The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of th...The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.展开更多
Amyotrophic lateral sclerosis(ALS)is a fatal,late-onset neurodegenerative disorder characterized by the progressive degeneration of motor neurons in the motor cortex,brainstem,and spinal cord(Feldman et al.,2022).
Amyotrophic lateral sclerosis(ALS)is a rapidly progressing neurodegenerative disease,leading to muscle weakness,paralysis and ultimately death due to respiratory failure.Currently licensed drugs have only very limited...Amyotrophic lateral sclerosis(ALS)is a rapidly progressing neurodegenerative disease,leading to muscle weakness,paralysis and ultimately death due to respiratory failure.Currently licensed drugs have only very limited effects on slowing down disease progression or biomarkers.Despite numerous successful preclinical analyses,most new drugs fail when translated to clinical trials(Petrov et al.,2017).This is believed to be,in part,due to the multilayer heterogeneity of ALS(e.g.,clinical,genetic,and molecular;Tzeplaeff et al.,2024).Studies integrating multi-omic data are still limited,making it difficult to fully understand the biological complexity that characterizes the disease.展开更多
Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease marked by motor neuron(MN)degeneration,neuromuscular junction disruption,and muscle atrophy,ultimately leading to paralysis and death.Despit...Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease marked by motor neuron(MN)degeneration,neuromuscular junction disruption,and muscle atrophy,ultimately leading to paralysis and death.Despite extensive research,no effective treatment exists,highlighting the need to elucidate mechanisms driving ALS pathogenesis.About 90%of ALS cases are sporadic ALS and lack a clear genetic cause;the remaining 10%are familial ALS,associated with mutations in over 25 genes.The most common mutations are in superoxide dismutase 1(SOD1)and C9ORF72,with rarer variants in FUS,TARDBP,TBK1,and VCP.展开更多
Based on the split hopkinson pressure bar(SHPB)tests results,the cubic specimens have been numerically modeled in this paper to investigate the impact of key factors,such as the rise time,duration,and incident pulse s...Based on the split hopkinson pressure bar(SHPB)tests results,the cubic specimens have been numerically modeled in this paper to investigate the impact of key factors,such as the rise time,duration,and incident pulse shape,on achieving stress uniformity.After analysis,the paper provides actionable methods aimed at optimizing the conditions for stress uniformity within the cubic specimen.Finally,the lateral inertia effect of cubic specimen has been scrutinized to address the existing gap in this academic area.展开更多
Objective The associations of serum trace element levels with disease progression and survival duration were assessed in individuals diagnosed with sporadic amyotrophic lateral sclerosis(sALS)in China.Methods Clinical...Objective The associations of serum trace element levels with disease progression and survival duration were assessed in individuals diagnosed with sporadic amyotrophic lateral sclerosis(sALS)in China.Methods Clinical data,including diagnostic indicators,clinical characteristics,Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores,and serum concentrations of calcium(Ca),magnesium(Mg),iron(Fe),copper(Cu),and zinc(Zn),were collected for hospitalized patients with sALS between 2018 and 2021.Correlation analysis,random forest analysis,and the Gehan-Breslow-Wilcoxon test were used to evaluate the relations between serum trace element levels,disease progression,and survival duration.Results Lower serum Ca levels and higher Mg levels were observed in patients with ALSFRS-R scores<39.Serum Mg was significantly negatively correlated with ALSFRS-R,trunk,and respiratory scores.Serum Cu and Zn also showed significant negative correlations with the respiratory score,whereas Ca and Fe were not significantly correlated with the ALSFRS-R score.The serum levels of Ca,Mg,Cu,Zn,and Fe remained consistent regardless of the site of disease onset.ALSFRS-R analysis revealed that serum Ca and Mg had a substantial effect on the total ALSFRS-R score,with serum Mg significantly influencing the course of the disease.Notably,low serum Mg levels were associated with extended survival times in patients with sALS.Conclusion Serum levels of Ca and Mg play critical roles in the progression of sALS,and a reduced serum Mg level is related to an extended survival time.展开更多
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration.Despite extensive research,effective treatments remain elusive,underscoring the need to explore ...Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration.Despite extensive research,effective treatments remain elusive,underscoring the need to explore the molecular mechanisms driving disease progression.The amyotrophic lateral sclerosis complexity is further compounded by its large heterogeneity,encompassing both genetic and sporadic forms,diverse phenotypic presentations,and highly variable progression rates.A key pathological feature of amyotrophic lateral sclerosis is the aggregation of TAR DNA-binding protein 43,which contributes to cellular toxicity,neuroinflammation,and neuronal dysfunction.This review explores the complex interplay between TAR DNA-binding protein 43 pathology,immunity dysregulation,and the gut-brain axis,with a focus on the role of microbiome-derived metabolites in amyotrophic lateral sclerosis.Neuroinflammation,mediated by both innate and adaptive immunity,plays a central role in disease pathogenesis,with TAR DNA-binding protein 43 influencing immune signaling and exacerbating neurotoxicity.Additionally,disruptions in gut microbiota composition and intestinal barrier integrity,frequently observed in amyotrophic lateral sclerosis patients,suggest a potential role for the gut-brain axis in modulating neurodegenerative processes.By integrating evidence from emerging studies,our aim is to clarify how TAR DNA-binding protein 43 aggregation contributes to neuroinflammation and immune dysfunction while exploring the gut microbiota role as both a modulator and potential biomarker of disease.Understanding these interactions could pave the way for novel therapeutic strategies,including microbiome-targeted interventions such as probiotics,dietary modifications,or immune-modulating therapies.Finally,unraveling the TAR DNA-binding protein 43-immune system-microbiome axis may offer new avenues for personalized treatments aimed at mitigating neuroinflammation,slowing amyotrophic lateral sclerosis progression,and improving patient outcomes and life quality.展开更多
