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
Reliability is important to design innovation.A new product should be not only innovative,but also reliable.For many existing comp on ents used in the new product,their reliability will change because the applied load...Reliability is important to design innovation.A new product should be not only innovative,but also reliable.For many existing comp on ents used in the new product,their reliability will change because the applied loads are different from the ones for which the components are originally designed and manufactured.Then the new reliability must be re-evaluated.The system designers of the new product,however,may not have enough information to perform this task.With a beam problem as a case study,this study explores a feasible way to reevaluate the component reliability with new loads given the following information:The original reliability of the component with respect to the component loads and the distributions of the new component loads.Physics-based methods are employed to build the equivalent component limit-state function that can predict the component failure under the new loads.Since the information is limited,the re-evaluated component reliability is given by its maximum and minimum values.The case study shows that good accuracy can be obtained even though the new reliability is provided with the aforementioned interval.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the National Science Foundation(Grant No.CMMI 1562593)Intelligent Systems Center at Missouri University of Science and Technology.
文摘Reliability is important to design innovation.A new product should be not only innovative,but also reliable.For many existing comp on ents used in the new product,their reliability will change because the applied loads are different from the ones for which the components are originally designed and manufactured.Then the new reliability must be re-evaluated.The system designers of the new product,however,may not have enough information to perform this task.With a beam problem as a case study,this study explores a feasible way to reevaluate the component reliability with new loads given the following information:The original reliability of the component with respect to the component loads and the distributions of the new component loads.Physics-based methods are employed to build the equivalent component limit-state function that can predict the component failure under the new loads.Since the information is limited,the re-evaluated component reliability is given by its maximum and minimum values.The case study shows that good accuracy can be obtained even though the new reliability is provided with the aforementioned interval.
