Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidati...Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.展开更多
The enhancement of industrial green total factor productivity is pivotal for achieving high-quality and sustainable economic development.This study assesses China’s performance using the SBM-GML model,employing provi...The enhancement of industrial green total factor productivity is pivotal for achieving high-quality and sustainable economic development.This study assesses China’s performance using the SBM-GML model,employing province-level panel data spanning from 2004 to 2020.Furthermore,we examine the influence of green finance and technological progress on industrial green total factor productivity using a spatial econometric model.The findings uncover that the relationship between the level of green financial development and industrial green total factor productivity follows a U-shaped curve.Initially,low levels of green financial development exert a suppressive effect on industrial green total factor productivity,proving ineffective in the short term.However,with the progression of green finance development,a positive and significant long-term impact on industrial green total factor productivity emerges.Moreover,technological progress demonstrates a noteworthy promotional effect on industrial green total factor productivity.The analysis delves deeper into revealing that industrial structure and environmental regulation intensity exhibit a significant negative relationship with industrial green total factor productivity.In contrast,both energy structure and education level showcase a substantial positive relationship with industrial green total factor productivity.展开更多
Recent text generation methods frequently learn node representations from graph‐based data via global or local aggregation,such as knowledge graphs.Since all nodes are connected directly,node global representation en...Recent text generation methods frequently learn node representations from graph‐based data via global or local aggregation,such as knowledge graphs.Since all nodes are connected directly,node global representation encoding enables direct communication between two distant nodes while disregarding graph topology.Node local representation encoding,which captures the graph structure,considers the connections between nearby nodes but misses out onlong‐range relations.A quantum‐like approach to learning bettercontextualised node embeddings is proposed using a fusion model that combines both encoding strategies.Our methods significantly improve on two graph‐to‐text datasets compared to state‐of‐the‐art models in various experiments.展开更多
Myocardial ischemia–reperfusion injury(MIRI)is a major hindrance to the success of cardiac reperfusion therapy.Although increased neutrophil infiltration is a hallmark of MIRI,the subtypes and alterations of neutroph...Myocardial ischemia–reperfusion injury(MIRI)is a major hindrance to the success of cardiac reperfusion therapy.Although increased neutrophil infiltration is a hallmark of MIRI,the subtypes and alterations of neutrophils in this process remain unclear.Here,we performed single-cell sequencing of cardiac CD45^(+)cells isolated from the murine myocardium subjected to MIRI at six-time points.We identified diverse types of infiltrating immune cells and their dynamic changes during MIRI.Cardiac neutrophils showed the most immediate response and largest changes and featured with functionally heterogeneous subpopulations,including Ccl3^(hi)Neu and Ym-1^(hi)Neu,which were increased at 6 h and 1 d after reperfusion,respectively.Ym-1^(hi)Neu selectively expressed genes with protective effects and was,therefore,identified as a novel specific type of cardiac cell in the injured heart.Further analysis indicated that neutrophils and their subtypes orchestrated subsequent immune responses in the cardiac tissues,especially instructing the response of macrophages.The abundance of Ym-1^(hi)Neu was closely correlated with the therapeutic efficacy of MIRI when neutrophils were specifically targeted by anti-Lymphocyte antigen 6 complex locus G6D(Ly6G)or anti-Intercellular cell adhesion molecule-1(ICAM-1)neutralizing antibodies.In addition,a neutrophil subtype with the same phenotype as Ym-1^(hi)Neu was detected in clinical samples and correlated with prognosis.Ym-1 inhibition exacerbated myocardial injury,whereas Ym-1 supplementation significantly ameliorated injury in MIRI mice,which was attributed to the tilt of Ym-1 on the polarization of macrophages toward the repair phenotype in myocardial tissue.Overall,our findings reveal the antiinflammatory phenotype of Ym-1^(hi)Neu and highlight its critical role in myocardial protection during the early stages of MIRI.展开更多
Apolipoprotein E(APOE)plays a pivotal role in lipid including cholesterol metabolism.The APOE 4(APOE4)allele is a major genetic risk factor for Alzheimer's and cardiovascular diseases.Although APOE has recently be...Apolipoprotein E(APOE)plays a pivotal role in lipid including cholesterol metabolism.The APOE 4(APOE4)allele is a major genetic risk factor for Alzheimer's and cardiovascular diseases.Although APOE has recently been associated with increased susceptibility to infections of several viruses,whether and how APOEand its isoforms affect SARS-CoV-2 infection remains unclear.Here,we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19 patients.Utilizing multiple protein interaction assays,we demonstrate that APOE3 and APOE4 interact with the SARS-CoV-2 receptor ACE2;and APOE/ACE2 interactions require zinc metallopeptidase domain of ACE2,a key docking site for SARS-CoV-2 Spike protein.In addition,immuno-imaging assays using confocal,super-resolution,and transmission electron microscopies reveal that both APOE3 and APOE4 reduce ACE2/Spikemediated viral entry into cells.Interestingly,while having a comparable binding affinity to ACE2,APOE4 inhibits viral entry to a lesser extent compared to APOE3,which is likely due to APOE4's more compact structure and smaller spatial obstacle to compete against Spike binding to ACE2.Furthermore,APOE e4 carriers clinically correlate with increased SARS-CoV-2 infection and elevated serum inflammatory factors in 142 COVID-19 patients assessed.Our study suggests a regulatory mechanism underlying SARS-CoV-2 infection through APOE interactions with ACE2,which may explain in part increased COVID-19 infection and disease severity in APOE e4 carriers.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82271444(to JP),82271268(to BZ),and 82001346(to YL)the National Key Research and Development Program of China,No.2022YFE0210100(to BZ)。
文摘Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.
