The Chicago Area Waterway System(CAWS)is a 133.9 km branching network of navigable waterways controlled by hydraulic structures,in which the majority of the flow is treated wastewater effluent and there are periods of...The Chicago Area Waterway System(CAWS)is a 133.9 km branching network of navigable waterways controlled by hydraulic structures,in which the majority of the flow is treated wastewater effluent and there are periods of substantial combined sewer overflows.The CAWS comprises a network of effluent dominated streams.More stringent dissolved oxygen(DO)standards and a reduced flow augmentation allowance have been recently applied to the CAWS.Therefore,a carefully calibrated and verified one-dimensional flow and water quality model was applied to the CAWS to determine emission-based real-time control guidelines for the operation of flow augmentation and aeration stations.The goal of these guidelines was to attain DO standards at least 95%of the time.The“optimal”guidelines were tested for representative normal,dry,and wet years.The finally proposed guidelines were found in the simulations to attain the 95%target for nearly all locations in the CAWS for the three test years.The developed operational guidelines have been applied since 2018 and have shown improved attainment of the DO standards throughout the CAWS while at the same time achieving similar energy use at the aeration stations on the Calumet River system,greatly lowered energy use on the Chicago River system,and greatly lowered discretionary diversion from Lake Michigan,meeting the recently enacted lower amount of allowed annual discretionary diversion.This case study indicates that emission-based real-time control developed from a well calibrated model holds potential to help many receiving water bodies achieve high attainment of water quality standards.展开更多
Background: Our aim was to investigate the impact of the extent of surgical resection on local recurrence and survival in high-risk patients treated with the Chicago Pilot II protocol. Methods: Retrospective chart rev...Background: Our aim was to investigate the impact of the extent of surgical resection on local recurrence and survival in high-risk patients treated with the Chicago Pilot II protocol. Methods: Retrospective chart review was performed on 30 patients enrolled in the Chicago Pilot II protocol between 1995 and 2003. Variables studied were location of tumor, extent of resection, timing and location of recurrence, MYCN amplification, surgical complications, event-free survival, and overall survival (OS).Operative reports and postoperative meta-iodobenzylguanidine scans were used to assess extent of resection. Complete resection (CR) was defined as no gross residual tumor including primary and nodal disease. Results: Three-year event-free survival and OS of this cohort of 30 patients was 58%and 82%, respectively. Only 1 patient developed a local recurrence, whereas metastatic recurrent disease was observed in 13 (43%)-of the 30; and this subset had a significantly worse OS (23%vs 94%, P = .001). The most common relapse location was in bone. Patients with incomplete resection (IR) (11/30) and CR (19/30) had recurrence rates of 64%(7/11) and 32%(6/19, P = .12), respectively. Event-free survival was significantly better for patients with CR (68%) vs IR(27%; P = .05; odds ratio, 2.9). Overall survival rates for patients with CR vs IR were 68%vs 55%, respectively (P = .25). Conclusions: Recurrence rate was the significant determinant of survival. Patients with CR had lower recurrence rates; however, they did not have improved local control. Final outcome of patients with unfavorable neuroblastoma will be determined by metastatic recurrence, not by extent of resection.展开更多
Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and geneti...Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).展开更多
The onset,cessation,and length of the rainy season are crucial for global water resources,agricultural practices,and food security.However,the response of precipitation seasonality to global warming remains uncertain....The onset,cessation,and length of the rainy season are crucial for global water resources,agricultural practices,and food security.However,the response of precipitation seasonality to global warming remains uncertain.In this study,we analyze how global warming levels(GWLs)of 1.5℃ and 2℃ could affect the timing of rainfall onset(RODs),rainfall cessation(RCDs),and the overall duration of the rainy season(LRS)over global land monsoon(GLM)regions using simulations from CMIP6 under the SSP2-4.5 and SSP5-8.5 scenarios.With high model consensus,our results reveal that RODs are projected to occur later over Southern Africa,North Africa,and South America,but earlier over South Asia and Australia,in a warmer climate.The projected early RODs in Australia are more pronounced at the 2℃ GWL under SSP5-8.5.On the other hand,early RCDs are projected over South America and East Asia,while late RCDs are projected over North Africa,with high inter-model agreement.These changes are associated with a future decrease in LRS in most GLM regions.Additionally,we found that continuous warming over 1.5℃ will further reduce the length of the rainy season,especially over the South America,North Africa,and Southern Africa monsoon regions.The findings underscore the urgent need to mitigate global warming.展开更多
