Dear Editor,The importance of the medial entorhinal cortex(MEC)for memory and spatial navigation has been shown repeatedly in many species,including mice and humans[1,2].It is,therefore,not surprising that the connect...Dear Editor,The importance of the medial entorhinal cortex(MEC)for memory and spatial navigation has been shown repeatedly in many species,including mice and humans[1,2].It is,therefore,not surprising that the connectivity of this structure has been studied extensively over the past century,mainly using a range of anterograde and retrograde anatomical tracers[3].展开更多
Alzheimer’s disease cannot be cured as of yet.Our current understanding on the causes of Alzheimer’s disease is limited.To develop treatments,experimental models that represent a particular cellular phase of the dis...Alzheimer’s disease cannot be cured as of yet.Our current understanding on the causes of Alzheimer’s disease is limited.To develop treatments,experimental models that represent a particular cellular phase of the disease and more rigorous scrutiny of the cellular pathological mechanisms are crucial.In recent years,Alzheimer’s disease research underwent a paradigm shift.According to this tendency,Alzheimer’s disease is increasingly being conceived of a disease where not only neurons but also multiple cell types synchronously partake to manifest the pathology.Knowledge on every cell type adds an alternative approach and hope for the efforts towards the treatment.Neural stem cells and their neurogenic ability are making an appearance as a new aspect of the disease manifestation based on the recent findings that neurogenesis reduces dramatically in Alzheimer’s disease patients compared to healthy individuals.Therefore,understanding how neural stem cells can form new neurons in Alzheimer’s disease brains holds an immense potential for clinics.However,this provocative idea requires further evidence and tools for investigation.Recently,single cell sequencing appeared as a revolutionary tool to understand cellular programs in unprecedented resolution and it will undoubtedly facilitate comprehensive investigation of different cell types in Alzheimer’s disease.In this mini-review,we will touch upon recent studies that use single cell sequencing for investigating cellular response in Alzheimer’s disease and some consideration pertaining to the utilization of neural regeneration for Alzheimer’s disease research.展开更多
Autosomal recessive mutations in the PARK7 gene,which encodes for the protein DJ-1,result in a loss of function and are a cause of familial Parkinson’s disease（PD）,while increased wild-type DJ-1protein levels are a...Autosomal recessive mutations in the PARK7 gene,which encodes for the protein DJ-1,result in a loss of function and are a cause of familial Parkinson’s disease（PD）,while increased wild-type DJ-1protein levels are associated with some forms of cancer.Several functions of DJ-1 have been described,with the greatest evidence indicating that DJ-1 is a redox-sensitive protein involved in the regulation of oxidative stress and cell survival.展开更多
Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the ...Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the dendritic processes,particularly in post-synaptic compartments,but also in the cytosolic compartment,being likely involved in the regulation of the intracellular calcium-calmodulin signaling pathway (Represa et al.,1990).In the last decade,a plethora of studies have demonstrated that cerebrospinal fluid (CSF) Ng is increased in AD patients and in individuals with an ADlike CSF profile (Kester et al.,2015a).This increase seems to be disease-specific because other neurodegenerative conditions including frontotemporal dementia,Lewy body dementia,Parkinson’s disease,progressive supranuclear palsy,multiple system atrophy or Huntington’s disease,present CSF Ng concentrations similar to controls (Wellington et al.,2016).Ng levels in CSF appear to be elevated in mild cognitive impairment (MCI)-affected individuals who progress to AD and are highly related to memory and cognitive function (Kester et al.,2015a;Tarawneh et al.,2016),which indicates that this protein may serve as an early AD biomarker with diagnostic utility in pre-dementia disease stages,and with prognostic utility to predict cognitive decline and MCI-to-AD conversion.展开更多
In recent years evidence has emerged suggesting that Mini-basketball training program(MBTP)can be an effec-tive intervention method to improve social communication(SC)impairments and restricted and repetitive beha-vio...In recent years evidence has emerged suggesting that Mini-basketball training program(MBTP)can be an effec-tive intervention method to improve social communication(SC)impairments and restricted and repetitive beha-viors(RRBs)in preschool children suffering from autism spectrum disorder(ASD).However,there is a considerable degree if interindividual variability concerning these social outcomes and thus not all preschool chil-dren with ASD profit from a MBTP intervention to the same extent.In order to make more accurate predictions which preschool children with ASD can benefit from an MBTP intervention or which preschool children with ASD need additional interventions to achieve behavioral improvements,further research is required.This study aimed to investigate which individual factors of preschool children with ASD can predict MBTP intervention out-comes concerning SC impairments and RRBs.Then,test the performance of machine learning models