As a controllable power generation method requiring no energy storage,Ocean Thermal Energy Conversion(OTEC)technology demonstrates characteristics of abundant reserves,low pollution,and round-the-clock stable operatio...As a controllable power generation method requiring no energy storage,Ocean Thermal Energy Conversion(OTEC)technology demonstrates characteristics of abundant reserves,low pollution,and round-the-clock stable operation.The free-standing cold-water pipe(CWP)in the system withstands various complex loads during operation,posing potential failure risks.To reveal the deformation and stress mechanisms of OTEC CWPs,this study first analyzes wave particle velocity and acceleration to determine wave loads at different water depths.Based on the Euler-Bernoulli beam model,a quasi-static load calculation model for OTEC CWPs was established.The governing equations were discretized using the finite difference method,and matrix equations were solved to analyze bending deformation,bending moments,and surface stresses at discrete points along the pipe.Results indicate that water depths within 50 m represent a critical zone where wave particle velocity,acceleration,and wave loads exhibit significant variations in harmonic patterns,while beyond 50 m depth wave loads decrease linearly.Ocean currents and surface wind-driven currents substantially influence the CWP’s lateral displacement.Considering the effect of clump weights,the maximum lateral displacement occurs at 600–800 m below sea level.Utilizing large-wall-thickness high-strength pipes at the top section significantly enhances the structural safety of the CWP system.展开更多
Non-right-handedness(NRH),encompassing left-handedness and mixed-handedness,has been frequently reported at elevated rates in individuals with various psychiatric disorders.The consistency of this association across m...Non-right-handedness(NRH),encompassing left-handedness and mixed-handedness,has been frequently reported at elevated rates in individuals with various psychiatric disorders.The consistency of this association across multiple conditions and its underlying mechanisms is the subject of ongoing investigation.This review synthesized current evidence to explore the association between NRH and psychiatric disorders from epidemiological,genetic,and neurobiological perspectives.We systematically identified and appraised relevant literature investigating NRH prevalence in psychiatric populations and potential explanatory mechanisms.Epidemiological evidence indicates an elevated prevalence of NRH,particularly within neurodevelopmental disorders.Potential contributing mechanisms identified include early developmental disruptions,shared genetic predispositions,and atypical patterns of brain lateralization.While the association between NRH and psychiatric conditions,especially neurodevelopmental disorders,is evident,the causal pathways and relative contributions of identified mechanisms are complex and debated.This review highlighted key areas requiring further research to elucidate these relationships.展开更多
The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident.However,there has yet to be a comprehensive analysis of the clinical characteristics and genetics of famil...The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident.However,there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population.This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland.Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023.A group-based trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis,as well as patients with sporadic amyotrophic lateral sclerosis(matched at a 1:4 ratio,with replacement).DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1,FUS,TDP43,and C9ORF72,of which 146 were also subjected to genome-wide next-generation sequencing.Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort.We found that rapid dynamic disease progression was associated with an older age at onset,shorter diagnostic delay,lower body mass index,bulbar onset,and≥1 affected first-degree relative.Certain attributes,such as age at onset and time from onset to diagnosis,had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis.Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis.Among the patients with familial amyotrophic lateral sclerosis,17.8%possessed≥2 pathogenic/likely pathogenic variants.Sequencing kernel association test analysis showed that the SOD1 rare variant burden(P=1.3e-15)was associated with a significant risk of familial amyotrophic lateral sclerosis.Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China,contributing to a deeper understanding of genotype-phenotype relationships in familial amyotrophic lateral sclerosis.This comprehensive evaluation of specific clinical characteristics,clinical prognosis,and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.展开更多
Detecting biomarkers in body fluids by optical lateral flow immune assay(LFIA) technology provides rapid access to disease information for early diagnosis.LFIA is based on an antigen-antibody reaction and is rapidly b...Detecting biomarkers in body fluids by optical lateral flow immune assay(LFIA) technology provides rapid access to disease information for early diagnosis.LFIA is based on an antigen-antibody reaction and is rapidly becoming the preferred choice of physicians and patients for point-of-care testing due to its simplicity,cost-effectiveness,and rapid detection.Observing the optical signal change from the colloidal gold of the traditional LFIA strip has been widely applied for various biomarkers detection in body fluids.Despite the significant progress,rapid real-time detection of color changes in the colloidal gold by the naked eye still faces many limitations,such as large errors and the inability to quantify and accurately detect.New optical LFIA strip technology has emerged in recent years to extend its application scenarios for achieving quantitative detection such as fluorescence,afterglow,and chemiluminescence.Herein,we summarized the development of optical LFIA technology from single to hyphenated optical signals for biomarkers detection in body fluids from invasive and non-invasive sources.Moreover,the challenge and outlook of optical LFIA strip technology are highlighted to inspire the designing of next-generation diagnostic platforms.展开更多
