Stimulus-Response Compatibility (SRC) refers to the fact that some tasks are performed easier and better than others because of the way stimuli and responses are paired with each other. To assess the brain responses t...Stimulus-Response Compatibility (SRC) refers to the fact that some tasks are performed easier and better than others because of the way stimuli and responses are paired with each other. To assess the brain responses to stimulus-response conflicts, we investigated the behavioral (accuracy and Reaction Times: RTs) as well as the physiological response (Lateralized Readiness Potentials: LRP) modulations in a positional blocked and a conditional mixed design in twelve university students. Results revealed that the performance was less accurate and the RTs, as well as the LRP onset, were delayed under the mixed conditional design. A greater compatibility effect was also noted on accuracy, RTs and LRP onset latency in the mixed design. Consistent with these findings, smaller peak activation at fronto-central areas suggests that more selective inhibition is needed in a mixed design context. Despite a smaller activation, the topographical distribution is similar in both designs. These results indicate that the translation time between stimulus- and response codes are greater under the mixed instruction, while the similar LRP topography suggests that common neural structures underlie LRPs in response to both type of designs.展开更多
Asymmetries in bilateral organisms attract a lot of curiosity given that they are conspicuous departures from the norm.They allow the investigation of the integration at different levels of biological organization.Her...Asymmetries in bilateral organisms attract a lot of curiosity given that they are conspicuous departures from the norm.They allow the investigation of the integration at different levels of biological organization.Here we study whether and how behavioral and asymmetrical anatomical traits coevolved and work together.We ask if asymmetry is determined locally for each trait or at a whole individual level in a species bearing conspicuous asymmetrical genitalia.Asymmetric genitalia evolved in many species;however,in most cases the direction of asymmetry is fixed.Therefore,it has been rarely determined if there is an association between the direction of asymmetry in genitalia and other traits.In onesided livebearer fish of the genus Jenynsia(Cyprinodontiformes,Anablepidae),the anal fin of males is modified into a gonopodium,an intromittent organ that serves to inseminate females.The gonopodium shows a conspicuous asymmetry,with its tip bending either to the left or the right.By surveying 13 natural populations of Jenynsia lineata,we found that both genital morphs are equally common in wild populations.In a series of experiments in a laboratory population,we discovered asymmetry and lateralization for multiple other traits;yet,the degree of integration varied highly among them.Lateralization in exploratory behavior in response to different stimuli was not associated with genital morphology.Interestingly,the direction of genital asymmetry was positively correlated with sidedness of mating preference and the number of neuromasts in the lateral line.This suggests integration of functionally linked asymmetric traits;however,there is no evidence that asymmetry is determined at the whole individual level in our study species.展开更多
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
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
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
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
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
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
Lateral movement represents the most covert and critical phase of Advanced Persistent Threats(APTs),and its detection still faces two primary challenges:sample scarcity and“cold start”of new entities.To address thes...Lateral movement represents the most covert and critical phase of Advanced Persistent Threats(APTs),and its detection still faces two primary challenges:sample scarcity and“cold start”of new entities.To address these challenges,we propose an Uncertainty-Driven Graph Embedding-Enhanced Lateral Movement Detection framework(UGEA-LMD).First,the framework employs event-level incremental encoding on a continuous-time graph to capture fine-grained behavioral evolution,enabling newly appearing nodes to retain temporal contextual awareness even in the absence of historical interactions and thereby fundamentally mitigating the cold-start problem.Second,in the embedding space,we model the dependency structure among feature dimensions using a Gaussian copula to quantify the uncertainty distribution,and generate augmented samples with consistent structural and semantic properties through adaptive sampling,thus expanding the representation space of sparse samples and enhancing the model’s generalization under sparse sample conditions.Unlike static graph methods that cannot model temporal dependencies or data augmentation techniques that depend on predefined structures,UGEA-LMD offers both superior temporaldynamic modeling and structural generalization.Experimental results on the large-scale LANL log dataset demonstrate that,under the transductive setting,UGEA-LMD achieves an AUC of 0.9254;even when 10%of nodes or edges are withheld during training,UGEA-LMD significantly outperforms baseline methods on metrics such as recall and AUC,confirming its robustness and generalization capability in sparse-sample and cold-start scenarios.展开更多
N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory lo...N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.展开更多