in predict-ing intervention outcomes based on these factors.Participants were 26 preschool children with ASD who enrolled in a quasi-experiment and received MBTP intervention.Baseline demographic variables(e.g.,age,body,mass index[BMI]),indicators of physicalfitness(e.g.,handgrip strength,balance performance),performance in execu-tive function,severity of ASD symptoms,level of SC impairments,and severity of RRBs were obtained to predict treatment outcomes after MBTP intervention.Machine learning models were established based on support vector machine algorithm were implemented.For comparison,we also employed multiple linear regression models in statistics.Ourfindings suggest that in preschool children with ASD symptomatic severity(r=0.712,p<0.001)and baseline SC impairments(r=0.713,p<0.001)are predictors for intervention outcomes of SC impair-ments.Furthermore,BMI(r=-0.430,p=0.028),symptomatic severity(r=0.656,p<0.001),baseline SC impair-ments(r=0.504,p=0.009)and baseline RRBs(r=0.647,p<0.001)can predict intervention outcomes of RRBs.Statistical models predicted 59.6%of variance in post-treatment SC impairments(MSE=0.455,RMSE=0.675,R2=0.596)and 58.9%of variance in post-treatment RRBs(MSE=0.464,RMSE=0.681,R2=0.589).Machine learning models predicted 83%of variance in post-treatment SC impairments(MSE=0.188,RMSE=0.434,R2=0.83)and 85.9%of variance in post-treatment RRBs(MSE=0.051,RMSE=0.226,R2=0.859),which were better than statistical models.Ourfindings suggest that baseline characteristics such as symptomatic severity of 144 IJMHP,2022,vol.24,no.2 ASD symptoms and SC impairments are important predictors determining MBTP intervention-induced improvements concerning SC impairments and RBBs.Furthermore,the current study revealed that machine learning models can successfully be applied to predict the MBTP intervention-related outcomes in preschool chil-dren with ASD,and performed better than statistical models.Ourfindings can help to inform which preschool children with ASD are most likely to benefit from an MBTP intervention,and they might provide a reference for the development of personalized intervention programs for preschool children with ASD.展开更多
Protein misfolding neurodegenerative diseases arisethrough neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, mo...Protein misfolding neurodegenerative diseases arisethrough neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding--induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion--like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, and suggest that these events contribute towards prion--induced neurotoxicity. In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease.展开更多
Background:The Canadian 24-hour movement behavior(24-HMB)guidelines suggest that a limited amount of screen time use,an adequate level of physical activity(PA),and sufficient sleep duration are beneficial for ensuring...Background:The Canadian 24-hour movement behavior(24-HMB)guidelines suggest that a limited amount of screen time use,an adequate level of physical activity(PA),and sufficient sleep duration are beneficial for ensuring and optimizing the health and quality of life(QoL)of children and adolescents.However,this topic has yet to be examined for children and adolescents with autism spectrum disorder(ASD)specifically.The aim of this cross-sectional observational study was to examine the associations between meeting 24-HMB guidelines and several QoLrelated indicators among a national sample of American children and adolescents with ASD.Methods:Data were taken from the 2020 U.S.National Survey of Children’s Health dataset.Participants(n=956)aged 617 years and currently diagnosed with ASD were included.The exposure of interest was adherence to the 24-HMB guidelines.Outcomes were QoL indicators,including learning interest/curiosity,repeating grades,adaptive ability,victimization by bullying,and behavioral problems.Categorical variables were described with unweighted sample counts and weighted percentages.Age,sex,race,preterm birth status,medication,behavioral treatment,household poverty level,and the educational level of the primary caregivers were included as covariates.Odds ratio(OR)and 95%confidence interval(95%CI)were used to present the strength of association between adherence to 24-HMB guidelines and QoL-related indicators.Results:Overall,452 participants(45.34%)met 1 of the 3 recommendations,216(22.65%)met 2 recommendations,whereas only 39 participants(5.04%)met all 3 recommendations.Compared with meeting none of the recommendations,meeting both sleep duration and PA recommendations(OR=3.92,95%CI:1.639.48,p<0.001)or all 3 recommendations(OR=2.11,95%CI:1.034.35,p=0.04)was associated with higher odds of showing learning interest/curiosity.Meeting both screen time and PA recommendations(OR=0.15,95%CI:0.040.61,p<0.05)or both sleep duration and PA recommendations(OR=0.24,95%CI:0.070.87,p<0.05)was associated with lower odds of repeating any grades.With respect to adaptive ability,participants who met only the PA recommendation of the 24-HMB were less likely to have difficulties dressing or bathing(OR=0.11,95%CI:0.020.66,p<0.05)than those who did not.For participants who met all 3 recommendations(OR=0.38,95%CI:0.150.99,p=0.05),the odds of being victimized by bullying was lower.Participants who adhered to both sleep duration and PA recommendations were less likely to present with severe behavioral problems(OR=0.17,95%CI:0.040.71,p<0.05)than those who did not meet those guidelines.Conclusion:Significant associations were found between adhering to 24-HMB guidelines and selected QoL indicators.These findings highlight the importance of maintaining a healthy lifestyle as a key factor in promoting and preserving the QoL of children with ASD.展开更多
