The activity in sensory cortices and the prefrontal cortex （PFC） throughout the delay interval of working memory （WM） tasks reflect two aspects of WM-quality and quantity, respectively. The delay activity in senso...The activity in sensory cortices and the prefrontal cortex （PFC） throughout the delay interval of working memory （WM） tasks reflect two aspects of WM-quality and quantity, respectively. The delay activity in sensory cortices is fine-tuned to sensory information and forms the neural basis of the precision of WM storage, while the delay activity in the PFC appears to represent behavioral goals and filters out irrelevant distractions, forming the neural basis of the quantity of task-relevant information in WM. The PFC and sensory cortices interact through different frequency bands of neuronal oscillation （theta, alpha, and gamma） to fulfill goal-directed behaviors.展开更多
Since the calcium channel blocker （CCB） has become one of the most prescribed agents for antihypertensive monotherapy in the world, this brief review will focus on the recent research and development of the dihydrop...Since the calcium channel blocker （CCB） has become one of the most prescribed agents for antihypertensive monotherapy in the world, this brief review will focus on the recent research and development of the dihydropyridine （DHP） CCB, addressing pharmacological mecha- nisms for the clinical efficacy of the third and fourth generations of the DHP CCBs, especially on their possible central mechanisms underlying lowering blood pressure.展开更多
BACKGROUND Recent studies suggest that traumatic brain injury(TBI)is a risk factor for subsequent ischemic stroke,even years after the initial insult.The mechanisms of the association remain unclear.The presence of tr...BACKGROUND Recent studies suggest that traumatic brain injury(TBI)is a risk factor for subsequent ischemic stroke,even years after the initial insult.The mechanisms of the association remain unclear.The presence of traumatic subarachnoid hemorrhage(t SAH)may mediate the effect of TBI on long-term stroke risk,as it has previously been linked to short-term vasospasm and delayed cerebral ischemia.METHODS Using administrative claims data,we conducted a retrospective cohort study of acute care hospitalizations.Patients discharged with a first-recorded diagnosis of t SAH were followed for a primary diagnosis of stroke.They were matched to patients with TBI but not t SAH.Cox proportional hazards modeling was used to assess the association between t SAH and stroke while adjusting for covariates.RESULTS:We identified 40 908 patients with TBI(20 454 patients with t SAH)who were followed for a mean of 4.3+1.8 years.A total of 531 had an ischemic stroke after discharge.There was no significant difference in stroke risk between those with t SAH(1.79%;95%confidence interval[CI]1.54%-2.08%)versus without t SAH(2.12%;95%CI 1.83%-2.44%).The same pattern was found in adjusted analyses even when the group was stratified by age-group or by proxies of TBI severity.CONCLU-SIONS:Our findings do not support a role of t SAH in mediating the association between TBI and protracted stroke risk.Further study is required to elucidate the mechanisms of long-term increased stroke risk after TBI.展开更多
Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebr...Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.展开更多
Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyl...Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril tangles.Currently,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).展开更多
There are roughly 282,000 individuals living with spinal cord injury in the United States alone（National Spinal Cord Injury Statistical Center,Birmingham,AL,USA）.Spinal cord injury often results in permanent functio...There are roughly 282,000 individuals living with spinal cord injury in the United States alone（National Spinal Cord Injury Statistical Center,Birmingham,AL,USA）.Spinal cord injury often results in permanent functional impairments with only a limited capacity for spontaneous recovery.For the return of motor function,such as locomotion or hand and arm dexterity,展开更多
Background Although previous studies have examined the effects of exercise training on other International Classification of Functioning,Disability and Health(ICF)component levels in persons with multiple sclerosis(MS...Background Although previous studies have examined the effects of exercise training on other International Classification of Functioning,Disability and Health(ICF)component levels in persons with multiple sclerosis(MS),the effects of exercise training on participation remain unclear.The objectives of this review were to:(1)characterize systematically the use of outcome measures that capture participation in exercise training studies;(2)quantify the effect of exercise training on participation in persons with MS.Methods A search of 6 electronic databases(CINAHL,SPORTDiscuss,Embase,MEDLINE,Cochrane Central,and Scopus)was conducted to identify controlled and noncontrolled trials involving exercise training and participation in persons with MS.Search strings were built from Medical Subject Headings and CINAHL headings.ICF linking rules were used to identify participation chapters and categories captured.Meta-analysis was used to quantify the effect of exercise training on participation in randomized controlled trials comparing exercise effects to no intervention/usual care.Results We included 49 articles involving controlled and noncontrolled exercise trials in the systematic review of outcome measures.We captured 16 different outcome measures that captured all 9 participation chapters and identified 89 unique participation categories.Across these 16 outcome measures,mobility was the most commonly represented participation chapter,with 108 items.A subsample of 23 randomized controlled trials was included in the meta-analysis.An overall effect of 0.60(standard error=0.12,95%confidence interval:0.36-0.84,z=4.9,p<0.001)was calculated,indicating a moderate,positive effect of exercise training on participation.Conclusion The current review provides information that can be used to guide the selection of outcome measures that capture participation in studies of exercise training in persons with MS.Exercise training has a positive effect on outcomes that capture participation,providing further evidence for the role of exercise training in promoting and maintaining engagement in everyday life.展开更多