Protein aggregation drives proteinopathies ranging from ALS to systemic amyloidosis,yet the multiscale determinants bridging sequence,structure,and kinetics remain elusive.We present SKALE,an interpretable machine lea...Protein aggregation drives proteinopathies ranging from ALS to systemic amyloidosis,yet the multiscale determinants bridging sequence,structure,and kinetics remain elusive.We present SKALE,an interpretable machine learning framework that integrates sequence motifs,AlphaFold-derived structural descriptors,and experimental kinetics to decode aggregation mechanisms.SKALE identifies latent hotspots that evade conventional tools and matches high-performing neural baselines while preserving computational efficiency.In ALS-linked SOD1 G86R,the model isolates a risk region at residues 72-91 where preserved β-sheet geometry coincides with weakened hydrogen bonding to drive nucleation.Similarly,analysis of TDP-43 S332N reveals that a locally unwound helix increases surface exposure,a prediction validated by showing that targeted deletion of model-identified regions significantly reduces cellular aggregation.The framework generalizes to Tau P301L and PRNP variants where it uncovers distal aggregation-prone regions to discriminate pathogenic drivers from neutral mutations.Interpretability analysis further disentangles global from mutation-local mechanisms to reveal that β-sheet propensity acts as a shared determinant while hydrogen bond dynamics define specific routes to nucleation.These findings establish SKALE as a scalable,disease-agnostic engine that combines high-fidelity prediction with biophysical resolution to decode the molecular logic of misfolding and guide therapeutic design.展开更多
Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis,even in the presymptomatic stage,implying an etiologic link.However,the genetic mechanism underlying altered lipid level...Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis,even in the presymptomatic stage,implying an etiologic link.However,the genetic mechanism underlying altered lipid levels in amyotrophic lateral sclerosis remains elusive.Therefore,in this study,we performed genetic correlation analysis,a cross-trait meta-analysis,tissue-specific enrichment analysis,and bidirectional two-sample Mendelian randomization analysis of European population to explore whether there is a genetic and causal relationship between lipids and amyotrophic lateral sclerosis.The effect of lipid-lowering drugs on amyotrophic lateral sclerosis was also evaluated using a drug target Mendelian randomization approach.The results showed a positive genetic correlation between amyotrophic lateral sclerosis and both high-density lipoprotein cholesterol and apolipoprotein A1 and identified 71 independent shared loci between amyotrophic lateral sclerosis and high-density lipoprotein cholesterol,as well as 55 independent shared loci between amyotrophic lateral sclerosis and apolipoprotein A1.These shared loci were enriched in the lipid metabolic pathway and the alcohol metabolic pathway.Further Mendelian randomization analysis targeting lipid-lowering drugs showed that single nucleotide polymorphisms within the ACLY and PCSK9 genes had a protective effect against amyotrophic lateral sclerosis risk by decreasing low-density lipoprotein cholesterol.The combination of ACLY and PCSK9 inhibitors has a greater protective effect on amyotrophic lateral sclerosis risk than that of PCSK9 inhibitors alone.In summary,there is a common genetic structure between lipids and amyotrophic lateral sclerosis.Mendelian randomization analysis supports an association between elevated blood lipids and the risk of developing amyotrophic lateral sclerosis,and the use of ACLY or PCSK9 inhibitors may improve disease prognosis.展开更多
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,para...Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,paralysis,and respiratory failure (Morgan and Orrell,2016).展开更多
Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute cour...Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.展开更多
Runway surface roughness significantly influences aircraft vibrations during takeoff and landing,affecting both flight safety and pavement durability.Aircraft operate at high speeds and wide gear spans,making them sen...Runway surface roughness significantly influences aircraft vibrations during takeoff and landing,affecting both flight safety and pavement durability.Aircraft operate at high speeds and wide gear spans,making them sensitive to long-wavelength(15–120 m)and lateral irregularities,which are often overlooked in traditional roughness models.This study aims to construct a three-dimensional runway roughness modeling framework integrating"precise detection-spectrum analysis-spatial reconstruction"in response to this issue.Combining the elevation data of 37 runways(5 asphalt runways and 32 cement runways)measured by a vehicle-mounted laser profilometer and the BeiDou positioning system,the power spectrum analysis was carried out by the Burg method and the spectrum models of asphalt and cement runways were fitted respectively.Meanwhile,a new exponential lateral coherence function was proposed.Finally,the three-dimensional spatial model was reconstructed by using the transfer function and genetic algorithm.The results show that the error of the measured elevation data is less than 1 cm.The spectral characteristics of different pavement types are significantly different.Among them,the R^(2) of the asphalt runway fitted with the Sussman model is greater than 0.9.The cement runway needs to be characterized by a piecewise function to represent the spectral mutation.The fitting error of the new index's lateral coherence function has been reduced to 0.012.The reconstructed three-dimensional model is in good agreement with the theoretical value and the error does not exceed 0.18 mm^(2) m/c.Finally,a three-dimensional model of 0–20 m in the lateral direction and 3000 m in the longitudinal direction is generated,providing support for aircraft vibration simulation and pavement maintenance.展开更多
