The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed...The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.展开更多
This study normalized the mixture's fatigue behavior at various temperatures,and the strength and fatigue tests of the mixture were conducted.The stress state of the asphalt mixture includes direct tensile,uniaxia...This study normalized the mixture's fatigue behavior at various temperatures,and the strength and fatigue tests of the mixture were conducted.The stress state of the asphalt mixture includes direct tensile,uniaxial compression,and indirect tensile.The Desai yield surface and fatigue path were proposed.And a normalized fatigue characteristics model of the mixture was established.The following conclusions were obtained.With the increases in the loading rate,the strength of the asphalt mixture increased.As the temperature increases,the strength of the mixture is reduced.At various temperatures and rates,the strength forms a closed curved surface.The Desai strength yield surface was established,which forms a closed curved surface.When the loading rate and temperature are below a certain critical line,the asphalt mixture will not undergo strength damage.At a fixed stress state,the fatigue damage path of the mixture was determined.The stress ratio was determined considering the influence of the loading rate.In this way,a normalized model can be described to express the asphalt mixture fatigue properties at various temperatures and stress levels.For the asphalt mixture in an indirect tensile state,the normalized fatigue equation parameter is 4.09.This model is more suitable for reflecting the viscous-elastic behavior of the mixtures than the fatigue equation determined by the notional stress ratio.展开更多
In order to investigate the behavior characteristics of asphalt components during the process of nano-cracks temperature self-healing(NTS),molecular simulation technology was used to simulate the temperature self-heal...In order to investigate the behavior characteristics of asphalt components during the process of nano-cracks temperature self-healing(NTS),molecular simulation technology was used to simulate the temperature self-healing of asphalt.Based on the determination of asphalts(virgin asphalt and aged asphalt),the proportional changes of asphalt components were confirmed.The distribution characteristics of asphalt components were obtained by marking different components in the process of NTS.At the same time,the rationality of the micro simulation findings was confirmed by asphalt performance tests and infrared spectroscopy results.The results show that different asphalt components have different behavior characteristics in the process of NTS.The content of asphaltene and resin plays a key role in the process of NTS,while saturation and aromatics play an active role in the temperature self-healing before and after aging.The NTS is the result of the comprehensive action of different components,and the self-healing efficiency is proportional to the relative molecular mass.The effect of aging on the NTS is also realized by changing the proportion of asphalt components.展开更多
基金supported by the National Natural Science Foundation of China,Nos.91849115 and U1904207(to YX),81974211 and 82171247(to CS)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No.2020-PT310-01(to YX).
文摘The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control system.In this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s disease.We used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse brain.CHIP overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated tau.CHIP also alleviated the concentration of microglia and astrocytes around plaques.In APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin expression.Levels of HSP70 and HSP40,which have functional relevance to CHIP,were also increased.Single nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of CHIP.Our research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 mice.Indeed,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.
基金This manuscript is supported by the National Natural Science Foundation of China(Grant numbers:52108398,52225806,52078063)the Open Fund of Key Laboratory of Special Environment Road Engineering of Hunan Province(kfj210502).
文摘This study normalized the mixture's fatigue behavior at various temperatures,and the strength and fatigue tests of the mixture were conducted.The stress state of the asphalt mixture includes direct tensile,uniaxial compression,and indirect tensile.The Desai yield surface and fatigue path were proposed.And a normalized fatigue characteristics model of the mixture was established.The following conclusions were obtained.With the increases in the loading rate,the strength of the asphalt mixture increased.As the temperature increases,the strength of the mixture is reduced.At various temperatures and rates,the strength forms a closed curved surface.The Desai strength yield surface was established,which forms a closed curved surface.When the loading rate and temperature are below a certain critical line,the asphalt mixture will not undergo strength damage.At a fixed stress state,the fatigue damage path of the mixture was determined.The stress ratio was determined considering the influence of the loading rate.In this way,a normalized model can be described to express the asphalt mixture fatigue properties at various temperatures and stress levels.For the asphalt mixture in an indirect tensile state,the normalized fatigue equation parameter is 4.09.This model is more suitable for reflecting the viscous-elastic behavior of the mixtures than the fatigue equation determined by the notional stress ratio.
基金Funded by the Fundamental Research Funds for the Central Universities(No.2572021AW10)。
文摘In order to investigate the behavior characteristics of asphalt components during the process of nano-cracks temperature self-healing(NTS),molecular simulation technology was used to simulate the temperature self-healing of asphalt.Based on the determination of asphalts(virgin asphalt and aged asphalt),the proportional changes of asphalt components were confirmed.The distribution characteristics of asphalt components were obtained by marking different components in the process of NTS.At the same time,the rationality of the micro simulation findings was confirmed by asphalt performance tests and infrared spectroscopy results.The results show that different asphalt components have different behavior characteristics in the process of NTS.The content of asphaltene and resin plays a key role in the process of NTS,while saturation and aromatics play an active role in the temperature self-healing before and after aging.The NTS is the result of the comprehensive action of different components,and the self-healing efficiency is proportional to the relative molecular mass.The effect of aging on the NTS is also realized by changing the proportion of asphalt components.
