Cognitive impairment is a particularly severe non-motor symptom of Parkinson's disease that significantly diminishes the quality of life of affected individuals.Identifying reliable biomarkers for cognitive impair...Cognitive impairment is a particularly severe non-motor symptom of Parkinson's disease that significantly diminishes the quality of life of affected individuals.Identifying reliable biomarkers for cognitive impairment in Parkinson's disease is essential for early diagnosis,prognostic assessments,and the development of targeted therapies.This review aims to summarize recent advancements in biofluid biomarkers for cognitive impairment in Parkinson's disease,focusing on the detection of specific proteins,metabolites,and other biomarkers in blood,cerebrospinal fluid,and saliva.These biomarkers can shed light on the multifaceted etiology of cognitive impairment in Parkinson's disease,which includes protein misfolding,neurodegeneration,inflammation,and oxidative stress.The integration of biofluid biomarkers with neuroimaging and clinical data can facilitate the development of predictive models to enhance early diagnosis and monitor the progression of cognitive impairment in patients with Parkinson's disease.This comprehensive approach can improve the existing understanding of the mechanisms driving cognitive decline and support the development of targeted therapeutic strategies aimed at modifying the course of cognitive impairment in Parkinson's disease.Despite the promise of these biomarkers in characterizing the mechanisms underlying cognitive decline in Parkinson's disease,further research is necessary to validate their clinical utility and establish a standardized framework for early detection and monitoring of cognitive impairment in Parkinson's disease.展开更多
Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein ...Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.展开更多
Over the recent years, it has been found that microglia pseudopodia contact synapses, detect sick ones and prune them, even in adult animals. Myelinated nerves also carry out plasticity in which microglia remove myeli...Over the recent years, it has been found that microglia pseudopodia contact synapses, detect sick ones and prune them, even in adult animals. Myelinated nerves also carry out plasticity in which microglia remove myelin debris by phagocytosis. However, it remains unknown whether microglia explore structures on nerve fibers, such as Ranvier’s node(RN) or myelin sheath, before they become debris. By double or triple staining RNs or myelin sheathes and microglia in healthy rat corpus callosum, this study unveiled direct contacts of microglia pseudopodia with RNs and with para-and inter-nodal myelin sheathes, which was then verified by electron microscopic observations. Our data indicated that microglia also explore unmyelinated nerve fibers. Furthermore, we used the animals with matured white matter;therefore, microglia may be actively involved in plasticity of matured white matter tracts as it does for synapse pruning, instead of only passively phagocytize myelin debris.展开更多
Microglia activation and white matter injury coexist after repeated episodes of mild brain trauma and ischemic stroke. Axon degeneration and demyelination can activate microglia; however, it is unclear whether early m...Microglia activation and white matter injury coexist after repeated episodes of mild brain trauma and ischemic stroke. Axon degeneration and demyelination can activate microglia; however, it is unclear whether early microglia activation can impair the function of white matter tracts and lead to injury. Rat corpus callosum（CC） slices were treated with lipopolysaccharide（LPS） or LPS ＋ Rhodobacter sphaeroides（RS）-LPS that is a toll-like receptor 4（TLR-4） antagonist. Functional changes reflected by the change of axon compound action potentials（CAPs） and the accumulation of β-amyloid precursor protein（β-APP） in CC nerve fibers. Microglia activation was monitored by ionized calcium binding adaptor-1 immunofluorescent stain, based on well-established morphological criteria and paralleled proportional area measurement. Input-output（I/O） curves of CAPs in response to increased stimuli were significantly downshifted in a dose-dependent manner in LPS（0.2, 0.5 and 1.0μg/mL）-treated slices, implying that axons neurophysiological function was undermined. LPS caused significant β-APP accumulation in CC tissues,reflecting the deterioration of fast axon transport. LPS-induced I/O curve downshift and P-APP accumulation were significantly reversed by the pre-treatment or co-incubation with RS-LPS. RS-LPS alone did not change the I/O curve.The degree of malfunction was correlated with microglia activation, as was shown by the measurements of proportional areas. Function of CC nerve fibers was evidently impaired by microglia activation and reversed by a TLP-4 antagonist, suggesting that the TLP-4 pathway lead to microglia activation.展开更多
