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Developmental regulation of neuronal gene expression by elongator complex protein 1 dosage

Journal of Genetics and Genomics 2022年第7期49卷 654-665页

作者： elisabetta Morini Dadi Gao emily M.Logan Monica Salani Aram J.Krauson Anil Chekuri Yei-Tsung Chen Ashok Ragavendran Probir Chakravarty Serkan erdin Alexei Stortchevoi Jesper Q.Svejstrup michael e.talkowski Susan A.Slaugenhaupt Center for Genomic Medicine Massachusetts General Hospital Research InstituteBostonMAUSA Department of Neurology Massachusetts General Hospital Research Institute and Harvard Medical SchoolBostonMAUSA Program in Medical and Population Genetics and Stanley Center for Psychiatric Research Broad Institute of Harvard and MITCambridgeMAUSA Department of Life Sciences and Institute of Genome Sciences National Yang Ming Chiao Tung UniversityTaiwanChina Bioinformatics and Biostatistics The Francis Crick InstituteLondonUK Mechanisms of Transcription Laboratory The Francis Crick InstituteLondonUK Department of Cellular and Molecular Medicine Panum InstituteUniversity of CopenhagenCopenhagenDenmark

Familial dysautonomia(FD), a hereditary sensory and autonomic neuropathy, is caused by a mutation in the elongator complex protein 1(eLP1) gene that leads to a tissue-specific reduction of eLP1 protein. Our work to generate a phenotypic mouse model for FD headed to the discovery that homozygous deletion of the mouse elp1 gene leads to embryonic lethality prior to mid-gestation. Given that FD is caused by a reduction, not loss, of eLP1, we generated two new mouse models by introducing different copy numbers of the human FD eLP1 transgene into the elp1 knockout mouse(elp1) and observed that human eLP1 expression rescues embryonic development in a dose-dependent manner. We then conducted a comprehensive transcriptome analysis in mouse embryos to identify genes and pathways whose expression correlates with the amount of eLP1. We found that eLP1 is essential for the expression of genes responsible for nervous system development. Further, gene length analysis of the differentially expressed genes showed that the loss of elp1 mainly impacts the expression of long genes and that by gradually restoring elongator, their expression is progressively rescued. Finally, through evaluation of co-expression modules, we identified gene sets with unique expression patterns that depended on eLP1 expression.

关键词： eLP1 elongator Transcriptional elongation Familial dysautonomia Neurodevelopmental disease

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NeCAB family of neuronal calcium-binding proteins in health and disease

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Neural Regeneration Research 2025年第5期20卷 1236-1243页

作者： Diones Bueno michael K.e.Schafer Sudena Wang michael J.Schmeisser Axel Methner Institute for Molecular Medicine University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Department of Anesthesiology University Medical Center of the Johannes Gutenberg-UniversityMainzGermany Institute of Anatomy University Medical Center of the Johannes Gutenberg-UniversityMainzGermany

The N-terminal eF-hand calcium-binding proteins 1–3(NeCAB1–3) constitute a family of predominantly neuronal proteins characterized by the presence of at least one eF-hand calcium-binding domain and a functionally less well characterized C-terminal antibiotic biosynthesis monooxygenase domain. All three family members were initially discovered due to their interactions with other proteins. NeCAB1 associates with synaptotagmin-1, a critical neuronal protein involved in membrane trafficking and synaptic vesicle exocytosis. NeCAB2 interacts with predominantly striatal G-protein-coupled receptors, while NeCAB3 partners with amyloid-β A4 precursor protein-binding family A members 2 and 3, key regulators of amyloid-β production. This demonstrates the capacity of the family for interactions with various classes of proteins. NeCAB proteins exhibit distinct subcellular localizations: NeCAB1 is found in the nucleus and cytosol, NeCAB2 resides in endosomes and the plasma membrane, and NeCAB3 is present in the endoplasmic reticulum and Golgi apparatus. The antibiotic biosynthesis monooxygenase domain, an evolutionarily ancient component, is akin to atypical heme oxygenases in prokaryotes but is not wellcharacterized in vertebrates. Prokaryotic antibiotic biosynthesis monooxygenase domains typically form dimers, suggesting that calcium-mediated conformational changes in NeCAB proteins may induce antibiotic biosynthesis monooxygenase domain dimerization, potentially activating some enzymatic properties. However, the substrate for this enzymatic activity remains uncertain. Alternatively, calcium-mediated conformational changes might influence protein interactions or the subcellular localization of NeCAB proteins by controlling the availability of protein–protein interaction domains situated between the eF hands and the antibiotic biosynthesis monooxygenase domain. This review summarizes what is known about genomic organization, tissue expression, intracellular localization, interac

