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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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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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Neuroprotection by resveratrol-glucuronide and quercetin-glucuronide via binding to polyphenol-and glycosaminoglycan-binding sites in the laminin receptor

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Neural Regeneration Research 2025年第3期20卷 819-820页

作者： Rayudu Gopalakrishna Jennifer Aguilar emily Lee William J.mack Department of Integrative Anatomical Sciences Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA Department of Neurological Surgery Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCAUSA

The dietary polyphenolic compounds resveratrol and quercetin prevent neurodegenerative diseases in experimental models;however, they reach the brain only in nanomolar concentrations in the glucuronidated and sulfated ... 详细信息

关键词： resveratrol molar dated

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Polyethylene glycol fusion repair of severed rat sciatic nerves reestablishes axonal continuity and reorganizes sensory terminal fields in the spinal cord

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Neural Regeneration Research 2025年第7期20卷 2095-2107页

作者： emily A.Hibbard Liwen Zhou Cathy Z.Yang Karthik Venkudusamy Yessenia montoya Alexa Olivarez George D.Bittner Dale R.Sengelaub Program in Neuroscience Indiana UniversityBloomingtonINUSA Department of Neuroscience University of Texas at AustinAustinTXUSA

Peripheral nerve injuries result in the rapid degeneration of distal nerve segments and immediate loss of motor and sensory functions;behavioral recovery is typically *** used a plasmalemmal fusogen,polyethylene glycol(PEG),to immediately fuse closely apposed open ends of severed proximal and distal axons in rat sciatic *** have previously reported that sciatic nerve axons repaired by PEG-fusion do not undergo Wallerian degeneration,and PEG-fused animals exhibit rapid(within 2–6 weeks)and extensive locomotor ***,our previous report showed that PEG-fusion of severed sciatic motor axons was non-specific,i.e.,spinal motoneurons in PEG-fused animals were found to project to appropriate as well as inappropriate target *** this study,we examined the consequences of PEG-fusion for sensory axons of the sciatic *** adult male and female rats(Sprague–Dawley)received either a unilateral single cut or ablation injury to the sciatic nerve and subsequent repair with or without(Negative Control)the application of *** action potentials recorded immediately after PEG-fusion repair confirmed conduction across the injury *** success of PEG-fusion was confirmed through Sciatic Functional Index testing with PEG-fused animals showing improvement in locomotor function beginning at 35 days *** 2–42 days postoperatively,we anterogradely labeled sensory afferents from the dorsal aspect of the hindpaw following bilateral intradermal injection of wheat germ agglutinin conjugated horseradish ***-fusion repair reestablished axonal *** to unoperated animals,labeled sensory afferents ipsilateral to the injury in PEG-fused animals were found in the appropriate area of the dorsal horn,as well as inappropriate mediolateral and rostrocaudal ***,despite having intact peripheral nerves,similar reorganizations of labeled sensory afferents were also observed contralateral to the injury and repa

关键词： axotomy dorsal horn peripheral nerve injury plasticity polyethylene glycol(PEG) sciatic nerve sensory terminals wheat germ agglutinin horseradish peroxidase

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Polyethylene glycol fusion repair of severed sciatic nerves accelerates recovery of nociceptive sensory perceptions in male and female rats of different strains

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Neural Regeneration Research 2025年第9期20卷 2667-2681页

作者： Liwen Zhou Karthik Venkudusamy emily A.Hibbard Yessenia montoya Alexa Olivarez Cathy Z.Yang Adelaide Leung Varun Gokhale Guhan Periyasamy Zeal Pathak Dale R.Sengelaub George D.Bittner Department of Neuroscience University of TexasAustinTXUSA Program in Neuroscience Indiana UniversityBloomingtonINUSA Department of molecular Biosciences University of TexasAustinTXUSA