Therapeutic intervention for spinal cord injury is limited,with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training.As compared with learning novel com...Therapeutic intervention for spinal cord injury is limited,with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training.As compared with learning novel compensatory strategies,rehabilitation focuses on resto ring movements lost to injury.Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning,or if it engages previously trained motor circuits without requiring novel learning remains an open question.In this study,mice we re randomly assigned to receive intrape ritoneal injection with the pan-nicotinic,non-competitive antagonist mecamylamine and the nicotinicα7 subunit selective antagonist methyllycaconitine citrate salt or vehicle(normal saline)prior to motor learning assays,then randomly reassigned after motor learning for rehabilitation study post-injury.Ce rvical spinal co rd dorsal column lesion was used as a model of in complete injury.Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury.Our findings indicate that critical diffe rences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.展开更多
The functional regeneration of damaged axons and severed connections in the mature central nervous sys- tem （CNS） remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regene...The functional regeneration of damaged axons and severed connections in the mature central nervous sys- tem （CNS） remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regeneration for two major reasons, one, because the ac- tivity of cell-intrinsic mechanisms that drive axon growth during development is low- and often further suppressed after an injury - and two, because certain molecules that are part of mature extracellular matrix and myelin act as strong inhibitors of axon growth. Genetic removal of growth inhibitory molecules can increase axon sprouting, but is not sufficient to enable long-range axon growth. Since axon growth is robust during early developmental stages, it has long been hypothesized that mature injured neurons may be ＂reprogrammed＂ to the earlier growth state by re-activation of the intracellular growth signaling cascades that drive axon elongation in the developing fetus.展开更多
Background: Neuroscience can assist clinical understanding and therapy by finding neurobiological markers for mental illness symptoms. Objectives: To quantify biomarkers for schizophrenia and schizoaffective disorder ...Background: Neuroscience can assist clinical understanding and therapy by finding neurobiological markers for mental illness symptoms. Objectives: To quantify biomarkers for schizophrenia and schizoaffective disorder and relate these to discrete symptoms of psychosis. Methods: Within a case-control design with multiple exclusion criteria to exclude organic causes and confounding variables, 67 DSM IV-R diagnosed and 67 control participants from a defined hospital, clinic and community catchment area were investigated for candidate markers. Participants underwent protocol-based diagnostic-checking and symptom rating via Brief Psychiatric Rating Scale and Positive and Negative Syndrome Scale, functional-rating scales, biological sample-collection and sensory-processing assessment. Blood and urine samples were analysed for monoamine neurotransmitters, their metabolites, vitamin cofactors and intermediate-substances related to oxidative stress and metabolism of monoamines. Neurocognitive assessment of visual and auditory processing was conducted at both peripheral and central levels. Biomarkers were defined by Receiver Operating Curve (ROC) analysis. Spearman’s analysis explored correlations between discrete symptoms and the biomarkers. Results: Receiver Operating Curve (ROC) analysis identified twenty-one biomarkers: elevated urinary dopamine, noradrenaline, adrenaline and hydroxy pyrroline-2-one as a marker of oxidative stress. Other biomarkers were deficits in vitamins D, B6 and folate, elevation of serum B12 and free serum copper to zinc ratio, along with deficits in dichotic listening, distance vision, visual and auditory speed of processing, visual and auditory working memory and six middle ear acoustic reflex parameters. Discrete symptoms such as delusions, hostility, suicidality and auditory hallucinations were biomarker-defined and symptom biomarker correlations assumed an understandable pattern in terms of the catecholamines and their relationship to biochemistry, brain function and disconnectivity. Conclusions: In the absence of a full diagnosis, biomarker-symptom-signatures inform psychiatry about the structure of psychosis and provide an understandable pattern that points in the direction of a new neurobiological system of symptom-formation and treatment.展开更多
