Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patien...Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patients,caregivers,and healthcare workers.Alzheimer’s disease(AD)and Parkinson’s disease represent the two most common neurodegenerative disorders in the population,affecting over 65 million people,worldwide.展开更多
In vivo imaging of neurodegenerative diseases provides valuable insights into disease mechanisms and potential therapeutic interventions.Many ocular diseases are closely linked to neurodegenerative conditions affectin...In vivo imaging of neurodegenerative diseases provides valuable insights into disease mechanisms and potential therapeutic interventions.Many ocular diseases are closely linked to neurodegenerative conditions affecting the brain,making the eye a unique and accessible model for studying these disorders.The transparency of eyes allows researchers to monitor disease progression non-invasively,offering a window into neural health.展开更多
The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral bloo...The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral blood biomarkers in neurological and psychiatric disorders based on the assertion that disease pathology is limited to the brain.The discovery that all tissues,including the brain,release extracellular vesicles(Raposo and Stoorvogel,2013)and cell free DNAs(Chan et al.,2013)into various body fluids has provided a potential way to measure activity from inaccessible tissues like the central nervous system(CNS)and has given rise to the term“liquid biopsy.”The development of liquid biopsies that can diagnose and predict the course of psychiatric and neurological disorders would be transformative.The ability to predict episodic events such as mania,depression,and risk for suicide would be particularly useful for psychiatric care as it would enable the development of interventions that prevent mortality and improve outcomes.Additionally,biomarkers that are informative about drug response and aid in treatment decisions would be a significant advance in psychiatric care as it would prevent patients from having to endure multiple courses of ineffective treatments and side effects.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
Unresectable hepatocellular carcinoma(HCC)remains a global challenge,with limited effective treatment options for advanced-stage disease.The HIMALAYA trial(phase III randomized study that evaluated the STRIDE regimen)...Unresectable hepatocellular carcinoma(HCC)remains a global challenge,with limited effective treatment options for advanced-stage disease.The HIMALAYA trial(phase III randomized study that evaluated the STRIDE regimen)introduced the Single Tremelimumab Regular Interval Durvalumab(STRIDE)regimen,an immunotherapy-based approach that achieved a median overall survival(OS)of 16.43 months compared to 13.77 months with sorafenib.While statistically significant,this~2.7 months OS gain warrants scrutiny in light of STRIDE’s increased immune-related toxicity and cost.This commentary evaluates STRIDE’s impact within the broader landscape of first-line systemic therapy for unresectable HCC,alongside other regimens such as atezolizumab plus bevacizumab and nivolumab plus ipilimumab.We explore STRIDE’s mechanism of action,safety profile,modest progression-free survival(PFS)improvement,and implementation challenges,incorporating insights from 2023-2025 research.In addition,we discussed its limitations in non-viral HCC and Child-Pugh B patients,the role of emerging biomarkers,and the potential of radiation to enhance immunotherapy efficacy.As a dual immune checkpoint inhibitor(ICI)strategy,STRIDE offers an important advance that may not only extend survival but also open the door to future curative approaches.However,optimizing its use will require refined patient selection and further investigation of synergistic combination therapies.展开更多
Colorectal cancer is the third most diagnosed cancer worldwide,and immune checkpoint inhibitors have shown promising therapeutic outcomes in selected patient groups.This study performed a comprehensive analysis of mul...Colorectal cancer is the third most diagnosed cancer worldwide,and immune checkpoint inhibitors have shown promising therapeutic outcomes in selected patient groups.This study performed a comprehensive analysis of multi-omics data from The Cancer Genome Atlas colorectal adenocarcinoma cohort(TCGA-COADREAD),accessed through cBioPortal,to develop machine learning models for predicting progression-free survival(PFS)following immunotherapy.The dataset included clinical variables,genomic alterations in Kirsten Rat Sarcoma Viral Oncogene Homolog(KRAS),B-Raf Proto-Oncogene(BRAF),and Neuroblastoma RAS Viral Oncogene Homolog(NRAS),microsatellite instability(MSI)status,tumor mutation burden(TMB),and expression of immune checkpoint genes.Kaplan–Meier analysis showed that KRAS mutations were significantly associated with reduced PFS,while BRAF and NRAS mutations had no significant impact.MSI-high tumors exhibited elevated TMB and increased immune checkpoint expression,reflecting their immunologically active phenotype.We developed both survival and classification models,with the Extra Trees classifier achieving the best performance(accuracy=0.86,precision=0.67,recall=0.70,F1-score=0.68,AUC=0.84).These findings highlight the potential of combining genomic and immune biomarkers with machine learning to improve patient stratification and guide personalized immunotherapy decisions.An interactive web application was also developed to enable clinicians to input patient-specific molecular and clinical data and visualize individualized PFS predictions,supporting timely,data-driven treatment planning.展开更多
Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated...Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated with increased levels of circulato ry pro-inflammatory marke rs up to 1 year postTBI(Eagle et al.,2023).展开更多
Parkinson's disease(PD)is the second most common neurodegenerative disease that affects movement and cognitive function,resulting from the loss of the neurotransmitter dopamine due to the death of dopaminergic neu...Parkinson's disease(PD)is the second most common neurodegenerative disease that affects movement and cognitive function,resulting from the loss of the neurotransmitter dopamine due to the death of dopaminergic neurons.It affects nearly one million people in the United States and 8.5 million worldwide.While there are some pharmacological and surgical options available,they only provide symptomatic relief,as there is currently no cure for PD.In contrast,exercise training,a non-pharmacological intervention,has emerged as a powerful strategy to enhance the psychological,cognitive,and physiological(motor)impairments associated with PD.Given that the beneficial effects of exercise differ based on the intensity and type of training,gaining a thorough understanding of the molecular mechanisms underlying exercise-induced protection is crucial for developing innovative therapies that improve the quality of life for PD patients around the globe.This review discusses PD pathogenesis and pathophysiology and provides recent clinical evidence of neuroprotective benefits from various exercise modalities and intensity.Furthermore,the molecular mechanisms of exercise in PD pathogenesis(e.g.,modulations on neurotrophic factors,oxidative stress,mitochondria dysfunction,endoplasmic reticulum stress,and autophagy)will be emphasized.展开更多
This study presents a comprehensive phylogenetic analysis on Batrachospermaceae based on key taxonomic identifiers(rbcL,psaA,psbA,and COI-5P)from some genera.To systematically explore the phylogenetic relationships an...This study presents a comprehensive phylogenetic analysis on Batrachospermaceae based on key taxonomic identifiers(rbcL,psaA,psbA,and COI-5P)from some genera.To systematically explore the phylogenetic relationships and taxonomy within Batrachospermaceae,we integrated molecular and morphological data,and explored the phylogeny,character evolution,and ancestral geographical origin and provided a theoretical support for the classification and geographic origination of Batrachospermaceae.Our findings reveal distinct relationships within the phylogenetic tree.Notably,10 genera(Sirodotia,Batrachospermum,Tuomeya,Volatus,Lympha,Nothocladus,Torularia,Sheathia,Nocturama,and Petrohua)are closely associated in the rbcL phylogenetic tree.Additionally,four genera(Kumanoa,Hoefkenia,Notohesperus,and Virescentia)exhibit high support ratios,indicating their close interrelations.Other genera,including Paludicola,Visia,Acarposporophycos,Macrosporophycos,Visioidea,Balliopsis,and Psilosiphon,exhibit clustering traits.Furthermore,the multigene sequences provide a robust support for Montagnia that forms a monophyletic group.Ancestral reconstruction of morphological characters identifies nine primitive character states,including whorl,fascicle length,cortical cells,secondary fascicles,the shape of carpogonical branch,spermatangia,carposporophyte,carpogonium and trichogyne,with Visia likely representing ancestral traits in Batrachospermaceae.Furthermore,geographical origin maps suggest a potential common ancestral of Batrachospermaceae origin in the American continent.Additional to conventional analyses,including evolutionary and ancestral reconstruction investigations into key morphological characters,we attempt to reconstruct the biogeography within the Batrachospermaceae,thus contributing to a nuanced understanding of its origin.展开更多
Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia.However,there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease.In th...Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia.However,there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease.In this study,we investigated the potential therapeutic effects of MCC950,a selective NOD-like receptor family pyrin domain-containing protein 3 inhibitor,on cerebral small vessel disease pathogenesis and cognitive decline in spontaneously hypertensive rats.Our results showed that chronic administration of MCC950(10 mg/kg)to spontaneously hypertensive rats inhibited NOD-like receptor family pyrin domain-containing protein 3 inflammasome activation,thereby considerably suppressing the production of pyroptosis executive protein gasdermin D and pro-inflammatory factors,including interleukin-1βand-18.A decrease in astrocytic and microglial activation was also observed.We also found that MCC950 significantly inhibited autophagy.More importantly,behavioral assessment indicated that MCC950 administration ameliorated impaired neurocognitive function,which was associated with improvements in neuropathological hallmarks in the cerebral small vessel disease brain,such as blood‒brain barrier breakdown,white matter damage,and endothelial dysfunction.Thus,our findings revealed that the NOD-like receptor family pyrin domain-containing protein 3 inflammasome is a key contributor to the onset or progression of cerebral small vessel disease and suggested the potential of NOD-like receptor family pyrin domain-containing protein 3-based therapy as a potential novel strategy for treating cerebral small vessel disease.展开更多
The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates ...The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.展开更多
Background:As an important indicator of subjective well-being(SWB),decent work is a key guarantee for the sustainable development of teachers and their psychological health and work quality.Faced with the rapid develo...Background:As an important indicator of subjective well-being(SWB),decent work is a key guarantee for the sustainable development of teachers and their psychological health and work quality.Faced with the rapid development of artificial intelligence and the global labor market,vocational college teachers are facing challenges such as workload pressure and limited career development,which may harm their well-being.This study aims to localize the measurement method of decent work in Chinese vocational education based on the theory of the Psychology of Working Theory,and explore the relationship mechanism between organizational support,career adaptability,decent work,and job satisfaction among vocational college teachers.Methods:A cross-sectional survey was conducted with 422 HVCU teachers in China(202 male,220 female)using the localized Perceived Organizational Support Scale,Career Adaptability Scale,Decent Work Scale,and Job Satisfaction Scale.Results:The overall level of HVCU teachers’decent work was above the median(Mean=4.09,SD=0.69),laying a foundation for their SWB.Decent work significantly and positively predicted job satisfaction(β=0.620,p<0.001).Organizational support(r=0.58,p<0.001)and career adaptability(r=0.82,p<0.001)can positively affect decent work,and further improve job satisfaction(collective R2 rising from 38.3%to 41.1%).Bootstrap analysis confirmed these mediating effects were robust.Conclusions:This study confirms that the combined effects of organizational support and career adaptability can enhance decent work,further improving teachers’job satisfaction and subsequent subjective well-being.Besides,this study provides an empirical basis for improving the well-being of higher vocational teachers and the sustainable development of vocational education,and has practical significance for improving the teacher incentive policy.展开更多
While oceanic and coastal acidification has gained increased attention,long-term pH trends and their drivers in large freshwater systems remain poorly understood.The Laurentian Great Lakes are the world’s largest fre...While oceanic and coastal acidification has gained increased attention,long-term pH trends and their drivers in large freshwater systems remain poorly understood.The Laurentian Great Lakes are the world’s largest freshwater system,and in many ways resemble marine ecosystems.However,unlike the open ocean and coastal waters where pH has declined due to rising atmospheric CO_(2),no significant pH trends have been observed in the Laurentian Great Lakes,despite significant ecosystem changes driven partly by the invasion of dreissenid mussels.This study examined 41 years of field observations from Lake Michigan to investigate the long-term carbonate chemistry dynamics.Observational results revealed substantial declines in both total alkalinity(TA)and dissolved inorganic carbon(DIC)over the four decades.Mussel shell calcification emerged as the primary mechanism behind these declines,accounting for 97%and 47%of the observed changes in TA and DIC,respectively,lowering water column pH by 0.24 units.Elevated carbon accumulation in soft mussel tissues,coupled with long-term changes in the air-water pCO_(2)gradient during summer,significantly contributed to long-term DIC variations,explaining 18%and 28%of the lake-wide DIC loss.These two mechanisms also resulted in an overall pH increase of 0.09 and 0.12 units,largely offsetting the calcification-driven pH decrease.These findings bridge a gap in acidification research for large freshwater systems and provide valuable insights for comprehensive lake-wide management strategies.展开更多