Accumulation of DNA damage and genomic instability are believed to have crucial effects in neurodegenerative conditions such as Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,premature aging diseases ...Accumulation of DNA damage and genomic instability are believed to have crucial effects in neurodegenerative conditions such as Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,premature aging diseases as well as amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD).Until recently these studies were largely correlative in nature,though raising the possibility that defects in the DNA damage response(DDR)underlie neurodegenerative diseases.展开更多
Amyotrophic lateral sclerosis (ALS) is one of the most dreadful neurodegenerative diseases leading to death within 1-5 years after symptom onset.The majority of ALS cases are sporadic(sALS),while the remaining 5-10%ar...Amyotrophic lateral sclerosis (ALS) is one of the most dreadful neurodegenerative diseases leading to death within 1-5 years after symptom onset.The majority of ALS cases are sporadic(sALS),while the remaining 5-10%are familial(fALS).Genetic discoveries have identified ALScausative mutations in more than 30 genes so far(Chia et al.,2018).Indeed,the four most common mutations observed in ALS genes in Europe are the hexanucleotide expansion repeat in Chromosome9 Open Reading Frame 72 (C9ORF72),Cu-Zn superoxide dismutase 1 (SOD1),tra nsactive response DNA Binding protein 43kDa (TARDBP)and fused in sa rcoma (FUS).展开更多
The field of therapy development for complex chronic brain disorders,which encompasses various forms of dementia including Alzheimer’s disease(AD),began to change dramatically during the last decade due to advances i...The field of therapy development for complex chronic brain disorders,which encompasses various forms of dementia including Alzheimer’s disease(AD),began to change dramatically during the last decade due to advances in knowledge about biology of the disease and technologies for detecting the progression of the condition.There is a growing consensus that the brain disorder commonly referred to as“Alzheimer disease”is not a single disease,but rather it is a cluster of syndromes.Therefore,a more accurate designation of the disorder is dementia-Alzheimer syndrome[1].Now,the options for interventions have expanded beyond short-term medication for symptomatic relief to include longer-lasting disease-modifying therapy(DMT).展开更多
Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remai...Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood.To identify natural activators of latent HIV-1,we screened a comprehensive peptide/protein library derived from human hemofiltrate,representing the entire blood peptidome,using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses.Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4(RBP4),the carrier of retinol(Vitamin A).We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines.Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production.High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1.Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads.As a potent natural HIV-1 latency-reversing agent,RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.展开更多
Cardiovascular diseases are the leading cause of morbidity and mortality worldwide.The central underlying mechanisms of cardiovascular diseases are vascular aging and associated arterial stiffness.Arterial stiffness i...Cardiovascular diseases are the leading cause of morbidity and mortality worldwide.The central underlying mechanisms of cardiovascular diseases are vascular aging and associated arterial stiffness.Arterial stiffness is characterized by structural(e.g.,tunica media calcification,alterations in vascular smooth muscle cells,and fibrosis)and functional(e.g.,loss of Windkessel function,elevated pulse pressure,and development of isolated systolic hypertension)vascular changes that cause microvascular dysfunction and end-organ damage(e.g.,heart failure,vascular dementia,hypertensive retinopathy,and chronic kidney disease).Current research indicates that arterial stiffness is an independent risk factor for cardiovascular diseases and represents a potential target for personalized prevention and therapeutic approaches.In this review,we summarize the pathophysiological mechanisms of vascular aging and arterial stiffness,outline the resulting end-organ damage,present different methods for the measurement of arterial stiffness,highlight the potential role of prevention and therapy,and provide future perspectives for arterial stiffness research.The purpose of this review is to provide a state-of-the-art interdisciplinary and translational approach to arterial stiffness,highlighting unique pathophysiological mechanisms(e.g.,perivascular adipose tissue,extracellular vesicles),clinical relevance,and future directions.展开更多
