According to the necessity of flexible workflow management system, the solution to set up the visualized workflow modelling system based on B/S structure is put forward, which conforms to the relevant specifications o...According to the necessity of flexible workflow management system, the solution to set up the visualized workflow modelling system based on B/S structure is put forward, which conforms to the relevant specifications of WfMC and the workflow process definition meta-model. The design for system structure is presented in detail, and the key technologies for system implementation are also introduced. Additionally, an example is illustrated to demonstrate the validity of system.展开更多
This paper analyzes advantages and disadvantages of the current several popular computer-aided English learning software. combined with modem English teaching philosophy, proposed learning system with synchronization,...This paper analyzes advantages and disadvantages of the current several popular computer-aided English learning software. combined with modem English teaching philosophy, proposed learning system with synchronization, interactivity, intelligence, and incentives in one of the English to students. System uses JavaEE framework to build, each module uses a low coupling between the way facilitate future extensions. The system can help students build confidence and motivate its progress.展开更多
The microstructural evolution and mechanical properties of a vacuum electron beam welded aerospace 5B70 aluminum alloy joint were studied.Quantitative analyses of the phase composition,microstructural evolution,grain ...The microstructural evolution and mechanical properties of a vacuum electron beam welded aerospace 5B70 aluminum alloy joint were studied.Quantitative analyses of the phase composition,microstructural evolution,grain size,grain boundary density,and texture changes were performed by X-ray diffraction,scanning electron microscopy,and electron backscatter diffraction.The fusion zone(FZ)comprises equiaxed cellular crystals,and a fine~20μm-thick crystal layer forms in the transition zone(TZ)between the FZ and heat affected zone(HAZ).The HAZ closely resembles the base material(BM),retaining the original rolling microstructure.Mechanical property testing shows that the fine-grained layer in the TZ exhibits the highest nanohardness,with the FZ corresponding to the lowest microhardness.The welded-joint sample has lower yield strength,ultimate tensile strength,and elongation after fracture than the BM.These reductions of mechanical properties are primarily influenced by the grain size and distribution of the precipitated phases.展开更多
MgO has been shown to facilitate the precipitation of MgO-rich crystalline phases within the MgO-CaO-Al_(2)O_(3)-SiO_(2)(MCAS)glassy inclusion system,which possesses a high liquidus temperature and a significant Young...MgO has been shown to facilitate the precipitation of MgO-rich crystalline phases within the MgO-CaO-Al_(2)O_(3)-SiO_(2)(MCAS)glassy inclusion system,which possesses a high liquidus temperature and a significant Young’s modulus.The underlying linkage between the structural evolution and the crystallization characteristics of the MCAS system was systematically investigated using molecular dynamics simulation and thermodynamic calculation.The results revealed that Mg^(2+) ions played a dual role,constructing networks through the formation of tricluster oxygens while consuming bridging oxygens(BOs)in a mechanism similar to Ca^(2+) ions.However,despite this dual role,the network connectivity was still decreased with the increase in MgO/(MgO+Al_(2)O_(3))(M/(M+A))and CaO/(CaO+SiO_(2))(C/(C+S))ratios,primarily due to the reduction in BOs.This microscopic structural evolution resulted in a reduction in viscosity and an enhancement of crystallization ability.Furthermore,the remarkable diffusion capability of Mg^(2+) ions,coupled with the increased proportion of 6-coordinated Mg^(2+)ions,unveiled the mechanism underlying the precipitation of MgSiO_(3) and Mg_(2)SiO_(4) crystals,which exhibited high Young’s moduli of 165.23 and 196.67 GPa,respectively.To prevent the precipitation of MgO-rich crystalline phases,it was crucial to maintain the M/(M+A)ratio below 0.42 and the C/(C+S)ratio below 0.16 within the MCAS system.展开更多
La-Mg-Ni-based hydrogen storage alloys with superlattice structures are the new generation anode material for nickel metal hydride(Ni-MH)batteries owing to the advantages of high capacity and exceptional activation pr...La-Mg-Ni-based hydrogen storage alloys with superlattice structures are the new generation anode material for nickel metal hydride(Ni-MH)batteries owing to the advantages of high capacity and exceptional activation properties.However,the cycling stability is not currently satisfactory enough which plagues its application.Herein,a strategy of partially substituting La with the Y element is proposed to boost the capacity durability of La-Mg-Ni-based alloys.Furthermore,phase structure regulation is implemented simultaneously to obtain the A5 B19-type alloy with good crystal stability specifically.It is found that Y promotes the phase formation of the Pr5 Co19-type phase after annealing at 985℃.The alloy containing Y contributes to the superior rate capability resulting from the promoted hydrogen diffusion rate.Notably,Y substitution enables strengthening the anti-pulverization ability of the alloy in terms of increasing the volume match between[A_(2)B_(4)]and[AB5]subunits,and effectively enhances the anti-corrosion ability of the alloy due to high electronegativity,realizing improved long-term cycling stability of the alloy from 74.2%to 78.5%after cycling 300 times.The work is expected to shed light on the composition and structure design of the La-Mg-Ni-based hydrogen storage alloy for Ni-MH batteries.展开更多