基金General Research Fund of Philosophy and Social Sciences in Colleges and Universities of Jiangsu Province in 2020(Grant Number 2020SJA1008)Fundamental Research Funds for the Central Universities(Grant Number 2023SK04)。
文摘The enhancement of industrial green total factor productivity is pivotal for achieving high-quality and sustainable economic development.This study assesses China’s performance using the SBM-GML model,employing province-level panel data spanning from 2004 to 2020.Furthermore,we examine the influence of green finance and technological progress on industrial green total factor productivity using a spatial econometric model.The findings uncover that the relationship between the level of green financial development and industrial green total factor productivity follows a U-shaped curve.Initially,low levels of green financial development exert a suppressive effect on industrial green total factor productivity,proving ineffective in the short term.However,with the progression of green finance development,a positive and significant long-term impact on industrial green total factor productivity emerges.Moreover,technological progress demonstrates a noteworthy promotional effect on industrial green total factor productivity.The analysis delves deeper into revealing that industrial structure and environmental regulation intensity exhibit a significant negative relationship with industrial green total factor productivity.In contrast,both energy structure and education level showcase a substantial positive relationship with industrial green total factor productivity.
基金supported by the National Natural Science Foundation of China under Grant(62077015)the Key Laboratory of Intelligent Education Technology and Application of Zhejiang Province,Zhejiang Normal University,Zhejiang,China,the Key Research and Development Program of Zhejiang Province(No.2021C03141)the National Key R&D Program of China under Grant(2022YFC3303600).
文摘Recent text generation methods frequently learn node representations from graph‐based data via global or local aggregation,such as knowledge graphs.Since all nodes are connected directly,node global representation encoding enables direct communication between two distant nodes while disregarding graph topology.Node local representation encoding,which captures the graph structure,considers the connections between nearby nodes but misses out onlong‐range relations.A quantum‐like approach to learning bettercontextualised node embeddings is proposed using a fusion model that combines both encoding strategies.Our methods significantly improve on two graph‐to‐text datasets compared to state‐of‐the‐art models in various experiments.
基金supported by the National Natural Science Foundation of China(82022076,81974249,82070136,82104488,and 82305194)the Postdoctoral Science Foundation of China(2023M731222,and 2020T130040ZX)the Foundation of Hubei Key Laboratory of Biological Targeted Therapy(2023swbx021)。
文摘Myocardial ischemia–reperfusion injury(MIRI)is a major hindrance to the success of cardiac reperfusion therapy.Although increased neutrophil infiltration is a hallmark of MIRI,the subtypes and alterations of neutrophils in this process remain unclear.Here,we performed single-cell sequencing of cardiac CD45^(+)cells isolated from the murine myocardium subjected to MIRI at six-time points.We identified diverse types of infiltrating immune cells and their dynamic changes during MIRI.Cardiac neutrophils showed the most immediate response and largest changes and featured with functionally heterogeneous subpopulations,including Ccl3^(hi)Neu and Ym-1^(hi)Neu,which were increased at 6 h and 1 d after reperfusion,respectively.Ym-1^(hi)Neu selectively expressed genes with protective effects and was,therefore,identified as a novel specific type of cardiac cell in the injured heart.Further analysis indicated that neutrophils and their subtypes orchestrated subsequent immune responses in the cardiac tissues,especially instructing the response of macrophages.The abundance of Ym-1^(hi)Neu was closely correlated with the therapeutic efficacy of MIRI when neutrophils were specifically targeted by anti-Lymphocyte antigen 6 complex locus G6D(Ly6G)or anti-Intercellular cell adhesion molecule-1(ICAM-1)neutralizing antibodies.In addition,a neutrophil subtype with the same phenotype as Ym-1^(hi)Neu was detected in clinical samples and correlated with prognosis.Ym-1 inhibition exacerbated myocardial injury,whereas Ym-1 supplementation significantly ameliorated injury in MIRI mice,which was attributed to the tilt of Ym-1 on the polarization of macrophages toward the repair phenotype in myocardial tissue.Overall,our findings reveal the antiinflammatory phenotype of Ym-1^(hi)Neu and highlight its critical role in myocardial protection during the early stages of MIRI.
文摘Apolipoprotein E(APOE)plays a pivotal role in lipid including cholesterol metabolism.The APOE 4(APOE4)allele is a major genetic risk factor for Alzheimer's and cardiovascular diseases.Although APOE has recently been associated with increased susceptibility to infections of several viruses,whether and how APOEand its isoforms affect SARS-CoV-2 infection remains unclear.Here,we show that serum concentrations of APOE correlate inversely with levels of cytokine/chemokine in 73 COVID-19 patients.Utilizing multiple protein interaction assays,we demonstrate that APOE3 and APOE4 interact with the SARS-CoV-2 receptor ACE2;and APOE/ACE2 interactions require zinc metallopeptidase domain of ACE2,a key docking site for SARS-CoV-2 Spike protein.In addition,immuno-imaging assays using confocal,super-resolution,and transmission electron microscopies reveal that both APOE3 and APOE4 reduce ACE2/Spikemediated viral entry into cells.Interestingly,while having a comparable binding affinity to ACE2,APOE4 inhibits viral entry to a lesser extent compared to APOE3,which is likely due to APOE4's more compact structure and smaller spatial obstacle to compete against Spike binding to ACE2.Furthermore,APOE e4 carriers clinically correlate with increased SARS-CoV-2 infection and elevated serum inflammatory factors in 142 COVID-19 patients assessed.Our study suggests a regulatory mechanism underlying SARS-CoV-2 infection through APOE interactions with ACE2,which may explain in part increased COVID-19 infection and disease severity in APOE e4 carriers.
