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
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
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
Hepatitis C virus(HCV)and hepatitis B virus(HBV)infections are increasingly recognized as significant etiological factors in the pathogenesis of B-cell non-Hodgkin’s lymphomas(B-NHLs).Epidemiological and molecular st...Hepatitis C virus(HCV)and hepatitis B virus(HBV)infections are increasingly recognized as significant etiological factors in the pathogenesis of B-cell non-Hodgkin’s lymphomas(B-NHLs).Epidemiological and molecular studies have demonstrated a consistent association between chronic viral infection and B-NHLs.Multiple pathogenic mechanisms have been implicated in lymphomagenesis,both direct and indirect,including chronic antigenic stimulation,direct infection of B cells,and viral protein-mediated oncogenic signaling,It is likely that a combination of several pathogenic conditions is required to eventually lead to the development of lymphoma.The prevalence of B-cell lymphomas among individuals with chronic HCV or HBV infection presents a complex pathogenetic scenario,given the tumor heterogeneity and variable clinical behavior,and poses therapeutic challenges,due to the partial efficacy of current treatment options.The advent of direct-acting antivirals(DAAs)for HCV and high-genetic barrier nucleos(t)ide analogues(NAs)for HBV has improved patient outcomes.In indolent HCV-associated B-NHLs,antiviral therapy with DAAs alone often achieves sustained virologic response and may lead to lymphoma regression.Conversely,aggressive subtypes like diffuse large B-cell lymphomas require combination treatment with immunochemotherapy.In the setting of HBV-associated lymphomas,antiviral prophylaxis with potent NAs(e.g.,entecavir or tenofovir)is essential to prevent HBV reactivation during rituximab-containing chemotherapy regimen.The integration of antiviral and anticancer therapies has been shown to enhance survival outcomes while mitigating hepatic toxicity.A comprehensive understanding of the biological interplay between chronic viral infection and B-cell transformation is critical for optimizing diagnostic and therapeutic strategies.Aim of this viewpoint is to provide evidence that early viral detection and prompt management remain the most effective strategies to improve survival rates and to reduce treatment-related morbidity in these patients.展开更多
Compared to the single-stranded and double-stranded types of classical nucleic acid structures,atypical nucleic acid structures(such as G4s,i-motif,Triplex,and cyclic nucleic acids)are gradually becoming hotspots in b...Compared to the single-stranded and double-stranded types of classical nucleic acid structures,atypical nucleic acid structures(such as G4s,i-motif,Triplex,and cyclic nucleic acids)are gradually becoming hotspots in biomedical research due to their important biological functions and the close correlation between their abnormal dynamics equilibrium in physiological environments and a variety of hard-tackle diseases.The traditional gel electrophoresis,nuclear magnetic resonance,and circular dichroism detection techniques have shortcomings such as low spatial resolution,high destructiveness,and lack of real-time dynamic monitoring capability.In recent years,fluorescence imaging has gradually become a cutting-edge tool for non-classical nucleic acid structure detection due to their high sensitivity,fast response and dynamic real-time observation performance.In this contribution,we review the fluorescence materials for lighting-up imaging of non-classical nucleic acid structures,including traditional fluorescent small molecules and aggregation-induced emission luminogens(AIEgens).The design principles,detection mechanisms and application scenarios are detailed.Current fluorescence probes have already improved qualities in recognition targetability and signal-to-noise ratio by tuning and optimizing molecular structure-property relationships,but still face challenges such as insufficient selectivity and poor penetration capability in vivo.In the future,it is necessary to integrate multimodal imaging,artificial intelligence-assisted design and targeted delivery system to build a highly sensitive and multi-channel responsive platform to thoroughly disclose the association between the dynamic conformation of nucleic acid and disease,and to promote the development of precise and novel therapeutic strategies.展开更多