关键词： calcium eF hand mitochondria nervous system signal transduction

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Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease

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Neural Regeneration Research 2025年第7期20卷 1981-1988页

作者： Shan Ping Yu emily Choi michael QJiang Ling Wei Department of Anesthesiology Emory University School of MedicineAtlantaGAUSA Center for Visual and Neurocognitive Rehabilitation Atlanta Veterans Affairs Medical CenterDecaturGAUSA

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same *** comorbidity of the two neurological disorders represents a grave health threat to older *** review presents a brief background of the development of novel concepts and their clinical *** activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal *** ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic *** Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute ***,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death *** on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic *** N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic *** stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time *** is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related

关键词： Ca^(2+)hypothesis cognitive deficits hyperactivity late-onset Alzheimer's disease neurodegeneration N-methyl-D-aspartate receptors N-methyl-D-aspartate receptor subunits pathogenesis preventive treatment

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Oligodendrocyte pathology in fetal alcohol spectrum disorders

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Neural Regeneration Research 2022年第3期17卷 497-502页

作者： Nune Darbinian michael e.Selzer Center for Neural Repair and Rehabilitation(Shriners Hospitals Pediatric Research Center) Lewis Katz School of Medicine at Temple UniversityPhiladelphiaPAUSA

The pathology of fetal alcohol syndrome and the less severe fetal alcohol spectrum disorders includes brain *** studies have shed light on the molecular mechanisms underlying these white matter *** models of fetal alcohol syndrome and human studies have shown suppressed oligodendrocyte differentiation and apoptosis of oligodendrocyte precursor *** exposure led to reduced expression of myelin basic protein and delayed myelin basic protein expression in rat and mouse models of fetal alcohol syndrome and in human histopathological *** studies have reported increased expression of many chemokines in dysmyelinating disorders in central nervous system,including multiple sclerosis and fetal alcohol *** ethanol exposure reduced levels of the neuroprotective insulin-like growth factor-1 in fetal and maternal sheep and in human fetal brain tissues,while ethanol increased the expression of tumor necrosis factor α in mouse and human *** matter lesions have been induced in the developing sheep brain by alcohol exposure in early *** fetal alcohol syndrome models have shown reduced axon diameters,with thinner myelin sheaths,as well as reduced numbers of oligodendrocytes,which were also morphologically aberrant *** of markers for mature myelination,including myelin basic protein,also were *** accumulating knowledge concerning the mechanisms of ethanol-induced dysmyelination could lead to the development of strategies to prevent dysmyelination in children exposed to ethanol during fetal *** studies using fetal oligodendrocyte-and oligodendrocyte precursor cell-derived exosomes isolated from the mother's blood may identify biomarkers for fetal alcohol syndrome and even implicate epigenetic changes in early development that affect oligodendrocyte precursor cell and oligodendrocyte function in *** combining various imaging modalities with mo

关键词： alcohol development dysmyelination ethanol fetal alcohol syndrome fetal brain myelin basic protein neurodegeneration oligodendrocyte injury oligodendrocyte precursor cells

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ecological restoration for sustainable development in China

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National Science Review 2023年第7期10卷 60-71页

作者： Bojie Fu Yanxu Liu michael e.Meadows State Key Laboratory of Urban and Regional ecology Research Center for Eco-Environmental Sciences Chinese Academy of Sciences State Key Laboratory of earth Surface Processes and Resource ecology Faculty of Geographical Science Beijing Normal University School of Geographic and Oceanographic Sciences Nanjing University College of Geography and environmental Sciences Zhejiang Normal University Department of environmental and Geographical Science University of Cape Town