Arabidopsis MSI1 has fundamental functions in plant development. MSI1 is a subunit of Polycomb group protein complexes and Chromatin assembly factor 1, and it interacts with the Retinoblastoma-related protein 1. Alter...Arabidopsis MSI1 has fundamental functions in plant development. MSI1 is a subunit of Polycomb group protein complexes and Chromatin assembly factor 1, and it interacts with the Retinoblastoma-related protein 1. Altered levels of MSI1 result in pleiotropic phenotypes, reflecting the complexity of MSI1 protein functions. In order to uncover additional functions of MSI1, we performed transcriptional profiling of wild-type and plants with highly reduced MSI1 levels （msil-cs）. Surprisingly, the known functions of MSI1 could only account for a minor part of the transcriptional changes in msil-cs plants. One of the most striking unexpected observations was the up-regulation of a subset of ABA-responsive genes eliciting the response to drought and salt stress. We report that MSI1 can bind to the chromatin of the drought-inducible downstream target RD20 and suggest a new role for MSI1 in the negative regulation of the Arabidopsis drought-stress response.展开更多
While early investigations into the physiological effects of spaceflight suggest the body’s ability to reversibly adapt,the corresponding effects of long-term spaceflight(>6months)aremuch less conclusive.Prolonged...While early investigations into the physiological effects of spaceflight suggest the body’s ability to reversibly adapt,the corresponding effects of long-term spaceflight(>6months)aremuch less conclusive.Prolonged exposure to microgravity and radiation yields profound effects on the cardiovascular system,including a massive cephalad fluid translocation and altered arterial pressure,which attenuate blood pressure regulatory mechanisms and increase cardiac output.Also,central venous pressure decreases as a result of the loss of venous compression.The stimulation of baroreceptors by the cephalad shift results in an approximately 10%–15%reduction in plasma volume,with fluid translocating from the vascular lumen to the interstitium.Despite possible increases in cardiac workload,myocyte atrophy and notable,yet unexplained,alterations in hematocrit have been observed.Atrophy is postulated to result from shunting of protein synthesis from the endoplasmic reticulum to the mitochondria via mortalin-mediated action.While data are scarce regarding their causative agents,arrhythmias have been frequently reported,albeit sublethal,during both Russian and American expeditions,with QT interval prolongation observed in long,but not short duration,spaceflight.Exposure of the heart to the proton and heavy ion radiation of deep space has also been shown to result in coronary artery degeneration,aortic stiffness,carotid intima thickening via collagen-mediated action,accelerated atherosclerosis,and induction of a pro-inflammatory state.Upon return,long-term spaceflight frequently results in orthostatic intolerance and altered sympathetic responses,which can prove hazardous should any rapidmobilization or evacuation be required,and indicates that these cardiac risks should be especially monitored for future missions.展开更多
Tyrosine hydroxylase （TH） is the rate-limiting enzyme in catecholamine biosynthesis and its gene proximal promoter （〈 1 kb upstream from the transcription start site） is essential for regulating transcription in ...Tyrosine hydroxylase （TH） is the rate-limiting enzyme in catecholamine biosynthesis and its gene proximal promoter （〈 1 kb upstream from the transcription start site） is essential for regulating transcription in both the developing and adult nervous systems. Several putative regulatory elements within the TH proximal promoter have been reported, but evolutionary conservation of these dements has not been thoroughly investigated. Since many vertebrate species are used to model development, function and disorders of human catecholaminergic neurons, identifying evolutionarily conserved transcription regulatory mechanisms is a high priority. In this study, we align TH proximal promoter nucleotide sequences from several vertebrate species to identify evolutionarUy conserved motifs. This analysis identified three elements （a TATA box, cyclic AMP response element （CRE） and a 5＇-GGTGG-3＇ site） that constitute the core of an ancient vertebrate TH promoter. Focusing on only eutherian mammals, two regions of high conservation within the proximal promoter were identified： a -250 bp region adjacent to the transcription start site and a -85 bp region located approximately 350 bp further upstream. Within both regions, conservation of previously reported cis-regulatory motifs and human single nucleotide variants was evaluated. Transcription reporter assays in a TH-expressing cell line demonstrated the functionality of highly conserved motifs in the proximal promoter regions and electromobility shift assays showed that brain-region specific complexes assemble on these motifs. These studies also identified a non-canonical CRE binding （CREB） protein recognition element in the proximal promoter. Together, these studies provide a detailed analysis of evolutionary conservation within the TH promoter and identify potential cisregulatory motifs that underlie a core set of regulatory mechanisms in mammals.展开更多
It is been shown that spaceflight-induced molecular,cellular,and physiologic changes cause alterations across many modalities of the human body,including cardiovascular,musculoskeletal,hematological,immunological,ocul...It is been shown that spaceflight-induced molecular,cellular,and physiologic changes cause alterations across many modalities of the human body,including cardiovascular,musculoskeletal,hematological,immunological,ocular,and neurological systems.The Twin Study,a multi-year,multi-omic study of human response to spaceflight,provided detailed and comprehensive molecular and cellular maps of the human response to radiation,microgravity,isolation,and stress.These rich data identified epigenetic,gene expression,inflammatory,and metabolic responses to spaceflight,facilitating a better biomedical roadmap of features that should be monitored and safe-guarded in upcoming missions.Further,by exploring new developments in pre-clinical models and clinical trials,we can begin to design potential cellular interventions for exploration-class missions to Mars and potentially farther.This paper will discuss the overall risks astronauts face during spaceflight,what is currently known about human response to these risks,what pharmaceutical interventions exist for use in space,and which tools of precision medicine and cellular engineering could be applied to aerospace and astronaut medicine.展开更多