After six years of development,the number of farmer cooperatives in Yanbian area was increased from 72 in 2007 to 2600 in 2012.It has become an important part of local modern agricultural operation.Through the survey ...After six years of development,the number of farmer cooperatives in Yanbian area was increased from 72 in 2007 to 2600 in 2012.It has become an important part of local modern agricultural operation.Through the survey and research of current status of farmer cooperatives in Yanbian area,we analyze the deficiencies in capital,technology and human resources during the operating to thoroughly understand its operating status.On this basis,we put forth some recommendations for the development of farmer cooperatives in Yanbian area:implementing industrialization operation;developing long-term development strategy;seeking the support of research institutions and colleges;increasing the types of services;enhancing the value-added.展开更多
Objective:To analyze the association between iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantification sequence(IDEAL-IQ)magnetic resonance imaging(MRI)of bone marrow fat...Objective:To analyze the association between iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantification sequence(IDEAL-IQ)magnetic resonance imaging(MRI)of bone marrow fat fraction and bone marrow reserve function during concurrent chemoradiotherapy for cervical cancer.Methods:The study retrospectively analyzed twenty-six patients with stage IB1 to IVA cervical cancer treated between February 2020 and November 2020.All patients received concurrent chemoradiotherapy that included platinum alone or combined paclitaxel and platinum.Pelvic IDEAL-IQ MRI(plain and enhanced)was performed before and after treatment.Regions of interest,including the fifth lumbar vertebra,sacrum,ilium,ischium,and femoral neck,were manually delineated,and the bone marrow fat fraction was measured.Peripheral blood cell counts were recorded during treatment,and the relationship between the fat fraction values and changes in the blood cell counts was explored.Results:IDEAL-IQ MRI bone marrow fat fraction was associated with platelet nadir and platelet decline during treatment.The average pelvic bone marrow fat fraction before chemoradiotherapy was moderately negatively correlated with platelet count nadir during concurrent chemoradiotherapy(r=-0.450,P?0.021).The change in average pelvic bone marrow fat fraction through chemoradiotherapy was moderately positively correlated with the degree of thrombocytopenia(r=0.399,P=0.044).Conclusion:Bone marrow fat content quantified by IDEAL-IQ was associated with platelet count nadir and the degree of thrombocytopenia in patients with cervical cancer undergoing concurrent chemoradiotherapy.展开更多
Background:Observational studies have indicated a link between liver enzymes and dementia,but the causal relationship remains uncertain.We conducted a two-sample Mendelian randomization(MR)study to investigate potenti...Background:Observational studies have indicated a link between liver enzymes and dementia,but the causal relationship remains uncertain.We conducted a two-sample Mendelian randomization(MR)study to investigate potential causal links between liver function markers(alanine aminotransferase[ALT],aspartate aminotransferase[AST],alkaline phosphatase[ALP],andγ-glutamyltransferase[GGT])and various forms of dementia(all-cause dementia,Alzheimer's disease[AD],vascular dementia[VaD],and frontotemporal dementia[FTD]).Methods:Genome-wide association study(GWAS)data of liver enzyme levels with 517 single nucleotide polymorphisms from 315,572 individuals of European descent were considered as exposures.Additional GWAS data on dementia from the FinnGen consortium and the UK Biobank were used as outcomes.The causal relationship was evaluated using univariable MR(UVMR)and multivariable MR(MVMR)methods.UVMR approaches such as inverse variance weighting(IVW),MR-Egger,weighted median,simple mode,and weighted mode were used,with IVW as primary.MVMR techniques,such as extended versions of IVW,MR-Egger,and Q-minimization methods,were used to assess causal effects.The robustness of the MR analysis findings was verified through heterogeneity,horizontal pleiotropy,and leave-one-out analyses.Results:MVMR analysis demonstrated that a genetically determined one standard deviation rise in blood GGT levels was associated with an increased risk of VaD(IVW:odds ratio=1.007,95%confidence interval=1.002-1.011,p=0.010).These findings remained consistent after adjusting for confounding variables in MVMR analysis.Sensitivity analyses further supported the causal relationship.However,no significant links were observed between ALT,AST,ALP,and all-cause dementia,VaD,AD,or FTD.Conclusions:Our study suggests clinical implications,demonstrating that high blood GGT concentrations are potential causal risk factors for VaD in European populations.Further research is needed to uncover the underlying biological mechanisms between GGT and VaD and validate the clinical relevance of early prevention and intervention strategies.展开更多
