Purkinje-neuron-specific down-regulation of p38 protects motoric function from the repeated use of benzodiazepine

Benzodiazepine (BZD) is the most prescribed CNS depressant in America to treat hyper-excitatory disorders such as anxiety and insomnia. However, the chronic use of BZD often creates adverse effects including psychomotor deficit. In this study, we investigated a novel mechanism by which chronic BZD impedes motoric function in female mice. We used female mice because BZD use is much more prevalent in female than male populations. We tested the hypothesis that the accumulation of p38 (stress-activated protein) in cerebellar Purkinje neurons mediates motoric deficit induced by chronic BZD. To test this hypothesis, we generated transgenic mice that lack p38 incerebellar Purkinje neurons by crossing Pcp2 (Purkinje cell protein 2)-Cre mice with p38loxP/loxP mice. p38-knockdown mice and wild-type mice received BZD (lorazepam, 0.5 mg/kg) for 14 days. During this period, they were tested for motoric performance using Rotarod assay in which a quicker fall from rotating rod indicates poorer motoric performance. Cerebellum was then collected to detect p38 inPurkinje neurons and to measure mitochondrial respiration using immunohistochemistry and real-time XF respirometry, respectively. Compared to vehicletreated mice, BZD-treated mice showed poorer motoric performance, a higher number of Purkinje neurons containing p38, and lower mitochondrial respiration. These effects of BZD were much smaller in p38-knockdown mice. These results suggest that the excessive accumulation of p38 incerebellar Purkinje neurons contributes to motoric deficit associated with chronic BZD. They also suggest that Purkinje neuronal p38 mediates BZD-induced mitochondrial respiratory inhibition in cerebellum. Our findings may provide a new mechanistic insight into chronic BZD-induced motoric deficit.

Determining Motoric Abilities of Perspective Judokas

The research was conducted on a sample of 237 perspective judokas with the objective of checking the efficiency of the factor analysis as an optimal method of establishing of the real structure of motor abilities.In order to assess motor abilities 20 motor tests have been applied,which have been selected so that analysis could be done on the basis of second order factors.All the data in this study were processed at the Multidisciplinary Research Center,Faculty of Sport and Physical Education,University of Pristina through the system of data processing software programs.Factor structure analysis of motor dimensions indicates that three factors were obtained:the first factor is responsible for movement structuring,the second factor is for the excitation intensity regulation and the third is responsible for the excitation duration.

Understanding the spectrum of non-motor symptoms in multiple sclerosis:insights from animal models

Multiple sclerosis is a chronic autoimmune disease of the central nervous system and is generally considered to be a non-traumatic,physically debilitating neurological disorder.In addition to experiencing motor disability,patients with multiple sclerosis also experience a variety of nonmotor symptoms,including cognitive deficits,anxiety,depression,sensory impairments,and pain.However,the pathogenesis and treatment of such non-motor symptoms in multiple scle rosis are still under research.Preclinical studies for multiple sclerosis benefit from the use of disease-appropriate animal models,including experimental autoimmune encephalomyelitis.Prior to understanding the pathophysiology and developing treatments for non-motor symptoms,it is critical to chara cterize the animal model in terms of its ability to replicate certain non-motor features of multiple sclerosis.As such,no single animal model can mimic the entire spectrum of symptoms.This review focuses on the non-motor symptoms that have been investigated in animal models of multiple sclerosis as well as possible underlying mechanisms.Further,we highlighted gaps in the literature to explain the nonmotor aspects of multiple sclerosis in expe rimental animal models,which will serve as the basis for future studies.