Successful polyethylene glycol fusion(PEG-fusion)of severed axons following peripheral nerve injuries for PEG-fused axons has been reported to:(1)rapidly restore electrophysiological continuity;(2)prevent distal Wallerian Degeneration and maintain their myelin sheaths;(3)promote primarily motor,voluntary behavioral recoveries as assessed by the Sciatic Functional Index;and,(4)rapidly produce correct and incorrect connections in many possible combinations that produce rapid and extensive recovery of functional peripheral nervous system/central nervous system connections and reflex(e.g.,toe twitch)or voluntary *** preceding companion paper describes sensory terminal field reo rganization following PEG-fusion repair of sciatic nerve transections or ablations;howeve r,sensory behavioral recovery has not been explicitly explored following PEG-fusion *** the current study,we confirmed the success of PEG-fusion surgeries according to criteria(1-3)above and more extensively investigated whether PEG-fusion enhanced mechanical nociceptive recovery following sciatic transection in male and female outbred Sprague-Dawley and inbred Lewis *** nociceptive responses were assessed by measuring withdrawal thresholds using von Frey filaments on the dorsal and midplantar regions of the *** von Frey filament tests were a more reliable method than plantar von Frey filament tests to assess mechanical nociceptive sensitivity following sciatic nerve *** withdrawal thresholds of the sciatic-mediated lateral dorsal region differed significantly across strain but not *** thresholds did not change significantly from baseline in chronic Unoperated and Sham-operated *** sciatic transection,all rats exhibited severe hyposensitivity to stimuli at the lateral dorsal region of the hindpaw ipsilateral to the ***,PEG-fused rats exhibited significantly earlier return to baseline withdrawal thresholds than Negative

关键词： autophagia axotomy collateral sprouting neuropathic pain peripheral nerve repair polyethylene glycol fusion(PEG-fusion) saphenous nerve sensory neurons sex and strain Wallerian degeneration

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Altered physiology of gastrointestinal vagal afferents following neurotrauma

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Neural Regeneration Research 2021年第2期16卷 254-263页

作者： emily N.Blanke Gregory m.Holmes emily m.Besecker Department of Health Sciences Gettysburg CollegeGettysburgPAUSA Department of Neural and Behavioral Sciences Penn State University College of MedicineHersheyPAUSA

The adaptability of the central nervous system has been revealed in several model *** particular interest to central nervous system-injured individuals is the ability for neural components to be modified for regain of *** both types of neurotrauma,traumatic brain injury and spinal cord injury,the primary parasympathetic control to the gastrointestinal tract,the vagus nerve,remains anatomically ***,individuals with traumatic brain injury or spinal cord injury are highly susceptible to gastrointestinal *** gastrointestinal dysfunctions attribute to higher morbidity and mortality following traumatic brain injury and spinal cord *** the vagal efferent output remains capable of eliciting motor responses following injury,evidence suggests impairment of the vagal *** sensory input drives motor output,this review will discuss the normal and altered anatomy and physiology of the gastrointestinal vagal afferents to better understand the contributions of vagal afferent plasticity following neurotrauma.

关键词： gastrointestinal functions microbiome neurotrauma nodose ganglia sensory neuropathy spinal cord injury traumatic brain injury vagal afferents visceral reflexes

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Global Change in Agricultural Flash Drought over the 21st Century

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Advances in Atmospheric Sciences 2024年第2期41卷 209-220,I0002-I0019页

作者： emily BLACK National Centre for Atmospheric Science Fairbairn House71-75 Clarendon RoadLeedsLS29PHU.K Department of meteorology Brian Hoskins BuildingUniversity of ReadingWhiteknights campusReadingRG66ETU.K.

Agricultural flash droughts are high-impact phenomena, characterized by rapid soil moisture dry down. The ensuing dry conditions can persist for weeks to months, with detrimental effects on natural ecosystems and crop cultivation. Increases in the frequency of these rare events in a future warmer climate would have significant societal impact. This study uses an ensemble of 10 Coupled model Intercomparison Project(CmIP) models to investigate the projected change in agricultural flash drought during the 21st century. Comparison across geographical regions and climatic zones indicates that individual events are preceded by anomalously low relative humidity and precipitation, with long-term trends governed by changes in temperature, relative humidity, and soil moisture. As a result of these processes, the frequency of both upperlevel and root-zone flash drought is projected to more than double in the mid-and high latitudes over the 21st century, with hot spots developing in the temperate regions of Europe, and humid regions of South America, Europe, and southern Africa.