Facing the need for transdisciplinary research to promote ecological restoration that achieves both social and ecological benefits,research on past restoration efforts that have directly or indirectly contributed to regional or national sustainable development warrants *** China as an example,in this review,we address three basic research questions that can be summarized as follows:ecological restoration—of what,for whom and to what purpose?Accordingly,a landscape pattern—ecosystem service—sustainable development’ co-evolutionary framework is proposed here to describe landscape-scale ecological restoration and its impact on landscape patterns and ecological processes,ecosystem services for human well-being,sustainable livelihoods and socioeconomic *** the strategic pattern of national ecological security to the pattern of major projects to protect and restore major national ecosystems,the spatial pattern of China’ s ecological restoration is more geographically *** major function-oriented zoning to systematic ecological protection and restoration,and for the purpose of achieving the Beautiful China Initiative,there are three stages of ecosystem services management:classification,synergy and integration,*** difference in geographic processes should be considered in the key re quirements of ecological restoration for China’ s five national strategies for regional sustainable-development *** understanding of the relationship between humans and nature in different geographical contexts is a scientific prerequisite to support policymaking related to ecological *** promote greater harmony between humans and nature,we propose four important research directions:(ⅰ) understanding coupling processes among key components,(ⅱ) identifying ecosystem service flows,(ⅲ) evaluating social-ecological benefits and(ⅳ) supporting adaptive management for regional sustainable development.

关键词： social-ecological system landscape pattern ecological process ecosystem services sustainable livelihoods policymaking

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Role of axon resealing in retrograde neuronal death and regeneration after spinal cord injury

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Neural Regeneration Research 2019年第3期14卷 399-404页

作者： William Rodemer michael e.Selzer Shriners Hospital Pediatric Research (Center Center for Neural Repair and Rehabilitation) Department of Neurology the Lewis Katz School of Medicine at Temple University

Spinal cord injury leads to persistent behavioral deficits because mammalian central nervous system axons fail to regenerate. A neuron's response to axon injury results from a complex interplay of neuron-intrinsic and environmental factors. The contribution of axotomy to the death of neurons in spinal cord injury is controversial because very remote axotomy is unlikely to result in neuronal death, whereas death of neurons near an injury may reflect environmental factors such as ischemia and inflammation. In lampreys, axotomy due to spinal cord injury results in delayed apoptosis of spinal-projecting neurons in the brain, beyond the extent of these environmental factors. This retrograde apoptosis correlates with delayed resealing of the axon, and can be reversed by inducing rapid membrane resealing with polyethylene glycol. Studies in mammals also suggest that polyethylene glycol may be neuroprotective, although the mechanism(s) remain unclear. This review examines the early, mechanical, responses to axon injury in both mammals and lampreys, and the potential of polyethylene glycol to reduce injury-induced pathology. Identifying the mechanisms underlying a neuron's response to axotomy will potentially reveal new therapeutic targets to enhance regeneration and functional recovery in humans with spinal cord injury.

关键词： axon resealing regeneration retrograde neuronal death spinal cord injury sea lamprey PeG mitochondrial dysfunction calcium signaling

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Heterogeneity in the regenerative abilities of central nervous system axons within species: why do some neurons regenerate better than others?

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Neural Regeneration Research 2020年第6期15卷 996-1005页

作者： William Rodemer Jianli Hu michael e.Selzer michael I.Shifman Shriners Hospitals Pediatric Research Center(Center for Neural Repair and Rehabilitation) the Lewis Katz School of Medicine at Temple UniversityPhiladelphiaPAUSA Department of Neurology the Lewis Katz School of Medicine at Temple UniversityPhiladelphiaPAUSA

Some neurons,especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system(CNS)regenerate after axotomy,while most mammalian CNS neurons fail to *** is an emerging consensus that neurons have different intrinsic regenerative capabilities,which theoretically could be manipulated therapeutically to improve ***-based comparisons between"good regenerating"and"bad regenerating"neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to *** least in part,this reflects the great diversity of cells in the mammalian *** mammalian nervous system imposes several methodical ***,the small sizes and large numbers of neurons in the CNS make it very difficult to distinguish regenerating neurons from non-regenerating ***,the lack of identifiable neurons makes it impossible to correlate biochemical changes in a neuron with axonal damage of the same neuron,and therefore,to dissect the molecular mechanisms of regeneration on the level of single *** review will survey the reported responses to axon injury and the determinants of axon regeneration,emphasizing non-mammalian model organisms,which are often under-utilized,but in which the data are especially easy to interpret.

关键词： axonal regeneration identifiable neurons intrinsic factors lamprey Mauthner cell Müller cell neuronal death non-mammalian model organisms spinal cord injury zebrafish

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Measurements of a 2-Stage Axial Turbine with Shrouded Rotor Cavities

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Journal of Thermal Science 2004年第4期13卷 310-314页

作者： Dieter e. BOHN Franz KReITMeIeR michael SeLL Institute of Steam and Gas Turbines Technical University of Aachen GermanyALSTOM Power CH-5401 Baden SwitzerlandALSTOM Power CH-5401 Baden Switzerland

This paper presents preliminary measurements of a 2-stage axial turbine with shrouded rotor cavities. The research facility and measurement techniques are reported. The flow field at both inlet and outlet was measured using 5-hole probes as well as temperature probes. The measurement results indicate that the inlet flow field is periodical in the tangential direction due to the influence of the first-stator leading-edge. The horse-shoe vortexes cause substantial flow blockage and turbulence near the endwall. Unsteady measurements of the rotor radial tip clearance show that one of the second-rotor blades has a little bigger clearance than the others.