P7C3-A20 treats traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis

Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain.3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine(P7C3-A20)can be neuroprotective in various diseases,including ischemic stroke and neurodegenerative diseases.However,whether P7C3-A20 has a therapeutic effect on traumatic brain injury and its possible molecular mechanisms are unclear.Therefore,in the present study,we investigated the therapeutic effects of P7C3-A20 on traumatic brain injury and explored the putative underlying molecular mechanisms.We established a traumatic brain injury rat model using a modified weight drop method.P7C3-A20 or vehicle was injected intraperitoneally after traumatic brain injury.Severe neurological deficits were found in rats after traumatic brain injury,with deterioration in balance,walking function,and learning memory.Furthermore,hematoxylin and eosin staining showed significant neuronal cell damage,while terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining indicated a high rate of apoptosis.The presence of autolysosomes was observed using transmission electron microscope.P7C3-A20 treatment reversed these pathological features.Western blotting showed that P7C3-A20 treatment reduced microtubule-associated protein 1 light chain 3-Ⅱ(LC3-Ⅱ)autophagy protein,apoptosis-related proteins(namely,Bcl-2/adenovirus E1B 19-kDa-interacting protein 3[BNIP3],and Bcl-2 associated x protein[Bax]),and elevated ubiquitin-binding protein p62(p62)autophagy protein expression.Thus,P7C3-A20 can treat traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.

基于CEEMDAN-HT的永磁同步电机匝间短路振动信号故障特征提取研究

由于长时间处于高负荷运行状态,永磁同步电机(permanent magnet synchronous motor, PMSM)定子绕组线圈匝与匝之间的绝缘性能容易降低,导致出现匝间短路,此时电机的振动强度会发生改变。针对此现象,提出将自适应噪声完备经验模态分解(complete ensemble empirical mode decomposition with adaptive noise, CEEMDAN)与希尔伯特变换(Hilbert transform, HT)结合,构成一种CEEMDAN-HT非线性信号分析方法,并将其应用于提取振动信号故障特征。首先,利用CEEMDAN算法分解振动信号,得到一系列本征模态函数(intrinsic mode function, IMF),并将主元分析中的方差贡献率用于识别包含故障特征信息的IMF。其次,使用HT对方差贡献率较高的IMF进行分析,并以三维联合时频图呈现时间、瞬时频率与幅值,得到了主要故障特征。最后,使用ANSYS有限元软件建立了电机短路故障模型,并搭建了短路故障试验平台,通过对比有限元仿真结果与试验结果,对提出的方法进行了有效性和准确性验证。

基于Ansys的笼型感应电动机优化设计

针对感应电动机设计过程中需要解决降低电机损耗高、工作效率低、功率因数小和操作特性差等问题,设计了一台额定功率20 kW,额定转速3000 r/min的笼型感应电动机,该设计采用Ansys EM中的RMxprt模块对感应电机进行快速建模和有限元分析,优化电机参数后利用Ansys Motor Cad对所设计的感应电机进行电磁场和温度场的耦合仿真.仿真结果表明,和国内外相同类型的感应电机相比,本文设计的感应电动机具有更高的效率,同时损耗和铁心温度也得到降低.

Elevated brain temperature under severe heat exposure impairs cortical motor activity and executive function

Background:Excessive heat exposure can lead to hyperthermia in humans,which impairs physical performance and disrupts cognitive function.While heat is a known physiological stressor,it is unclear how severe heat stress affects brain physiology and function.Methods:Eleven healthy participants were subjected to heat stress from prolonged exercise or warm water immersion until their rectal temperatures(T_(re))attained 39.5℃,inducing exertional or passive hyperthermia,respectively.In a separate trial,blended ice was ingested before and during exercise as a cooling strategy.Data were compared to a control condition with seated rest(normothermic).Brain temperature(T_(br)),cerebral perfusion,and task-based brain activity were assessed using magnetic resonance imaging techniques.Results:T_(br)in motor cortex was found to be tightly regulated at rest(37.3℃±0.4℃(mean±SD))despite fluctuations in T_(re).With the development of hyperthermia,T_(br)increases and dovetails with the rising T_(re).Bilateral motor cortical activity was suppressed during high-intensity plantarflexion tasks,implying a reduced central motor drive in hyperthermic participants(T_(re)=38.5℃±0.1℃).Global gray matter perfusion and regional perfusion in sensorimotor cortex were reduced with passive hyperthermia.Executive function was poorer under a passive hyperthermic state,and this could relate to compromised visual processing as indicated by the reduced activation of left lateral-occipital cortex.Conversely,ingestion of blended ice before and during exercise alleviated the rise in both T_(re)and T_(bc)and mitigated heat-related neural perturbations.Conclusion:Severe heat exposure elevates T_(br),disrupts motor cortical activity and executive function,and this can lead to impairment of physical and cognitive performance.

