Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

Characteristic changes in astrocyte properties during astrocyte-to-neuron conversion induced by NeuroD1/Ascl1/Dlx2

Direct in vivo conversion of astrocytes into functional new neurons induced by neural transcription factors has been recognized as a potential new therapeutic intervention for neural injury and degenerative disorders. However, a few recent studies have claimed that neural transcription factors cannot convert astrocytes into neurons, attributing the converted neurons to pre-existing neurons mis-expressing transgenes. In this study, we overexpressed three distinct neural transcription factors––NeuroD1, Ascl1, and Dlx2––in reactive astrocytes in mouse cortices subjected to stab injury, resulting in a series of significant changes in astrocyte properties. Initially, the three neural transcription factors were exclusively expressed in the nuclei of astrocytes. Over time, however, these astrocytes gradually adopted neuronal morphology, and the neural transcription factors was gradually observed in the nuclei of neuron-like cells instead of astrocytes. Furthermore,we noted that transcription factor-infected astrocytes showed a progressive decrease in the expression of astrocytic markers AQP4(astrocyte endfeet signal), CX43(gap junction signal), and S100β. Importantly, none of these changes could be attributed to transgene leakage into preexisting neurons. Therefore, our findings suggest that neural transcription factors such as NeuroD1, Ascl1, and Dlx2 can effectively convert reactive astrocytes into neurons in the adult mammalian brain.

Differential distribution of PINK1 and Parkin in the primate brain implies distinct roles

The vast majority of in vitro studies have demonstrated that PINK1 phosphorylates Parkin to work together in mitophagy to protect against neuronal degeneration.However,it remains largely unclear how PINK1 and Parkin are expressed in mammalian brains.This has been difficult to address because of the intrinsically low levels of PINK1 and undetectable levels of phosphorylated Parkin in small animals.Understanding this issue is critical for elucidating the in vivo roles of PINK1 and Parkin.Recently,we showed that the PINK1 kinase is selectively expressed as a truncated form(PINK1–55)in the primate brain.In the present study,we used multiple antibodies,including our recently developed monoclonal anti-PINK1,to validate the selective expression of PINK1 in the primate brain.We found that PINK1 was stably expressed in the monkey brain at postnatal and adulthood stages,which is consistent with the findings that depleting PINK1 can cause neuronal loss in developing and adult monkey brains.PINK1 was enriched in the membrane-bound fractionations,whereas Parkin was soluble with a distinguishable distribution.Immunofluorescent double staining experiments showed that PINK1 and Parkin did not colocalize under physiological conditions in cultured monkey astrocytes,though they did colocalize on mitochondria when the cells were exposed to mitochondrial stress.These findings suggest that PINK1 and Parkin may have distinct roles beyond their well-known function in mitophagy during mitochondrial damage.

Commentary on:“Human neural stem cell-derived artificial organelles to improve oxidative phosphorylation”

Mitochondrial function is fundamental to neuroregeneration,particularly in neurons,where high energy demands are essential for repair and recovery(Patrón and Zinsmaier,2016;Beckervordersandforth et al.,2017;Iwata et al.,2023).Mitochondrial dysfunction,characterized by an imbalance in ATP levels and excessive production of mitochondrial reactive oxygen species,is a key factor that impedes neural regeneration in neurodegenerative diseases and after neuronal injury(Han et al.,2016,2020;Zheng et al.,2016;Zong et al.,2024).

Exercise preconditioning alleviates ischemia-induced memory deficits by increasing circulating adiponectin

Cerebral ischemia is a major health risk that requires preventive approaches in addition to drug therapy.Physical exercise enhances neurogenesis and synaptogenesis,and has been widely used for functional rehabilitation after stroke.In this study,we determined whether exercise training before disease onset can alleviate the severity of cerebral ischemia.We also examined the role of exercise-induced circulating factors in these effects.Adult mice were subjected to 14 days of treadmill exercise training before surgery for middle cerebral artery occlusion.We found that this exercise pre-conditioning strategy effectively attenuated brain infarct area,inhibited gliogenesis,protected synaptic proteins,and improved novel object and spatial memory function.Further analysis showed that circulating adiponectin plays a critical role in these preventive effects of exercise.Agonist activation of adiponectin receptors by Adipo Ron mimicked the effects of exercise,while inhibiting receptor activation abolished the exercise effects.In summary,our results suggest a crucial role of circulating adiponectin in the effects of exercise pre-conditioning in protecting against cerebral ischemia and supporting the health benefits of exercise.

