Maintenance of protein homeostasis or“proteostasis”is essential for the functioning and viability of cells.This is in particular the case for cells like neurons that cannot self-renew and acquire unique functional p...Maintenance of protein homeostasis or“proteostasis”is essential for the functioning and viability of cells.This is in particular the case for cells like neurons that cannot self-renew and acquire unique functional properties during their lifetime.Cellular proteostatic stress responses are in place to protect cells from damage in case of proteostatic challenges.The integrated stress response(ISR)is one of the key proteostatic stress responses in the cell(Costa-Mattioli and Walter,2020).The ISR is the downstream convergence point for the four stress-induced eIF2αkinases(EIF2AK1-4)that control stress-regulated protein translation via phosphorylation of the translation factor eIF2α.ISR activation results in a transient reduction of global translation while it concomitantly enhances the translation of specific mRNAs,including that encoding the activating transcription factor 4(ATF4).Together,the translational control mediated by the ISR results in a temporary reduction of the overall protein load and the selectively increased expression of proteins that contribute to restoration of the proteostatic balance.展开更多
Background: International research and innovation efforts for neglected tropical diseases have increased in recent decades due to disparities in overall health research funding in relation to global burden of disease....Background: International research and innovation efforts for neglected tropical diseases have increased in recent decades due to disparities in overall health research funding in relation to global burden of disease. However, within the field of neglected tropical diseases some seem far more neglected than others. In this research the aim is to investigate the distribution of resources and efforts, as well as the mechanisms that underpin funding allocation for neglected tropical diseases. Methodology: A systematic literature review was conducted to establish a comprehensive overview of known indicators for innovation efforts related to a wide range of neglected tropical diseases. Articles were selected based on a subjective evaluation of their relevance, the presence of original data, and the breadth of their scope. This was followed by thirteen in-depth open-ended interviews with representatives of private, public and philanthropic funding organizations, concerning evaluation criteria for funding research proposals. Results: The findings reveal a large difference in the extent to which the individual diseases are neglected with notable differences between absolute and relative efforts. Criteria used in the evaluation of research proposals relate to potential impact, the probability of success and strategic fit. Private organizations prioritize strategic fit and economic impact;philanthropic organizations prioritize short-term societal impact;and public generally prioritize the probability of success by accounting for follow-up funding and involvement of industry. Funding decisions of different types of organizations are highly interrelated. Conclusions: This study shows that the evaluation of funding proposals introduces and retains unequal funding distribution, reinforcing the relative neglect of diseases. Societal impact is the primary rationale for funding but application of it as a funding criterion is associated with significant challenges. Furthermore, current application of evaluation criteria leads to a primary focus on short-term impact. Through current practice, the relatively most neglected diseases will remain so, and a long-term strategy is needed to resolve this.展开更多
Concurrent extreme weather events in geographically distant areas potentially cause high-end risks for societies.By using network analysis,the present study managed to identify significant nearly-simultaneous occurren...Concurrent extreme weather events in geographically distant areas potentially cause high-end risks for societies.By using network analysis,the present study managed to identify significant nearly-simultaneous occurrences of heatwaves between the grid cells in East Asia and Eastern Europe,even though they are geographically far away from each other.By further composite analysis,this study revealed that hot events first occurred in Eastern Europe,typically with a time lag of3-4 days before the East Asian heatwave events.An eastward propagating atmospheric wave train,known as the circumglobal teleconnection(CGT)pattern,bridged the sequent occurrences of extreme events in these two remote regions.Atmospheric blockings,amplified by surface warming over Eastern Europe,not only enhanced local heat extremes but also excited a CGT-like pattern characterized by alternative anomalies of high and low pressures.Subsequent downstream anticyclones in the middle and upper troposphere reduced local cloud cover and increased downward solar radiation,thereby facilitating the formation of heatwaves over East Asia.Nearly half of East Asian heatwave events were preceded by Eastern European heatwave events in the 10-day time range before East Asian heatwave events.This investigation of heatwave teleconnection in the two distant regions exhibits strong potential to improve the prediction accuracy of East Asian heatwaves.展开更多