RNA sequencing(RNA-seq) has greatly facilitated the exploring of transcriptome landscape for diverse organisms.However,transcriptome reconstruction is still challenging due to various limitations of current tools and ...RNA sequencing(RNA-seq) has greatly facilitated the exploring of transcriptome landscape for diverse organisms.However,transcriptome reconstruction is still challenging due to various limitations of current tools and sequencing technologies.Here,we introduce an efficient tool,QuaPra(Quadratic Programming combined with Apriori),for accurate transcriptome assembly and quantification.QuaPra could detect at least 26.5% more low abundance(0.1–1 FPKM) transcripts with over 2.7% increase of sensitivity and precision on simulated data compared to other currently popular tools.Moreover,around one-quarter more known transcripts were correctly assembled by QuaPra than other assemblers on real sequencing data.QuaPra is freely available at http://www.megabionet.org/QuaPra/.展开更多
BACKGROUND： Neuronal activity in cortical areas regulates neurodevelopment by interacting with defined genetic programs to shape the mature central nervous system. Electrical activity is conveyed to sensory cortical ...BACKGROUND： Neuronal activity in cortical areas regulates neurodevelopment by interacting with defined genetic programs to shape the mature central nervous system. Electrical activity is conveyed to sensory cortical areas via intracortical and thalamocortical neurons, and includes oscillatory patterns that have been measured across cortical regions. OBJECTIVE： In this work, we review the most recent findings about how electrical activity shapes the developmental assembly of functional circuitry in the somatosensory cortex, with an emphasis on intemeuron maturation and integration. We include studies on the effect of various neurotransmitters and on the influence of thalamocortical afferent activity on circuit development. We additionally reviewed studies describing network activity patterns. METHODS： We conducted an extensive literature search using both the PubMed and Google Scholar search engines. The following keywords were used in various iterations： ＂intemeuron＂, ＂somatosensory＂, ＂development＂, ＂activity＂, ＂network patterns＂, ＂thalamocortical＂, ＂NMDA receptor＂, ＂plasticity＂. We additionally selected papers known to us from past reading, and those recommended to us by reviewers and members of our lab. RESULTS： We reviewed a total of 132 articles that focused on the role of activity in interneuronal migration, maturation, and circuit development, as well as the source of electrical inputs and pattems of cortical activity in the somatosensory cortex. 79 of these papers included in this timely review were written between 2007 and 2016. CONCLUSIONS： Neuronal activity shapes the developmental assembly of functional circuitry in the somatosensory cortical interneurons. This activity impacts nearly every aspect of development and acquisition of mature neuronal characteristics, and may contribute to changing phenotypes, altered transmitter expression, and plasticity in the adult. Progressively changing oscillatory network patterns contribute to this activity in the early postnatal period, although a direct requirement for specific patterns and origins of activity remains to be demonstrated.展开更多
Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains mu...Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation exposure.Methods To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA extraction.Telomere length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational burden.Result Telomere elongation occurred during spaceflight and shortened after return to Earth.Cell-free DNA analysis revealed increased immune cell signatures post-flight.No significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was observed.The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.Conclusion Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth.CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career astronauts.This study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.展开更多
基金supported by the National Basic Research Development Program (973 Program) of China (2013CB329501)a Scientific Project of the Science and Technology Commission of Shanghai Municipality, China (11140900600)+2 种基金the Shanghai Committee of Science and Technology (15ZR1410600)the National Natural Science Foundation of China (31100742)funds from the MIND Research Institute, Irvine, CA, USA
文摘The activity in sensory cortices and the prefrontal cortex （PFC） throughout the delay interval of working memory （WM） tasks reflect two aspects of WM-quality and quantity, respectively. The delay activity in sensory cortices is fine-tuned to sensory information and forms the neural basis of the precision of WM storage, while the delay activity in the PFC appears to represent behavioral goals and filters out irrelevant distractions, forming the neural basis of the quantity of task-relevant information in WM. The PFC and sensory cortices interact through different frequency bands of neuronal oscillation （theta, alpha, and gamma） to fulfill goal-directed behaviors.
