Promising use of metformin in treating neurological disorders:biomarker-guided therapies

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.

Exercise training improves participation in persons with multiple sclerosis:A systematic review and meta-analysis

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.

Nicotinic acetylcholine signaling is required for motor learning but not for rehabilitation from spinal cord injury

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.

通过预处理短暂诱导缺氧适应不能提高脊髓损伤后雪旺细胞移植的存活率

缺氧预处理在多种损伤和疾病模型中具有保护作用,但它是否对移植到脊髓损伤(SCI)部位的细胞有益在很大程度上尚待探索。本研究分析了缺氧相关的预处理是否能保护移植到挫伤的大鼠胸髓中的雪旺细胞(SC)。雪旺细胞在移植前通过暴露于低氧(1%O2)或药物制剂(去铁胺或adaptaquin)诱导缺氧预处理。所有预处理方法均诱导缺氧适应,包括HIF-1α及其靶基因的表达增加。然而这些适应是短暂的,并在移植后24 h内消失。药理学预处理减弱了脊髓氧化应激,并增强了移植血管形成,但它并没有改善移植细胞的存活或感觉/运动功能的恢复。总之,这些实验结果表明,与缺氧相关的预处理在改善脊髓损伤后移植雪旺细胞的细胞存活或功能方面是无效的。本研究还揭示了在细胞移植疗法中由预处理引起的缺氧相关适应的益处并不普遍。

New generations of dihydropyridines for treatment of hypertension

自从钙隧道， blocker ( CCB )在世界上为 antihypertensive monotherapy 成为了大多数规定代理人之一，这简短评论将集中于 dihydropyridine ( DHP )的最近的研究和发展 CCB ，为 DHP CCB 的第三和第四代的临床的功效探讨药理学机制，特别在他们位于阴沉的血压下面的可能的中央机制上。

创伤性脑损伤后蛛网膜下腔出血与长期卒中风险的关系（英文）

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.

Biomarker-guided drug therapy: personalized medicine for treating Alzheimer’s disease

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).

The role of motor network reorganization during rehabilitation

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,

RAFting the rapids of axon regeneration signaling

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.

Long-term spaceflight and the cardiovascular system

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.

Nucleotide sequence conservation of novel and established cis-regulatory sites within the tyrosine hydroxylase gene promoter

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.

Genome and clonal hematopoiesis stability contrasts with immune,cfDNA,mitochondrial,and telomere length changes during short duration spaceflight

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.

皮质下小血管病诊断的共识声明

血管性认知损害是用于描述一组涉及大血管和小血管的散发性和遗传性异质性疾病的诊断术语。皮质下小血管病可导致腔隙性梗死和进行性白质损害。被称为宾斯旺格病（Binswanger＇s disease, BD）的进行性白质损害患者构成了从单纯血管性疾病到合并神经变性病变的疾病谱。BD患者是一个相对同质性的亚组，存在缺氧缺血、腔隙性梗死和炎症，它们协同作用破坏血脑屏障和髓鞘。通过临床、脑脊液、神经心理学和影像学检查获得的多模式疾病标记物能促进该亚组患者的鉴别。本共识声明确定了一系列基于基础病理学改变的潜在生物学标记物，这将有助于诊断以及将来协作性治疗试验的患者选择。

Arabidopsis MSI1 Is Required for Negative Regulation of the Response to Drought Stress

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.

Translating current biomedical therapies for long duration,deep space missions

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.

Neuronal activity controls the development of interneurons in the somatosensory cortex

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.