Recently Zhang et al.(2024) published their study entitled “Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: A long-term follow-up pilot study....Recently Zhang et al.(2024) published their study entitled “Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: A long-term follow-up pilot study.” The authors present three metachromatic leukodystrophy(MLD) patients treated with gene therapy and claim stabilization or even improvement, despite advanced symptomatic disease stage. The metachromatic leukodystrophy initiative(MLDi)(Schoenmakers et al., 2022), an international collaborative network and registry for MLD, urges caution in interpreting these results, as the evidence raises several critical concerns. These claims risk fostering false hope among MLD patients and their families, particularly given the significant gaps in the data provided(Fig. 1).展开更多
Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific ge...Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline- encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein （HMGB1）, interleukin （IL）-1α, IL-33 and the Ca^2＋-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.展开更多
Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of cells to maintain sp...Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of cells to maintain specific signaling pathways. A component of such intercellular cross-talk is the exchange of various types of extracellular vesicles (EVs). Exosomes are a subset of EVs, which are increasingly being known for the role they play in the pathogenesis and progression of neurodegenerative diseases, e.g., synucleinopathies and tauopathies. The ability of the central nervous system exosomes to cross the blood-brain barrier into blood has generated enthusiasm in their study as potential biomarkers. However, the lack of standardized, efficient, and ultra-sensitive methods for the isolation and detection of brain-derived exosomes has hampered the development of effective biomarkers. Exosomes mirror heterogeneous biological changes that occur during the progression of these incurable illnesses, potentially offering a more comprehensive outlook of neurodegenerative disease diagnosis, progression and treatment. In this review, we aim to discuss the challenges and opportunities of peripheral biofluid-based brain-exosomes in the diagnosis and biomarker discovery of Alzheimer’s and Parkinson’s diseases. In the later part, we discuss the traditional and emerging methods used for the isolation of exosomes and compare their advantages and disadvantages in clinical settings.展开更多
Neurons synthesizing the neurotransmitter dopamine exert crucial functions in the mammalian brain. The biggest and most important population of dopamine-synthesizing neurons is located in the mammalian ventral midbra...Neurons synthesizing the neurotransmitter dopamine exert crucial functions in the mammalian brain. The biggest and most important population of dopamine-synthesizing neurons is located in the mammalian ventral midbrain （VM）, and controls and modulates the exe- cution of motor, cognitive, affective, motivational, and rewarding behaviours. Degeneration of these neurons leads to motor deficits that are characteristic of Parkinson＇s disease, while their dysfunction is involved in the pathogenesis of psychiatric disorders including schizophrenia and addiction. Because the aetiology and therapeutic prospects for these diseases include neurodevelopmental aspects, substantial scientific interest has been focused on deciphering the mechanistic pathways that control the generation and sur- vival of these neurons during embryonic development. Researches during the last decade revealed the pivotal role of the secreted Wntl ligand and its signaUing cascade in the generation of the dopamine-synthesizing neurons in the mammalian VM. Here, we summarize the initial and more recent findings that have unravelled several Wntl-controUed genetic networks required for the proliferation and commitment of VM progenitors to the dopaminergic cell fate during midgestational embryonic stages, and for the correct differentiation of these progenitors into postmitotic dopamine-synthesizing neurons at late midgestational embryonic and foetal stages.展开更多
Background:In vivo diffusion tensor imaging(DTI)of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis(ALS).Methods:Ten mice with TDP-43^(G298S) overex...Background:In vivo diffusion tensor imaging(DTI)of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis(ALS).Methods:Ten mice with TDP-43^(G298S) overexpression under control of the Thy1.2 promoter and 10 wild type(wt)underwent longitudinal DTI scans at 11.7 T,including one baseline and one follow-up scan with an interval of about 5months.Whole brain-based spatial statistics(WBSS)of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43^(G298S) mice compared to wt at the cohort level.Results were supplemented by tractwise fractional anisotropy statistics(TFAS)and histological evaluation of motor cortex for signs of neuronal loss.Results:Alterations at the cohort level in TDP-43^(G298S) mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract.Neuronal loss in layer V of motor cortex was detected in TDP-43^(G298S) at the later(but not at the earlier)timepoint compared to wt.Conclusion:DTI mapping of TDP-43^(G298S) mice demonstrated progression in motor areas M1/M2.WBSS and TFAS are useful techniques to localize TDP-43^(G298S) associated alterations over time in this ALS mouse model,as a biological marker.展开更多
文摘Dear Editor,The importance of the medial entorhinal cortex(MEC)for memory and spatial navigation has been shown repeatedly in many species,including mice and humans[1,2].It is,therefore,not surprising that the connectivity of this structure has been studied extensively over the past century,mainly using a range of anterograde and retrograde anatomical tracers[3].