Metastatic brain tumors undergo profound metabolic-epigenetic reprogramming driven by the unique constraints of the brain microenvironment.Hypoxia-inducible factor-1α(HIF1α)enhances glycolytic flux,lactate accumulat...Metastatic brain tumors undergo profound metabolic-epigenetic reprogramming driven by the unique constraints of the brain microenvironment.Hypoxia-inducible factor-1α(HIF1α)enhances glycolytic flux,lactate accumulation,and histone lactylation,collectively supporting metastatic colonization and immune evasion.Key metabolites including acetyl-CoA,S-adenosylmethionine(SAM),α-ketoglutarate(α-KG),fumarate,and 2-hydroxyglutarate(2-HG)-directly modify chromatin states by regulating histone acetyltransferases,DNA/histone methyltransferases,andα-KG dependent dioxygenases such as Ten-Eleven Translocation(TET)enzymes and lysine demethylases(KDMs).These metabolic shifts result in aberrant DNA methylation,histone lysine residue at position 27 on Histone H3(H3K27)trimethylation,and depletion of 5-hydroxymethylcytosine(5hmC),all of which are hallmark epigenetic alterations in brain metastasis and primary Central Nervous System(CNS)tumors.Additionally,the blood-brain barrier(BBB)and blood-tumor barrier(BTB)impose nutrient restrictions and induce metabolic dependency on glutamine,acetate,and lactate shuttling,thereby reshaping epigenetic enzyme activity.We synthesize current mechanistic evidence showing how metabolic pressures in the brain microenvironment remodel the epigenome to promote tumor plasticity,stemness,and therapeutic resistance.Understanding these coupled pathways reveals vulnerable nodes such as HIF1αsignaling,α-KG-dependent demethylation,and lactate-driven epigenetic remodeling that may be exploited for targeted treatment of metastatic brain tumors.The present review aims to provide in-depth insights into epigenetic regulation,including chromatin and histone modifications as well as noncoding RNAs and metabolic reprogramming,highlighting how the two interplay in the development and progression of metastatic brain tumors and their therapeutic potential.展开更多
Objectives:Phosphodiesterase 1A(PDE1A)regulates intracellular cyclic nucleotide signaling and has been implicated in tumor progression,but its clinical relevance and functional role in epithelial ovarian cancer(EOC),p...Objectives:Phosphodiesterase 1A(PDE1A)regulates intracellular cyclic nucleotide signaling and has been implicated in tumor progression,but its clinical relevance and functional role in epithelial ovarian cancer(EOC),particularly in relation to the response to platinum remain unclear.This study aimed to evaluate the clinical significance of PDE1A in EOG and to clarify its functional role in tumor progression and response to platinum-based chemotherapy.Methods:PDE1A mRNA and protein levels were analyzed using public databases,RNA sequencing,and immunohistochemistry.Correlations between PDE1A expression,clinicopathological features,and prognosis were assessed.Functional roles were investigated in ovarian cancer cell lines.Results:PDE1A was significantly overexpressed in EOC tissues compared with that in normal ovarian epithelial tissues.Overexpression correlated with advanced International Federation of Gynecology and Obstetrics(FIGO)stage,poor tumor grade,and reduced response to platinum-based chemotherapy.High PDE1A levels were linked to worse disease-free survival and overall survival,and multivariate analysis confirmed PDE1A as an independent prognostic factor.To elucidate its functional role,we performed in vitro experiments showing that PDE1A knockdown suppressed cell proliferation and colony formation,induced G1 arrest,and downregulatedβ-catenin signaling with reduced cyclin D1 and c-Myc expression.Notably,these inhibitory effects were partially rescued by lithium chloride(LiCl),a Wingless-related integration site(Wnt)/β-catenin activator.Conclusions:In conclusion,our findings identify PDE1A as a Wnt/β-catenin-linked biomarker of tumor progression and platinum resistance in EOC and provide a biological rationale for further investigation of PDE1A-targeted strategies in preclinical models.展开更多
基金supported by the Canadian Institutes of Health Research(DFD-181599)the National Institutes of Health(T32AG058527)to RJB and R0190106435 to VM.
文摘Neurodegenerative disorders represent an increasingly pertinent public health crisis.As a greater proportion of the population ages,neurodegenerative disorders and other diseases of aging place undue burdens on patients,caregivers,and healthcare workers.Alzheimer’s disease(AD)and Parkinson’s disease represent the two most common neurodegenerative disorders in the population,affecting over 65 million people,worldwide.
基金supported[in part]by the IntramuralResearch Program of the National Institutes ofHealth(NIH)(to KJM),and also supported by theOffice by the Office of the Assistant Secretary ofDefense for Health Affairs and the Defense HealthAgency J9,Research and Development Directorate,through the Vision Research Program under AwardNo.(CDMRPL-18-0-VR180205 to KJM and FMN-N).
文摘In vivo imaging of neurodegenerative diseases provides valuable insights into disease mechanisms and potential therapeutic interventions.Many ocular diseases are closely linked to neurodegenerative conditions affecting the brain,making the eye a unique and accessible model for studying these disorders.The transparency of eyes allows researchers to monitor disease progression non-invasively,offering a window into neural health.