基金supported by Applied Basic Research Foundation of Yunnan Province,Nos.202301AS070045,202101AY070001-115(to XY and BL)National Natural Science Foundation of China,No.81960242(to XY)。
文摘Cognitive impairment is a particularly severe non-motor symptom of Parkinson's disease that significantly diminishes the quality of life of affected individuals.Identifying reliable biomarkers for cognitive impairment in Parkinson's disease is essential for early diagnosis,prognostic assessments,and the development of targeted therapies.This review aims to summarize recent advancements in biofluid biomarkers for cognitive impairment in Parkinson's disease,focusing on the detection of specific proteins,metabolites,and other biomarkers in blood,cerebrospinal fluid,and saliva.These biomarkers can shed light on the multifaceted etiology of cognitive impairment in Parkinson's disease,which includes protein misfolding,neurodegeneration,inflammation,and oxidative stress.The integration of biofluid biomarkers with neuroimaging and clinical data can facilitate the development of predictive models to enhance early diagnosis and monitor the progression of cognitive impairment in patients with Parkinson's disease.This comprehensive approach can improve the existing understanding of the mechanisms driving cognitive decline and support the development of targeted therapeutic strategies aimed at modifying the course of cognitive impairment in Parkinson's disease.Despite the promise of these biomarkers in characterizing the mechanisms underlying cognitive decline in Parkinson's disease,further research is necessary to validate their clinical utility and establish a standardized framework for early detection and monitoring of cognitive impairment in Parkinson's disease.
基金supported by Applied Basic Research Joint Fund Project of Yunnan Province,No.202301AY070001-200Middle-aged Academic and Technical Training Project for High-Level Talents,No.202105AC160065+1 种基金Yunnan Clinical Medical Center for Neurological and Cardiovascular Diseases,No.YWLCYXZX2023300077Key Clinical Specialty of Neurology in Yunnan Province,No.300064(all to CL)。
文摘Research into lactylation modifications across various target organs in both health and disease has gained significant attention.Many essential life processes and the onset of diseases are not only related to protein abundance but are also primarily regulated by various post-translational protein modifications.Lactate,once considered merely a byproduct of anaerobic metabolism,has emerged as a crucial energy substrate and signaling molecule involved in both physiological and pathological processes within the nervous system.Furthermore,recent studies have emphasized the significant role of lactate in numerous neurological diseases,including Alzheimer's disease,Parkinson's disease,acute cerebral ischemic stroke,multiple sclerosis,Huntington's disease,and myasthenia gravis.The purpose of this review is to synthesize the current research on lactate and lactylation modifications in neurological diseases,aiming to clarify their mechanisms of action and identify potential therapeutic targets.As such,this work provides an overview of the metabolic regulatory roles of lactate in various disorders,emphasizing its involvement in the regulation of brain function.Additionally,the specific mechanisms of brain lactate metabolism are discussed,suggesting the unique roles of lactate in modulating brain function.As a critical aspect of lactate function,lactylation modifications,including both histone and non-histone lactylation,are explored,with an emphasis on recent advancements in identifying the key regulatory enzymes of such modifications,such as lactylation writers and erasers.The effects and specific mechanisms of abnormal lactate metabolism in diverse neurological diseases are summarized,revealing that lactate acts as a signaling molecule in the regulation of brain functions and that abnormal lactate metabolism is implicated in the progression of various neurological disorders.Future research should focus on further elucidating the molecular mechanisms underlying lactate and lactylation modifications and exploring their potential as therapeutic targets for neurological diseases.
