure.As frequency and amplitude increase,the degradation rate of deformation modulus decreases slightly,disturbance dissipated energy increases significantly,and disturbance deformation anisotropy strengthens obviously.A damage model has been proposed to quantitatively characterize the disturbance-induced damage evolution at different frequency and amplitude under true triaxial stress.Before disturbance failure,the micro-tensile crack mechanism is dominant,and the micro-shear crack mechanism increases significantly at failure.With the increase of amplitude and frequency,the micro-shear crack mechanism increases.When approaching disturbance failure,the acoustic emission fractal dimension changes from a stable value to local large oscillation,and finally increases sharply to a high value at failure.Finally,the disturbance-induced failure mechanism of surrounding rock in deep engineering is clearly elucidated.

Mechanical behavior and failure mechanisms of rock bolts subjected to static-dynamic loads

This study explores the effects of dynamic and static loading on rock bolt performance a key factor in maintaining the structural safety of coal mine roadways susceptible to coal bursts.Employing a housemade load frame to simulate various failure scenarios,pretension-impact-pull tests on rock bolts were conducted to scrutinize their dynamic responses under varied static load conditions and their failure traits under combined loads.The experimental results denote that with increased impact energy,maximum and average impact loads on rock bolts escalate significantly under pretension,initiating plastic deformation beyond a certain threshold.Despite minor reductions in the yield load due to impactinduced damage,pretension aids in constraining post-impact deformation rate and fluctuation degree of rock bolts.Moreover,impact-induced plastic deformation causes internal microstructure dislocation,fortifying the stiffness of the rock bolt support system.The magnitude of this fortification is directly related to the plastic deformation induced by the impact.These findings provide crucial guidance for designing rock bolt support in coal mine roadway excavation,emphasizing the necessity to consider both static and dynamic loads for improved safety and efficiency.

Uncertainty quantification of mechanism motion based on coupled mechanism—motor dynamic model for ammunition delivery system

In this paper,a dynamic modeling method of motor driven electromechanical system is presented,and the uncertainty quantification of mechanism motion is investigated based on this method.The main contribution is to propose a novel mechanism-motor coupling dynamic modeling method,in which the relationship between mechanism motion and motor rotation is established according to the geometric coordination of the system.The advantages of this include establishing intuitive coupling between the mechanism and motor,facilitating the discussion for the influence of both mechanical and electrical parameters on the mechanism,and enabling dynamic simulation with controller to take the randomness of the electric load into account.Dynamic simulation considering feedback control of ammunition delivery system is carried out,and the feasibility of the model is verified experimentally.Based on probability density evolution theory,we comprehensively discuss the effects of system parameters on mechanism motion from the perspective of uncertainty quantization.Our work can not only provide guidance for engineering design of ammunition delivery mechanism,but also provide theoretical support for modeling and uncertainty quantification research of mechatronics system.

A molecular dynamics study on mechanical performance and deformation mechanisms in nanotwinned NiCo-based alloys with nano-precipitates under high temperatures

Molecular dynamics simulations are performed to investigate the mechanical behavior of nanotwinned NiCo-based alloys containing coherent L12 nano-precipitates at different temperatures,as well as the interactions between the dislocations and nano-precipitates within the nanotwins.The simulation results demonstrate that both the yield stress and flow stress in the nanotwinned NiCo-based alloys with nano-precipitates decrease as the temperature rises,because the higher temperatures lead to the generation of more defects during yielding and lower dislocation density during plastic deformation.Moreover,the coherent L12 phase exhibits excellent thermal stability,which enables the hinderance of dislocation motion at elevated temperatures via the wrapping and cutting mechanisms of dislocations.The synergistic effect of nanotwins and nano-precipitates results in more significant strengthening behavior in the nanotwinned NiCo-based alloys under high temperatures.In addition,the high-temperature mechanical behavior of nanotwinned NiCo-based alloys with nano-precipitates is sensitive to the size and volume fraction of the microstructures.These findings could be helpful for the design of nanotwins and nano-precipitates to improve the high-temperature mechanical properties of NiCo-based alloys.