With the growing discovery of exposed vulnerabilities in the Industrial Control Components(ICCs),identification of the exploitable ones is urgent for Industrial Control System(ICS)administrators to proactively forecas...With the growing discovery of exposed vulnerabilities in the Industrial Control Components(ICCs),identification of the exploitable ones is urgent for Industrial Control System(ICS)administrators to proactively forecast potential threats.However,it is not a trivial task due to the complexity of the multi-source heterogeneous data and the lack of automatic analysis methods.To address these challenges,we propose an exploitability reasoning method based on the ICC-Vulnerability Knowledge Graph(KG)in which relation paths contain abundant potential evidence to support the reasoning.The reasoning task in this work refers to determining whether a specific relation is valid between an attacker entity and a possible exploitable vulnerability entity with the help of a collective of the critical paths.The proposed method consists of three primary building blocks:KG construction,relation path representation,and query relation reasoning.A security-oriented ontology combines exploit modeling,which provides a guideline for the integration of the scattered knowledge while constructing the KG.We emphasize the role of the aggregation of the attention mechanism in representation learning and ultimate reasoning.In order to acquire a high-quality representation,the entity and relation embeddings take advantage of their local structure and related semantics.Some critical paths are assigned corresponding attentive weights and then they are aggregated for the determination of the query relation validity.In particular,similarity calculation is introduced into a critical path selection algorithm,which improves search and reasoning performance.Meanwhile,the proposed algorithm avoids redundant paths between the given pairs of entities.Experimental results show that the proposed method outperforms the state-of-the-art ones in the aspects of embedding quality and query relation reasoning accuracy.展开更多
This study discusses the European Union’s proposal for a Regulation on Markets in Crypto-Assets,now subject to formal approval by the European Parliament.The objective is to explore whether it will positively impact ...This study discusses the European Union’s proposal for a Regulation on Markets in Crypto-Assets,now subject to formal approval by the European Parliament.The objective is to explore whether it will positively impact the adoption of crypto-assets in the financial sector.The use of crypto-assets is growing.However,some stakeholders in the financial service sector remain skeptical and hesitant to adopt assets that are yet to be defined and have an unclear legal status.This regulatory uncertainty has been identified as the primary reason for the reluctant adoption.The proposed regulation(part of the EU’s Digital Finance Strategy)aims to provide this legal certainty for currently unregulated crypto-assets.This study investigates whether or not the proposed regulation can be expected to have the intended effect by reviewing the proposed regulation itself,the opinions and reactions of the various stakeholders,and secondary literature.Findings reveal that such regulation will most likely not accelerate the adoption of crypto-assets in the EU financial services sector,at least not sufficiently or as intended.Some suggestions are made to improve the proposal.展开更多
Dear Editor,The skin barrier can be impaired by acute skin wounds,which may lead to a series of complications.It is essential to accelerate wound healing and rapidly restore the structural integrity and functionality ...Dear Editor,The skin barrier can be impaired by acute skin wounds,which may lead to a series of complications.It is essential to accelerate wound healing and rapidly restore the structural integrity and functionality of skin.One of the promising bioactive agents is human salivary histatin 1(Hst1),a 38-amino acid histidine-rich peptide that functions to maintain the homeostasis of oral mucosa with a cellular mechanism of promoting the adhesion,spreading,migration of epithelial cells and thus re-epithelialization[1].In recent years,Hst1 has been shown to be effective against various skin-related cell types,such as fibroblasts,myo-fibroblasts,keratinocytes and endothelial cells.In our latest in-vivo study,Hst1 not only promotes angiogenesis,re-epithelialization and collagen production,but also suppresses inflammation,thereby significantly accelerating acute skin wound healing in mice[2].All these studies show that Hst1 is a potent bioactive agent for accelerating acute skin wound healing.展开更多
INTRODUCTIONThe strongest evidence that H.pylori infection isthe cause of peptic ulcer is that treatment withantibiotics as the only regimen,is not only effectivefor the clearance and eradication of the infection,but ...INTRODUCTIONThe strongest evidence that H.pylori infection isthe cause of peptic ulcer is that treatment withantibiotics as the only regimen,is not only effectivefor the clearance and eradication of the infection,but more importantly for the healing of the ulcer orthe remission of gastric lymphoma.However,it isstill a matter of controversy and research as to展开更多