The nervous system processes a vast amount of information,performing computations that underlie perception,cognition,and behavior.During development,neuronal guidance genes,which encode extracellular cues,their recept...The nervous system processes a vast amount of information,performing computations that underlie perception,cognition,and behavior.During development,neuronal guidance genes,which encode extracellular cues,their receptors,and downstream signal transducers,organize neural wiring to generate the complex architecture of the nervous system.It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system.This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system.Supporting this view,these pathways continue to regulate synaptic connectivity,plasticity,and remodeling,and overall brain homeostasis throughout adulthood.Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders.Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified,emerging evidence points to several common themes,including dysfunction in neurons,microglia,astrocytes,and endothelial cells,along with dysregulation of neuron-microglia-astrocyte,neuroimmune,and neurovascular interactions.In this review,we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions.For instance,recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation.We discuss the challenges ahead,along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases.Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions.Specifically,we examine the crosstalk between neuronal guidance signaling and TREM2,a master regulator of microglial function,in the context of pathogenic protein aggregates.It is well-established that age is a major risk factor for neurodegeneration.Future research should address how aging and neuronal guidance signaling interact to influence an individual’s susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.展开更多
In recent years,there has been an increasing need for climate information across diverse sectors of society.This demand has arisen from the necessity to adapt to and mitigate the impacts of climate variability and cha...In recent years,there has been an increasing need for climate information across diverse sectors of society.This demand has arisen from the necessity to adapt to and mitigate the impacts of climate variability and change.Likewise,this period has seen a significant increase in our understanding of the physical processes and mechanisms that drive precipitation and its variability across different regions of Africa.By leveraging a large volume of climate model outputs,numerous studies have investigated the model representation of African precipitation as well as underlying physical processes.These studies have assessed whether the physical processes are well depicted and whether the models are fit for informing mitigation and adaptation strategies.This paper provides a review of the progress in precipitation simulation overAfrica in state-of-the-science climate models and discusses the major issues and challenges that remain.展开更多
目的分析2016—2024年成长型思维应用于医学教育的国际研究趋势及前沿热点,以期为国内开展相关研究提供思路和借鉴。方法检索Web of Science核心合集数据库和Scopus数据库,纳入2016年1月1日—2024年12月15日成长型思维应用于医学教育的...目的分析2016—2024年成长型思维应用于医学教育的国际研究趋势及前沿热点,以期为国内开展相关研究提供思路和借鉴。方法检索Web of Science核心合集数据库和Scopus数据库,纳入2016年1月1日—2024年12月15日成长型思维应用于医学教育的相关英文文献。采用VOSviewer(v.1.6.18)软件提取文献信息,并绘制国家/地区、作者合作网络图;采用CiteSpace(v.6.1.R6)软件对文献作者、国家/地区等信息进行共现和聚类分析。结果2016—2024年成长型思维应用于医学教育相关文献共109篇(论著92篇、综述17篇),年发文量整体呈快速上升趋势。美国是该领域发文量(77篇,70.6%)和被引频次(1191次,57.5%)最多的国家;美国健康科学统一服务大学(423次)和梅奥诊所(417次)是该领域发文被引频次最多的2所机构;斯坦福大学学者Carol S.Dweck教授是该领域发文共被引频次最高的作者(128次);健康科学统一服务大学学者Anthony R.Artino是发文被引频次最多的作者(383次)。高频关键词主要包括:聚焦医学教育成果的“academic success”“academic performance”“resilience”“professional development”“faculty development”,聚焦医学教育目标人群的“undergraduate medical education”“graduate medical education”,以及聚焦教学方法的“coaching”“feedback”“competency-based education”。结论2016年以来,成长型思维应用于医学教育相关研究具有良好的学科关注度,以美国为代表的发达国家在该领域处于领先地位。目前,该领域的研究重点为成长型思维应用于医学教育的教学方法、教学目标和教育心理学,以及其在促进医学生福祉和身心健康方面的作用。在实践层面,芝加哥大学普利兹克医学院应用成长型思维的经验对国内医疗机构开展相关研究具有借鉴价值。展开更多
Objective Selective estrogen receptor modulators(SERMs)have demonstrated efficacy in the treatment of hypogonadism in males and male factor infertility.Two SERMs,clomiphene citrate and tamoxifen,are now prescribed for...Objective Selective estrogen receptor modulators(SERMs)have demonstrated efficacy in the treatment of hypogonadism in males and male factor infertility.Two SERMs,clomiphene citrate and tamoxifen,are now prescribed for off-label use to treat both conditions in males.However,existing literature compares mixed protocols with active management.We aimed to conduct a meta-analysis to evaluate the effect of clomiphene and tamoxifen versus placebo on natural pregnancy rates.Methods We conducted a comprehensive systematic review of electronic databases:MEDLINE,PubMed/PMC,EMBASE,CINAHL,Cochrane Central Register of Controlled Trials(CENTRAL),Scopus,Google Scholar,and Web of Science.Articles satisfying all selection criteria were analyzed.The primary outcome was the incidence of pregnancy after receiving the