Origin of tradeoff between movement velocity and attachment duration of kinesin motor on a microtubule

Kinesin-1 motor protein is a homodimer containing two identical motor domains connected by a common long coiledcoil stalk via two flexible neck linkers. The motor can step on a microtubule with a velocity of about 1 μm·s-1and an attachment duration of about 1 s under physiological conditions. The available experimental data indicate a tradeoff between velocity and attachment duration under various experimental conditions, such as variation of the solution temperature,variation of the strain between the two motor domains, and so on. However, the underlying mechanism of the tradeoff is unknown. Here, the mechanism is explained by a theoretical study of the dynamics of the motor under various experimental conditions, reproducing quantitatively the available experimental data and providing additional predictions. How the various experimental conditions lead to different decreasing rates of attachment duration versus velocity is also explained.

Collective Molecular Machines: Multidimensionality and Reconfigurability

Molecular machines are key to cellular activity where they are involved in converting chemical and light energy into efficient mechanical work.During the last 60 years,designing molecular structures capable of generating unidirectional mechanical motion at the nanoscale has been the topic of intense research.Effective progress has been made,attributed to advances in various fields such as supramolecular chemistry,biology and nanotechnology,and informatics.However,individual molecular machines are only capable of producing nanometer work and generally have only a single functionality.In order to address these problems,collective behaviors realized by integrating several or more of these individual mechanical units in space and time have become a new paradigm.In this review,we comprehensively discuss recent developments in the collective behaviors of molecular machines.In particular,collective behavior is divided into two paradigms.One is the appropriate integration of molecular machines to efficiently amplify molecular motions and deformations to construct novel functional materials.The other is the construction of swarming modes at the supramolecular level to perform nanoscale or microscale operations.We discuss design strategies for both modes and focus on the modulation of features and properties.Subsequently,in order to address existing challenges,the idea of transferring experience gained in the field of micro/nano robotics is presented,offering prospects for future developments in the collective behavior of molecular machines.

A Loss-model-based Efficiency Optimization Control Method for Induction Traction System of High-speed Train under Emergency Self-propelled Mode

Increasing attention has been paid to the efficiency improvement of the induction traction system of high-speed trains due to the high demand for energy saving. In emergency self-propelled mode, however, the dc-link voltage and the traction power of the motor are significantly reduced, resulting in decreased traction efficiency due to the low load and low speed operations. Aiming to tackle this problem, a novel efficiency improved control method is introduced to the emergency mode of high-speed train traction system in this paper. In the proposed method, a total loss model of induction motor considering the behaviors of both iron and copper loss is established. An improved iterative algorithm with decreased computational burden is then introduced, resulting in a fast solving of the optimal flux reference for loss minimization at each control period. In addition, considering the parameter variation problem due to the low load and low speed operations, a parameter estimation method is integrated to improve the controller's robustness. The effectiveness of the proposed method on efficiency improvement at low voltage and low load conditions is demonstrated by simulated and experimental results.

Engineering The Neck Hinge Reshapes The Processive Movement of Kinesin-3

Objective In kinesin-3,the neck coil correlates with the following segments to form an extended neck that contains a characteristic hinge diverse from a proline in KIF13B to a long flexible linker in KIF1A.The function of this neck hinge for controlling processive movement,however,remains unclear.Methods We made a series of modifications to the neck hinges of KIF13B and KIF1A and tested their movement using a single-molecule motility assay.Results In KIF13B,the insertion of flexible residues before or after the proline differentially impacts the processivity or velocity,while the removal of this proline increases the both.In KIF1A,the deletion of entire flexible neck hinge merely enhances the processivity.The engineering of these hinge-truncated necks of kinesin-3 into kinesin-1 similarly boosts the processive movement of kinesin-1.Conclusion The neck hinge in kinesin-3 controls its processive movement and proper modifications tune the motor motility,which provides a novel strategy to reshape the processive movement of kinesin motors.

Pathological mechanisms of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system,the cause of which remains unexplained despite several years of research.Thus,the journey to understanding or treating amyotrophic lateral sclerosis is still a long one.According to current research,amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways.The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis.Here,we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis,as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis.In addition,we discuss current emerging strategies for the treatment of amyotrophic lateral sclerosis.Studying the emergence of these new therapies may help to further our understanding of the pathogenic mechanisms of the disease.