Port structures constitute the main link in the maritime transport chain of coastal countries and therefore contribute to their economic development. But it should be noted that the installation of said works is not w...Port structures constitute the main link in the maritime transport chain of coastal countries and therefore contribute to their economic development. But it should be noted that the installation of said works is not without consequences for the countries concerned. Benin, a country in the Gulf of Guinea, is no exception to this phenomenon because, due to its maritime history, it has a heritage of port structures. These structures, built on its coastline, cause a wide variety of environmental problems such as silting and erosion on either side of them. The general objective of this article is to contribute to the proper functionality of port facilities while minimizing environmental problems that may arise. It aims to provide managers with a tool allowing them to fully understand the state of their assets in order to rationalize maintenance actions. In order to achieve this objective, an assessment of the state of the structure, and then a structural diagnosis are necessary and recommendations can be established to restore the level of service of the latter. As a result, two examples were presented: the wharf of the Sèmè-Podji pipeline project and the maritime piles project of the Wasco de Gama bridge (control project), and recommendations adapted to this objective were established. The comparative analysis of the two examples, both maritime works, revealed an under-sizing at the level of the spans of the wharf bridge of the Sèmè-Podji pipeline project (spans of 7 m in length), while these spans vary on average by 45 m to 62 m for the Wasco da Gama bridge. Bringing the piles closer together at the Sèmè-Podji wharf reduces the energy of the current which promotes the accumulation of sediment. The structure no longer experiences a flow capable of setting in motion the sands accumulated since at least 2022. This element appears to be a fundamental characteristic explaining the erosion observed to the east of the structure.展开更多
Metallic glass matrix composites(BMGCs)with compositions of[(Zr_(0.5)Cu_(0.5))_(0.925)Al_(0.07)Sn_(0.005)]_(100-x)Ta_(x)(atomic fraction,%,x=3,5,7)were successfully prepared via dealloying in metallic melt.The reinfor...Metallic glass matrix composites(BMGCs)with compositions of[(Zr_(0.5)Cu_(0.5))_(0.925)Al_(0.07)Sn_(0.005)]_(100-x)Ta_(x)(atomic fraction,%,x=3,5,7)were successfully prepared via dealloying in metallic melt.The reinforcing phase in these alloys has core-shell hybrid structure with Ta-rich particles as core and B2-CuZr as shell.In this method,the dealloyed Ta from Zr-Ta pre-alloys maintained in solid state and aggregated to form the fine Ta-rich phase in the final products.This effectively decreases the size of Ta-rich phase compared with that prepared via conventional arc-melting,where the Ta-rich phase was formed through dissolving and precipitation.Among the three compositions,[(Zr_(0.5)Cu_(0.5))_(0.925)Al_(0.07)Sn_(0.005)]_(95)Ta_(5) showed the highest plastic strain of 11.2%,much higher than that of the arc-melted counterparts(4.3%).Such improvement in mechanical properties was related with the refined core-shell hybrid reinforcing structure,which could hinder the rapid propagation of main shear band more efficiently and cause them to branch and proliferate at the interface.展开更多
In order to ameliorate the electrochemical hydrogen storage performance of La-Mg-Ni system A2B7-type electrode alloys, a small amount of Si was added. The La0.8Mg0.2Ni3.3Co0.2Six （x=0-0.2） electrode alloys were prep...In order to ameliorate the electrochemical hydrogen storage performance of La-Mg-Ni system A2B7-type electrode alloys, a small amount of Si was added. The La0.8Mg0.2Ni3.3Co0.2Six （x=0-0.2） electrode alloys were prepared by casting and annealing. The effects of adding Si on the structure and electrochemical hydrogen storage characteristics of the alloys were investigated systematically. The results indicate that the as-cast and annealed alloys hold multiple structures, involving two major phases of （La, Mg）2Ni7 with a Ce2Ni7-type hexagonal structure and LaNi5 with a CaCu5-type hexagonal structure as well as one residual phase LaNi3. The addition of Si results in a decrease in （La, Mg）2Ni7 phase and an increase in LaNi5 phase without changing the phase structure of the alloys. What is more, it brings on an obvious effect on electrochemical hydrogen storage characteristics of the alloys. The discharge capacities of the as-cast and annealed alloys decline with the increase of Si content, but their cycle stabilities clearly grow under the same condition. Furthermore, the measurements of the high rate discharge ability, the limiting current density, hydrogen diffusion coefficient as well as electrochemical impedance spectra all indicate that the electrochemical kinetic properties of the electrode alloys first increase and then decrease with the rising of Si content.展开更多