Energy mechanism of bolt supporting effect to fissured rock under static and dynamic loads in deep coal mines

The stability control of fissured rock is difficult,especially under static and dynamic loads in deep coal mines.In this paper,the dynamic mechanical properties,strain rate evolution and energy dissipation of fissured and anchored rocks were respectively obtained by SHPB tests.It was found that bolt can provide supporting efficiency-improving effect for fissured rock against dynamic disturbance,and this effect increased quadratically with decrease in anchoring angles.Then,the energy dissipation mechanism of anchored rock was obtained by slipping model.Furthermore,bolt energy-absorbing mechanism by instantaneous tensile-shear deformation was expressed based on material mechanics,which was the larger the anchoring angle,the smaller the energy absorption,and the less the contribution to supporting efficiency improvement.On this basis,the functional relationship between energy dissipation of anchored rock and energy absorption of bolt was established.Taking the coal-gangue separation system of Longgu coal mine as an example,the optimal anchoring angle can be determined as 57.5°–67.5°.Field monitoring showed fissured rock with the optimal anchoring angle,can not only effectively control the deformation,but also fully exert the energy-absorbing and efficiency-improving effect of bolt itself.This study provides guidance to the stability control and supporting design for deep engineering under the same or similar conditions.

Dynamic Modeling and Experimental Verification of an RPR Type Compliant Paralle Mechanism with Low Orders

Efficiency of calculating a dynamic response is an important point of the compliant mechanism for posture adjustment.Dynamic modeling with low orders of a 2R1T compliant parallel mechanism is studied in the paper.The mechanism with two out-of-plane rotational and one lifting degrees of freedom(DoFs)plays an important role in posture adjustment.Based on elastic beam theory,the stiffness matrix and mass matrix of the beam element are established where the moment of inertia is considered.To improve solving efficiency,a dynamic model with low orders of the mechanism is established based on a modified modal synthesis method.Firstly,each branch of the RPR type mechanism is divided into a substructure.Subsequently,a set of hypothetical modes of each substructure is obtained based on the C-B method.Finally,dynamic equation of the whole mechanism is established by the substructure assembly.A dynamic experiment is conducted to verify the dynamic characteristics of the compliant mechanism.

Dynamic analysis of a novel multilink-spring mechanism for vibration isolation and energy harvesting

Due to technical limitations,existing vibration isolation and energy harvesting(VIEH)devices have poor performance at low frequency.This paper proposes a new multilink-spring mechanism(MLSM)that can be used to solve this problem.The VIEH performance of the MLSM under harmonic excitation and Gaussian white noise was analyzed.It was found that the MLSM has good vibration isolation performance for low-frequency isolation and the frequency band can be widened by adjusting parameters to achieve a higher energy harvesting power.By comparison with two special cases,the results show that the MLSM is basically the same as the other two oscillators in terms of vibration isolation but has better energy harvesting performance under multistable characteristics.The MLSM is expected to reduce the impact of vibration on high-precision sensitive equipment in some special sites such as subways and mines,and at the same time supply power to structural health monitoring devices.

A comparative study on kinetics and dynamics of two dump truck lifting mechanisms using MATLAB simscape

In this paper,two lifting mechanism models with opposing placements,which use the same hydraulic hoist model and have the same angle of 50°,have been developed.The mechanical and hydraulic simulation models are established using MATLAB Simscape to analyze their kinetics and dynamics in the lifting and holding stages.The simulation findings are compared to the analytical calculation results in the steady state,and both methods show good agreement.In the early lifting stage,Model 1 produces greater force and discharges goods in the container faster than Model 2.Meanwhile,Model 2 reaches a higher force and ejects goods from the container cleaner than its counterpart at the end lifting stage.The established simulation models can consider the effects of dynamic loads due to inertial moments and forces generated during the system operation.It is crucial in studying,designing,and optimizing the structure of hydraulic-mechanical systems.