基金supported by Helmholtz Association(Helmholtz Young Investigator Award)Deutsche Forschungsgemeinschaft(DFG)+1 种基金German Center for Neurodegenerative Diseases(DZNE)TU Dresden(all to CK)
文摘Alzheimer’s disease cannot be cured as of yet.Our current understanding on the causes of Alzheimer’s disease is limited.To develop treatments,experimental models that represent a particular cellular phase of the disease and more rigorous scrutiny of the cellular pathological mechanisms are crucial.In recent years,Alzheimer’s disease research underwent a paradigm shift.According to this tendency,Alzheimer’s disease is increasingly being conceived of a disease where not only neurons but also multiple cell types synchronously partake to manifest the pathology.Knowledge on every cell type adds an alternative approach and hope for the efforts towards the treatment.Neural stem cells and their neurogenic ability are making an appearance as a new aspect of the disease manifestation based on the recent findings that neurogenesis reduces dramatically in Alzheimer’s disease patients compared to healthy individuals.Therefore,understanding how neural stem cells can form new neurons in Alzheimer’s disease brains holds an immense potential for clinics.However,this provocative idea requires further evidence and tools for investigation.Recently,single cell sequencing appeared as a revolutionary tool to understand cellular programs in unprecedented resolution and it will undoubtedly facilitate comprehensive investigation of different cell types in Alzheimer’s disease.In this mini-review,we will touch upon recent studies that use single cell sequencing for investigating cellular response in Alzheimer’s disease and some consideration pertaining to the utilization of neural regeneration for Alzheimer’s disease research.
基金funded by a Medical Research Council(UK)Experimental Medicine grant[MR/M006646/1]
文摘Autosomal recessive mutations in the PARK7 gene,which encodes for the protein DJ-1,result in a loss of function and are a cause of familial Parkinson’s disease（PD）,while increased wild-type DJ-1protein levels are associated with some forms of cancer.Several functions of DJ-1 have been described,with the greatest evidence indicating that DJ-1 is a redox-sensitive protein involved in the regulation of oxidative stress and cell survival.
基金funded by the Spanish Ministry of Health-Instituto Carlos Ⅲ(Miguel Servet programme-CP/00041) to FL
文摘Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the dendritic processes,particularly in post-synaptic compartments,but also in the cytosolic compartment,being likely involved in the regulation of the intracellular calcium-calmodulin signaling pathway (Represa et al.,1990).In the last decade,a plethora of studies have demonstrated that cerebrospinal fluid (CSF) Ng is increased in AD patients and in individuals with an ADlike CSF profile (Kester et al.,2015a).This increase seems to be disease-specific because other neurodegenerative conditions including frontotemporal dementia,Lewy body dementia,Parkinson’s disease,progressive supranuclear palsy,multiple system atrophy or Huntington’s disease,present CSF Ng concentrations similar to controls (Wellington et al.,2016).Ng levels in CSF appear to be elevated in mild cognitive impairment (MCI)-affected individuals who progress to AD and are highly related to memory and cognitive function (Kester et al.,2015a;Tarawneh et al.,2016),which indicates that this protein may serve as an early AD biomarker with diagnostic utility in pre-dementia disease stages,and with prognostic utility to predict cognitive decline and MCI-to-AD conversion.
基金supported by grants from the National Natural Science Foundation of China(31771243)the Fok Ying Tong Education Foundation(141113)to Aiguo Chen.