treatment.Secondary outcomes included serum follicle-stimulating hormone,luteinizing hormone,and testosterone levels,and sperm count and motility.We calculated the pooled odds ratio,risk ratio,and risk difference to ascertain possible alterations in the direction of the pooled effect size.Results Ten randomized controlled trials were ultimately included and underwent data extraction.Clomiphene citrate and placebo groups had similar pregnancy rates(10.4%and 7.1%,respectively;odds ratio 1.30[95%confidence interval 0.27–6.17];p=0.74).No meta-analysis could be calculated for pregnancy rates in tamoxifen versus placebo groups.Heterogeneity among the studies of both SERMs ranged from low to high.Conclusion Although clomiphene citrate and tamoxifen are often used off-label for the treatment of male infertility secondary to hypogonadism,studies of SERMs in the treatment of idiopathic male factor infertility are limited and heterogenous,preventing this meta-analysis from investigating the efficacy of SERMs on male infertility.The effect of clomiphene citrate or tamoxifen on the pregnancy rate remains uncertain.展开更多
Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understan...Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.展开更多
Axonal degeneration underlies many debilitating diseases including hereditary spastic paraplegia(HSP),a genetically and clinically diverse group of disorders characterized by spasticity and weakness of the lower extre...Axonal degeneration underlies many debilitating diseases including hereditary spastic paraplegia(HSP),a genetically and clinically diverse group of disorders characterized by spasticity and weakness of the lower extremities.HSP is one significant cause of chronic neurodisability due to the lack of effective treatments and a wide range of onset ages from early childhood to 70 years.展开更多
基金supported by the Metropolitan Water Reclamation District of Greater Chicago(Requisition No.1449764).
文摘The Chicago Area Waterway System(CAWS)is a 133.9 km branching network of navigable waterways controlled by hydraulic structures,in which the majority of the flow is treated wastewater effluent and there are periods of substantial combined sewer overflows.The CAWS comprises a network of effluent dominated streams.More stringent dissolved oxygen(DO)standards and a reduced flow augmentation allowance have been recently applied to the CAWS.Therefore,a carefully calibrated and verified one-dimensional flow and water quality model was applied to the CAWS to determine emission-based real-time control guidelines for the operation of flow augmentation and aeration stations.The goal of these guidelines was to attain DO standards at least 95%of the time.The“optimal”guidelines were tested for representative normal,dry,and wet years.The finally proposed guidelines were found in the simulations to attain the 95%target for nearly all locations in the CAWS for the three test years.The developed operational guidelines have been applied since 2018 and have shown improved attainment of the DO standards throughout the CAWS while at the same time achieving similar energy use at the aeration stations on the Calumet River system,greatly lowered energy use on the Chicago River system,and greatly lowered discretionary diversion from Lake Michigan,meeting the recently enacted lower amount of allowed annual discretionary diversion.This case study indicates that emission-based real-time control developed from a well calibrated model holds potential to help many receiving water bodies achieve high attainment of water quality standards.
文摘Background: Our aim was to investigate the impact of the extent of surgical resection on local recurrence and survival in high-risk patients treated with the Chicago Pilot II protocol. Methods: Retrospective chart review was performed on 30 patients enrolled in the Chicago Pilot II protocol between 1995 and 2003. Variables studied were location of tumor, extent of resection, timing and location of recurrence, MYCN amplification, surgical complications, event-free survival, and overall survival (OS).Operative reports and postoperative meta-iodobenzylguanidine scans were used to assess extent of resection. Complete resection (CR) was defined as no gross residual tumor including primary and nodal disease. Results: Three-year event-free survival and OS of this cohort of 30 patients was 58%and 82%, respectively. Only 1 patient developed a local recurrence, whereas metastatic recurrent disease was observed in 13 (43%)-of the 30; and this subset had a significantly worse OS (23%vs 94%, P = .001). The most common relapse location was in bone. Patients with incomplete resection (IR) (11/30) and CR (19/30) had recurrence rates of 64%(7/11) and 32%(6/19, P = .12), respectively. Event-free survival was significantly better for patients with CR (68%) vs IR(27%; P = .05; odds ratio, 2.9). Overall survival rates for patients with CR vs IR were 68%vs 55%, respectively (P = .25). Conclusions: Recurrence rate was the significant determinant of survival. Patients with CR had lower recurrence rates; however, they did not have improved local control. Final outcome of patients with unfavorable neuroblastoma will be determined by metastatic recurrence, not by extent of resection.