In this study,the casting process is used to fabricate modified polyvinyl alcohol(PVA),starch(S),and carboxymethyl cellulose(CMC)polymer blend films(PVA/S/CMC)loaded with various concentrations of irondoped carbon qua...In this study,the casting process is used to fabricate modified polyvinyl alcohol(PVA),starch(S),and carboxymethyl cellulose(CMC)polymer blend films(PVA/S/CMC)loaded with various concentrations of irondoped carbon quantum dots(Fe-CQDs)and denoted as(PVA/S/CMC@Fe-CQDs).A one-step microwave strategy was employed as a facile method to prepare Fe-CQDs.Through a series of characterization techniques,fourier-transform infrared(FTIR)spectroscopy,x-ray diffraction(XRD)analysis,and scanning electron microscopy(SEM)have been used to show the successful integration of Fe-CQDs into the PVA/S/CMCmatrix.Loading the synthesized Fe-CQDs to the polymeric matrix significantly enhanced the mechanical properties of the films represented in the tensile strength,Young’s modulus,and hardness.However,the elongation decreased noticeably upon increasing the iron-doped carbon dots.The surface wettability was also studied by measuring the contact angle of the prepared films.The findings showed a noticeable elevation in these measurements by increasing the Fe-CQDs content,declaring the role of a hydrophobic character in these nanoparticles when introduced into a hydrophilic polymeric system.The dielectric characteristics of the reinforced polymer composite films were evaluated.These results revealed that the ac-conductivity of the investigated films was boosted with increasing Fe-CQDs’ratio and frequency.The PVA/S/CMC@Fe-CQDs films possess substantial potential for efficient energy storage applications.展开更多
According to specifications for Welding Procedure Qualification of ASME IX Section and Chinese code, JB 4708 2000, a software package for managing welding documents has been rebuilt. Consequently, the new software pa...According to specifications for Welding Procedure Qualification of ASME IX Section and Chinese code, JB 4708 2000, a software package for managing welding documents has been rebuilt. Consequently, the new software package can be used in a Limited Area Network (LAN) with 4 different levels of authorities for different users. Therefore, the welding documents, including DWPS (Design for Welding Procedure Specifications), PQRs (Procedure Qualification Records) and WPS (Welding Procedure Specifications) can be shared within a company. At the same time, the system provides users various functions such as browsing, copying, editing, searching and printing records, and helps users to make decision of whether a new PQR test is necessary or not according to the codes above as well. Furthermore, super users can also browse the history of record modification and retrieve the records when needed.展开更多
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.
基金supported by the National Italian Research Council(CNR)“Progetto DSB.AD007.305.001”to Monica Rinaldi。
文摘Hepatitis C virus(HCV)and hepatitis B virus(HBV)infections are increasingly recognized as significant etiological factors in the pathogenesis of B-cell non-Hodgkin’s lymphomas(B-NHLs).Epidemiological and molecular studies have demonstrated a consistent association between chronic viral infection and B-NHLs.Multiple pathogenic mechanisms have been implicated in lymphomagenesis,both direct and indirect,including chronic antigenic stimulation,direct infection of B cells,and viral protein-mediated oncogenic signaling,It is likely that a combination of several pathogenic conditions is required to eventually lead to the development of lymphoma.The prevalence of B-cell lymphomas among individuals with chronic HCV or HBV infection presents a complex pathogenetic scenario,given the tumor heterogeneity and variable clinical behavior,and poses therapeutic challenges,due to the partial efficacy of current treatment options.The advent of direct-acting antivirals(DAAs)for HCV and high-genetic barrier nucleos(t)ide analogues(NAs)for HBV has improved patient outcomes.In indolent HCV-associated B-NHLs,antiviral therapy with DAAs alone often achieves sustained virologic response and may lead to lymphoma regression.Conversely,aggressive subtypes like diffuse large B-cell lymphomas require combination treatment with immunochemotherapy.In the setting of HBV-associated lymphomas,antiviral prophylaxis with potent NAs(e.g.,entecavir or tenofovir)is essential to prevent HBV reactivation during rituximab-containing chemotherapy regimen.The integration of antiviral and anticancer therapies has been shown to enhance survival outcomes while mitigating hepatic toxicity.A comprehensive understanding of the biological interplay between chronic viral infection and B-cell transformation is critical for optimizing diagnostic and therapeutic strategies.Aim of this viewpoint is to provide evidence that early viral detection and prompt management remain the most effective strategies to improve survival rates and to reduce treatment-related morbidity in these patients.