Unveiling the crystallization mechanism of cadmium selenide via molecular dynamics simulation with machine-learning-based deep potential

Cadmium selenide(CdSe)is an inorganic semiconductor with unique optical and electronic properties that make it useful in various applications,including solar cells,light-emitting diodes,and biofluorescent tagging.In order to synthesize high-quality crystals and subsequently integrate them into devices,it is crucial to understand the atomic scale crystallization mechanism of CdSe.Unfortunately,such studies are still absent in the literature.To overcome this limitation,we employed an enhanced sampling-accelerated active learning approach to construct a deep neural potential with ab initio accuracy for studying the crystallization of CdSe.Our brute-force molecular dynamics simulations revealed that a spherical-like nu-cleus formed spontaneously and stochastically,resulting in a stacking disordered structure where the competition between hexagonal wurtzite and cubic zinc blende polymorphs is temperature-dependent.We found that pure hexagonal crystal can only be obtained approximately above 1430 K,which is 35 K below its melting temperature.Furthermore,we observed that the solidification dynamics of Cd and Se atoms were distinct due to their different diffusion coefficients.The solidification process was initiated by lower mobile Se atoms forming tetrahedral frameworks,followed by Cd atoms occupying these tetra-hedral centers and settling down until the third-shell neighbor of Se atoms sited on their lattice posi-tions.Therefore,the medium-range ordering of Se atoms governs the crystallization process of CdSe.Our findings indicate that understanding the complex dynamical process is the key to comprehending the crystallization mechanism of compounds like CdSe,and can shed lights in the synthesis of high-quality crystals.

Evolutionary analysis of green credit and automobile enterprises under the mechanism of dynamic reward and punishment based on government regulation

To explore the green development of automobile enterprises and promote the achievement of the“dual carbon”target,based on the bounded rationality assumptions,this study constructed a tripartite evolutionary game model of gov-ernment,commercial banks,and automobile enterprises;introduced a dynamic reward and punishment mechanism;and analyzed the development process of the three parties’strategic behavior under the static and dynamic reward and punish-ment mechanism.Vensim PLE was used for numerical simulation analysis.Our results indicate that the system could not reach a stable state under the static reward and punishment mechanism.A dynamic reward and punishment mechanism can effectively improve the system stability and better fit real situations.Under the dynamic reward and punishment mechan-ism,an increase in the initial probabilities of the three parties can promote the system stability,and the government can im-plement effective supervision by adjusting the upper limit of the reward and punishment intensity.Finally,the implementa-tion of green credit by commercial banks plays a significant role in promoting the green development of automobile enter-prises.

Mechanism,prevention,and control of mining-induced dynamic disasters in underground metal mines in China:Challenges and solutions

Metal mineral resources play an indispensable role in the development of the national economy.Dynamic disasters in underground metal mines seriously threaten mining safety,which are major scientific and technological problems to be solved urgently.In this article,the occurrence status and grand challenges of some typical dynamic disasters involving roof falling,spalling,collapse,large deformation,rockburst,surface subsidence,and water inrush in metal mines in China are systematically presented,the characteristics of mining-induced dynamic disasters are analyzed,the examples of dynamic disasters occurring in some metal mines in China are summarized,the occurrence mechanism,monitoring and early warning methods,and prevention and control techniques of these disasters are highlighted,and some new opinions,suggestions,and solutions are proposed simultaneously.Moreover,some shortcomings in current disaster research are pointed out,and the direction of efforts to improve the prevention and control level of dynamic disasters in China’s metal mines in the future is prospected.The integration of forward-looking key innovative theories and technologies in the abovementioned aspects will greatly enhance the cognitive level of disaster prevention and mitigation in China’s metal mining industry and achieve a significant shift from passive disaster relief to active disaster prevention.

Microstructural evolution and dynamic recrystallization mechanisms of additively manufactured TiAl alloy with heterogeneous microstructure during hot compression

Microstructural evolution and dynamic recrystallization(DRX)mechanisms of a Ti-48Al-2Cr-2Nb(at.%)alloy prepared by selective electron beam melting(SEBM)during hot deformation at 1150℃and 0.1 s^(-1)were investigated by hot compression tests,optical microscope(OM),scanning electron microscope(SEM),electron back-scattered diffraction(EBSD)and transmission electron microscope(TEM).The results show that the initial microstructure of the as-SEBMed alloy exhibits layers of coarseγgrains and fineγ+α_(2)+(α_(2)/γ)lamellar mixture grains alternately along the building direction.During the early stage of hot deformation,deformation twins tend to form within the coarse grains,facilitating subsequent deformation,and a small number of DRX grains appear in the fine-grained regions.With the increase of strain,extensive DRX grains are formed through different DRX mechanisms in both coarse and fine-grained regions,involving discontinuous dynamic recrystallization mechanism(DDRX)in the fine-grained regions and a coexistence of DDRX and continuous dynamic recrystallization(CDRX)in the coarsegrained regions.