文摘Since the calcium channel blocker （CCB） has become one of the most prescribed agents for antihypertensive monotherapy in the world, this brief review will focus on the recent research and development of the dihydropyridine （DHP） CCB, addressing pharmacological mecha- nisms for the clinical efficacy of the third and fourth generations of the DHP CCBs, especially on their possible central mechanisms underlying lowering blood pressure.
文摘BACKGROUND Recent studies suggest that traumatic brain injury(TBI)is a risk factor for subsequent ischemic stroke,even years after the initial insult.The mechanisms of the association remain unclear.The presence of traumatic subarachnoid hemorrhage(t SAH)may mediate the effect of TBI on long-term stroke risk,as it has previously been linked to short-term vasospasm and delayed cerebral ischemia.METHODS Using administrative claims data,we conducted a retrospective cohort study of acute care hospitalizations.Patients discharged with a first-recorded diagnosis of t SAH were followed for a primary diagnosis of stroke.They were matched to patients with TBI but not t SAH.Cox proportional hazards modeling was used to assess the association between t SAH and stroke while adjusting for covariates.RESULTS:We identified 40 908 patients with TBI(20 454 patients with t SAH)who were followed for a mean of 4.3+1.8 years.A total of 531 had an ischemic stroke after discharge.There was no significant difference in stroke risk between those with t SAH(1.79%;95%confidence interval[CI]1.54%-2.08%)versus without t SAH(2.12%;95%CI 1.83%-2.44%).The same pattern was found in adjusted analyses even when the group was stratified by age-group or by proxies of TBI severity.CONCLU-SIONS:Our findings do not support a role of t SAH in mediating the association between TBI and protracted stroke risk.Further study is required to elucidate the mechanisms of long-term increased stroke risk after TBI.
文摘Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.
基金This work was supported by Ottawa Hospital Foundation,Scottish Rite Charitable Foundation research grant,NSERC and CIHR project grant(to JW).
文摘Alzheimer’s disease(AD)is a progressive neurodegenerative disorder associated with significant memory decline and cognitive impairment.AD is characterized by two classical neuropathological hal lmarks,namely the amyloid-beta(Aβ)plaques and neurofibril tangles.Currently,there are no disease-modifying treatments available for AD,except for a couple of the US Food and Drug Administration(FDA)-approved drugs to improve cognitive function by blocking N-methyl-D-aspartate receptors or cholinesterase activity(Panza et al.,2019).
基金supported by funding to Edmund R.Hollis II(The Winifred Masterson Burke Foundation)
文摘There are roughly 282,000 individuals living with spinal cord injury in the United States alone（National Spinal Cord Injury Statistical Center,Birmingham,AL,USA）.Spinal cord injury often results in permanent functional impairments with only a limited capacity for spontaneous recovery.For the return of motor function,such as locomotion or hand and arm dexterity,
基金provided by the Canadian Institutes of Health Research Canada Graduate Scholarshipsthe Michael Smith Foreign Study Supplement program (Funding number:162728)
文摘Background Although previous studies have examined the effects of exercise training on other International Classification of Functioning,Disability and Health(ICF)component levels in persons with multiple sclerosis(MS),the effects of exercise training on participation remain unclear.The objectives of this review were to:(1)characterize systematically the use of outcome measures that capture participation in exercise training studies;(2)quantify the effect of exercise training on participation in persons with MS.Methods A search of 6 electronic databases(CINAHL,SPORTDiscuss,Embase,MEDLINE,Cochrane Central,and Scopus)was conducted to identify controlled and noncontrolled trials involving exercise training and participation in persons with MS.Search strings were built from Medical Subject Headings and CINAHL headings.ICF linking rules were used to identify participation chapters and categories captured.Meta-analysis was used to quantify the effect of exercise training on participation in randomized controlled trials comparing exercise effects to no intervention/usual care.Results We included 49 articles involving controlled and noncontrolled exercise trials in the systematic review of outcome measures.We captured 16 different outcome measures that captured all 9 participation chapters and identified 89 unique participation categories.Across these 16 outcome measures,mobility was the most commonly represented participation chapter,with 108 items.A subsample of 23 randomized controlled trials was included in the meta-analysis.An overall effect of 0.60(standard error=0.12,95%confidence interval:0.36-0.84,z=4.9,p<0.001)was calculated,indicating a moderate,positive effect of exercise training on participation.Conclusion The current review provides information that can be used to guide the selection of outcome measures that capture participation in studies of exercise training in persons with MS.Exercise training has a positive effect on outcomes that capture participation,providing further evidence for the role of exercise training in promoting and maintaining engagement in everyday life.