文摘Compared to the single-stranded and double-stranded types of classical nucleic acid structures,atypical nucleic acid structures(such as G4s,i-motif,Triplex,and cyclic nucleic acids)are gradually becoming hotspots in biomedical research due to their important biological functions and the close correlation between their abnormal dynamics equilibrium in physiological environments and a variety of hard-tackle diseases.The traditional gel electrophoresis,nuclear magnetic resonance,and circular dichroism detection techniques have shortcomings such as low spatial resolution,high destructiveness,and lack of real-time dynamic monitoring capability.In recent years,fluorescence imaging has gradually become a cutting-edge tool for non-classical nucleic acid structure detection due to their high sensitivity,fast response and dynamic real-time observation performance.In this contribution,we review the fluorescence materials for lighting-up imaging of non-classical nucleic acid structures,including traditional fluorescent small molecules and aggregation-induced emission luminogens(AIEgens).The design principles,detection mechanisms and application scenarios are detailed.Current fluorescence probes have already improved qualities in recognition targetability and signal-to-noise ratio by tuning and optimizing molecular structure-property relationships,but still face challenges such as insufficient selectivity and poor penetration capability in vivo.In the future,it is necessary to integrate multimodal imaging,artificial intelligence-assisted design and targeted delivery system to build a highly sensitive and multi-channel responsive platform to thoroughly disclose the association between the dynamic conformation of nucleic acid and disease,and to promote the development of precise and novel therapeutic strategies.
文摘In this study,the casting process is used to fabricate modified polyvinyl alcohol(PVA),starch(S),and carboxymethyl cellulose(CMC)polymer blend films(PVA/S/CMC)loaded with various concentrations of irondoped carbon quantum dots(Fe-CQDs)and denoted as(PVA/S/CMC@Fe-CQDs).A one-step microwave strategy was employed as a facile method to prepare Fe-CQDs.Through a series of characterization techniques,fourier-transform infrared(FTIR)spectroscopy,x-ray diffraction(XRD)analysis,and scanning electron microscopy(SEM)have been used to show the successful integration of Fe-CQDs into the PVA/S/CMCmatrix.Loading the synthesized Fe-CQDs to the polymeric matrix significantly enhanced the mechanical properties of the films represented in the tensile strength,Young’s modulus,and hardness.However,the elongation decreased noticeably upon increasing the iron-doped carbon dots.The surface wettability was also studied by measuring the contact angle of the prepared films.The findings showed a noticeable elevation in these measurements by increasing the Fe-CQDs content,declaring the role of a hydrophobic character in these nanoparticles when introduced into a hydrophilic polymeric system.The dielectric characteristics of the reinforced polymer composite films were evaluated.These results revealed that the ac-conductivity of the investigated films was boosted with increasing Fe-CQDs’ratio and frequency.The PVA/S/CMC@Fe-CQDs films possess substantial potential for efficient energy storage applications.
文摘According to specifications for Welding Procedure Qualification of ASME IX Section and Chinese code, JB 4708 2000, a software package for managing welding documents has been rebuilt. Consequently, the new software package can be used in a Limited Area Network (LAN) with 4 different levels of authorities for different users. Therefore, the welding documents, including DWPS (Design for Welding Procedure Specifications), PQRs (Procedure Qualification Records) and WPS (Welding Procedure Specifications) can be shared within a company. At the same time, the system provides users various functions such as browsing, copying, editing, searching and printing records, and helps users to make decision of whether a new PQR test is necessary or not according to the codes above as well. Furthermore, super users can also browse the history of record modification and retrieve the records when needed.