Emerging evidence suggests that the gut microbiota is closely associated with the pathological manifestations of multiple neurodegenerative diseases via the gut-brain axis,which refers to the crosstalk between the gut...Emerging evidence suggests that the gut microbiota is closely associated with the pathological manifestations of multiple neurodegenerative diseases via the gut-brain axis,which refers to the crosstalk between the gut and the central nervous system.More importantly,mitochondria have been considered prominent mediators of the interplay between the gut microbiota and the brain.Intestinal microbes may modulate mitochondrial function in the central nervous system to affect the progression of neurodegenerative diseases.Mitochondria are essential for meeting the host’s substantial neuronal metabolic demands,maintaining excitability,and facilitating synaptic transmission.Dysfunctional mitochondria are considered critical hallmarks of various neurodegenerative diseases.Therefore,this review provides novel insights into the intricate roles of gut microbiota-mitochondrial crosstalk in the underlying mechanisms during the progression of neurodegeneration,as well as the existing potential therapeutic strategies for neurodegenerative disorders.These suggest intestinal microbiota-mitochondrial interaction play a crucial role in the occurrence and development of neurodegenerative diseases,and targeting this interaction may be a promising therapeutic approach to neurodegenerative diseases.However,this review found that there was relatively little research on the effect of this crosstalk on other neurodegenerative diseases,such as Huntington’s disease and Multiple sclerosis,and the potential therapeutic strategies were translated into clinical trials,which face many challenges in developing personalized treatment plans based on the unique gut microbiota of different individuals.展开更多
N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)...N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.展开更多
The adult subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal dentate gyrus(DG)are the two brain regions where neurogenesis occurs throughout life in the adult mammalian brain(Min...The adult subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal dentate gyrus(DG)are the two brain regions where neurogenesis occurs throughout life in the adult mammalian brain(Ming and Song,2011).Adult quiescent hippocampal neural stem cells(NSCs)are bona fide stem cells and,when activated,give rise to newborn granule neurons in the adult brain,which play vital roles in learning,memory,mood,and affective cognition(Bonaguidi et al.,2011;Ming and Song,2011).展开更多
With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of th...With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.展开更多
Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system,leading to a decline in patients'cognitive,motor,and emotional abilities.Neuroinflammati...Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system,leading to a decline in patients'cognitive,motor,and emotional abilities.Neuroinflammation plays a significant role in the progression of these diseases.However,there is limited research on therapeutic approaches to specifically target neuroinflammation.The role of T lymphocytes,which are crucial mediators of the adaptive immune response,in neurodegenerative diseases has been increasingly recognized.This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases.The pathogenesis of neurodegenerative diseases is complex,involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons,and T cells are a key component of these processes.One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells,including microglia,astrocytes,B cells,and natural killer cells.Different subsets of CD4~+T cells,such as Th1,Th2,Th17,and regulatory T cells,can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases.Additionally,CD8~+T cells,which can directly regulate immune responses and kill target cells,also play several important roles in neurodegenerative diseases.Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that,while some patients respond positively,others may not respond as well and may even experience adverse effects.Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system,which can lead to undesirable side effects.However,with new insights into the pathophysiology of neurodegenerative diseases,there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.展开更多
Functional laterality is known as an intrinsic property of the brain.Since several studies have shown the presence of laterality in many species other than humans,it has been suggested that this is an adaptive mechani...Functional laterality is known as an intrinsic property of the brain.Since several studies have shown the presence of laterality in many species other than humans,it has been suggested that this is an adaptive mechanism to aid survival.Previous studies have shown that lateralized behavior observed during exposure to different environmental stimuli is not constant in normal animals,depending on the geometrical form of the exploratory field.In these exploratory fields,animals showed right-or left-biased exploratory behavior,according to the nature of the geometrical properties of the environment.Previously,it was found that tellurium(Te)was able to block spontaneous left-biased exploration in one defined geometrical environment.In the present work,the influence of Te and selenium(Se)in animals exposed to novel geometrically different environments were studied.Three geometrically different testing fields(square,rectangle,and T-shaped)were presented to Se-and Te-treated groups of rats.The results show that in the square field,only the Se treatment was able to block spontaneous right-biased exploratory responses;in the rectangular field,both Se and Te treatments blocked right-biased exploratory responses,and in the T-shaped field,only Te was able to block spontaneous left-biased exploratory responses.Data suggest that trace elements modify lateralized behavioral responses independently of the form of the novel exploratory field,suggesting the presence of a specific action in the brain.展开更多