Molecular dynamics simulation of the flow mechanism of shear-thinning fluids in a microchannel

Shear-thinning fluids have been widely used in microfluidic systems,but their internal flow mechanism is still unclear.Therefore,in this paper,molecular dynamics simulations are used to study the laminar flow of shear-thinning fluid in a microchannel.We validated the feasibility of our simulation method by evaluating the mean square displacement and Reynolds number of the solution layers.The results show that the change rule of the fluid system's velocity profile and interaction energy can reflect the shear-thinning characteristics of the fluids.The velocity profile resembles a top-hat shape,intensifying as the fluid's power law index decreases.The interaction energy between the wall and the fluid decreases gradually with increasing velocity,and a high concentration of non-Newtonian fluid reaches a plateau sooner.Moreover,the velocity profile of the fluid is related to the molecule number density distribution and their values are inversely proportional.By analyzing the radial distribution function,we found that the hydrogen bonds between solute and water molecules weaken with the increase in velocity.This observation offers an explanation for the shear-thinning phenomenon of the non-Newtonian flow from a micro perspective.

The chemical environment and structural ordering in liquid Mg-Y-Zn system:An ab-initio molecular dynamics investigation of melt for the formation mechanism of LPSO structure

In an effort to clarify the formation mechanism of LPSO structure in Mg-Y-Zn alloy,the chemical environment and structural ordering in liquid Mg-rich Mg-Y-Zn system are investigated with the aid of ab-initio molecular dynamics simulation.In liquid Mg-rich Mg-Y alloys,the strong Mg-Y interaction is determined,which promotes the formation of fivefold symmetric local structure.For Mg-Zn alloys,the weak Mg-Zn interaction results in the fivefold symmetry weakening in the liquid structure.Due to the coexistence of Y and Zn,the strong attractive interaction is introduced in liquid Mg-Y-Zn ternary alloy,and contributes to the clustering of Mg,Y,Zn launched from Zn.What is more,the distribution of local structures becomes closer to that in pure Mg compared with that in binary Mg-Y and Mg-Zn alloys.These results should relate to the origins of the Y/Zn segregation zone and close-packed stacking mode in LPSO structure,which provides a new insight into the formation mechanism of LPSO structure at atomic level.

Study on the Mechanism of Nanopatterning in Printed Electronics Based on Molecular Dynamics Simulation

In order to research the feasibility of using the selective adsorption principle to achieve automatic shaping of nano patterns,in this study,using the liquid gallium as the conductive ink and graphene as the printing plate surface,by changing the surface wettability of patterned areas on the nanoscale of graphene printed boards,the automatic formation of liquid gallium patterns on the graphene printed plate surface was simulated.The results indicated that liquid gallium can achieve automatic patterning on the surface of graphene patterned areas;the greater the interaction energy between gallium and carbon atoms,the clearer the pattern;gallium liquid is prone to remain in complex local positions of the pattern,making it difficult to shape the pattern;if the spacing between adjacent pattern lines is too large or too small,it will result in residual gallium liquid between the lines;increasing the thickness of the gallium film will cause the pattern to expand beyond the boundary,but increasing the thickness of the gallium film can also enhance the thickness and uniformity of the pattern lines.In summary,the principle of selective adsorption can be used to achieve the automatic formation of nano patterns,and the pattern formation effect is influenced by factors such as atomic interaction energy and pattern configuration.

Improvement Mechanism of Adhesion Performance of Anti-stripping Agents and Coupling Agents on Asphalt-Aggregate Interface Based on Molecular Dynamics

This study examined the mechanisms for improving the adhesion performance of the asphalt-aggregate interface with two anti-stripping agents and two coupling agents.The investigation of contact behavior between various asphalt-aggregate surfaces was conducted using molecular dynamics(MD)simulations.The interaction energy and the relative concentration distribution were employed as the parameters to analyze the enhancement mechanisms of anti-stripping agents and coupling agents on the asphalt-aggregate interface.Results indicated that the adhesion at the asphalt-aggregate interface could be strengthened by both anti-stripping agents and coupling agents.Anti-stripping agents primarily improve adhesion through the reinforcement of electrostatic attraction,while coupling agents primarily upgrade adhesion by strengthening the van der Waals.Hence,the molecular dynamics modeling and calculation techniques presented in this study can be utilized to elucidate the development mechanism of the asphalt-aggregate interface through the use of anti-stripping agents and coupling agents.