基金supported by the Burke Foundation and the National Institutes of Health Common Fund,No.DP2 NS106663(to ERH)the New York State Department of Health Spinal Cord Injury Research Board Postdoctoral Fellowship,No.C32633GG(to YL)。
文摘Therapeutic intervention for spinal cord injury is limited,with many approaches relying on strengthening the remaining substrate and driving recovery through rehabilitative training.As compared with learning novel compensatory strategies,rehabilitation focuses on resto ring movements lost to injury.Whether rehabilitation of previously learned movements after spinal cord injury requires the molecular mechanisms of motor learning,or if it engages previously trained motor circuits without requiring novel learning remains an open question.In this study,mice we re randomly assigned to receive intrape ritoneal injection with the pan-nicotinic,non-competitive antagonist mecamylamine and the nicotinicα7 subunit selective antagonist methyllycaconitine citrate salt or vehicle(normal saline)prior to motor learning assays,then randomly reassigned after motor learning for rehabilitation study post-injury.Ce rvical spinal co rd dorsal column lesion was used as a model of in complete injury.Results of this study showed that nicotinic acetylcholine signaling was required for motor learning of the single pellet-reaching task but it was dispensable for the rehabilitation of the same task after injury.Our findings indicate that critical diffe rences exist between the molecular mechanisms supporting compensatory motor learning strategies and the restoration of behavior lost to spinal cord injury.
基金funding from the National Eye Institute (R01EY022409)the Craig H. Neilsen Foundation (296098)+2 种基金the Wings for Life Foundation (WFL-US-028/14)the New York State Spinal Cord Injury Research Trust Fundthe Burke Foundation
文摘The functional regeneration of damaged axons and severed connections in the mature central nervous sys- tem （CNS） remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regeneration for two major reasons, one, because the ac- tivity of cell-intrinsic mechanisms that drive axon growth during development is low- and often further suppressed after an injury - and two, because certain molecules that are part of mature extracellular matrix and myelin act as strong inhibitors of axon growth. Genetic removal of growth inhibitory molecules can increase axon sprouting, but is not sufficient to enable long-range axon growth. Since axon growth is robust during early developmental stages, it has long been hypothesized that mature injured neurons may be ＂reprogrammed＂ to the earlier growth state by re-activation of the intracellular growth signaling cascades that drive axon elongation in the developing fetus.
文摘Background: Neuroscience can assist clinical understanding and therapy by finding neurobiological markers for mental illness symptoms. Objectives: To quantify biomarkers for schizophrenia and schizoaffective disorder and relate these to discrete symptoms of psychosis. Methods: Within a case-control design with multiple exclusion criteria to exclude organic causes and confounding variables, 67 DSM IV-R diagnosed and 67 control participants from a defined hospital, clinic and community catchment area were investigated for candidate markers. Participants underwent protocol-based diagnostic-checking and symptom rating via Brief Psychiatric Rating Scale and Positive and Negative Syndrome Scale, functional-rating scales, biological sample-collection and sensory-processing assessment. Blood and urine samples were analysed for monoamine neurotransmitters, their metabolites, vitamin cofactors and intermediate-substances related to oxidative stress and metabolism of monoamines. Neurocognitive assessment of visual and auditory processing was conducted at both peripheral and central levels. Biomarkers were defined by Receiver Operating Curve (ROC) analysis. Spearman’s analysis explored correlations between discrete symptoms and the biomarkers. Results: Receiver Operating Curve (ROC) analysis identified twenty-one biomarkers: elevated urinary dopamine, noradrenaline, adrenaline and hydroxy pyrroline-2-one as a marker of oxidative stress. Other biomarkers were deficits in vitamins D, B6 and folate, elevation of serum B12 and free serum copper to zinc ratio, along with deficits in dichotic listening, distance vision, visual and auditory speed of processing, visual and auditory working memory and six middle ear acoustic reflex parameters. Discrete symptoms such as delusions, hostility, suicidality and auditory hallucinations were biomarker-defined and symptom biomarker correlations assumed an understandable pattern in terms of the catecholamines and their relationship to biochemistry, brain function and disconnectivity. Conclusions: In the absence of a full diagnosis, biomarker-symptom-signatures inform psychiatry about the structure of psychosis and provide an understandable pattern that points in the direction of a new neurobiological system of symptom-formation and treatment.