The presence or absence of adult neural stem cells in the mammalian forebrain ependyma has been debated for two decades.In this study,we performed single-cell RNA sequencing to investigate the cellular composition of ...The presence or absence of adult neural stem cells in the mammalian forebrain ependyma has been debated for two decades.In this study,we performed single-cell RNA sequencing to investigate the cellular composition of the ependymal surface of the adult mouse forebrain using whole mounts of lateral walls of lateral ventricles.We identified 12 different cell subtypes in the ependymal surface.Immunocytochemical analyses revealed that CD133^(+)multi-ciliated cells comprised 67.6%of ependymal cells,while the remaining 32.4%were CD133^(-).CD133^(+)ependymal cells can be further classified into FOXJ1^(+)/SOX2^(+)/ACTA2^(+)cells,FLT1^(+)/CD31^(+)/CLDN5^(+)endothelial-like cells,and PDGFRB^(+)/VTN^(+)/NG2^(+)pericyte-like cells,as well as endothelial-pericyte-like cells and Foxj1^(+)endothelial-like cells.CD133^(-)ependymal cells can be further divided into endothelial-like cells,Foxj1^(+)ependymal cells,Foxj1^(+)endothelial-like cells,pericyte-like cells,endothelial-pericyte-like cells,VIM^(+)cells,and cells negative for all of these markers.This comprehensive profiling confirms the heterogeneity of the ependymal surface in the adult mouse forebrain.Debate regarding whether adult ependymal cells contain neural stem cells has arisen because different researchers have examined different populations of ependymal cells.Our study provides a new perspective for investigation of clinical endogenous neural stem cells,ultimately paving the way for stem cell therapies in neurological diseases.展开更多
Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system.Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders...Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system.Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders that adversely affect the lives of millions of people worldwide.Therefore,it is necessary to elucidate the mechanism of neurodegenerative diseases further and find effective new therapies.In recent years,increasing evidence has shown that the immune system plays a significant role in the pathophysiology of neurodegenerative diseases and regulates this process.The central and peripheral immune systems exert different roles in the disease progression.The development of neurodegenerative diseases is influenced by interactions between them.This review focuses on how the immune system,including microglia mediated nucleotide-binding oligomerization domain-like receptor protein 3 inflammation activation and T cell-mediated neuroinflammation,interactions with neurodegenerative diseases by modulating protein aggregation and blood-brain barrier permeability.Besides,we gave particular attention to glial cell-centered multicellular interactions and the inflammatory signaling pathway.Insight into the immune system’s functions and cellular interactions is essential for progressing disease research.In addition,the functions and mechanisms of these immune cells also suggest new ideas and targets for treatment.Therefore,this review summarizes some of the existing treatment strategies for amyloid-beta,tau,neuroinflammation,α-synuclein,associated microbiota,immune modulation,and neural injury repair.In addition,this review summarizes and compares animal models of different common neurodegenerative diseases and clinical research progress.In view of the current research status,new research directions and suggestions are proposed.展开更多
Objective Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis(ALS).In this study,we investigated the functional mechanisms of T cell subtypes and assessed the causal lin...Objective Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis(ALS).In this study,we investigated the functional mechanisms of T cell subtypes and assessed the causal links between CD4+cytotoxic T cell-related genes and ALS risk.Methods Single-cell RNA sequencing(scRNA-seq)of peripheral blood mononuclear cells(PBMCs)from patients with ALS and healthy controls(HC)was used to identify differentially expressed genes(DEGs)in CD4+cytotoxic T cells.Comprehensive analyses of CD4+cytotoxic T cells,including pseudotemporal trajectory,intercellular communication,and metabolic pathway analysis,were performed.Mendelian randomization(MR)analysis evaluated the causal effects of DEGs on ALS risk,with validation using independent genome-wide association study(GWAS)data.Expression patterns of the causal genes were further verified using scRNA-seq,bulk-seq,and clinical samples.Results CD4+cytotoxic T cells were significantly expanded in patients with ALS.The upregulated genes S100A6,SERPINB6,SMAD7,and TPST2 were positively correlated with ALS susceptibility,whereas DIP2A showed a protective association.Conclusion S100A6,SERPINB6,SMAD7,TPST2,and DIP2A were identified as causal genes and potential therapeutic targets in ALS,implicating CD4+cytotoxic T cells in the disease mechanisms.Further studies targeting these genes and neuroinflammatory pathways are warranted.展开更多
基金partly supported by the Yan’an University Qin Chuanyuan“Scientist+Engineer”Team Special Fund,No.2023KXJ-012(to YL)Yan’an University Transformation of Scientific and Technological Achievements Fund,No.2023CGZH-001(to YL)+2 种基金College Students Innovation and Entrepreneurship Training Program,Nos.D2023158,202410719056(to XS,JM)Yan’an University Production and Cultivation Project,No.CXY202001(to YL)Kweichow Moutai Hospital Research and Talent Development Fund Project,No.MTyk2022-25(to XO)。
文摘The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.
基金supported by the Else Kröner-Fresenius-Stiftung(2021-EKSE.95)the Deutsche Forschungsgemeinschaft(CRC1678 and Germany’s Excellence Strategy-CECAD,EXC 2030-390661388)(to DV).
文摘Amyotrophic lateral sclerosis(ALS)is a fatal,late-onset neurodegenerative disorder characterized by the progressive degeneration of motor neurons in the motor cortex,brainstem,and spinal cord(Feldman et al.,2022).
