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
Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzhei...Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.展开更多
In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of A...In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.展开更多
In this study,batch experiments were conducted to investigate the performance of microscale Fe/Cu bimetallic particles-air-persulfate system(mFe/Cu-air-PS)for p-nitrophenol(PNP)treatment in aqueous solution.First,the ...In this study,batch experiments were conducted to investigate the performance of microscale Fe/Cu bimetallic particles-air-persulfate system(mFe/Cu-air-PS)for p-nitrophenol(PNP)treatment in aqueous solution.First,the optimal operating parameters(i.e.,aeration rate of 1.0 L/min,theoretical Cu mass loading(TMLCu)of 0.110 g Cu/g Fe,mFe/Cu dosage of 15 g/L,PS total dosage of 15 mmol/L,feeding times of PS of 5,initial pH 5.4)were obtained successively by single-factor experiments.Under the optimal conditions,high COD and TOC removal efficiencies(71.0%,65.8%)were obtained after 60 min treatment.Afterword,compared with control experiments(i.e.,mFe/Cu,air,PS,mFe/Cu-air,mFe/Cu–PS,air-PS and mFe-air-PS),mFe/Cu-air-PS system exerted superior performance for pollutants removal due to the synergistic effect between mFe/Cu,air and PS.In addition,the results of control experiments and radical quenching experiments indicate this reinforcement by feeding of PS was greater than by aeration in m Fe/Cu-air-PS system.Furthermore,the degradation intermediates of PNP in mFe/Cu-air-PS process were identified and measured by HPLC.Based on the detected intermediates,the degradation pathways of PNP were proposed comprehensively,which revealed that toxic and refractory PNP in aqueous solution could be decomposed effectively and transformed into lower toxicity intermediates.As a result,m Fe/Cu-air-PS system with the performance of oxidation combined reduction can be also a potential technology for the treatment of toxic and refractory PNP contained wastewater.展开更多
Wi-Fi devices have limited battery life because of which conserving battery life is imperative. The 802.11 Wi-Fi standard provides power management feature that allows stations(STAs) to enter into sleep state to prese...Wi-Fi devices have limited battery life because of which conserving battery life is imperative. The 802.11 Wi-Fi standard provides power management feature that allows stations(STAs) to enter into sleep state to preserve energy without any frame losses. After the STA wakes up, it sends a null data or PS-Poll frame to retrieve frame(s) buffered by the access point(AP), if any during its sleep period. An attacker can launch a power save denial of service(PS-DoS) attack on the sleeping STA(s) by transmitting a spoofed null data or PS-Poll frame(s) to retrieve the buffered frame(s) of the sleeping STA(s) from the AP causing frame losses for the targeted STA(s). Current approaches to prevent or detect the PS-DoS attack require encryption,change in protocol or installation of proprietary hardware. These solutions suffer from expensive setup, maintenance, scalability and deployment issues. The PS-DoS attack does not differ in semantics or statistics under normal and attack circumstances.So signature and anomaly based intrusion detection system(IDS) are unfit to detect the PS-DoS attack. In this paper we propose a timed IDS based on real time discrete event system(RTDES) for detecting PS-DoS attack. The proposed DES based IDS overcomes the drawbacks of existing systems and detects the PS-DoS attack with high accuracy and detection rate. The correctness of the RTDES based IDS is proved by experimenting all possible attack scenarios.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financially supported by the National Natural Science Foundation of China,No.823 74552 (to WP)the Science and Technology Innovation Program of Hunan Province,No.2022RC1220 (to WP)+1 种基金the Natural Science Foundation of Hunan Province of China,Nos.2020JJ4803 (to WP),2022JJ40723 (to MY)the Scientific Research Launch Project for New Employees of the Second Xiangya Hospital of Central South University (to MY)
文摘Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.
基金supported by STI2030-Major Projects,No.2021ZD 0201801(to JG)Shanxi Province Basic Research Program,No.20210302123429(to QS).
文摘In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
基金the financial support from the National Natural Science Foundation of China(No.51878423)China Postdoctoral Science Foundation(No.2018M631077)
文摘In this study,batch experiments were conducted to investigate the performance of microscale Fe/Cu bimetallic particles-air-persulfate system(mFe/Cu-air-PS)for p-nitrophenol(PNP)treatment in aqueous solution.First,the optimal operating parameters(i.e.,aeration rate of 1.0 L/min,theoretical Cu mass loading(TMLCu)of 0.110 g Cu/g Fe,mFe/Cu dosage of 15 g/L,PS total dosage of 15 mmol/L,feeding times of PS of 5,initial pH 5.4)were obtained successively by single-factor experiments.Under the optimal conditions,high COD and TOC removal efficiencies(71.0%,65.8%)were obtained after 60 min treatment.Afterword,compared with control experiments(i.e.,mFe/Cu,air,PS,mFe/Cu-air,mFe/Cu–PS,air-PS and mFe-air-PS),mFe/Cu-air-PS system exerted superior performance for pollutants removal due to the synergistic effect between mFe/Cu,air and PS.In addition,the results of control experiments and radical quenching experiments indicate this reinforcement by feeding of PS was greater than by aeration in m Fe/Cu-air-PS system.Furthermore,the degradation intermediates of PNP in mFe/Cu-air-PS process were identified and measured by HPLC.Based on the detected intermediates,the degradation pathways of PNP were proposed comprehensively,which revealed that toxic and refractory PNP in aqueous solution could be decomposed effectively and transformed into lower toxicity intermediates.As a result,m Fe/Cu-air-PS system with the performance of oxidation combined reduction can be also a potential technology for the treatment of toxic and refractory PNP contained wastewater.
基金supported by TATA Consultancy Servies(TCS)Research Fellowship Program,India
文摘Wi-Fi devices have limited battery life because of which conserving battery life is imperative. The 802.11 Wi-Fi standard provides power management feature that allows stations(STAs) to enter into sleep state to preserve energy without any frame losses. After the STA wakes up, it sends a null data or PS-Poll frame to retrieve frame(s) buffered by the access point(AP), if any during its sleep period. An attacker can launch a power save denial of service(PS-DoS) attack on the sleeping STA(s) by transmitting a spoofed null data or PS-Poll frame(s) to retrieve the buffered frame(s) of the sleeping STA(s) from the AP causing frame losses for the targeted STA(s). Current approaches to prevent or detect the PS-DoS attack require encryption,change in protocol or installation of proprietary hardware. These solutions suffer from expensive setup, maintenance, scalability and deployment issues. The PS-DoS attack does not differ in semantics or statistics under normal and attack circumstances.So signature and anomaly based intrusion detection system(IDS) are unfit to detect the PS-DoS attack. In this paper we propose a timed IDS based on real time discrete event system(RTDES) for detecting PS-DoS attack. The proposed DES based IDS overcomes the drawbacks of existing systems and detects the PS-DoS attack with high accuracy and detection rate. The correctness of the RTDES based IDS is proved by experimenting all possible attack scenarios.