文摘Arabidopsis MSI1 has fundamental functions in plant development. MSI1 is a subunit of Polycomb group protein complexes and Chromatin assembly factor 1, and it interacts with the Retinoblastoma-related protein 1. Altered levels of MSI1 result in pleiotropic phenotypes, reflecting the complexity of MSI1 protein functions. In order to uncover additional functions of MSI1, we performed transcriptional profiling of wild-type and plants with highly reduced MSI1 levels （msil-cs）. Surprisingly, the known functions of MSI1 could only account for a minor part of the transcriptional changes in msil-cs plants. One of the most striking unexpected observations was the up-regulation of a subset of ABA-responsive genes eliciting the response to drought and salt stress. We report that MSI1 can bind to the chromatin of the drought-inducible downstream target RD20 and suggest a new role for MSI1 in the negative regulation of the Arabidopsis drought-stress response.
基金Thisworkwas funded byNASA(GrantNos.NNX14AH50G and NNX17AB26G)the National Institutes of Health(Grant No.R25EB020393).
文摘While early investigations into the physiological effects of spaceflight suggest the body’s ability to reversibly adapt,the corresponding effects of long-term spaceflight(>6months)aremuch less conclusive.Prolonged exposure to microgravity and radiation yields profound effects on the cardiovascular system,including a massive cephalad fluid translocation and altered arterial pressure,which attenuate blood pressure regulatory mechanisms and increase cardiac output.Also,central venous pressure decreases as a result of the loss of venous compression.The stimulation of baroreceptors by the cephalad shift results in an approximately 10%–15%reduction in plasma volume,with fluid translocating from the vascular lumen to the interstitium.Despite possible increases in cardiac workload,myocyte atrophy and notable,yet unexplained,alterations in hematocrit have been observed.Atrophy is postulated to result from shunting of protein synthesis from the endoplasmic reticulum to the mitochondria via mortalin-mediated action.While data are scarce regarding their causative agents,arrhythmias have been frequently reported,albeit sublethal,during both Russian and American expeditions,with QT interval prolongation observed in long,but not short duration,spaceflight.Exposure of the heart to the proton and heavy ion radiation of deep space has also been shown to result in coronary artery degeneration,aortic stiffness,carotid intima thickening via collagen-mediated action,accelerated atherosclerosis,and induction of a pro-inflammatory state.Upon return,long-term spaceflight frequently results in orthostatic intolerance and altered sympathetic responses,which can prove hazardous should any rapidmobilization or evacuation be required,and indicates that these cardiac risks should be especially monitored for future missions.
文摘Tyrosine hydroxylase （TH） is the rate-limiting enzyme in catecholamine biosynthesis and its gene proximal promoter （〈 1 kb upstream from the transcription start site） is essential for regulating transcription in both the developing and adult nervous systems. Several putative regulatory elements within the TH proximal promoter have been reported, but evolutionary conservation of these dements has not been thoroughly investigated. Since many vertebrate species are used to model development, function and disorders of human catecholaminergic neurons, identifying evolutionarily conserved transcription regulatory mechanisms is a high priority. In this study, we align TH proximal promoter nucleotide sequences from several vertebrate species to identify evolutionarUy conserved motifs. This analysis identified three elements （a TATA box, cyclic AMP response element （CRE） and a 5＇-GGTGG-3＇ site） that constitute the core of an ancient vertebrate TH promoter. Focusing on only eutherian mammals, two regions of high conservation within the proximal promoter were identified： a -250 bp region adjacent to the transcription start site and a -85 bp region located approximately 350 bp further upstream. Within both regions, conservation of previously reported cis-regulatory motifs and human single nucleotide variants was evaluated. Transcription reporter assays in a TH-expressing cell line demonstrated the functionality of highly conserved motifs in the proximal promoter regions and electromobility shift assays showed that brain-region specific complexes assemble on these motifs. These studies also identified a non-canonical CRE binding （CREB） protein recognition element in the proximal promoter. Together, these studies provide a detailed analysis of evolutionary conservation within the TH promoter and identify potential cisregulatory motifs that underlie a core set of regulatory mechanisms in mammals.
基金We would like to thank the Epigenomics Core Facility at Weill Cornell Medicine,the Scientific Computing Unit(SCU),as well as the Starr Cancer Consortium(I9-A9-071)funding from the Irma T.Hirschl and MoniqueWeill-Caulier Charitable Trusts,Bert L and N Kuggie Vallee Foundation,the WorldQuant Foundation,the Pershing Square Sohn Cancer Research Alliance,NASA(Grants No.NNX14AH50G,NNX17AB26G)+4 种基金the National Institutes of Health(Grants No.R25EB020393,R01NS076465,R01AI125416,R01ES021006,1R21AI129851,P01HD067244,1R01MH117406)TRISH(Grants No.NNX16AO69A:0107,NNX16AO69A:0061)the Bill and Melinda Gates Foundation(Grants No.OPP1151054)the Leukemia and Lymphoma Society(LLS)grants(No.LLS 9238-16,Mak,No.LLS-MCL-982,Chen-Kiang)and the NSF(Grants No.1840275)the Alfred P.Sloan Foundation(Grants No.G-2015-13964).We thank Francine Garrett-Bakelman for her comments on the study and development of the protocols.