The S38C railway axle undergoes induction hardening,resulting in a gradient-distributed microstructure and mechanical properties.The accurate identification of gradient-distributed plastic parameters for the S38C axle...The S38C railway axle undergoes induction hardening,resulting in a gradient-distributed microstructure and mechanical properties.The accurate identification of gradient-distributed plastic parameters for the S38C axle remains a challenging task.To tackle this challenge,the present study proposes a novel approach for identifying the gradient-distributed plastic parameters for the S38C axle by integrating nano-indentation techniques with the machine learning method.Firstly,nano-indentation tests are conducted along the radial direction of the S38C axle to obtain the gradient-distributed load-displacement curves,nano-hardness,and elastic modulus.Subsequently,the dimensionless analysis is performed to obtain the representative stress,strain,and yield stress from load-displacement curves.These parameters are then incorporated into the machine learning method as physical information to identify the gradient-distributed plastic parameters of the S38C axle.The results indicate that the proposed method based on the physics-informed neural network and multi-fidelity neural network successfully identifies the gradient-distributed plastic parameters of the S38C axles and demonstrates superior prediction accuracy and generalization compared with the purely data-driven machine learning method.展开更多
Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms.We showed previously that astrocytes cultured from mice transgenic for human P30...Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms.We showed previously that astrocytes cultured from mice transgenic for human P301S-tau(P301S-mice)recapitulate the deficit in production and secretion of thrombospondin1 found in symptomatic P301S mouse brains,causing both reduced synapse formation and survival of cultured neurons.To further characterize how P301S-derived astrocytes differ from controls,we have compared the astrocyte-conditioned media of cultured astrocytes from postnatal day 7/8 P301S mice(P301S-astrocyte-conditioned media)versus controls(C57-astrocyte-conditioned media)using label-free liquid chromatography-mass spectrometry.We verified that thrombospondin1 secretion was significantly reduced in the P301S-astrocyte-conditioned media versus C57-astrocyte-conditioned media,demonstrating the robustness of the analysis.The most notable distinction was that~57%of the P301S-astrocyte-conditioned media-enriched proteins were cytoplasmic proteins linked to cellular metabolism that are not predicted to be secreted via classical or non-classical secretion pathways,whereas~88%of C57-astrocyte-conditioned media-enriched proteins comprised classically secreted proteins enriched in extracellular matrix components.These differences are associated with the finding that P301S-derived cultured astrocytes were smaller and in vivo appeared less mature in the cortex of P301S mice.The unconventional secretion pathway that P301S-astrocyte-conditioned media display shares similarities with several amyloid-β-exposed astrocyte-conditioned media,indicating that stimuli induced by tau and amyloid-βmay induce a common adverse response pathway.Altogether,members of this adverse pathway may serve as a potential set of biomarkers to aid the clinical diagnosis of Alzheimer’s disease and other tauopathies,while the list of reduced neurosupportive factors could indicate new approaches to enhance neuronal survival by factor supplementation in tauopathies.展开更多
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 ...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.展开更多
基金Shanghai Municipal Science Committee key project(061612058,06JC14066,06DZ12001,061111006)Nationalscience and technology supporting project(2006BAF01A46)
文摘According to the necessity of flexible workflow management system, the solution to set up the visualized workflow modelling system based on B/S structure is put forward, which conforms to the relevant specifications of WfMC and the workflow process definition meta-model. The design for system structure is presented in detail, and the key technologies for system implementation are also introduced. Additionally, an example is illustrated to demonstrate the validity of system.