This review provides an overview of the literature on aspects of reproductive endocrinology wherein Asian menmay differ from Caucasian, notably, prostatic nioplasm and the sensivity to pharmacological regimens of male...This review provides an overview of the literature on aspects of reproductive endocrinology wherein Asian menmay differ from Caucasian, notably, prostatic nioplasm and the sensivity to pharmacological regimens of male contra-ception. Both genetic and environmental factors, such as nutrition, might be relevant. Asian men residing in Asia seemto be relatively protected from clinical prostatic nioplasm while the prevalence of preclinical prostatic nioplasm is notdifferent. Migration to an area with a higher prevalence reduces this difference but does not undo it. With regard toprostatic nioplasm the following factors have been considered as relevant in Asian men: 1) a reduction in 5α-reductaselevel, 2) decreased levels of androgenic ketosteroid precursors of 5α-reduced androgen metabolites, 3) the decreasedpresence of a P53 mutation, 4) a higher CAG-repeat length of the androgen receptor, 5) a possible higher level ofphysical activity, 6) differences in sexual activity. Furthermore, Asian men respond to a higher degree with azoosper-mia in response to contraceptive steroids. Possible explanations offered for the more pronounced response to contracep-tive steroids are: 1) differences in testicular structure and decreased spermatogenic potential, 2) an earlier and moremarked suppression in LH secretion by exogenous androgens. The differences may be due to genetical and/or environ-mental factors influencing the peripheral testosterone metabolism. Dietary factors such as the higher intake of phytoe-strogens in Asians might exert effects on 5α-reductase activity and/or on sex hormone binding globulin (SHBG) levels,thus having an impact on the biological efficay of circulating androgens. ( Asian J Androl 2000; 2: 13 - 20)展开更多
Frailty is a critical intermediate status of the aging process with a multidimensional and multisystem nature and at higher risk for adverse health-related outcomes,including falls,disability,hospitalizations,institut...Frailty is a critical intermediate status of the aging process with a multidimensional and multisystem nature and at higher risk for adverse health-related outcomes,including falls,disability,hospitalizations,institutionalization,mortality,dementia,and Alzheimer’s disease.Among different frailty phenotypes,oral frailty has been recently suggested as a novel construct defined as a decrease in oral function with a coexisting decline in cognitive and physical functions.We briefly reviewed existing evidence on operational definitions of oral frailty,assessment and screening tools,and possible relationships among oral frailty,oral microbiota,and Alzheimer’s disease neurodegeneration.Several underlying mechanism may explain the oral health-frailty links including undernutrition,sarcopenia linked to both poor nutrition and frailty,psychosocial factors,and the chronic inflammation typical of oral disease.Oral microbiota may influence Alzheimer’s disease risk through circulatory or neural access to the brain and the interplay with periodontal disease,often causing tooth loss also linked to an increased Alzheimer’s disease risk.On this bases,COR388,a bacterial protease inhibitor targeting Porphyromonas gingivalis implicated in periodontal disease,is now being tested in a double-blind,placebocontrolled Phase II/III study in mild-to-moderate Alzheimer’s disease.Therefore,oral status may be an important contributor to general health,including Alzheimer’s disease and latelife cognitive disorders,suggesting the central role of preventive strategies targeting the novel oral frailty phenotype and including maintenance and improvement of oral function and nutritional status to reduce the burden of both oral dysfunction and frailty.展开更多
基金supported by ZonMW and Stichting Proefdiervrij (#114022506)PPP Allo wance made available by Health~Holland,Top Sector Life Sciences&Health,to stimulate public-private partnerships (#LSHM17014 and LSHM18024)+3 种基金Alzheimer Nederland (grant WE.03-2017-10)European Commission (Joint Programming Initiative Neurodegenerative Diseases/JPco-fuND (ZonMW#733051062)Weston Brain Institute (#NR1 60014)ZonMW Memorabel/Alzheimer Nederland (#733050101)(to WS)
文摘Maintenance of protein homeostasis or“proteostasis”is essential for the functioning and viability of cells.This is in particular the case for cells like neurons that cannot self-renew and acquire unique functional properties during their lifetime.Cellular proteostatic stress responses are in place to protect cells from damage in case of proteostatic challenges.The integrated stress response(ISR)is one of the key proteostatic stress responses in the cell(Costa-Mattioli and Walter,2020).The ISR is the downstream convergence point for the four stress-induced eIF2αkinases(EIF2AK1-4)that control stress-regulated protein translation via phosphorylation of the translation factor eIF2α.ISR activation results in a transient reduction of global translation while it concomitantly enhances the translation of specific mRNAs,including that encoding the activating transcription factor 4(ATF4).Together,the translational control mediated by the ISR results in a temporary reduction of the overall protein load and the selectively increased expression of proteins that contribute to restoration of the proteostatic balance.