基金supported by R01 NS063878 and P30 MH062261 (to H.X., H.S.F.)
文摘Over the recent years, it has been found that microglia pseudopodia contact synapses, detect sick ones and prune them, even in adult animals. Myelinated nerves also carry out plasticity in which microglia remove myelin debris by phagocytosis. However, it remains unknown whether microglia explore structures on nerve fibers, such as Ranvier’s node(RN) or myelin sheath, before they become debris. By double or triple staining RNs or myelin sheathes and microglia in healthy rat corpus callosum, this study unveiled direct contacts of microglia pseudopodia with RNs and with para-and inter-nodal myelin sheathes, which was then verified by electron microscopic observations. Our data indicated that microglia also explore unmyelinated nerve fibers. Furthermore, we used the animals with matured white matter;therefore, microglia may be actively involved in plasticity of matured white matter tracts as it does for synapse pruning, instead of only passively phagocytize myelin debris.
文摘Microglia activation and white matter injury coexist after repeated episodes of mild brain trauma and ischemic stroke. Axon degeneration and demyelination can activate microglia; however, it is unclear whether early microglia activation can impair the function of white matter tracts and lead to injury. Rat corpus callosum（CC） slices were treated with lipopolysaccharide（LPS） or LPS ＋ Rhodobacter sphaeroides（RS）-LPS that is a toll-like receptor 4（TLR-4） antagonist. Functional changes reflected by the change of axon compound action potentials（CAPs） and the accumulation of β-amyloid precursor protein（β-APP） in CC nerve fibers. Microglia activation was monitored by ionized calcium binding adaptor-1 immunofluorescent stain, based on well-established morphological criteria and paralleled proportional area measurement. Input-output（I/O） curves of CAPs in response to increased stimuli were significantly downshifted in a dose-dependent manner in LPS（0.2, 0.5 and 1.0μg/mL）-treated slices, implying that axons neurophysiological function was undermined. LPS caused significant β-APP accumulation in CC tissues,reflecting the deterioration of fast axon transport. LPS-induced I/O curve downshift and P-APP accumulation were significantly reversed by the pre-treatment or co-incubation with RS-LPS. RS-LPS alone did not change the I/O curve.The degree of malfunction was correlated with microglia activation, as was shown by the measurements of proportional areas. Function of CC nerve fibers was evidently impaired by microglia activation and reversed by a TLP-4 antagonist, suggesting that the TLP-4 pathway lead to microglia activation.
基金Supported by Soft Science Research Project of Jilin Provincial Department of Science and Technology(20130420030FG)Project of Yanbian University(201216)
文摘After six years of development,the number of farmer cooperatives in Yanbian area was increased from 72 in 2007 to 2600 in 2012.It has become an important part of local modern agricultural operation.Through the survey and research of current status of farmer cooperatives in Yanbian area,we analyze the deficiencies in capital,technology and human resources during the operating to thoroughly understand its operating status.On this basis,we put forth some recommendations for the development of farmer cooperatives in Yanbian area:implementing industrialization operation;developing long-term development strategy;seeking the support of research institutions and colleges;increasing the types of services;enhancing the value-added.
基金financially supported by Affiliated Cancer Hospital&Institute of Guangzhou Medical University Clinical Research 5555 Program,China[IIT-2020-002(FL5)]Guangzhou Regional Clinical Characteristic Technology Project,China(2023C-TS06).