文摘In recent years evidence has emerged suggesting that Mini-basketball training program(MBTP)can be an effec-tive intervention method to improve social communication(SC)impairments and restricted and repetitive beha-viors(RRBs)in preschool children suffering from autism spectrum disorder(ASD).However,there is a considerable degree if interindividual variability concerning these social outcomes and thus not all preschool chil-dren with ASD profit from a MBTP intervention to the same extent.In order to make more accurate predictions which preschool children with ASD can benefit from an MBTP intervention or which preschool children with ASD need additional interventions to achieve behavioral improvements,further research is required.This study aimed to investigate which individual factors of preschool children with ASD can predict MBTP intervention out-comes concerning SC impairments and RRBs.Then,test the performance of machine learning models in predict-ing intervention outcomes based on these factors.Participants were 26 preschool children with ASD who enrolled in a quasi-experiment and received MBTP intervention.Baseline demographic variables(e.g.,age,body,mass index[BMI]),indicators of physicalfitness(e.g.,handgrip strength,balance performance),performance in execu-tive function,severity of ASD symptoms,level of SC impairments,and severity of RRBs were obtained to predict treatment outcomes after MBTP intervention.Machine learning models were established based on support vector machine algorithm were implemented.For comparison,we also employed multiple linear regression models in statistics.Ourfindings suggest that in preschool children with ASD symptomatic severity(r=0.712,p<0.001)and baseline SC impairments(r=0.713,p<0.001)are predictors for intervention outcomes of SC impair-ments.Furthermore,BMI(r=-0.430,p=0.028),symptomatic severity(r=0.656,p<0.001),baseline SC impair-ments(r=0.504,p=0.009)and baseline RRBs(r=0.647,p<0.001)can predict intervention outcomes of RRBs.Statistical models predicted 59.6%of variance in post-treatment SC impairments(MSE=0.455,RMSE=0.675,R2=0.596)and 58.9%of variance in post-treatment RRBs(MSE=0.464,RMSE=0.681,R2=0.589).Machine learning models predicted 83%of variance in post-treatment SC impairments(MSE=0.188,RMSE=0.434,R2=0.83)and 85.9%of variance in post-treatment RRBs(MSE=0.051,RMSE=0.226,R2=0.859),which were better than statistical models.Ourfindings suggest that baseline characteristics such as symptomatic severity of 144 IJMHP,2022,vol.24,no.2 ASD symptoms and SC impairments are important predictors determining MBTP intervention-induced improvements concerning SC impairments and RBBs.Furthermore,the current study revealed that machine learning models can successfully be applied to predict the MBTP intervention-related outcomes in preschool chil-dren with ASD,and performed better than statistical models.Ourfindings can help to inform which preschool children with ASD are most likely to benefit from an MBTP intervention,and they might provide a reference for the development of personalized intervention programs for preschool children with ASD.
文摘Protein misfolding neurodegenerative diseases arisethrough neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding--induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion--like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, and suggest that these events contribute towards prion--induced neurotoxicity. In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease.
基金supported by Start-up Research Grant of Shenzhen University(20200807163056003)Start-Up Research Grant(PeacockPlan:20191105534C).
文摘Background:The Canadian 24-hour movement behavior(24-HMB)guidelines suggest that a limited amount of screen time use,an adequate level of physical activity(PA),and sufficient sleep duration are beneficial for ensuring and optimizing the health and quality of life(QoL)of children and adolescents.However,this topic has yet to be examined for children and adolescents with autism spectrum disorder(ASD)specifically.The aim of this cross-sectional observational study was to examine the associations between meeting 24-HMB guidelines and several QoLrelated indicators among a national sample of American children and adolescents with ASD.Methods:Data were taken from the 2020 U.S.National Survey of Children’s Health dataset.Participants(n=956)aged 617 years and currently diagnosed with ASD were included.The exposure of interest was adherence to the 24-HMB guidelines.Outcomes were QoL indicators,including learning interest/curiosity,repeating grades,adaptive ability,victimization by bullying,and behavioral problems.Categorical variables were described with unweighted sample counts and weighted percentages.Age,sex,race,preterm birth status,medication,behavioral treatment,household poverty level,and the educational level of the primary caregivers were included as covariates.Odds ratio(OR)and 95%confidence interval(95%CI)were used to present the strength of association between adherence to 24-HMB guidelines and QoL-related indicators.Results:Overall,452 participants(45.34%)met 1 of the 3 recommendations,216(22.65%)met 2 recommendations,whereas only 39 participants(5.04%)met all 3 recommendations.Compared with meeting none of the recommendations,meeting both sleep duration and PA recommendations(OR=3.92,95%CI:1.639.48,p<0.001)or all 3 recommendations(OR=2.11,95%CI:1.034.35,p=0.04)was associated with higher odds of showing learning interest/curiosity.Meeting both screen time and PA recommendations(OR=0.15,95%CI:0.040.61,p<0.05)or both sleep duration and PA recommendations(OR=0.24,95%CI:0.070.87,p<0.05)was associated with lower odds of repeating any grades.With respect to adaptive ability,participants who met only the PA recommendation of the 24-HMB were less likely to have difficulties dressing or bathing(OR=0.11,95%CI:0.020.66,p<0.05)than those who did not.For participants who met all 3 recommendations(OR=0.38,95%CI:0.150.99,p=0.05),the odds of being victimized by bullying was lower.Participants who adhered to both sleep duration and PA recommendations were less likely to present with severe behavioral problems(OR=0.17,95%CI:0.040.71,p<0.05)than those who did not meet those guidelines.Conclusion:Significant associations were found between adhering to 24-HMB guidelines and selected QoL indicators.These findings highlight the importance of maintaining a healthy lifestyle as a key factor in promoting and preserving the QoL of children with ASD.