Adjustment mechanism of blasting dynamic-static action in the water decoupling charge

Water decoupling charge blasting excels in rock breaking,relying on its uniform pressure transmission and low energy dissipation.The water decoupling coefficients can adjust the contributions of the stress wave and quasi-static pressure.However,the quantitative relationship between the two contributions is unclear,and it is difficult to provide reasonable theoretical support for the design of water decoupling blasting.In this study,a theoretical model of blasting fracturing partitioning is established.The mechanical mechanism and determination method of the optimal decoupling coefficient are obtained.The reliability is verified through model experiments and a field test.The results show that with the increasing of decoupling coefficient,the rock breaking ability of blasting dynamic action decreases,while quasi-static action increases and then decreases.The ability of quasi-static action to wedge into cracks changes due to the spatial adjustment of the blast hole and crushed zone.The quasi-static action plays a leading role in the fracturing range,determining an optimal decoupling coefficient.The optimal water decoupling coefficient is not a fixed value,which can be obtained by the proposed theoretical model.Compared with the theoretical results,the maximum error in the model experiment results is 8.03%,and the error in the field test result is 3.04%.

Exploring the molecular mechanism of action of curcumin for the treatment of diabetic retinopathy,using network pharmacology,molecular docking,and molecular dynamics simulation

Background:Based on network pharmacology and molecular docking,the present study investigated the mechanism of curcumin(CUR)in diabetic retinopathy treatment.Methods:Based on the DisGeNET,Swiss TargetPrediction,GeneCards,Online Mendelian Inheritance in Man,Gene Expression Omnibus,and Comparative Toxicogenomics Database,the intersection core targets of CUR and diabetic retinopathy were identified.The intersection target was imported into the STRING database to obtain the protein-protein interaction map.According to the Database for Annotation,Visualization and Integrated Discovery database,the intersected targets were enriched in Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes pathways.Then Cytoscape 3.9.1 is used to make the drug-target-disease-pathway network.The mechanism of CUR and diabetic retinopathy was further verified by molecular docking and molecular dynamics simulation.Results:There were 203 intersecting targets of CUR and diabetic retinopathy identified.1320 GO entries were enriched for GO functions,which were primarily involved in the composition of cells such as identical protein binding,protein binding,enzyme binding,etc.It was found that 175 pathways were enriched using Kyoto Encyclopedia of Genes and Genomes pathway enrichment methods,which were mainly included in the lipid and atherosclerosis,AGE-RAGE signaling pathway in diabetic complications,pathways in cancer,etc.In the molecular docking analysis,CUR was found to have a good ability to bind to the core targets of albumin,IL-1B,and IL-6.The binding of albumin to CUR was further verified by molecular dynamics simulation.Conclusion:As a result of this study,CUR may exert a role in the treatment of diabetic retinopathy through multi-target and multi-pathway regulation,which indicates a possible direction of future research.

Research on the Damping Mechanism of Time-Delay Coupled Negative Stiffness Dynamic Absorber in Nonlinear Vibration Damping System

A study was conducted on the effect of time delay and structural parameters on the vibration reduction of a time delayed coupled negative stiffness dynamic absorber in nonlinear vibration reduction systems. Taking dynamic absorbers with different structural and control parameters as examples, the effects of third-order nonlinear coefficients, time-delay control parameters, and negative stiffness coefficients on reducing the replication of the main system were discussed. The nonlinear dynamic absorber has a very good vibration reduction effect at the resonance point of the main system and a nearby area, and when 1 increases to a certain level, the stable region of the system continues to increase. The amplitude curve of the main system of a nonlinear dynamic absorber will generate Hop bifurcation and saddle node bifurcation in the region far from the resonance point, resulting in almost periodic motion and jumping phenomena in the system. For nonlinear dynamic absorbers with determined structural parameters, time-delay feedback control can be adopted to control the amplitude of the main system. For different negative stiffness coefficients, there exists a minimum damping point for the amplitude of the main system under the determined system structural parameters and time-delay feedback control parameters.