文摘This paper analyzes advantages and disadvantages of the current several popular computer-aided English learning software. combined with modem English teaching philosophy, proposed learning system with synchronization, interactivity, intelligence, and incentives in one of the English to students. System uses JavaEE framework to build, each module uses a low coupling between the way facilitate future extensions. The system can help students build confidence and motivate its progress.
基金supported by the National Natural Science Foundation of China(Nos.52175206,52205187,52130509)the Science and Technology Planning Project of Guizhou Province,China(No.ZK[2022]013)。
文摘The microstructural evolution and mechanical properties of a vacuum electron beam welded aerospace 5B70 aluminum alloy joint were studied.Quantitative analyses of the phase composition,microstructural evolution,grain size,grain boundary density,and texture changes were performed by X-ray diffraction,scanning electron microscopy,and electron backscatter diffraction.The fusion zone(FZ)comprises equiaxed cellular crystals,and a fine~20μm-thick crystal layer forms in the transition zone(TZ)between the FZ and heat affected zone(HAZ).The HAZ closely resembles the base material(BM),retaining the original rolling microstructure.Mechanical property testing shows that the fine-grained layer in the TZ exhibits the highest nanohardness,with the FZ corresponding to the lowest microhardness.The welded-joint sample has lower yield strength,ultimate tensile strength,and elongation after fracture than the BM.These reductions of mechanical properties are primarily influenced by the grain size and distribution of the precipitated phases.
基金support from the National Key R&D Program of China(Grant Nos.2023YFB3709900 and 2023YFB3709903)the National Natural Science Foundation of China(Grant Nos.52174293 and U22A20171)+1 种基金the High Steel Center(HSC)at North China University of TechnologyUniversity of Science and Technology Beijing(USTB).
文摘MgO has been shown to facilitate the precipitation of MgO-rich crystalline phases within the MgO-CaO-Al_(2)O_(3)-SiO_(2)(MCAS)glassy inclusion system,which possesses a high liquidus temperature and a significant Young’s modulus.The underlying linkage between the structural evolution and the crystallization characteristics of the MCAS system was systematically investigated using molecular dynamics simulation and thermodynamic calculation.The results revealed that Mg^(2+) ions played a dual role,constructing networks through the formation of tricluster oxygens while consuming bridging oxygens(BOs)in a mechanism similar to Ca^(2+) ions.However,despite this dual role,the network connectivity was still decreased with the increase in MgO/(MgO+Al_(2)O_(3))(M/(M+A))and CaO/(CaO+SiO_(2))(C/(C+S))ratios,primarily due to the reduction in BOs.This microscopic structural evolution resulted in a reduction in viscosity and an enhancement of crystallization ability.Furthermore,the remarkable diffusion capability of Mg^(2+) ions,coupled with the increased proportion of 6-coordinated Mg^(2+)ions,unveiled the mechanism underlying the precipitation of MgSiO_(3) and Mg_(2)SiO_(4) crystals,which exhibited high Young’s moduli of 165.23 and 196.67 GPa,respectively.To prevent the precipitation of MgO-rich crystalline phases,it was crucial to maintain the M/(M+A)ratio below 0.42 and the C/(C+S)ratio below 0.16 within the MCAS system.
基金the financial support by the National Nat-ural Science Foundation of China(Nos.52201282,52071281,52371239)the China Postdoctoral Science Foundation(No.2023M742945)+4 种基金Hebei Provincial Postdoctoral Science Foundation(No.B2023003023)the Science Research Project of Hebei Education Department(No.BJK2022033)the Natural Science Foundation of Hebei Province(No.C2022203003)the Inner Mongolia Science and Technology Major Project(No.2020ZD0012)the Baotou Science and Technology Planning Project(No.XM2022BT09).
文摘La-Mg-Ni-based hydrogen storage alloys with superlattice structures are the new generation anode material for nickel metal hydride(Ni-MH)batteries owing to the advantages of high capacity and exceptional activation properties.However,the cycling stability is not currently satisfactory enough which plagues its application.Herein,a strategy of partially substituting La with the Y element is proposed to boost the capacity durability of La-Mg-Ni-based alloys.Furthermore,phase structure regulation is implemented simultaneously to obtain the A5 B19-type alloy with good crystal stability specifically.It is found that Y promotes the phase formation of the Pr5 Co19-type phase after annealing at 985℃.The alloy containing Y contributes to the superior rate capability resulting from the promoted hydrogen diffusion rate.Notably,Y substitution enables strengthening the anti-pulverization ability of the alloy in terms of increasing the volume match between[A_(2)B_(4)]and[AB5]subunits,and effectively enhances the anti-corrosion ability of the alloy due to high electronegativity,realizing improved long-term cycling stability of the alloy from 74.2%to 78.5%after cycling 300 times.The work is expected to shed light on the composition and structure design of the La-Mg-Ni-based hydrogen storage alloy for Ni-MH batteries.