FK506 contributes to peripheral nerve regeneration by inhibiting neuroinflammatory responses and promoting neuron survival

FK506(Tacrolimus)is a systemic immunosuppressant approved by the U.S.Food and Drug Administration.FK506 has been shown to promote peripheral nerve regeneration,however,its precise mechanism of action and its pathways remain unclear.In this study,we established a rat model of sciatic nerve injury and found that FK506 improved the morphology of the injured sciatic nerve,increased the numbers of motor and sensory neurons,reduced inflammatory responses,markedly improved the conduction function of the injured nerve,and promoted motor function recovery.These findings suggest that FK506 promotes peripheral nerve structure recovery and functional regeneration by reducing the intensity of inflammation after neuronal injury and increasing the number of surviving neurons.

Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats withα-synucleinopathy

Parkinsonism by unilateral,intranigralβ-sitosterolβ-D-glucoside administration in rats is distinguished in that theα-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time,thus replicating several clinical features of Parkinson’s disease,a typicalα-synucleinopathy.As Nurr1 repressesα-synuclein,we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateralβ-sitosterolβ-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection.This study found that rNurr1-V5 expression but not that of the green fluorescent protein(the negative control)reducedβ-sitosterolβ-D-glucoside-induced neuropathology.Accordingly,a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum.In addition,tyrosine hydroxylase-positive cells displayed less senescence markerβ-galactosidase and more neuron-cytoskeleton markerβIII-tubulin and brain-derived neurotrophic factor.A significant decrease in activated microglia(positive to ionized calcium-binding adaptor molecule 1)and neurotoxic astrocytes(positive to glial fibrillary acidic protein and complement component 3)and increased neurotrophic astrocytes(positive to glial fibrillary acidic protein and S100 calcium-binding protein A10)also occurred in the substantia nigra.These effects followed the bilateral reduction inα-synuclein aggregates in the nigrostriatal system,improving sensorimotor behavior.Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration(senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells),neuroinflammation(activated microglia,neurotoxic astrocytes),α-synuclein aggregation,and sensorimotor deficits.Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect,supporting its potential clinical use in the treatment of Parkinson’s disease.

Regulation of specific abnormal calcium signals in the hippocampal CA1 and primary cortex M1 alleviates the progression of temporal lobe epilepsy

Temporal lobe epilepsy is a multifactorial neurological dysfunction syndrome that is refractory,resistant to antiepileptic drugs,and has a high recurrence rate.The pathogenesis of temporal lobe epilepsy is complex and is not fully understood.Intracellular calcium dynamics have been implicated in temporal lobe epilepsy.However,the effect of fluctuating calcium activity in CA1 pyramidal neurons on temporal lobe epilepsy is unknown,and no longitudinal studies have investigated calcium activity in pyramidal neurons in the hippocampal CA1 and primary motor cortex M1 of freely moving mice.In this study,we used a multichannel fiber photometry system to continuously record calcium signals in CA1 and M1 during the temporal lobe epilepsy process.We found that calcium signals varied according to the grade of temporal lobe epilepsy episodes.In particular,cortical spreading depression,which has recently been frequently used to represent the continuously and substantially increased calcium signals,was found to correspond to complex and severe behavioral characteristics of temporal lobe epilepsy ranging from gradeⅡto gradeⅤ.However,vigorous calcium oscillations and highly synchronized calcium signals in CA1 and M1 were strongly related to convulsive motor seizures.Chemogenetic inhibition of pyramidal neurons in CA1 significantly attenuated the amplitudes of the calcium signals corresponding to gradeⅠepisodes.In addition,the latency of cortical spreading depression was prolonged,and the above-mentioned abnormal calcium signals in CA1 and M1 were also significantly reduced.Intriguingly,it was possible to rescue the altered intracellular calcium dynamics.Via simultaneous analysis of calcium signals and epileptic behaviors,we found that the progression of temporal lobe epilepsy was alleviated when specific calcium signals were reduced,and that the end-point behaviors of temporal lobe epilepsy were improved.Our results indicate that the calcium dynamic between CA1 and M1 may reflect specific epileptic behaviors corresponding to different grades.Furthermore,the selective regulation of abnormal calcium signals in CA1 pyramidal neurons appears to effectively alleviate temporal lobe epilepsy,thereby providing a potential molecular mechanism for a new temporal lobe epilepsy diagnosis and treatment strategy.