基金supported by Department of Defense grant HT9425-24-1-0030 a grant from the Stanley Medical Research Institute(to SS).
文摘The inability to access brain tissue has greatly hindered our ability to study and care for individuals suffering from psychiatric and neurological conditions.Critics have questioned efforts to develop peripheral blood biomarkers in neurological and psychiatric disorders based on the assertion that disease pathology is limited to the brain.The discovery that all tissues,including the brain,release extracellular vesicles(Raposo and Stoorvogel,2013)and cell free DNAs(Chan et al.,2013)into various body fluids has provided a potential way to measure activity from inaccessible tissues like the central nervous system(CNS)and has given rise to the term“liquid biopsy.”The development of liquid biopsies that can diagnose and predict the course of psychiatric and neurological disorders would be transformative.The ability to predict episodic events such as mania,depression,and risk for suicide would be particularly useful for psychiatric care as it would enable the development of interventions that prevent mortality and improve outcomes.Additionally,biomarkers that are informative about drug response and aid in treatment decisions would be a significant advance in psychiatric care as it would prevent patients from having to endure multiple courses of ineffective treatments and side effects.
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.
文摘Unresectable hepatocellular carcinoma(HCC)remains a global challenge,with limited effective treatment options for advanced-stage disease.The HIMALAYA trial(phase III randomized study that evaluated the STRIDE regimen)introduced the Single Tremelimumab Regular Interval Durvalumab(STRIDE)regimen,an immunotherapy-based approach that achieved a median overall survival(OS)of 16.43 months compared to 13.77 months with sorafenib.While statistically significant,this~2.7 months OS gain warrants scrutiny in light of STRIDE’s increased immune-related toxicity and cost.This commentary evaluates STRIDE’s impact within the broader landscape of first-line systemic therapy for unresectable HCC,alongside other regimens such as atezolizumab plus bevacizumab and nivolumab plus ipilimumab.We explore STRIDE’s mechanism of action,safety profile,modest progression-free survival(PFS)improvement,and implementation challenges,incorporating insights from 2023-2025 research.In addition,we discussed its limitations in non-viral HCC and Child-Pugh B patients,the role of emerging biomarkers,and the potential of radiation to enhance immunotherapy efficacy.As a dual immune checkpoint inhibitor(ICI)strategy,STRIDE offers an important advance that may not only extend survival but also open the door to future curative approaches.However,optimizing its use will require refined patient selection and further investigation of synergistic combination therapies.
基金funded by the Research,Development,and Innovation Authority(RDIA)—Kingdom of Saudi Arabia(Grant No.13292-psu-2023-PSNU-R-3-1-EF-).
文摘Colorectal cancer is the third most diagnosed cancer worldwide,and immune checkpoint inhibitors have shown promising therapeutic outcomes in selected patient groups.This study performed a comprehensive analysis of multi-omics data from The Cancer Genome Atlas colorectal adenocarcinoma cohort(TCGA-COADREAD),accessed through cBioPortal,to develop machine learning models for predicting progression-free survival(PFS)following immunotherapy.The dataset included clinical variables,genomic alterations in Kirsten Rat Sarcoma Viral Oncogene Homolog(KRAS),B-Raf Proto-Oncogene(BRAF),and Neuroblastoma RAS Viral Oncogene Homolog(NRAS),microsatellite instability(MSI)status,tumor mutation burden(TMB),and expression of immune checkpoint genes.Kaplan–Meier analysis showed that KRAS mutations were significantly associated with reduced PFS,while BRAF and NRAS mutations had no significant impact.MSI-high tumors exhibited elevated TMB and increased immune checkpoint expression,reflecting their immunologically active phenotype.We developed both survival and classification models,with the Extra Trees classifier achieving the best performance(accuracy=0.86,precision=0.67,recall=0.70,F1-score=0.68,AUC=0.84).These findings highlight the potential of combining genomic and immune biomarkers with machine learning to improve patient stratification and guide personalized immunotherapy decisions.An interactive web application was also developed to enable clinicians to input patient-specific molecular and clinical data and visualize individualized PFS predictions,supporting timely,data-driven treatment planning.
文摘Obese individuals who subsequently sustain a traumatic brain injury(TBI)exhibit worsened outcomes including longer periods of rehabilitation(Eagle et al.,2023).In obese individuals,prolonged symptomology is associated with increased levels of circulato ry pro-inflammatory marke rs up to 1 year postTBI(Eagle et al.,2023).