基金AH was supported by the Hermann and Lilly Schilling-Stiftung für medizinische Forschung im Stifterverband.
文摘Accumulation of DNA damage and genomic instability are believed to have crucial effects in neurodegenerative conditions such as Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,premature aging diseases as well as amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD).Until recently these studies were largely correlative in nature,though raising the possibility that defects in the DNA damage response(DDR)underlie neurodegenerative diseases.
基金Hermann und Lilly Schilling Stiftung für Medizinische Forschung im Stifterverbond (to AH)。
文摘Amyotrophic lateral sclerosis (ALS) is one of the most dreadful neurodegenerative diseases leading to death within 1-5 years after symptom onset.The majority of ALS cases are sporadic(sALS),while the remaining 5-10%are familial(fALS).Genetic discoveries have identified ALScausative mutations in more than 30 genes so far(Chia et al.,2018).Indeed,the four most common mutations observed in ALS genes in Europe are the hexanucleotide expansion repeat in Chromosome9 Open Reading Frame 72 (C9ORF72),Cu-Zn superoxide dismutase 1 (SOD1),tra nsactive response DNA Binding protein 43kDa (TARDBP)and fused in sa rcoma (FUS).
基金supported by National Key Research and Development Program of China(2022YFC3602600)National Natural Science Foundation of China(82220108009)+1 种基金Beijing Outstanding Young Scientist Program(JWZQ20240101023)STI2030-Major Projects(2021ZD0201801).
文摘The field of therapy development for complex chronic brain disorders,which encompasses various forms of dementia including Alzheimer’s disease(AD),began to change dramatically during the last decade due to advances in knowledge about biology of the disease and technologies for detecting the progression of the condition.There is a growing consensus that the brain disorder commonly referred to as“Alzheimer disease”is not a single disease,but rather it is a cluster of syndromes.Therefore,a more accurate designation of the disorder is dementia-Alzheimer syndrome[1].Now,the options for interventions have expanded beyond short-term medication for symptomatic relief to include longer-lasting disease-modifying therapy(DMT).
基金supported by the DFG(CRC 1279)the NIH(AI164570,P30 AI045008)+2 种基金the Robert I.Jacobs Fund of the Philadelphia Foundation(LM),and a Herbert Kean,M.D.,Family Professorship(LM)Additionally,we thank the Human Immunology Core(HIC)at the Perelman School of Medicine at the University of Pennsylvania for their support with the Simoa assay,with partial funding from NIH P30 AI045008 and P30 CA016520The HIC is also supported by NIH grants and is identified by RRID:SCR_022380.G.M.L.was supported by NIH U24AI143502.
文摘Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood.To identify natural activators of latent HIV-1,we screened a comprehensive peptide/protein library derived from human hemofiltrate,representing the entire blood peptidome,using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses.Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4(RBP4),the carrier of retinol(Vitamin A).We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines.Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production.High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1.Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads.As a potent natural HIV-1 latency-reversing agent,RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.
基金supported by the Polycarp-Leporin-Program(Medical faculty University Magdeburg,PLP23/5,to PM)the DZPG(German Center for Mental Health,to PM),the DIKAP project(European Regional Development Fund EFRE,ZS/2024/02/184014 to PM,SS and RBD)the cardiovascular prevention and sports medicine project(European Regional Development Fund EFRE,ZS/2024/05/187256 to PM).
文摘Cardiovascular diseases are the leading cause of morbidity and mortality worldwide.The central underlying mechanisms of cardiovascular diseases are vascular aging and associated arterial stiffness.Arterial stiffness is characterized by structural(e.g.,tunica media calcification,alterations in vascular smooth muscle cells,and fibrosis)and functional(e.g.,loss of Windkessel function,elevated pulse pressure,and development of isolated systolic hypertension)vascular changes that cause microvascular dysfunction and end-organ damage(e.g.,heart failure,vascular dementia,hypertensive retinopathy,and chronic kidney disease).Current research indicates that arterial stiffness is an independent risk factor for cardiovascular diseases and represents a potential target for personalized prevention and therapeutic approaches.In this review,we summarize the pathophysiological mechanisms of vascular aging and arterial stiffness,outline the resulting end-organ damage,present different methods for the measurement of arterial stiffness,highlight the potential role of prevention and therapy,and provide future perspectives for arterial stiffness research.The purpose of this review is to provide a state-of-the-art interdisciplinary and translational approach to arterial stiffness,highlighting unique pathophysiological mechanisms(e.g.,perivascular adipose tissue,extracellular vesicles),clinical relevance,and future directions.