Laterality is conceived as a functional property of the brain,where parallel neural circuits modulate complementary aspects of one function.Well known examples are handedness and speech in humans.Laterality also is pr...Laterality is conceived as a functional property of the brain,where parallel neural circuits modulate complementary aspects of one function.Well known examples are handedness and speech in humans.Laterality also is present in animals indicating a general evolutionary functional aspect and not a single distinctive trait of humans.In the present work,the consistency of one lateralized response in the spontaneous behaviour of exploration,driven by novel environments with different geometrical proportions was studied in rats.Consistency of response was considered when the animal shows the same preferential display in different testing contexts.Three geometrical forms of environments(square,rectangle and T shaped environment)were presented to normal intact rats.Exploratory activity measured by a digital counting device was video‐taped in a 3 min duration tests.In these environments,rats had the choice to explore the right or the left aspect of the devices.Results show that in the square box,animals showed a right‐biased exploration,and show no preference in the rectangular box,and left‐biased exploration in the T shaped environment.Data reveal that animals show inconsistency in the lateralized behavioural response,where the geometrical characteristics of the environment are important to display some biased response.展开更多
Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is...Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.展开更多
文摘Stimulus-Response Compatibility (SRC) refers to the fact that some tasks are performed easier and better than others because of the way stimuli and responses are paired with each other. To assess the brain responses to stimulus-response conflicts, we investigated the behavioral (accuracy and Reaction Times: RTs) as well as the physiological response (Lateralized Readiness Potentials: LRP) modulations in a positional blocked and a conditional mixed design in twelve university students. Results revealed that the performance was less accurate and the RTs, as well as the LRP onset, were delayed under the mixed conditional design. A greater compatibility effect was also noted on accuracy, RTs and LRP onset latency in the mixed design. Consistent with these findings, smaller peak activation at fronto-central areas suggests that more selective inhibition is needed in a mixed design context. Despite a smaller activation, the topographical distribution is similar in both designs. These results indicate that the translation time between stimulus- and response codes are greater under the mixed instruction, while the similar LRP topography suggests that common neural structures underlie LRPs in response to both type of designs.
基金This work was supported by the Deutsche Forschungsgemeinschaft,Grant Number TO914/2-1 to J.T-D.
文摘Asymmetries in bilateral organisms attract a lot of curiosity given that they are conspicuous departures from the norm.They allow the investigation of the integration at different levels of biological organization.Here we study whether and how behavioral and asymmetrical anatomical traits coevolved and work together.We ask if asymmetry is determined locally for each trait or at a whole individual level in a species bearing conspicuous asymmetrical genitalia.Asymmetric genitalia evolved in many species;however,in most cases the direction of asymmetry is fixed.Therefore,it has been rarely determined if there is an association between the direction of asymmetry in genitalia and other traits.In onesided livebearer fish of the genus Jenynsia(Cyprinodontiformes,Anablepidae),the anal fin of males is modified into a gonopodium,an intromittent organ that serves to inseminate females.The gonopodium shows a conspicuous asymmetry,with its tip bending either to the left or the right.By surveying 13 natural populations of Jenynsia lineata,we found that both genital morphs are equally common in wild populations.In a series of experiments in a laboratory population,we discovered asymmetry and lateralization for multiple other traits;yet,the degree of integration varied highly among them.Lateralization in exploratory behavior in response to different stimuli was not associated with genital morphology.Interestingly,the direction of genital asymmetry was positively correlated with sidedness of mating preference and the number of neuromasts in the lateral line.This suggests integration of functionally linked asymmetric traits;however,there is no evidence that asymmetry is determined at the whole individual level in our study species.
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.
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.
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 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 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 Zhongyuan University of Technology Discipline Backbone Teacher Support Program Project(No.GG202417)the Key Research and Development Program of Henan under Grant 251111212000.
文摘Lateral movement represents the most covert and critical phase of Advanced Persistent Threats(APTs),and its detection still faces two primary challenges:sample scarcity and“cold start”of new entities.To address these challenges,we propose an Uncertainty-Driven Graph Embedding-Enhanced Lateral Movement Detection framework(UGEA-LMD).First,the framework employs event-level incremental encoding on a continuous-time graph to capture fine-grained behavioral evolution,enabling newly appearing nodes to retain temporal contextual awareness even in the absence of historical interactions and thereby fundamentally mitigating the cold-start problem.Second,in the embedding space,we model the dependency structure among feature dimensions using a Gaussian copula to quantify the uncertainty distribution,and generate augmented samples with consistent structural and semantic properties through adaptive sampling,thus expanding the representation space of sparse samples and enhancing the model’s generalization under sparse sample conditions.Unlike static graph methods that cannot model temporal dependencies or data augmentation techniques that depend on predefined structures,UGEA-LMD offers both superior temporaldynamic modeling and structural generalization.Experimental results on the large-scale LANL log dataset demonstrate that,under the transductive setting,UGEA-LMD achieves an AUC of 0.9254;even when 10%of nodes or edges are withheld during training,UGEA-LMD significantly outperforms baseline methods on metrics such as recall and AUC,confirming its robustness and generalization capability in sparse-sample and cold-start scenarios.