基金supported by an AIMS fellowship grant from the University of West Florida(04523:YL)partially by the National Institutes of Health grant under Award Number R16-GM149358the National Science Foundation grant DUE 2344997.
文摘Parkinson's disease(PD)is the second most common neurodegenerative disease that affects movement and cognitive function,resulting from the loss of the neurotransmitter dopamine due to the death of dopaminergic neurons.It affects nearly one million people in the United States and 8.5 million worldwide.While there are some pharmacological and surgical options available,they only provide symptomatic relief,as there is currently no cure for PD.In contrast,exercise training,a non-pharmacological intervention,has emerged as a powerful strategy to enhance the psychological,cognitive,and physiological(motor)impairments associated with PD.Given that the beneficial effects of exercise differ based on the intensity and type of training,gaining a thorough understanding of the molecular mechanisms underlying exercise-induced protection is crucial for developing innovative therapies that improve the quality of life for PD patients around the globe.This review discusses PD pathogenesis and pathophysiology and provides recent clinical evidence of neuroprotective benefits from various exercise modalities and intensity.Furthermore,the molecular mechanisms of exercise in PD pathogenesis(e.g.,modulations on neurotrophic factors,oxidative stress,mitochondria dysfunction,endoplasmic reticulum stress,and autophagy)will be emphasized.
基金Supported by the National Natural Science Foundation of China(No.32170204)。
文摘This study presents a comprehensive phylogenetic analysis on Batrachospermaceae based on key taxonomic identifiers(rbcL,psaA,psbA,and COI-5P)from some genera.To systematically explore the phylogenetic relationships and taxonomy within Batrachospermaceae,we integrated molecular and morphological data,and explored the phylogeny,character evolution,and ancestral geographical origin and provided a theoretical support for the classification and geographic origination of Batrachospermaceae.Our findings reveal distinct relationships within the phylogenetic tree.Notably,10 genera(Sirodotia,Batrachospermum,Tuomeya,Volatus,Lympha,Nothocladus,Torularia,Sheathia,Nocturama,and Petrohua)are closely associated in the rbcL phylogenetic tree.Additionally,four genera(Kumanoa,Hoefkenia,Notohesperus,and Virescentia)exhibit high support ratios,indicating their close interrelations.Other genera,including Paludicola,Visia,Acarposporophycos,Macrosporophycos,Visioidea,Balliopsis,and Psilosiphon,exhibit clustering traits.Furthermore,the multigene sequences provide a robust support for Montagnia that forms a monophyletic group.Ancestral reconstruction of morphological characters identifies nine primitive character states,including whorl,fascicle length,cortical cells,secondary fascicles,the shape of carpogonical branch,spermatangia,carposporophyte,carpogonium and trichogyne,with Visia likely representing ancestral traits in Batrachospermaceae.Furthermore,geographical origin maps suggest a potential common ancestral of Batrachospermaceae origin in the American continent.Additional to conventional analyses,including evolutionary and ancestral reconstruction investigations into key morphological characters,we attempt to reconstruct the biogeography within the Batrachospermaceae,thus contributing to a nuanced understanding of its origin.
基金supported by the National Natural Science Foundation of China,No.82201626(to CC)the Natural Science Foundation of LiaoningProvince,No.2022-MS-442(to CC)the Dalian Municipal Medical Key Specialty Climbing Project,No.2024ZZ040(to MZ).
文摘Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia.However,there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease.In this study,we investigated the potential therapeutic effects of MCC950,a selective NOD-like receptor family pyrin domain-containing protein 3 inhibitor,on cerebral small vessel disease pathogenesis and cognitive decline in spontaneously hypertensive rats.Our results showed that chronic administration of MCC950(10 mg/kg)to spontaneously hypertensive rats inhibited NOD-like receptor family pyrin domain-containing protein 3 inflammasome activation,thereby considerably suppressing the production of pyroptosis executive protein gasdermin D and pro-inflammatory factors,including interleukin-1βand-18.A decrease in astrocytic and microglial activation was also observed.We also found that MCC950 significantly inhibited autophagy.More importantly,behavioral assessment indicated that MCC950 administration ameliorated impaired neurocognitive function,which was associated with improvements in neuropathological hallmarks in the cerebral small vessel disease brain,such as blood‒brain barrier breakdown,white matter damage,and endothelial dysfunction.Thus,our findings revealed that the NOD-like receptor family pyrin domain-containing protein 3 inflammasome is a key contributor to the onset or progression of cerebral small vessel disease and suggested the potential of NOD-like receptor family pyrin domain-containing protein 3-based therapy as a potential novel strategy for treating cerebral small vessel disease.