基金supported by the Belle Carnell Regenerative Neurorehabilitation Fundthe National Institutes of Health(R01NS113935 to CKF)。
文摘Human spinal cord organoids(hSCOs)offer a promising platform to study neurotrauma by addressing many limitations of traditional research models.These organoids provide access to human-specific physiological and genetic mechanisms and can be derived from an individual's somatic cells(e.g.,blood or skin).This enables patient-specific paradigms for precision neurotrauma research,pa rticula rly relevant to the over 300,000 people in the United States living with chronic effects of spinal cord injury(SCI).
基金supported by the Australian Research Council(Grant No.CE230100012)。
文摘The onset,cessation,and length of the rainy season are crucial for global water resources,agricultural practices,and food security.However,the response of precipitation seasonality to global warming remains uncertain.In this study,we analyze how global warming levels(GWLs)of 1.5℃ and 2℃ could affect the timing of rainfall onset(RODs),rainfall cessation(RCDs),and the overall duration of the rainy season(LRS)over global land monsoon(GLM)regions using simulations from CMIP6 under the SSP2-4.5 and SSP5-8.5 scenarios.With high model consensus,our results reveal that RODs are projected to occur later over Southern Africa,North Africa,and South America,but earlier over South Asia and Australia,in a warmer climate.The projected early RODs in Australia are more pronounced at the 2℃ GWL under SSP5-8.5.On the other hand,early RCDs are projected over South America and East Asia,while late RCDs are projected over North Africa,with high inter-model agreement.These changes are associated with a future decrease in LRS in most GLM regions.Additionally,we found that continuous warming over 1.5℃ will further reduce the length of the rainy season,especially over the South America,North Africa,and Southern Africa monsoon regions.The findings underscore the urgent need to mitigate global warming.
基金supported by JSPS(KAKENHI:21K06205,23K06937,24K23419)AMED(to JYK,SaY,TM,SiY,YT,and NH)JYW had long been supported by the NIH.
文摘The nervous system processes a vast amount of information,performing computations that underlie perception,cognition,and behavior.During development,neuronal guidance genes,which encode extracellular cues,their receptors,and downstream signal transducers,organize neural wiring to generate the complex architecture of the nervous system.It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system.This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system.Supporting this view,these pathways continue to regulate synaptic connectivity,plasticity,and remodeling,and overall brain homeostasis throughout adulthood.Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders.Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified,emerging evidence points to several common themes,including dysfunction in neurons,microglia,astrocytes,and endothelial cells,along with dysregulation of neuron-microglia-astrocyte,neuroimmune,and neurovascular interactions.In this review,we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions.For instance,recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation.We discuss the challenges ahead,along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases.Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions.Specifically,we examine the crosstalk between neuronal guidance signaling and TREM2,a master regulator of microglial function,in the context of pathogenic protein aggregates.It is well-established that age is a major risk factor for neurodegeneration.Future research should address how aging and neuronal guidance signaling interact to influence an individual’s susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.
基金the World Climate Research Programme(WCRP),Climate Variability and Predictability(CLIVAR),and Global Energy and Water Exchanges(GEWEX)for facilitating the coordination of African monsoon researchsupport from the Center for Earth System Modeling,Analysis,and Data at the Pennsylvania State Universitythe support of the Office of Science of the U.S.Department of Energy Biological and Environmental Research as part of the Regional&Global Model Analysis(RGMA)program area。
文摘In recent years,there has been an increasing need for climate information across diverse sectors of society.This demand has arisen from the necessity to adapt to and mitigate the impacts of climate variability and change.Likewise,this period has seen a significant increase in our understanding of the physical processes and mechanisms that drive precipitation and its variability across different regions of Africa.By leveraging a large volume of climate model outputs,numerous studies have investigated the model representation of African precipitation as well as underlying physical processes.These studies have assessed whether the physical processes are well depicted and whether the models are fit for informing mitigation and adaptation strategies.This paper provides a review of the progress in precipitation simulation overAfrica in state-of-the-science climate models and discusses the major issues and challenges that remain.