文摘Objective:To analyze the association between iterative decomposition of water and fat with echo asymmetry and least-squares estimation quantification sequence(IDEAL-IQ)magnetic resonance imaging(MRI)of bone marrow fat fraction and bone marrow reserve function during concurrent chemoradiotherapy for cervical cancer.Methods:The study retrospectively analyzed twenty-six patients with stage IB1 to IVA cervical cancer treated between February 2020 and November 2020.All patients received concurrent chemoradiotherapy that included platinum alone or combined paclitaxel and platinum.Pelvic IDEAL-IQ MRI(plain and enhanced)was performed before and after treatment.Regions of interest,including the fifth lumbar vertebra,sacrum,ilium,ischium,and femoral neck,were manually delineated,and the bone marrow fat fraction was measured.Peripheral blood cell counts were recorded during treatment,and the relationship between the fat fraction values and changes in the blood cell counts was explored.Results:IDEAL-IQ MRI bone marrow fat fraction was associated with platelet nadir and platelet decline during treatment.The average pelvic bone marrow fat fraction before chemoradiotherapy was moderately negatively correlated with platelet count nadir during concurrent chemoradiotherapy(r=-0.450,P?0.021).The change in average pelvic bone marrow fat fraction through chemoradiotherapy was moderately positively correlated with the degree of thrombocytopenia(r=0.399,P=0.044).Conclusion:Bone marrow fat content quantified by IDEAL-IQ was associated with platelet count nadir and the degree of thrombocytopenia in patients with cervical cancer undergoing concurrent chemoradiotherapy.
基金Ministry of Science and Technology of China (No.2013YQ190467)Chinese Academy of Sciences (No.XDA09030305)+1 种基金the National Natural Science Foundation of China (Nos.81361140345,51373043, and 21535001)the Natural Science Foundation of Shandong Province (No.ZR201709250460)for financial support.
基金the consortium studies for making the summary association statistics data publicly available.This research was supported by the Applied Basic Research Foundation of Yunnan Province(grant numbers:202301AS070045 and 202101AY070001-115)the National Natural Science Foundation of China(grant number:81960242)+1 种基金the Yunnan Province Clinical Research Center for Geriatric Disease(grant number:202102AA310069)the Innovative Team of Yunnan Province(grant number:202305AS350019).
文摘Background:Observational studies have indicated a link between liver enzymes and dementia,but the causal relationship remains uncertain.We conducted a two-sample Mendelian randomization(MR)study to investigate potential causal links between liver function markers(alanine aminotransferase[ALT],aspartate aminotransferase[AST],alkaline phosphatase[ALP],andγ-glutamyltransferase[GGT])and various forms of dementia(all-cause dementia,Alzheimer's disease[AD],vascular dementia[VaD],and frontotemporal dementia[FTD]).Methods:Genome-wide association study(GWAS)data of liver enzyme levels with 517 single nucleotide polymorphisms from 315,572 individuals of European descent were considered as exposures.Additional GWAS data on dementia from the FinnGen consortium and the UK Biobank were used as outcomes.The causal relationship was evaluated using univariable MR(UVMR)and multivariable MR(MVMR)methods.UVMR approaches such as inverse variance weighting(IVW),MR-Egger,weighted median,simple mode,and weighted mode were used,with IVW as primary.MVMR techniques,such as extended versions of IVW,MR-Egger,and Q-minimization methods,were used to assess causal effects.The robustness of the MR analysis findings was verified through heterogeneity,horizontal pleiotropy,and leave-one-out analyses.Results:MVMR analysis demonstrated that a genetically determined one standard deviation rise in blood GGT levels was associated with an increased risk of VaD(IVW:odds ratio=1.007,95%confidence interval=1.002-1.011,p=0.010).These findings remained consistent after adjusting for confounding variables in MVMR analysis.Sensitivity analyses further supported the causal relationship.However,no significant links were observed between ALT,AST,ALP,and all-cause dementia,VaD,AD,or FTD.Conclusions:Our study suggests clinical implications,demonstrating that high blood GGT concentrations are potential causal risk factors for VaD in European populations.Further research is needed to uncover the underlying biological mechanisms between GGT and VaD and validate the clinical relevance of early prevention and intervention strategies.