文摘Amyotrophic lateral sclerosis(ALS)is a rapidly progressing neurodegenerative disease,leading to muscle weakness,paralysis and ultimately death due to respiratory failure.Currently licensed drugs have only very limited effects on slowing down disease progression or biomarkers.Despite numerous successful preclinical analyses,most new drugs fail when translated to clinical trials(Petrov et al.,2017).This is believed to be,in part,due to the multilayer heterogeneity of ALS(e.g.,clinical,genetic,and molecular;Tzeplaeff et al.,2024).Studies integrating multi-omic data are still limited,making it difficult to fully understand the biological complexity that characterizes the disease.
文摘Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease marked by motor neuron(MN)degeneration,neuromuscular junction disruption,and muscle atrophy,ultimately leading to paralysis and death.Despite extensive research,no effective treatment exists,highlighting the need to elucidate mechanisms driving ALS pathogenesis.About 90%of ALS cases are sporadic ALS and lack a clear genetic cause;the remaining 10%are familial ALS,associated with mutations in over 25 genes.The most common mutations are in superoxide dismutase 1(SOD1)and C9ORF72,with rarer variants in FUS,TARDBP,TBK1,and VCP.
基金Funded by the National Natural Science Foundation of China(Nos.52278518 and 51938011)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(No.24KJB560021)。
文摘Based on the split hopkinson pressure bar(SHPB)tests results,the cubic specimens have been numerically modeled in this paper to investigate the impact of key factors,such as the rise time,duration,and incident pulse shape,on achieving stress uniformity.After analysis,the paper provides actionable methods aimed at optimizing the conditions for stress uniformity within the cubic specimen.Finally,the lateral inertia effect of cubic specimen has been scrutinized to address the existing gap in this academic area.
文摘Objective The associations of serum trace element levels with disease progression and survival duration were assessed in individuals diagnosed with sporadic amyotrophic lateral sclerosis(sALS)in China.Methods Clinical data,including diagnostic indicators,clinical characteristics,Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores,and serum concentrations of calcium(Ca),magnesium(Mg),iron(Fe),copper(Cu),and zinc(Zn),were collected for hospitalized patients with sALS between 2018 and 2021.Correlation analysis,random forest analysis,and the Gehan-Breslow-Wilcoxon test were used to evaluate the relations between serum trace element levels,disease progression,and survival duration.Results Lower serum Ca levels and higher Mg levels were observed in patients with ALSFRS-R scores<39.Serum Mg was significantly negatively correlated with ALSFRS-R,trunk,and respiratory scores.Serum Cu and Zn also showed significant negative correlations with the respiratory score,whereas Ca and Fe were not significantly correlated with the ALSFRS-R score.The serum levels of Ca,Mg,Cu,Zn,and Fe remained consistent regardless of the site of disease onset.ALSFRS-R analysis revealed that serum Ca and Mg had a substantial effect on the total ALSFRS-R score,with serum Mg significantly influencing the course of the disease.Notably,low serum Mg levels were associated with extended survival times in patients with sALS.Conclusion Serum levels of Ca and Mg play critical roles in the progression of sALS,and a reduced serum Mg level is related to an extended survival time.
文摘Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration.Despite extensive research,effective treatments remain elusive,underscoring the need to explore the molecular mechanisms driving disease progression.The amyotrophic lateral sclerosis complexity is further compounded by its large heterogeneity,encompassing both genetic and sporadic forms,diverse phenotypic presentations,and highly variable progression rates.A key pathological feature of amyotrophic lateral sclerosis is the aggregation of TAR DNA-binding protein 43,which contributes to cellular toxicity,neuroinflammation,and neuronal dysfunction.This review explores the complex interplay between TAR DNA-binding protein 43 pathology,immunity dysregulation,and the gut-brain axis,with a focus on the role of microbiome-derived metabolites in amyotrophic lateral sclerosis.Neuroinflammation,mediated by both innate and adaptive immunity,plays a central role in disease pathogenesis,with TAR DNA-binding protein 43 influencing immune signaling and exacerbating neurotoxicity.Additionally,disruptions in gut microbiota composition and intestinal barrier integrity,frequently observed in amyotrophic lateral sclerosis patients,suggest a potential role for the gut-brain axis in modulating neurodegenerative processes.By integrating evidence from emerging studies,our aim is to clarify how TAR DNA-binding protein 43 aggregation contributes to neuroinflammation and immune dysfunction while exploring the gut microbiota role as both a modulator and potential biomarker of disease.Understanding these interactions could pave the way for novel therapeutic strategies,including microbiome-targeted interventions such as probiotics,dietary modifications,or immune-modulating therapies.Finally,unraveling the TAR DNA-binding protein 43-immune system-microbiome axis may offer new avenues for personalized treatments aimed at mitigating neuroinflammation,slowing amyotrophic lateral sclerosis progression,and improving patient outcomes and life quality.
基金supported by a grant from NIH(R01AI132695)to RM。
文摘Chronic wasting disease—a prion disease affecting cervids:Many neurological conditions,including Alzheimer's and Parkinson's diseases,amyotrophic lateral sclerosis,frontotemporal dementias,among others,are caused by the accumulation of misfolded proteins in the brain.These diseases affect not only humans,but also animals.