Activation of adult endogenous neurogenesis by a hyaluronic acid collagen gel containing basic fibroblast growth factor promotes remodeling and functional recovery of the injured cerebral cortex

The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.

Spinal cord injury regenerative therapy development:integration of design of experiments

Spinal cord injury(SCI)can cause motor and sensory paralysis,and autonomic nervous system disorders including malfunction of urination and defecation,thereby significantly impairing the quality of life.Researchers continue to explo re new stem cell strategies for the treatment of paralysis by transpla nting human induced pluripotent stem cell-derived neural ste m/progenitor cells(hiPSCNS/PCs)into spinal cord injured tissues.

Comprehensive view of suicide:A neuro-immune-endocrine approach

Suicide is defined as the act of a person attempting to take their own life by causing death.Suicide is a complex phenomenon that is influenced by a multitude of factors,including psychosocial,cultural,and religious aspects,as well as genetic,biochemical,and environmental factors.From a biochemical perspective,it is crucial to consider the communication between the endocrine,immune,and nervous systems when studying the etiology of suicide.Several pathologies involve the bidirectional communication between the peripheral activity and the central nervous system by the action of molecules such as cytokines,hormones,and neurotransmitters.These humoral signals,when present in optimal quantities,are responsible for maintaining physiological homeostasis,including mood states.Stress elevates the cortisol and proinflammatory cytokines levels and alter neurotransmitters balance,thereby increasing the risk of developing a psychiatric disorder and subsequently the risk of suicidal behavior.This review provides an integrative perspective about the neurochemical,immunological,and endocrinological disturbances associated with suicidal behavior,with a particular focus on those alterations that may serve as potential risk markers and/or indicators of the state preceding such a tragic act.

2019 CNS Diseases: Advanced Diagnostics and Treatment Conference

1.Yeast studies on the benefit of simvastatin in reducing levels of amyloid betaian Macreadie,Sudip Dhakal,Mishal Subhan,Ken Gardiner,Joshua Fraser RMIT University,Melbourne,Victoria,Australia A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia.Since amyloid beta(Aβ42)is the protein that is most associated with Alzheimer's disease,this study has focused on how simvastatin influences the turnover of native Aβ42 and Aβ42 fused with green昀uorescent protein(GFP),in the simplest eukaryotic model organism,saccharomyces cerevisiae.Previous studies have established that yeast constitutively producing Aβ42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aβ42.

更高速下轮轨瞬态“滚-滑-跳”接触行为及中/短波不平顺临界限值研究

简述轮轨滚动接触行为预测方法现状的基础上,选择最适于400 km/h及以上更高速和中/短波不平顺激励下轮轨“滚-滑-跳”接触行为分析的瞬态滚动接触显式有限元建模方法,建立更高速轮轨三维瞬态滚动接触时域分析模型,数值模拟了轮对在典型曲线轨道上的瞬态曲线通过行为。根据现营高速轮轨的中/短波不平顺调研,以波长30~210 mm钢轨波磨为典型不平顺,考虑波磨激励下左右两侧轮轨动力作用相互影响,分析波磨几何等因素对速度500 km/h及以下轮轨瞬态“滚-滑-跳”接触行为的影响。考虑低、中频动力减载等因素的前提下,仅从轮轨接触脱离角度,提出轮轨中/短波不平顺的临界管理限值建议,讨论其重要性、合理性和应用局限,并与《高速铁路钢轨打磨管理办法》规定的波磨整治限度进行对比。

铁路道砟材质选型分析与建议

我国铁路覆盖范围广,沿线所处地质环境复杂、气候多变,铁路运维面临巨大挑战。有砟道床作为铁路重要组成部分,其养护维修一直以来倍受关注,然而,岩石材料具有多样性和分布不均衡性,且我国道砟材质标准及选型较为单一,并未考虑地质及气候环境等因素,给铁路建设及运维带来一系列问题。针对此,总结世界各国道砟选型方式及方法,对比复杂环境道砟材质选型标准,归纳新型道砟材料,并且解释了标准中用于道砟性能量化的指标及其试验方法。对比各国所道砟材质及其配套的选型标准,得到以下主要结论:(1)针对我国现有道砟规范问题,可以考虑根据铁路沿线地质和气候等因素选择道砟材质;(2)目前仍没有方法可以快速、准确并且不破坏道床的方式来得到道床堆积密度;(3)为实现双碳目标,在有条件的新建或改建线路上可考虑选用建筑固废、工业固废等新型道砟材料。