基金supported by grants PID2020-120308RB-I00 and PID2023-147802OB-I00 funded by MICIU/AEI/10.13039/501100011033FEDER,UE,by Aligning Science Across Parkinson’s(ref.ASAP-020505)through the Michael J.Fox Foundation for Parkinson’s Research+1 种基金by CiberNed Intramural Collaborative Projects(ref.PI2020/09)by the Spanish Fundación Mutua Madrile?a de Investigación Médica(to JLL)。
文摘The development of clinical candidates that modify the natural progression of sporadic Parkinson's disease and related synucleinopathies is a praiseworthy endeavor,but extremely challenging.Therapeutic candidates that were successful in preclinical Parkinson's disease animal models have repeatedly failed when tested in clinical trials.While these failures have many possible explanations,it is perhaps time to recognize that the problem lies with the animal models rather than the putative candidate.In other words,the lack of adequate animal models of Parkinson's disease currently represents the main barrier to preclinical identification of potential disease-modifying therapies likely to succeed in clinical trials.However,this barrier may be overcome by the recent introduction of novel generations of viral vectors coding for different forms of alpha-synuclein species and related genes.Although still facing several limitations,these models have managed to mimic the known neuropathological hallmarks of Parkinson's disease with unprecedented accuracy,delineating a more optimistic scenario for the near future.
基金funded by Nanjing University of Posts and Telecommunications Humanities and Social Sciences Research Fund Project(NYY222055)Special research project on teaching reform of innovation and entrepreneurship education in Nanjing University of Posts and Telecommunications(GCSJG202528)+2 种基金General Subject of Educational Science Planning in Jiangsu Province(C/2024/01/76)General project of educational science research in Shanghai(C24288)Key funded project of Shandong Vocational Education Teaching Reform Research in 2022(2022052).
文摘Background:As an important indicator of subjective well-being(SWB),decent work is a key guarantee for the sustainable development of teachers and their psychological health and work quality.Faced with the rapid development of artificial intelligence and the global labor market,vocational college teachers are facing challenges such as workload pressure and limited career development,which may harm their well-being.This study aims to localize the measurement method of decent work in Chinese vocational education based on the theory of the Psychology of Working Theory,and explore the relationship mechanism between organizational support,career adaptability,decent work,and job satisfaction among vocational college teachers.Methods:A cross-sectional survey was conducted with 422 HVCU teachers in China(202 male,220 female)using the localized Perceived Organizational Support Scale,Career Adaptability Scale,Decent Work Scale,and Job Satisfaction Scale.Results:The overall level of HVCU teachers’decent work was above the median(Mean=4.09,SD=0.69),laying a foundation for their SWB.Decent work significantly and positively predicted job satisfaction(β=0.620,p<0.001).Organizational support(r=0.58,p<0.001)and career adaptability(r=0.82,p<0.001)can positively affect decent work,and further improve job satisfaction(collective R2 rising from 38.3%to 41.1%).Bootstrap analysis confirmed these mediating effects were robust.Conclusions:This study confirms that the combined effects of organizational support and career adaptability can enhance decent work,further improving teachers’job satisfaction and subsequent subjective well-being.Besides,this study provides an empirical basis for improving the well-being of higher vocational teachers and the sustainable development of vocational education,and has practical significance for improving the teacher incentive policy.
基金Supported by the National Natural Science Foundation of China(No.43277051)the Key Laboratory of Integrated Regulation and Resources Development of Shallow Lakes of Ministry of Education(No.B230203006).
文摘While oceanic and coastal acidification has gained increased attention,long-term pH trends and their drivers in large freshwater systems remain poorly understood.The Laurentian Great Lakes are the world’s largest freshwater system,and in many ways resemble marine ecosystems.However,unlike the open ocean and coastal waters where pH has declined due to rising atmospheric CO_(2),no significant pH trends have been observed in the Laurentian Great Lakes,despite significant ecosystem changes driven partly by the invasion of dreissenid mussels.This study examined 41 years of field observations from Lake Michigan to investigate the long-term carbonate chemistry dynamics.Observational results revealed substantial declines in both total alkalinity(TA)and dissolved inorganic carbon(DIC)over the four decades.Mussel shell calcification emerged as the primary mechanism behind these declines,accounting for 97%and 47%of the observed changes in TA and DIC,respectively,lowering water column pH by 0.24 units.Elevated carbon accumulation in soft mussel tissues,coupled with long-term changes in the air-water pCO_(2)gradient during summer,significantly contributed to long-term DIC variations,explaining 18%and 28%of the lake-wide DIC loss.These two mechanisms also resulted in an overall pH increase of 0.09 and 0.12 units,largely offsetting the calcification-driven pH decrease.These findings bridge a gap in acidification research for large freshwater systems and provide valuable insights for comprehensive lake-wide management strategies.