基金funded by Nansha District Science and Technology Project(Grant Number.2024ZD008)funded by China Geological Survey(Grant number:No.DD20230066,DD20242659).
文摘As a controllable power generation method requiring no energy storage,Ocean Thermal Energy Conversion(OTEC)technology demonstrates characteristics of abundant reserves,low pollution,and round-the-clock stable operation.The free-standing cold-water pipe(CWP)in the system withstands various complex loads during operation,posing potential failure risks.To reveal the deformation and stress mechanisms of OTEC CWPs,this study first analyzes wave particle velocity and acceleration to determine wave loads at different water depths.Based on the Euler-Bernoulli beam model,a quasi-static load calculation model for OTEC CWPs was established.The governing equations were discretized using the finite difference method,and matrix equations were solved to analyze bending deformation,bending moments,and surface stresses at discrete points along the pipe.Results indicate that water depths within 50 m represent a critical zone where wave particle velocity,acceleration,and wave loads exhibit significant variations in harmonic patterns,while beyond 50 m depth wave loads decrease linearly.Ocean currents and surface wind-driven currents substantially influence the CWP’s lateral displacement.Considering the effect of clump weights,the maximum lateral displacement occurs at 600–800 m below sea level.Utilizing large-wall-thickness high-strength pipes at the top section significantly enhances the structural safety of the CWP system.
文摘Non-right-handedness(NRH),encompassing left-handedness and mixed-handedness,has been frequently reported at elevated rates in individuals with various psychiatric disorders.The consistency of this association across multiple conditions and its underlying mechanisms is the subject of ongoing investigation.This review synthesized current evidence to explore the association between NRH and psychiatric disorders from epidemiological,genetic,and neurobiological perspectives.We systematically identified and appraised relevant literature investigating NRH prevalence in psychiatric populations and potential explanatory mechanisms.Epidemiological evidence indicates an elevated prevalence of NRH,particularly within neurodevelopmental disorders.Potential contributing mechanisms identified include early developmental disruptions,shared genetic predispositions,and atypical patterns of brain lateralization.While the association between NRH and psychiatric conditions,especially neurodevelopmental disorders,is evident,the causal pathways and relative contributions of identified mechanisms are complex and debated.This review highlighted key areas requiring further research to elucidate these relationships.
基金supported by the Natural Science Foundation of Beijing,Nos.7244428(to WZ)and 7222215(to JH)the Peking University Medicine Sailing Program forYoung Scholars’Scientific and Technological Innovation,No.BMU2023YFJHPY034(to WZ)+4 种基金the National Natural Science Foundation of China,Nos.81873784,82071426(to DF),and81974197(to JH)the Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(to DF)Beijing Physician-Scientist TrainingProgram,No.BJPSTP-2024-03(to JH)the China Postdoctoral Science Foundation,Nos.2022TQ0014(to LX),2022M720284(to LX)the E-Town Cooperation&Development Foundation,No.YCXJ-JZ-2023-017(to LX).
文摘The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident.However,there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population.This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland.Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023.A group-based trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis,as well as patients with sporadic amyotrophic lateral sclerosis(matched at a 1:4 ratio,with replacement).DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1,FUS,TDP43,and C9ORF72,of which 146 were also subjected to genome-wide next-generation sequencing.Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort.We found that rapid dynamic disease progression was associated with an older age at onset,shorter diagnostic delay,lower body mass index,bulbar onset,and≥1 affected first-degree relative.Certain attributes,such as age at onset and time from onset to diagnosis,had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis.Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis.Among the patients with familial amyotrophic lateral sclerosis,17.8%possessed≥2 pathogenic/likely pathogenic variants.Sequencing kernel association test analysis showed that the SOD1 rare variant burden(P=1.3e-15)was associated with a significant risk of familial amyotrophic lateral sclerosis.Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China,contributing to a deeper understanding of genotype-phenotype relationships in familial amyotrophic lateral sclerosis.This comprehensive evaluation of specific clinical characteristics,clinical prognosis,and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.
基金supported by the National Natural Science Foundation of China (Nos.22234005,22494632,22404081)the Natural Science Foundation of Jiangsu Province (Nos.BK20222015,BK20240534)。
文摘Detecting biomarkers in body fluids by optical lateral flow immune assay(LFIA) technology provides rapid access to disease information for early diagnosis.LFIA is based on an antigen-antibody reaction and is rapidly becoming the preferred choice of physicians and patients for point-of-care testing due to its simplicity,cost-effectiveness,and rapid detection.Observing the optical signal change from the colloidal gold of the traditional LFIA strip has been widely applied for various biomarkers detection in body fluids.Despite the significant progress,rapid real-time detection of color changes in the colloidal gold by the naked eye still faces many limitations,such as large errors and the inability to quantify and accurately detect.New optical LFIA strip technology has emerged in recent years to extend its application scenarios for achieving quantitative detection such as fluorescence,afterglow,and chemiluminescence.Herein,we summarized the development of optical LFIA technology from single to hyphenated optical signals for biomarkers detection in body fluids from invasive and non-invasive sources.Moreover,the challenge and outlook of optical LFIA strip technology are highlighted to inspire the designing of next-generation diagnostic platforms.