焊接残余应力对钢桥面疲劳性能的影响与处理措施

为改善正交异性钢桥面的抗疲劳性能,对钢桥面进行退火处理以降低关键焊缝的焊接残余应力。首先系统性地回顾和探讨钢桥面焊接残余应力分布模式,同时就残余应力对疲劳裂纹发展的影响进行了文献分析。随后,归纳和总结了国内外主流焊接残余应力消除方法,并开展对比分析。借鉴压力容器制造方法,建议在正交异性钢桥面制造中引入退火处理工艺以降低焊接残余应力。研究聚焦钢桥面中疲劳问题较突出的顶板与U肋连接焊缝,设计了16个(其中9个退火处理,7未作处理)局部足尺单U肋试件进行残余应力测试与疲劳试验。试验结果表明,退火处理后焊缝残余应力实测值降低约80%,疲劳强度提高约23%。可以看出,退火处理可以大幅降低焊接残余应力,从而有效提升钢桥面抗疲劳性能。

Genetically modified non-human primate models for research on neurodegenerative diseases

Neurodegenerative diseases(NDs)are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS).Currently,there are no therapies available that can delay,stop,or reverse the pathological progression of NDs in clinical settings.As the population ages,NDs are imposing a huge burden on public health systems and affected families.Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments.While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms,the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap.Old World nonhuman primates(NHPs),such as rhesus,cynomolgus,and vervet monkeys,are phylogenetically,physiologically,biochemically,and behaviorally most relevant to humans.This is particularly evident in the similarity of the structure and function of their central nervous systems,rendering such species uniquely valuable for neuroscience research.Recently,the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms.This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained,as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

Treadmill exercise improves hippocampal neural plasticity and relieves cognitive deficits in a mouse model of epilepsy

Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited.Although regular exercise effectively improves learning and memory functions across multiple neurological diseases,its application in patients with epilepsy remains controversial.Here,we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy.Cognitive assays confirmed the improvement of object and spatial memory after endurance training,and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise.Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons,probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier.In summary,this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.

Activation of endogenous neurogenesis and angiogenesis by basic fibroblast growth factor-chitosan gel in an adult rat model of ischemic stroke

Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.

Large animal models for Huntington's disease research

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

Comparative analysis of primate and pig cells reveals primate-specific PINK1 expression and phosphorylation

PTEN-induced putative kinase 1(PINK1),a mitochondrial kinase that phosphorylates Parkin and other proteins,plays a crucial role in mitophagy and protection against neurodegeneration.Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson's disease.However,there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration.Additionally,PINK1 knockout pigs(Sus scrofa)do not appear to exhibit neurodegeneration.In our recent work involving non-human primates,we found that PINK1 is selectively expressed in primate brains,while absent in rodent brains.To extend this to other species,we used multiple antibodies to examine the expression of PINK1 in pig tissues.In contrast to tissues from cynomolgus monkeys(Macaca fascicularis),our data did not convincingly demonstrate detectable PINK1expression in pig tissues.Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation,as observed in cultured monkey cells.A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain.Consistently,PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD.These findings provide new evidence that PINK1expression is specific to primates,underscoring the importance of non-human primates in investigating PINK1function and pathology related to PINK1 deficiency.

二氧化碳养护水泥基材料的研究进展

水泥基材料通过碳化反应可以快速形成以碳酸盐和高聚度硅胶为主要产物的固碳制品。固碳制品因其可以兼顾CO_(2)消纳能力与优良的力学性能受到了广泛的关注。国内外研究团队在原材料开发、组成与工艺优化、养护制度设计等基础上,开发了多种应用场景,主要包括板材、小型砌块、骨料等。从碳化反应机理与动力学出发,归纳了反应条件对结构与产物组成的影响规律,总结了现有制品的种类、性能与应用现状,以期为建材工业的碳减排提供新的思路。

INTERFACE BEHAVIOR AND DECAY RATES OF COMPRESSIBLE NAVIER-STOKES SYSTEM WITH DENSITY-DEPENDENT VISCOSITY AND A VACUUM

In this paper,we study the one-dimensional motion of viscous gas near a vacuum,with the gas connecting to a vacuum state with a jump in density.The interface behavior,the pointwise decay rates of the density function and the expanding rates of the interface are obtained with the viscosity coefficientμ(ρ)=ρ^(α)for any 0<α<1;this includes the timeweighted boundedness from below and above.The smoothness of the solution is discussed.Moreover,we construct a class of self-similar classical solutions which exhibit some interesting properties,such as optimal estimates.The present paper extends the results in[Luo T,Xin Z P,Yang T.SIAM J Math Anal,2000,31(6):1175-1191]to the jump boundary conditions case with density-dependent viscosity.