关键词： axial turbine shrouded rotor measurement.

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The structure of natural microbial enemy-victim networks

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ecological Processes 2013年第1期2卷 130-138页

作者： Timothée Poisot Manon Lounnas michael e Hochberg UniversitéMontpellier II Institut des Sciences de l'EvolutionUMR 5554Place Eugène Bataillon34095Montpellier CEDEX 05France Département de biologie chimie et géographieUniversitédu QuébecàRimouski300 Allée des UrsulinesRimouskiQC G5L 3A1Canada Québec Centre for Biodiversity Sciences Stewart Biological Sciences Building1205 Dr.Penfield AvenueMontréalQC H3A 1B1Canada Santa Fe Institute 1399 Hyde Park RoadSanta FeNM 87501USA MIVeGeC UMR IRD 224 CNRS5 290 UM1-UM2911Avenue AgropolisBP 6450134394 Montpellier Cedex 5France

Introduction:The persistence of generalists and specialists is a topical question in community ecology and results from both ecological and evolutionary *** fine taxonomical scales,ecological specialisation,*** preferentially exploiting a subset of available habitats,is thought to be a driver promoting niche *** is not clear,however,how different mechanisms interact to shape specialist-generalist ***:We reconstruct the structure of five bacteria-phage networks from soil isolates,and perform an analysis of the relationships between host phylogenetic diversity,parasite specialism,and parasite ***:We show that the co-occurrence of species on a continuum of specialism/generalism is influenced by niche overlap,phage impact on bacterial hosts,and host phylogenetic *** addition,using a null-model analysis we show that infection strategies of the phages have more explanatory power than bacterial defenses on key structural features of these antagonistic ***:We report that generalists have more impact on their hosts than specialists,even when the phylogenetic heterogeneity of hosts is controlled *** discuss our results in the light of their implications for the evolution of biotic interactions.

关键词： Pseudomonas fluorescens Bipartite networks Specialisation Phylogeny Food webs Species coexistence

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Forecast Hesitancy: Why are People Reluctant to Believe, Accept, or Respond to Various Weather, Water, and Climate Hazard-Related Forecasts?

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International Journal of Disaster Risk Science 2021年第4期12卷 600-609页

作者： michael H.Glantz Gregory e.Pierce Consortium for Capacity Building(CCB) Institute for Arctic and Alpine Research(INSTAAR)University of ColoradoBoulderCO80301USA

Current discussions of the social phenomenon of“vaccine hesitancy”with regard to Covid-19 provide an opportunity to use hesitancy as a means to shift thinking about untimely and delayed responses to forecasts of hydrometeorological ***,that is,provides a paradigm through which such regrettably delayed responses to hydromet hazards might be better understood and effectively *** exaggeration,just about every hydromet event provides an example of how hesitancy hinders individual,community,and national government risk-reducing preventive and mitigative responses to forecasts of foreseeable,relatively near-term climate,water,or weather *** for such hesitancy(for vaccine and forecast use alike)include—among others—lack of trust in the science,lack of confidence in government,and persistent concern about the uncertainties that surround forecasting—both meteorological and public *** such,a better understanding of the causes that lead to individual and group hesitancy can better inform hydromet forecasters and affected communities about ways in which beneficial actions in response to timely forecasts are often *** better understanding will facilitate,where necessary,targeted interventions to enhance the societal value of forecasting by reducing this long-observed challenge of“forecast hesitancy.”First,this article focuses on incidents of“vaccine hesitancy”that,for various reasons,people around the world are even now experiencing with regard to several now-available,and confirmed efficacious,Covid-19 *** of such incidents of indecisiveness first increased dramatically over the first few months of 2021,despite the strong scientific confidence that vaccination would significantly lower personal risk of contracting as well as spreading the ***,the notion of forecast hesitancy with regard to hydrometeorological hazards is discussed.

关键词： Disaster risk reduction Forecast Forecast hesitancy Hesitancy Hydromet hazards Vaccine hesitancy

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