文摘Metastatic brain tumors undergo profound metabolic-epigenetic reprogramming driven by the unique constraints of the brain microenvironment.Hypoxia-inducible factor-1α(HIF1α)enhances glycolytic flux,lactate accumulation,and histone lactylation,collectively supporting metastatic colonization and immune evasion.Key metabolites including acetyl-CoA,S-adenosylmethionine(SAM),α-ketoglutarate(α-KG),fumarate,and 2-hydroxyglutarate(2-HG)-directly modify chromatin states by regulating histone acetyltransferases,DNA/histone methyltransferases,andα-KG dependent dioxygenases such as Ten-Eleven Translocation(TET)enzymes and lysine demethylases(KDMs).These metabolic shifts result in aberrant DNA methylation,histone lysine residue at position 27 on Histone H3(H3K27)trimethylation,and depletion of 5-hydroxymethylcytosine(5hmC),all of which are hallmark epigenetic alterations in brain metastasis and primary Central Nervous System(CNS)tumors.Additionally,the blood-brain barrier(BBB)and blood-tumor barrier(BTB)impose nutrient restrictions and induce metabolic dependency on glutamine,acetate,and lactate shuttling,thereby reshaping epigenetic enzyme activity.We synthesize current mechanistic evidence showing how metabolic pressures in the brain microenvironment remodel the epigenome to promote tumor plasticity,stemness,and therapeutic resistance.Understanding these coupled pathways reveals vulnerable nodes such as HIF1αsignaling,α-KG-dependent demethylation,and lactate-driven epigenetic remodeling that may be exploited for targeted treatment of metastatic brain tumors.The present review aims to provide in-depth insights into epigenetic regulation,including chromatin and histone modifications as well as noncoding RNAs and metabolic reprogramming,highlighting how the two interplay in the development and progression of metastatic brain tumors and their therapeutic potential.
基金supported by the National Research Foundation of Korea(NRF)grant,funded by the Korean government(MIST),Jae-Hoon Kim(NRF-2020R1A2C2004782)Hanbyoul Cho(NRF-RS-2025-00522191)of Funderssupported by the Bio&Medical Technology Development Program of the National Research Foundation(NRF),funded by the Korean Government(MSIT),Jae-Hoon Kim of Funder(NRF-2017M3A9B 8069610).
文摘Objectives:Phosphodiesterase 1A(PDE1A)regulates intracellular cyclic nucleotide signaling and has been implicated in tumor progression,but its clinical relevance and functional role in epithelial ovarian cancer(EOC),particularly in relation to the response to platinum remain unclear.This study aimed to evaluate the clinical significance of PDE1A in EOG and to clarify its functional role in tumor progression and response to platinum-based chemotherapy.Methods:PDE1A mRNA and protein levels were analyzed using public databases,RNA sequencing,and immunohistochemistry.Correlations between PDE1A expression,clinicopathological features,and prognosis were assessed.Functional roles were investigated in ovarian cancer cell lines.Results:PDE1A was significantly overexpressed in EOC tissues compared with that in normal ovarian epithelial tissues.Overexpression correlated with advanced International Federation of Gynecology and Obstetrics(FIGO)stage,poor tumor grade,and reduced response to platinum-based chemotherapy.High PDE1A levels were linked to worse disease-free survival and overall survival,and multivariate analysis confirmed PDE1A as an independent prognostic factor.To elucidate its functional role,we performed in vitro experiments showing that PDE1A knockdown suppressed cell proliferation and colony formation,induced G1 arrest,and downregulatedβ-catenin signaling with reduced cyclin D1 and c-Myc expression.Notably,these inhibitory effects were partially rescued by lithium chloride(LiCl),a Wingless-related integration site(Wnt)/β-catenin activator.Conclusions:In conclusion,our findings identify PDE1A as a Wnt/β-catenin-linked biomarker of tumor progression and platinum resistance in EOC and provide a biological rationale for further investigation of PDE1A-targeted strategies in preclinical models.