文摘Background: International research and innovation efforts for neglected tropical diseases have increased in recent decades due to disparities in overall health research funding in relation to global burden of disease. However, within the field of neglected tropical diseases some seem far more neglected than others. In this research the aim is to investigate the distribution of resources and efforts, as well as the mechanisms that underpin funding allocation for neglected tropical diseases. Methodology: A systematic literature review was conducted to establish a comprehensive overview of known indicators for innovation efforts related to a wide range of neglected tropical diseases. Articles were selected based on a subjective evaluation of their relevance, the presence of original data, and the breadth of their scope. This was followed by thirteen in-depth open-ended interviews with representatives of private, public and philanthropic funding organizations, concerning evaluation criteria for funding research proposals. Results: The findings reveal a large difference in the extent to which the individual diseases are neglected with notable differences between absolute and relative efforts. Criteria used in the evaluation of research proposals relate to potential impact, the probability of success and strategic fit. Private organizations prioritize strategic fit and economic impact;philanthropic organizations prioritize short-term societal impact;and public generally prioritize the probability of success by accounting for follow-up funding and involvement of industry. Funding decisions of different types of organizations are highly interrelated. Conclusions: This study shows that the evaluation of funding proposals introduces and retains unequal funding distribution, reinforcing the relative neglect of diseases. Societal impact is the primary rationale for funding but application of it as a funding criterion is associated with significant challenges. Furthermore, current application of evaluation criteria leads to a primary focus on short-term impact. Through current practice, the relatively most neglected diseases will remain so, and a long-term strategy is needed to resolve this.
基金Guangdong Major Project of Basic and Applied Basic Research (2020B0301030004)National Natural Science Foundation of China (42275020)+1 种基金Innovation Group Project of Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai) (311021001)Guangdong Province Key Laboratory for Climate Change and Natural Disaster Studies (2020B1212060025)。
文摘Concurrent extreme weather events in geographically distant areas potentially cause high-end risks for societies.By using network analysis,the present study managed to identify significant nearly-simultaneous occurrences of heatwaves between the grid cells in East Asia and Eastern Europe,even though they are geographically far away from each other.By further composite analysis,this study revealed that hot events first occurred in Eastern Europe,typically with a time lag of3-4 days before the East Asian heatwave events.An eastward propagating atmospheric wave train,known as the circumglobal teleconnection(CGT)pattern,bridged the sequent occurrences of extreme events in these two remote regions.Atmospheric blockings,amplified by surface warming over Eastern Europe,not only enhanced local heat extremes but also excited a CGT-like pattern characterized by alternative anomalies of high and low pressures.Subsequent downstream anticyclones in the middle and upper troposphere reduced local cloud cover and increased downward solar radiation,thereby facilitating the formation of heatwaves over East Asia.Nearly half of East Asian heatwave events were preceded by Eastern European heatwave events in the 10-day time range before East Asian heatwave events.This investigation of heatwave teleconnection in the two distant regions exhibits strong potential to improve the prediction accuracy of East Asian heatwaves.
基金Our work is supported by the National Key R&D Program of China(2021YFB2012400).
文摘With the growing discovery of exposed vulnerabilities in the Industrial Control Components(ICCs),identification of the exploitable ones is urgent for Industrial Control System(ICS)administrators to proactively forecast potential threats.However,it is not a trivial task due to the complexity of the multi-source heterogeneous data and the lack of automatic analysis methods.To address these challenges,we propose an exploitability reasoning method based on the ICC-Vulnerability Knowledge Graph(KG)in which relation paths contain abundant potential evidence to support the reasoning.The reasoning task in this work refers to determining whether a specific relation is valid between an attacker entity and a possible exploitable vulnerability entity with the help of a collective of the critical paths.The proposed method consists of three primary building blocks:KG construction,relation path representation,and query relation reasoning.A security-oriented ontology combines exploit modeling,which provides a guideline for the integration of the scattered knowledge while constructing the KG.We emphasize the role of the aggregation of the attention mechanism in representation learning and ultimate reasoning.In order to acquire a high-quality representation,the entity and relation embeddings take advantage of their local structure and related semantics.Some critical paths are assigned corresponding attentive weights and then they are aggregated for the determination of the query relation validity.In particular,similarity calculation is introduced into a critical path selection algorithm,which improves search and reasoning performance.Meanwhile,the proposed algorithm avoids redundant paths between the given pairs of entities.Experimental results show that the proposed method outperforms the state-of-the-art ones in the aspects of embedding quality and query relation reasoning accuracy.
文摘This study discusses the European Union’s proposal for a Regulation on Markets in Crypto-Assets,now subject to formal approval by the European Parliament.The objective is to explore whether it will positively impact the adoption of crypto-assets in the financial sector.The use of crypto-assets is growing.However,some stakeholders in the financial service sector remain skeptical and hesitant to adopt assets that are yet to be defined and have an unclear legal status.This regulatory uncertainty has been identified as the primary reason for the reluctant adoption.The proposed regulation(part of the EU’s Digital Finance Strategy)aims to provide this legal certainty for currently unregulated crypto-assets.This study investigates whether or not the proposed regulation can be expected to have the intended effect by reviewing the proposed regulation itself,the opinions and reactions of the various stakeholders,and secondary literature.Findings reveal that such regulation will most likely not accelerate the adoption of crypto-assets in the EU financial services sector,at least not sufficiently or as intended.Some suggestions are made to improve the proposal.