文摘目的分析2016—2024年成长型思维应用于医学教育的国际研究趋势及前沿热点,以期为国内开展相关研究提供思路和借鉴。方法检索Web of Science核心合集数据库和Scopus数据库,纳入2016年1月1日—2024年12月15日成长型思维应用于医学教育的相关英文文献。采用VOSviewer(v.1.6.18)软件提取文献信息,并绘制国家/地区、作者合作网络图;采用CiteSpace(v.6.1.R6)软件对文献作者、国家/地区等信息进行共现和聚类分析。结果2016—2024年成长型思维应用于医学教育相关文献共109篇(论著92篇、综述17篇),年发文量整体呈快速上升趋势。美国是该领域发文量(77篇,70.6%)和被引频次(1191次,57.5%)最多的国家;美国健康科学统一服务大学(423次)和梅奥诊所(417次)是该领域发文被引频次最多的2所机构;斯坦福大学学者Carol S.Dweck教授是该领域发文共被引频次最高的作者(128次);健康科学统一服务大学学者Anthony R.Artino是发文被引频次最多的作者(383次)。高频关键词主要包括:聚焦医学教育成果的“academic success”“academic performance”“resilience”“professional development”“faculty development”,聚焦医学教育目标人群的“undergraduate medical education”“graduate medical education”,以及聚焦教学方法的“coaching”“feedback”“competency-based education”。结论2016年以来,成长型思维应用于医学教育相关研究具有良好的学科关注度,以美国为代表的发达国家在该领域处于领先地位。目前,该领域的研究重点为成长型思维应用于医学教育的教学方法、教学目标和教育心理学,以及其在促进医学生福祉和身心健康方面的作用。在实践层面,芝加哥大学普利兹克医学院应用成长型思维的经验对国内医疗机构开展相关研究具有借鉴价值。
文摘Objective Selective estrogen receptor modulators(SERMs)have demonstrated efficacy in the treatment of hypogonadism in males and male factor infertility.Two SERMs,clomiphene citrate and tamoxifen,are now prescribed for off-label use to treat both conditions in males.However,existing literature compares mixed protocols with active management.We aimed to conduct a meta-analysis to evaluate the effect of clomiphene and tamoxifen versus placebo on natural pregnancy rates.Methods We conducted a comprehensive systematic review of electronic databases:MEDLINE,PubMed/PMC,EMBASE,CINAHL,Cochrane Central Register of Controlled Trials(CENTRAL),Scopus,Google Scholar,and Web of Science.Articles satisfying all selection criteria were analyzed.The primary outcome was the incidence of pregnancy after receiving the treatment.Secondary outcomes included serum follicle-stimulating hormone,luteinizing hormone,and testosterone levels,and sperm count and motility.We calculated the pooled odds ratio,risk ratio,and risk difference to ascertain possible alterations in the direction of the pooled effect size.Results Ten randomized controlled trials were ultimately included and underwent data extraction.Clomiphene citrate and placebo groups had similar pregnancy rates(10.4%and 7.1%,respectively;odds ratio 1.30[95%confidence interval 0.27–6.17];p=0.74).No meta-analysis could be calculated for pregnancy rates in tamoxifen versus placebo groups.Heterogeneity among the studies of both SERMs ranged from low to high.Conclusion Although clomiphene citrate and tamoxifen are often used off-label for the treatment of male infertility secondary to hypogonadism,studies of SERMs in the treatment of idiopathic male factor infertility are limited and heterogenous,preventing this meta-analysis from investigating the efficacy of SERMs on male infertility.The effect of clomiphene citrate or tamoxifen on the pregnancy rate remains uncertain.
基金funded by NIH-NIA R01AG061708 (to PHO)Patrick Grange Memorial Foundation (to PHO)+1 种基金A Long Swim (to PHO)CureSPG4 Foundation (to PHO)。
文摘Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.
基金supported by the NIH grant(RO1 NS118066)the Blazer Foundation(to XJL)。
文摘Axonal degeneration underlies many debilitating diseases including hereditary spastic paraplegia(HSP),a genetically and clinically diverse group of disorders characterized by spasticity and weakness of the lower extremities.HSP is one significant cause of chronic neurodisability due to the lack of effective treatments and a wide range of onset ages from early childhood to 70 years.