基金supported by the National Institute on Aging(Nos.AG000723 and AG000578)(to VAB)the Fondation Sante(No.19656),Greece 2.0+1 种基金the National Recovery and Resilience Plan’s flagship program TAEDR-0535850the European Research Council(No.101077374-Synapto Mitophagy)(to KP)。
文摘N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.
基金supported by General Program of National Natural Science Foundation of China,No.82370986(to LAW)Shaanxi Provincial NaturalScience Foundation Key Project,No.2023-JC-ZD-56(to SS).
文摘Emerging evidence suggests that the gut microbiota is closely associated with the pathological manifestations of multiple neurodegenerative diseases via the gut-brain axis,which refers to the crosstalk between the gut and the central nervous system.More importantly,mitochondria have been considered prominent mediators of the interplay between the gut microbiota and the brain.Intestinal microbes may modulate mitochondrial function in the central nervous system to affect the progression of neurodegenerative diseases.Mitochondria are essential for meeting the host’s substantial neuronal metabolic demands,maintaining excitability,and facilitating synaptic transmission.Dysfunctional mitochondria are considered critical hallmarks of various neurodegenerative diseases.Therefore,this review provides novel insights into the intricate roles of gut microbiota-mitochondrial crosstalk in the underlying mechanisms during the progression of neurodegeneration,as well as the existing potential therapeutic strategies for neurodegenerative disorders.These suggest intestinal microbiota-mitochondrial interaction play a crucial role in the occurrence and development of neurodegenerative diseases,and targeting this interaction may be a promising therapeutic approach to neurodegenerative diseases.However,this review found that there was relatively little research on the effect of this crosstalk on other neurodegenerative diseases,such as Huntington’s disease and Multiple sclerosis,and the potential therapeutic strategies were translated into clinical trials,which face many challenges in developing personalized treatment plans based on the unique gut microbiota of different individuals.
基金supported by the National Nature Science Foundation of China(General Program),Nos.82271237,82071218(both to JC),and 82230042(to ZY)the Foundation of Key Laboratory of Neurology,Hebei Medical University,Ministry of Education,China,No.2023001(to JC).
文摘N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.
基金supported by National Institutes of Health(R35NS137480,R35NS116843,and RF1AG079557)by Dr.Miriam and Sheldon G.Adelson Medical Research Foundation.
文摘The adult subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal dentate gyrus(DG)are the two brain regions where neurogenesis occurs throughout life in the adult mammalian brain(Ming and Song,2011).Adult quiescent hippocampal neural stem cells(NSCs)are bona fide stem cells and,when activated,give rise to newborn granule neurons in the adult brain,which play vital roles in learning,memory,mood,and affective cognition(Bonaguidi et al.,2011;Ming and Song,2011).
基金supported by the National Natural Science Foundation of China,No.82160255(to RX)the Natural Science Foundation of Jiangxi Province,No.20212BAB216026(to HL)+2 种基金Science and Technology Plan Project of Health Commission of Jiangxi Province,No.202110016(to HL)Science and Technology Plan Project of Jiangxi Provincial Administration of Traditional Chinese Medicine,No.2022B975(to HL)a grant from Jiangxi Province Key Laboratory of Neurology,No.2024SSY06081(to RX).
文摘With the gradual advancement of research methods and technologies,various biological processes have been identified as playing roles in the pathogenesis of neurodegenerative diseases.However,current descriptions of these biological processes do not fully explain the onset,progression,and development of these conditions.Therefore,exploration of the pathogenesis of neurodegenerative diseases remains a valuable area of research.This review summarizes the potential common pathogeneses of Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis,Huntington’s disease,frontotemporal lobar dementia,and Lewy body disease.Research findings have indicated that several common biological processes,including aging,genetic factors,progressive neuronal dysfunction,neuronal death and apoptosis,protein misfolding and aggregation,neuroinflammation,mitochondrial dysfunction,axonal transport defects,and gut microbiota dysbiosis,are involved in the pathogenesis of these six neurodegenerative diseases.Based on current information derived from diverse areas of research,these biological processes may form complex pathogenic networks that lead to distinctive types of neuronal death in neurodegenerative diseases.Furthermore,promoting the regeneration of damaged neurons may be achievable through the repair of affected neural cells if the underlying pathogenesis can be prevented or reversed.Hence,these potential common biological processes may represent only very small,limited elements within numerous intricate pathogenic networks associated with neurodegenerative diseases.In clinical treatment,interfering with any single biological process has proven insufficient to completely halt the progression of neurodegenerative diseases.Therefore,future research on the pathogenesis of neurodegenerative diseases should focus on uncovering the complex pathogenic networks,rather than isolating individual biological processes.Based on this,therapies that aim to block or reverse various targets involved in the potential pathogenic mechanisms of neurodegenerative diseases may be promising directions,as current treatment methods that focus on halting a single pathogenic factor have not achieved satisfactory efficacy.