关键词： flash drought climate change soil moisture agricultural drought CmIP

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A multicriteria Decision Analytic Approach to Systems Resilience

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International Journal of Disaster Risk Science 2024年第5期15卷 657-672页

作者： Jeff rey m.Keisler emily m.Wells Igor Linkov University of massachusetts Boston US Army Engineer Research and Development Center University of Florida

This article develops a novel decision-oriented framework that strategically deconstructs systems resilience in a way that focuses on systems' design, capabilities, and management. The framework helps evaluate and compare how system design choices impact system resilience. First, we propose a resilience score based on a piecewise linear approximation to a resilience curve. Using multicriteria decision analysis principles, we score system design alternatives in terms of system-specific capabilities. We estimate the relevance of these capabilities to resilience curve parameters associated with resilience ***, we interpret the derivatives of resilience with respect to the curve parameter values as the leverage of these parameters. Using multiple levels of weighted sums of the scores, we calculate the first order impact of system design choices first on a proxy for the generic resilience parameters and then on resilience, which allows situational characteristics to be incorporated in their natural terminology while mapping their impact on resilience with a traceable logic. We illustrate the approach by using existing materials to develop an example comparing engineered designs for minimizing post-wildfire flood impacts.

关键词： Decision analysis multicriteria decision analysis Resilience System design

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Aberrant Th2 inflammation drives dysfunction of alveolar macrophages and susceptibility to bacterial pneumonia

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Cellular & molecular Immunology 2018年第5期15卷 480-492页

作者： emily K moser Natania S Field Paula m Oliver Cell Pathology Division Children’s Hospital of PhiladelphiaPhiladelphiaPA 19104USA Cell and molecular Biology Program Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104USA Department of Pathology and Laboratory medicine University of PennsylvaniaPhiladelphiaPA 19104USA

The ubiquitin ligase,Itch,is required to prevent autoinflammatory disease in mice and ***-deficient mice develop lethal pulmonary inflammation characterized by the production of Th2 cytokines(for example,interleukin-4(IL-4));however,the contribution of Itch to immune defense against respiratory pathogens has not been *** found that Itch-deficient mice were highly susceptible to intranasal infection with the respiratory pathogen Klebsiella *** Itch-deficient mice exhibited increased immune cell infiltration,cytokine levels and bacterial burden in the respiratory tract compared with control ***,numbers of resident alveolar macrophages were reduced in the lungs from Itch-deficient mice both before and after *** levels of Th2 cytokines in the respiratory tract correlated with deceased alveolar macrophages,and genetic ablation of IL-4 restored alveolar macrophages and host defense to *** in Itch-deficient mice,suggesting that loss of alveolar macrophages occurred as a consequence of Th2 *** transfer of Itch−/−CD4+T cells into Rag−/−mice was sufficient to drive reduction in numbers of Itch-replete alveolar ***,we found that Stat6 signaling downstream of the IL-4 receptor directly reduced fitness of alveolar macrophages when these cells were exposed to the Itch−/−inflamed respiratory *** data suggest that Th2 inflammation directly impairs alveolar macrophage fitness in Itch−/−mice,and elucidate a previously unappreciated link between Th2 cells,alveolar macrophages and susceptibility to bacterial infection.

关键词： alveolar macrophage bacterial pneumonia Itch Th2 cell

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Toward three-dimensional in vitro models to study neurovascular unit functions in health and disease

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Neural Regeneration Research 2021年第11期16卷 2132-2140页

作者： Tara m.Caffrey emily B.Button Jerome Robert Djavad mowafaghian Center for Brain Health University of British ColumbiaVancouverBCCanada Department of Pathology University of British ColumbiaVancouverBCCanada Institute of Clinical Chemistry University Hospital of ZurichZurichSwitzerland

The high metabolic demands of the brain require an efficient vascular system to be coupled with neural activity to supply adequate nutrients and *** supply is coordinated by the action of neurons,glial and vascular cells,known collectively as the neurovascular unit,which temporally and spatially regulate local cerebral blood flow through a process known as neurovascular *** many neurodegenerative diseases,changes in functions of the neurovascular unit not only impair neurovascular coupling but also permeability of the blood-brain barrier,cerebral blood flow and clearance of waste from the *** order to study disease mechanisms,we need improved physiologicallyrelevant human models of the neurovascular *** towards modeling the cellular complexity of the neurovascular unit in vitro have been made using stem-cell derived organoids and more recently,vascularized organoids,enabling intricate studies of non-cell autonomous *** and design innovations in microfluidic devices and tissue engineering are progressing our ability to interrogate the *** advanced models are being used to gain a better understanding of neurodegenerative disease processes and potential *** innovation is required to build more physiologically-relevant models of the neurovascular unit encompassing both the cellular complexity and designed features to interrogate neurovascular unit functionality.

关键词： Alzheimer’s disease cerebrovasculature in vitro model neurodegeneration neurovascular unit

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