基金International Brain Research Organization(IBRO)Rising Star Awardee and received an IBRO Early Career Principal Investigator Grant(No.PM010CNI000148)supported by Sunway University internal grant(No.GRTIN-IGS[02]-CVVR-11-2023)+2 种基金supported by the Fundamental Research Funds from the Central of Public Welfare Research Institute,China Rehabilitation Institutesupported by the research initiation funding scheme provided by Henan University of Technology(No.0004/31401568)Shenzhen Vaccine Biopharmaceuticals Limited(No.0004/51100292).
文摘Protein aggregation drives proteinopathies ranging from ALS to systemic amyloidosis,yet the multiscale determinants bridging sequence,structure,and kinetics remain elusive.We present SKALE,an interpretable machine learning framework that integrates sequence motifs,AlphaFold-derived structural descriptors,and experimental kinetics to decode aggregation mechanisms.SKALE identifies latent hotspots that evade conventional tools and matches high-performing neural baselines while preserving computational efficiency.In ALS-linked SOD1 G86R,the model isolates a risk region at residues 72-91 where preserved β-sheet geometry coincides with weakened hydrogen bonding to drive nucleation.Similarly,analysis of TDP-43 S332N reveals that a locally unwound helix increases surface exposure,a prediction validated by showing that targeted deletion of model-identified regions significantly reduces cellular aggregation.The framework generalizes to Tau P301L and PRNP variants where it uncovers distal aggregation-prone regions to discriminate pathogenic drivers from neutral mutations.Interpretability analysis further disentangles global from mutation-local mechanisms to reveal that β-sheet propensity acts as a shared determinant while hydrogen bond dynamics define specific routes to nucleation.These findings establish SKALE as a scalable,disease-agnostic engine that combines high-fidelity prediction with biophysical resolution to decode the molecular logic of misfolding and guide therapeutic design.
基金funded by the National Natural Science Foundation of China,Nos.82401670(to KX),81873784(to DF),and 82071426(to DF)the Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(to DF)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation,No.GZC20230152(to KX).
文摘Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis,even in the presymptomatic stage,implying an etiologic link.However,the genetic mechanism underlying altered lipid levels in amyotrophic lateral sclerosis remains elusive.Therefore,in this study,we performed genetic correlation analysis,a cross-trait meta-analysis,tissue-specific enrichment analysis,and bidirectional two-sample Mendelian randomization analysis of European population to explore whether there is a genetic and causal relationship between lipids and amyotrophic lateral sclerosis.The effect of lipid-lowering drugs on amyotrophic lateral sclerosis was also evaluated using a drug target Mendelian randomization approach.The results showed a positive genetic correlation between amyotrophic lateral sclerosis and both high-density lipoprotein cholesterol and apolipoprotein A1 and identified 71 independent shared loci between amyotrophic lateral sclerosis and high-density lipoprotein cholesterol,as well as 55 independent shared loci between amyotrophic lateral sclerosis and apolipoprotein A1.These shared loci were enriched in the lipid metabolic pathway and the alcohol metabolic pathway.Further Mendelian randomization analysis targeting lipid-lowering drugs showed that single nucleotide polymorphisms within the ACLY and PCSK9 genes had a protective effect against amyotrophic lateral sclerosis risk by decreasing low-density lipoprotein cholesterol.The combination of ACLY and PCSK9 inhibitors has a greater protective effect on amyotrophic lateral sclerosis risk than that of PCSK9 inhibitors alone.In summary,there is a common genetic structure between lipids and amyotrophic lateral sclerosis.Mendelian randomization analysis supports an association between elevated blood lipids and the risk of developing amyotrophic lateral sclerosis,and the use of ACLY or PCSK9 inhibitors may improve disease prognosis.
文摘Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,paralysis,and respiratory failure (Morgan and Orrell,2016).
基金supported by the National Key Research and Development Program of China,No.2022YFC2703101(to YC)the National Natural Science Fundation of China,No.82371422(to YC)+1 种基金the National Innovation and Entrepreneurship Training Program for College Students,No.202310611408(to XW)the 1·3·5 Project for Disciplines of Excellence Clinical Research Fund,West China Hospital,Sichuan University,No.2023HXFH032(to YC)。
文摘Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.
基金supported by the National Natural Science Foundation of China(Grant No.52402430,52572380)the Natural Science Foundation of Shanghai(Grant No.23ZR1466300).
文摘Runway surface roughness significantly influences aircraft vibrations during takeoff and landing,affecting both flight safety and pavement durability.Aircraft operate at high speeds and wide gear spans,making them sensitive to long-wavelength(15–120 m)and lateral irregularities,which are often overlooked in traditional roughness models.This study aims to construct a three-dimensional runway roughness modeling framework integrating"precise detection-spectrum analysis-spatial reconstruction"in response to this issue.Combining the elevation data of 37 runways(5 asphalt runways and 32 cement runways)measured by a vehicle-mounted laser profilometer and the BeiDou positioning system,the power spectrum analysis was carried out by the Burg method and the spectrum models of asphalt and cement runways were fitted respectively.Meanwhile,a new exponential lateral coherence function was proposed.Finally,the three-dimensional spatial model was reconstructed by using the transfer function and genetic algorithm.The results show that the error of the measured elevation data is less than 1 cm.The spectral characteristics of different pavement types are significantly different.Among them,the R^(2) of the asphalt runway fitted with the Sussman model is greater than 0.9.The cement runway needs to be characterized by a piecewise function to represent the spectral mutation.The fitting error of the new index's lateral coherence function has been reduced to 0.012.The reconstructed three-dimensional model is in good agreement with the theoretical value and the error does not exceed 0.18 mm^(2) m/c.Finally,a three-dimensional model of 0–20 m in the lateral direction and 3000 m in the longitudinal direction is generated,providing support for aircraft vibration simulation and pavement maintenance.