文摘It is been shown that spaceflight-induced molecular,cellular,and physiologic changes cause alterations across many modalities of the human body,including cardiovascular,musculoskeletal,hematological,immunological,ocular,and neurological systems.The Twin Study,a multi-year,multi-omic study of human response to spaceflight,provided detailed and comprehensive molecular and cellular maps of the human response to radiation,microgravity,isolation,and stress.These rich data identified epigenetic,gene expression,inflammatory,and metabolic responses to spaceflight,facilitating a better biomedical roadmap of features that should be monitored and safe-guarded in upcoming missions.Further,by exploring new developments in pre-clinical models and clinical trials,we can begin to design potential cellular interventions for exploration-class missions to Mars and potentially farther.This paper will discuss the overall risks astronauts face during spaceflight,what is currently known about human response to these risks,what pharmaceutical interventions exist for use in space,and which tools of precision medicine and cellular engineering could be applied to aerospace and astronaut medicine.
基金supported by the National High Technology Research and Development Program of China(2015AA020108)the National Key Research and Development Program of China(2016YFC0902100)+2 种基金the China Human Proteome Project(2014DFB30010,2014DFB30030)the National Science Foundation of China(31671377,31401133,31771460,91629103)the Program of Introducing Talents of Discipline to Universities of China(B14019)
文摘RNA sequencing(RNA-seq) has greatly facilitated the exploring of transcriptome landscape for diverse organisms.However,transcriptome reconstruction is still challenging due to various limitations of current tools and sequencing technologies.Here,we introduce an efficient tool,QuaPra(Quadratic Programming combined with Apriori),for accurate transcriptome assembly and quantification.QuaPra could detect at least 26.5% more low abundance(0.1–1 FPKM) transcripts with over 2.7% increase of sensitivity and precision on simulated data compared to other currently popular tools.Moreover,around one-quarter more known transcripts were correctly assembled by QuaPra than other assemblers on real sequencing data.QuaPra is freely available at http://www.megabionet.org/QuaPra/.
文摘BACKGROUND： Neuronal activity in cortical areas regulates neurodevelopment by interacting with defined genetic programs to shape the mature central nervous system. Electrical activity is conveyed to sensory cortical areas via intracortical and thalamocortical neurons, and includes oscillatory patterns that have been measured across cortical regions. OBJECTIVE： In this work, we review the most recent findings about how electrical activity shapes the developmental assembly of functional circuitry in the somatosensory cortex, with an emphasis on intemeuron maturation and integration. We include studies on the effect of various neurotransmitters and on the influence of thalamocortical afferent activity on circuit development. We additionally reviewed studies describing network activity patterns. METHODS： We conducted an extensive literature search using both the PubMed and Google Scholar search engines. The following keywords were used in various iterations： ＂intemeuron＂, ＂somatosensory＂, ＂development＂, ＂activity＂, ＂network patterns＂, ＂thalamocortical＂, ＂NMDA receptor＂, ＂plasticity＂. We additionally selected papers known to us from past reading, and those recommended to us by reviewers and members of our lab. RESULTS： We reviewed a total of 132 articles that focused on the role of activity in interneuronal migration, maturation, and circuit development, as well as the source of electrical inputs and pattems of cortical activity in the somatosensory cortex. 79 of these papers included in this timely review were written between 2007 and 2016. CONCLUSIONS： Neuronal activity shapes the developmental assembly of functional circuitry in the somatosensory cortical interneurons. This activity impacts nearly every aspect of development and acquisition of mature neuronal characteristics, and may contribute to changing phenotypes, altered transmitter expression, and plasticity in the adult. Progressively changing oscillatory network patterns contribute to this activity in the early postnatal period, although a direct requirement for specific patterns and origins of activity remains to be demonstrated.
基金supported by the Leukemia and Lymphoma Society (Grants No.LLS 9238-16 and MCL7001-18)the National Institutes of Health (Grants No.P01CA214274,R01CA249054 and R01MH117406)the WorldQuant Foundation,NASA (Grants No.80NSSC19K0432,80NSSC22K0254,NNH18ZTT001N-FG2,NNX13AE45G,NNX14AH50G,NNX17AB26G).
文摘Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation exposure.Methods To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA extraction.Telomere length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational burden.Result Telomere elongation occurred during spaceflight and shortened after return to Earth.Cell-free DNA analysis revealed increased immune cell signatures post-flight.No significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was observed.The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.Conclusion Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth.CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career astronauts.This study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.