Symmetric Brownian motor subjected to Lévy noise

In the past few years,attention has mainly been focused on the symmetric Brownian motor(BM)with Gaussian noises,whose current and energy conversion efficiency are very low.Here,we investigate the operating performance of the symmetric BM subjected to Lévy noise.Through numerical simulations,it is found that the operating performance of the motor can be greatly improved in asymmetric Lévy noise.Without any load,the Lévy noises with smaller stable indexes can let the motor give rise to a much greater current.With a load,the energy conversion efficiency of the motor can be enhanced by adjusting the stable indexes of the Lévy noises with symmetry breaking.The results of this research are of great significance for opening up BM’s intrinsic physical mechanism and promoting the development of nanotechnology.

Device-assisted enteroscopy: Are we ready to dismiss the spiral?

Motorized spiral enteroscopy(MSE)is the latest advance in device-assisted enteroscopy.Adverse events related to MSE were discussed in a recent large systematic review and meta-analysis and were directly compared with those of balloon enteroscopy in a case-matched study and a randomized controlled trial.Following the real-life application of MSE,an unexpected safety issue emerged regarding esophageal injury and the technique has been withdrawn from the global market,despite encouraging results in terms of diagnostic and therapeutic yield.We conducted an Italian multicenter real-life prospective study,which was prematurely terminated after the withdrawal of MSE from the market.The primary goals were the evaluation of MSE performance(both diagnostic and therapeutic)and its safety in routine endoscopic practice,particularly in the early phase of introduction in the endoscopic unit.A subanalysis,which involved patients who underwent MSE after unsuccessful balloon enteroscopy,demonstrated,for the first time,the promising performance of MSE as a rescue procedure.Given its remarkable performance in clinical practice and its potential role as a backup technique following a previously failed enteroscopy,it may be more appropriate to refine and enhance MSE in the future rather than completely abandoning it.

Enhancement of motor functional recovery in thoracic spinal cord injury: voluntary wheel running versus forced treadmill exercise

Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group(10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury.

Integration of bio-inspired limb-like structure damping into motor suspension of high-speed trains to enhance bogie hunting stability

Hunting stability is an important performance criterion in railway vehicles.This study proposes an incorporation of a bio-inspired limb-like structure(LLS)-based nonlinear damping into the motor suspension system for traction units to improve the nonlinear critical speed and hunting stability of high-speed trains(HSTs).Initially,a vibration transmission analysis is conducted on a HST vehicle and a metro vehicle that suffered from hunting motion to explore the effect of different motor suspension systems from on-track tests.Subsequently,a simplified lateral dynamics model of an HST bogie is established to investigate the influence of the motor suspension on the bogie hunting behavior.The bifurcation analysis is applied to optimize the motor suspension parameters for high critical speed.Then,the nonlinear damping of the bio-inspired LLS,which has a positive correlation with the relative displacement,can further improve the modal damping of hunting motion and nonlinear critical speed compared with the linear motor suspension system.Furthermore,a comprehensive numerical model of a high-speed train,considering all nonlinearities,is established to investigate the influence of different types of motor suspension.The simulation results are well consistent with the theoretical analysis.The benefits of employing nonlinear damping of the bio-inspired LLS into the motor suspension of HSTs to enhance bogie hunting stability are thoroughly validated.

Insights into spinal muscular atrophy from molecular biomarkers

Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness.It is one of the most common genetic causes of mortality among infants aged less than 2 years.Biomarker research is currently receiving more attention,and new candidate biomarkers are constantly being discovered.This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons.We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy,which are classified as either specific or non-specific biomarkers.This review provides new insights into the pathogenesis of spinal muscular atrophy,the mechanism of biomarkers in response to drug-modified therapies,the selection of biomarker candidates,and would promote the development of future research.Furthermore,the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.