基金supported by the State Key Program of the National Natural Science Foundation of China,No.82030035(to YES)Peak Disciplines(Type IV)of Institutions of Higher Learning in Shanghai(to LZ).
文摘The presence or absence of adult neural stem cells in the mammalian forebrain ependyma has been debated for two decades.In this study,we performed single-cell RNA sequencing to investigate the cellular composition of the ependymal surface of the adult mouse forebrain using whole mounts of lateral walls of lateral ventricles.We identified 12 different cell subtypes in the ependymal surface.Immunocytochemical analyses revealed that CD133^(+)multi-ciliated cells comprised 67.6%of ependymal cells,while the remaining 32.4%were CD133^(-).CD133^(+)ependymal cells can be further classified into FOXJ1^(+)/SOX2^(+)/ACTA2^(+)cells,FLT1^(+)/CD31^(+)/CLDN5^(+)endothelial-like cells,and PDGFRB^(+)/VTN^(+)/NG2^(+)pericyte-like cells,as well as endothelial-pericyte-like cells and Foxj1^(+)endothelial-like cells.CD133^(-)ependymal cells can be further divided into endothelial-like cells,Foxj1^(+)ependymal cells,Foxj1^(+)endothelial-like cells,pericyte-like cells,endothelial-pericyte-like cells,VIM^(+)cells,and cells negative for all of these markers.This comprehensive profiling confirms the heterogeneity of the ependymal surface in the adult mouse forebrain.Debate regarding whether adult ependymal cells contain neural stem cells has arisen because different researchers have examined different populations of ependymal cells.Our study provides a new perspective for investigation of clinical endogenous neural stem cells,ultimately paving the way for stem cell therapies in neurological diseases.
基金supported by the Natural Science Foundation of Zhejiang Province of China,Nos.LZYQ25H270001(to LY),LY24H270007(to WJ)Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project,No.2023ZR011(to LY)+2 种基金China Postdoctoral Science Foundation,No.2023TQ0295(to LY)Postdoctoral Research Projects Merit-based Funding in Zhejiang Province(First-class funding),No.ZJ2023021(to LY)Xinmiao Talents Project of Zhejiang Province,No.2024R410A022(to YC).
文摘Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system.Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders that adversely affect the lives of millions of people worldwide.Therefore,it is necessary to elucidate the mechanism of neurodegenerative diseases further and find effective new therapies.In recent years,increasing evidence has shown that the immune system plays a significant role in the pathophysiology of neurodegenerative diseases and regulates this process.The central and peripheral immune systems exert different roles in the disease progression.The development of neurodegenerative diseases is influenced by interactions between them.This review focuses on how the immune system,including microglia mediated nucleotide-binding oligomerization domain-like receptor protein 3 inflammation activation and T cell-mediated neuroinflammation,interactions with neurodegenerative diseases by modulating protein aggregation and blood-brain barrier permeability.Besides,we gave particular attention to glial cell-centered multicellular interactions and the inflammatory signaling pathway.Insight into the immune system’s functions and cellular interactions is essential for progressing disease research.In addition,the functions and mechanisms of these immune cells also suggest new ideas and targets for treatment.Therefore,this review summarizes some of the existing treatment strategies for amyloid-beta,tau,neuroinflammation,α-synuclein,associated microbiota,immune modulation,and neural injury repair.In addition,this review summarizes and compares animal models of different common neurodegenerative diseases and clinical research progress.In view of the current research status,new research directions and suggestions are proposed.
文摘Objective Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis(ALS).In this study,we investigated the functional mechanisms of T cell subtypes and assessed the causal links between CD4+cytotoxic T cell-related genes and ALS risk.Methods Single-cell RNA sequencing(scRNA-seq)of peripheral blood mononuclear cells(PBMCs)from patients with ALS and healthy controls(HC)was used to identify differentially expressed genes(DEGs)in CD4+cytotoxic T cells.Comprehensive analyses of CD4+cytotoxic T cells,including pseudotemporal trajectory,intercellular communication,and metabolic pathway analysis,were performed.Mendelian randomization(MR)analysis evaluated the causal effects of DEGs on ALS risk,with validation using independent genome-wide association study(GWAS)data.Expression patterns of the causal genes were further verified using scRNA-seq,bulk-seq,and clinical samples.Results CD4+cytotoxic T cells were significantly expanded in patients with ALS.The upregulated genes S100A6,SERPINB6,SMAD7,and TPST2 were positively correlated with ALS susceptibility,whereas DIP2A showed a protective association.Conclusion S100A6,SERPINB6,SMAD7,TPST2,and DIP2A were identified as causal genes and potential therapeutic targets in ALS,implicating CD4+cytotoxic T cells in the disease mechanisms.Further studies targeting these genes and neuroinflammatory pathways are warranted.