基金supported by Yunnan Provincial Science and Technology Department,Nos.202403AC100007(to NZ),202301AY070001-239(to JY)Yunnan Revitalization Talent Support Program,Nos.2019-069(to ZY)and 2019-300(to JY)+1 种基金the National Natural Science Foundation of China,Nos.32260196(to JY)a grant from Kunming Medical University,No.2024S085(to KL)。
文摘Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system,leading to a decline in patients'cognitive,motor,and emotional abilities.Neuroinflammation plays a significant role in the progression of these diseases.However,there is limited research on therapeutic approaches to specifically target neuroinflammation.The role of T lymphocytes,which are crucial mediators of the adaptive immune response,in neurodegenerative diseases has been increasingly recognized.This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases.The pathogenesis of neurodegenerative diseases is complex,involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons,and T cells are a key component of these processes.One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells,including microglia,astrocytes,B cells,and natural killer cells.Different subsets of CD4~+T cells,such as Th1,Th2,Th17,and regulatory T cells,can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases.Additionally,CD8~+T cells,which can directly regulate immune responses and kill target cells,also play several important roles in neurodegenerative diseases.Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that,while some patients respond positively,others may not respond as well and may even experience adverse effects.Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system,which can lead to undesirable side effects.However,with new insights into the pathophysiology of neurodegenerative diseases,there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.
基金supported by Secretaría de Ciencia,Técnica y Postgrado of Universidad Nacional de Cuyo,and Consejo de Investigaciones de la Universidad del Aconcagua,Mendoza,Argentina.
文摘Functional laterality is known as an intrinsic property of the brain.Since several studies have shown the presence of laterality in many species other than humans,it has been suggested that this is an adaptive mechanism to aid survival.Previous studies have shown that lateralized behavior observed during exposure to different environmental stimuli is not constant in normal animals,depending on the geometrical form of the exploratory field.In these exploratory fields,animals showed right-or left-biased exploratory behavior,according to the nature of the geometrical properties of the environment.Previously,it was found that tellurium(Te)was able to block spontaneous left-biased exploration in one defined geometrical environment.In the present work,the influence of Te and selenium(Se)in animals exposed to novel geometrically different environments were studied.Three geometrically different testing fields(square,rectangle,and T-shaped)were presented to Se-and Te-treated groups of rats.The results show that in the square field,only the Se treatment was able to block spontaneous right-biased exploratory responses;in the rectangular field,both Se and Te treatments blocked right-biased exploratory responses,and in the T-shaped field,only Te was able to block spontaneous left-biased exploratory responses.Data suggest that trace elements modify lateralized behavioral responses independently of the form of the novel exploratory field,suggesting the presence of a specific action in the brain.
文摘Laterality is conceived as a functional property of the brain,where parallel neural circuits modulate complementary aspects of one function.Well known examples are handedness and speech in humans.Laterality also is present in animals indicating a general evolutionary functional aspect and not a single distinctive trait of humans.In the present work,the consistency of one lateralized response in the spontaneous behaviour of exploration,driven by novel environments with different geometrical proportions was studied in rats.Consistency of response was considered when the animal shows the same preferential display in different testing contexts.Three geometrical forms of environments(square,rectangle and T shaped environment)were presented to normal intact rats.Exploratory activity measured by a digital counting device was video‐taped in a 3 min duration tests.In these environments,rats had the choice to explore the right or the left aspect of the devices.Results show that in the square box,animals showed a right‐biased exploration,and show no preference in the rectangular box,and left‐biased exploration in the T shaped environment.Data reveal that animals show inconsistency in the lateralized behavioural response,where the geometrical characteristics of the environment are important to display some biased response.
基金supported by the Notional Natural Science Foundation of Chino,No.82160690Colloborotive Innovation Center of Chinese Ministry of Education,No.2020-39Science and Technology Foundation of Guizhou Province,No.ZK[2021]-014(all to FZ)。
文摘Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.