文摘Recently Zhang et al.(2024) published their study entitled “Lentivirus-modified hematopoietic stem cell gene therapy for advanced symptomatic juvenile metachromatic leukodystrophy: A long-term follow-up pilot study.” The authors present three metachromatic leukodystrophy(MLD) patients treated with gene therapy and claim stabilization or even improvement, despite advanced symptomatic disease stage. The metachromatic leukodystrophy initiative(MLDi)(Schoenmakers et al., 2022), an international collaborative network and registry for MLD, urges caution in interpreting these results, as the evidence raises several critical concerns. These claims risk fostering false hope among MLD patients and their families, particularly given the significant gaps in the data provided(Fig. 1).
文摘Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline- encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein （HMGB1）, interleukin （IL）-1α, IL-33 and the Ca^2＋-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.
文摘Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of cells to maintain specific signaling pathways. A component of such intercellular cross-talk is the exchange of various types of extracellular vesicles (EVs). Exosomes are a subset of EVs, which are increasingly being known for the role they play in the pathogenesis and progression of neurodegenerative diseases, e.g., synucleinopathies and tauopathies. The ability of the central nervous system exosomes to cross the blood-brain barrier into blood has generated enthusiasm in their study as potential biomarkers. However, the lack of standardized, efficient, and ultra-sensitive methods for the isolation and detection of brain-derived exosomes has hampered the development of effective biomarkers. Exosomes mirror heterogeneous biological changes that occur during the progression of these incurable illnesses, potentially offering a more comprehensive outlook of neurodegenerative disease diagnosis, progression and treatment. In this review, we aim to discuss the challenges and opportunities of peripheral biofluid-based brain-exosomes in the diagnosis and biomarker discovery of Alzheimer’s and Parkinson’s diseases. In the later part, we discuss the traditional and emerging methods used for the isolation of exosomes and compare their advantages and disadvantages in clinical settings.
文摘Neurons synthesizing the neurotransmitter dopamine exert crucial functions in the mammalian brain. The biggest and most important population of dopamine-synthesizing neurons is located in the mammalian ventral midbrain （VM）, and controls and modulates the exe- cution of motor, cognitive, affective, motivational, and rewarding behaviours. Degeneration of these neurons leads to motor deficits that are characteristic of Parkinson＇s disease, while their dysfunction is involved in the pathogenesis of psychiatric disorders including schizophrenia and addiction. Because the aetiology and therapeutic prospects for these diseases include neurodevelopmental aspects, substantial scientific interest has been focused on deciphering the mechanistic pathways that control the generation and sur- vival of these neurons during embryonic development. Researches during the last decade revealed the pivotal role of the secreted Wntl ligand and its signaUing cascade in the generation of the dopamine-synthesizing neurons in the mammalian VM. Here, we summarize the initial and more recent findings that have unravelled several Wntl-controUed genetic networks required for the proliferation and commitment of VM progenitors to the dopaminergic cell fate during midgestational embryonic stages, and for the correct differentiation of these progenitors into postmitotic dopamine-synthesizing neurons at late midgestational embryonic and foetal stages.
文摘Background:In vivo diffusion tensor imaging(DTI)of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis(ALS).Methods:Ten mice with TDP-43^(G298S) overexpression under control of the Thy1.2 promoter and 10 wild type(wt)underwent longitudinal DTI scans at 11.7 T,including one baseline and one follow-up scan with an interval of about 5months.Whole brain-based spatial statistics(WBSS)of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43^(G298S) mice compared to wt at the cohort level.Results were supplemented by tractwise fractional anisotropy statistics(TFAS)and histological evaluation of motor cortex for signs of neuronal loss.Results:Alterations at the cohort level in TDP-43^(G298S) mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract.Neuronal loss in layer V of motor cortex was detected in TDP-43^(G298S) at the later(but not at the earlier)timepoint compared to wt.Conclusion:DTI mapping of TDP-43^(G298S) mice demonstrated progression in motor areas M1/M2.WBSS and TFAS are useful techniques to localize TDP-43^(G298S) associated alterations over time in this ALS mouse model,as a biological marker.