文摘Port structures constitute the main link in the maritime transport chain of coastal countries and therefore contribute to their economic development. But it should be noted that the installation of said works is not without consequences for the countries concerned. Benin, a country in the Gulf of Guinea, is no exception to this phenomenon because, due to its maritime history, it has a heritage of port structures. These structures, built on its coastline, cause a wide variety of environmental problems such as silting and erosion on either side of them. The general objective of this article is to contribute to the proper functionality of port facilities while minimizing environmental problems that may arise. It aims to provide managers with a tool allowing them to fully understand the state of their assets in order to rationalize maintenance actions. In order to achieve this objective, an assessment of the state of the structure, and then a structural diagnosis are necessary and recommendations can be established to restore the level of service of the latter. As a result, two examples were presented: the wharf of the Sèmè-Podji pipeline project and the maritime piles project of the Wasco de Gama bridge (control project), and recommendations adapted to this objective were established. The comparative analysis of the two examples, both maritime works, revealed an under-sizing at the level of the spans of the wharf bridge of the Sèmè-Podji pipeline project (spans of 7 m in length), while these spans vary on average by 45 m to 62 m for the Wasco da Gama bridge. Bringing the piles closer together at the Sèmè-Podji wharf reduces the energy of the current which promotes the accumulation of sediment. The structure no longer experiences a flow capable of setting in motion the sands accumulated since at least 2022. This element appears to be a fundamental characteristic explaining the erosion observed to the east of the structure.
基金supported by the National Natural Science Foundation of China(Nos.52101138,52201075)Natural Science Foundation of Hubei Province,China(Nos.2023AFB798,2022CFB614)+3 种基金Shenzhen Science and Technology Program,China(No.JCYJ20220530160813032)State Key Laboratory of Solidification Processing in NWPU,China(Nos.SKLSP202309,SKLSP202308)Guangdong Basic and Applied Basic Research Foundation,China(No.2022A1515011227)State Key Laboratory of Powder Metallurgy of Central South University,China(No.Sklpm-KF-05).
文摘Metallic glass matrix composites(BMGCs)with compositions of[(Zr_(0.5)Cu_(0.5))_(0.925)Al_(0.07)Sn_(0.005)]_(100-x)Ta_(x)(atomic fraction,%,x=3,5,7)were successfully prepared via dealloying in metallic melt.The reinforcing phase in these alloys has core-shell hybrid structure with Ta-rich particles as core and B2-CuZr as shell.In this method,the dealloyed Ta from Zr-Ta pre-alloys maintained in solid state and aggregated to form the fine Ta-rich phase in the final products.This effectively decreases the size of Ta-rich phase compared with that prepared via conventional arc-melting,where the Ta-rich phase was formed through dissolving and precipitation.Among the three compositions,[(Zr_(0.5)Cu_(0.5))_(0.925)Al_(0.07)Sn_(0.005)]_(95)Ta_(5) showed the highest plastic strain of 11.2%,much higher than that of the arc-melted counterparts(4.3%).Such improvement in mechanical properties was related with the refined core-shell hybrid reinforcing structure,which could hinder the rapid propagation of main shear band more efficiently and cause them to branch and proliferate at the interface.
基金Projects(50961009,51161015)supported by the National Natural Science Foundation of ChinaProject(2011AA03A408)supported by the High-tech Research and Development Program of ChinaProjects(2011ZD10,2010ZD05)supported by the Natural Science Foundation of Inner Mongolia,China
文摘In order to ameliorate the electrochemical hydrogen storage performance of La-Mg-Ni system A2B7-type electrode alloys, a small amount of Si was added. The La0.8Mg0.2Ni3.3Co0.2Six （x=0-0.2） electrode alloys were prepared by casting and annealing. The effects of adding Si on the structure and electrochemical hydrogen storage characteristics of the alloys were investigated systematically. The results indicate that the as-cast and annealed alloys hold multiple structures, involving two major phases of （La, Mg）2Ni7 with a Ce2Ni7-type hexagonal structure and LaNi5 with a CaCu5-type hexagonal structure as well as one residual phase LaNi3. The addition of Si results in a decrease in （La, Mg）2Ni7 phase and an increase in LaNi5 phase without changing the phase structure of the alloys. What is more, it brings on an obvious effect on electrochemical hydrogen storage characteristics of the alloys. The discharge capacities of the as-cast and annealed alloys decline with the increase of Si content, but their cycle stabilities clearly grow under the same condition. Furthermore, the measurements of the high rate discharge ability, the limiting current density, hydrogen diffusion coefficient as well as electrochemical impedance spectra all indicate that the electrochemical kinetic properties of the electrode alloys first increase and then decrease with the rising of Si content.