基金funded by the National Natural Science Foundation of China(82172223)the National Key Research and Development Plan of China(2017YFC1103301)+1 种基金the Military Medical Innovation Special Projects(18CXZ029)the Key Research and Development Plan of Zhejiang Province(2021C04013).
文摘Dear Editor,The skin barrier can be impaired by acute skin wounds,which may lead to a series of complications.It is essential to accelerate wound healing and rapidly restore the structural integrity and functionality of skin.One of the promising bioactive agents is human salivary histatin 1(Hst1),a 38-amino acid histidine-rich peptide that functions to maintain the homeostasis of oral mucosa with a cellular mechanism of promoting the adhesion,spreading,migration of epithelial cells and thus re-epithelialization[1].In recent years,Hst1 has been shown to be effective against various skin-related cell types,such as fibroblasts,myo-fibroblasts,keratinocytes and endothelial cells.In our latest in-vivo study,Hst1 not only promotes angiogenesis,re-epithelialization and collagen production,but also suppresses inflammation,thereby significantly accelerating acute skin wound healing in mice[2].All these studies show that Hst1 is a potent bioactive agent for accelerating acute skin wound healing.
文摘INTRODUCTIONThe strongest evidence that H.pylori infection isthe cause of peptic ulcer is that treatment withantibiotics as the only regimen,is not only effectivefor the clearance and eradication of the infection,but more importantly for the healing of the ulcer orthe remission of gastric lymphoma.However,it isstill a matter of controversy and research as to
文摘This review provides an overview of the literature on aspects of reproductive endocrinology wherein Asian menmay differ from Caucasian, notably, prostatic nioplasm and the sensivity to pharmacological regimens of male contra-ception. Both genetic and environmental factors, such as nutrition, might be relevant. Asian men residing in Asia seemto be relatively protected from clinical prostatic nioplasm while the prevalence of preclinical prostatic nioplasm is notdifferent. Migration to an area with a higher prevalence reduces this difference but does not undo it. With regard toprostatic nioplasm the following factors have been considered as relevant in Asian men: 1) a reduction in 5α-reductaselevel, 2) decreased levels of androgenic ketosteroid precursors of 5α-reduced androgen metabolites, 3) the decreasedpresence of a P53 mutation, 4) a higher CAG-repeat length of the androgen receptor, 5) a possible higher level ofphysical activity, 6) differences in sexual activity. Furthermore, Asian men respond to a higher degree with azoosper-mia in response to contraceptive steroids. Possible explanations offered for the more pronounced response to contracep-tive steroids are: 1) differences in testicular structure and decreased spermatogenic potential, 2) an earlier and moremarked suppression in LH secretion by exogenous androgens. The differences may be due to genetical and/or environ-mental factors influencing the peripheral testosterone metabolism. Dietary factors such as the higher intake of phytoe-strogens in Asians might exert effects on 5α-reductase activity and/or on sex hormone binding globulin (SHBG) levels,thus having an impact on the biological efficay of circulating androgens. ( Asian J Androl 2000; 2: 13 - 20)
文摘Frailty is a critical intermediate status of the aging process with a multidimensional and multisystem nature and at higher risk for adverse health-related outcomes,including falls,disability,hospitalizations,institutionalization,mortality,dementia,and Alzheimer’s disease.Among different frailty phenotypes,oral frailty has been recently suggested as a novel construct defined as a decrease in oral function with a coexisting decline in cognitive and physical functions.We briefly reviewed existing evidence on operational definitions of oral frailty,assessment and screening tools,and possible relationships among oral frailty,oral microbiota,and Alzheimer’s disease neurodegeneration.Several underlying mechanism may explain the oral health-frailty links including undernutrition,sarcopenia linked to both poor nutrition and frailty,psychosocial factors,and the chronic inflammation typical of oral disease.Oral microbiota may influence Alzheimer’s disease risk through circulatory or neural access to the brain and the interplay with periodontal disease,often causing tooth loss also linked to an increased Alzheimer’s disease risk.On this bases,COR388,a bacterial protease inhibitor targeting Porphyromonas gingivalis implicated in periodontal disease,is now being tested in a double-blind,placebocontrolled Phase II/III study in mild-to-moderate Alzheimer’s disease.Therefore,oral status may be an important contributor to general health,including Alzheimer’s disease and latelife cognitive disorders,suggesting the central role of preventive strategies targeting the novel oral frailty phenotype and including maintenance and improvement of oral function and nutritional status to reduce the burden of both oral dysfunction and frailty.
