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。

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.

New generations of dihydropyridines for treatment of hypertension

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.

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.

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.

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。

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.