基金supported by the National Key Research and Development Plan(Grant No.2022YFB3401901)the National Natural Science Foundation of China(Grant Nos.12192210,12192214,12072295,and 12222209)+1 种基金Independent Project of State Key Laboratory of Rail Transit Vehicle System(Grant No.2023TPL-T03)Fundamental Research Funds for the Central Universities(Grant No.2682023CG004).
文摘The S38C railway axle undergoes induction hardening,resulting in a gradient-distributed microstructure and mechanical properties.The accurate identification of gradient-distributed plastic parameters for the S38C axle remains a challenging task.To tackle this challenge,the present study proposes a novel approach for identifying the gradient-distributed plastic parameters for the S38C axle by integrating nano-indentation techniques with the machine learning method.Firstly,nano-indentation tests are conducted along the radial direction of the S38C axle to obtain the gradient-distributed load-displacement curves,nano-hardness,and elastic modulus.Subsequently,the dimensionless analysis is performed to obtain the representative stress,strain,and yield stress from load-displacement curves.These parameters are then incorporated into the machine learning method as physical information to identify the gradient-distributed plastic parameters of the S38C axle.The results indicate that the proposed method based on the physics-informed neural network and multi-fidelity neural network successfully identifies the gradient-distributed plastic parameters of the S38C axles and demonstrates superior prediction accuracy and generalization compared with the purely data-driven machine learning method.
基金MGS from the Alzheimer Society(#384,AS-PG-17-026,Alzheimer’s Research UK(ART-PG2011-20 and ARUK-EXT2015B-2)the BBSRC(BB/T509085/1)+1 种基金The Fondation Recherche Alzheimer(G112606)the Scholl Foundation,and to MGS and AMT from the National Center for the Replacement,Refinement,&Reduction of Animals in Research(NC3R)(#NC/L000741/1).
文摘Astrocytes have important neurosupportive functions in the brain that are altered in neurodegenerative diseases by unresolved mechanisms.We showed previously that astrocytes cultured from mice transgenic for human P301S-tau(P301S-mice)recapitulate the deficit in production and secretion of thrombospondin1 found in symptomatic P301S mouse brains,causing both reduced synapse formation and survival of cultured neurons.To further characterize how P301S-derived astrocytes differ from controls,we have compared the astrocyte-conditioned media of cultured astrocytes from postnatal day 7/8 P301S mice(P301S-astrocyte-conditioned media)versus controls(C57-astrocyte-conditioned media)using label-free liquid chromatography-mass spectrometry.We verified that thrombospondin1 secretion was significantly reduced in the P301S-astrocyte-conditioned media versus C57-astrocyte-conditioned media,demonstrating the robustness of the analysis.The most notable distinction was that~57%of the P301S-astrocyte-conditioned media-enriched proteins were cytoplasmic proteins linked to cellular metabolism that are not predicted to be secreted via classical or non-classical secretion pathways,whereas~88%of C57-astrocyte-conditioned media-enriched proteins comprised classically secreted proteins enriched in extracellular matrix components.These differences are associated with the finding that P301S-derived cultured astrocytes were smaller and in vivo appeared less mature in the cortex of P301S mice.The unconventional secretion pathway that P301S-astrocyte-conditioned media display shares similarities with several amyloid-β-exposed astrocyte-conditioned media,indicating that stimuli induced by tau and amyloid-βmay induce a common adverse response pathway.Altogether,members of this adverse pathway may serve as a potential set of biomarkers to aid the clinical diagnosis of Alzheimer’s disease and other tauopathies,while the list of reduced neurosupportive factors could indicate new approaches to enhance neuronal survival by factor supplementation in tauopathies.
基金supported in part by Award 2121063 from National Science Foundation(to YM)AG66986 from the National Institutes of Health(to MSW).
文摘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.
