Biobanks bridge the gap between basic and translational research.Traditional cancer biobanks typically contain normal and tumor tissues,and matched blood.However,biospecimens in traditional biobanks are usually nonren...Biobanks bridge the gap between basic and translational research.Traditional cancer biobanks typically contain normal and tumor tissues,and matched blood.However,biospecimens in traditional biobanks are usually nonrenewable.In recent years,increased interest has focused on establishing living biobanks,including organoid biobanks,for the collection and storage of viable and functional tissues for long periods of time.The organoid model is based on a 3D in vitro cell culture system,is highly similar to primary tissues and organs in vivo,and can recapitulate the phenotypic and genetic characteristics of target organs.Publications on cancer organoids have recently increased,and many types of cancer organoids have been used for modeling cancer processes,as well as for drug discovery and screening.On the basis of the current research status,more exploration of cancer organoids through technical advancements is required to improve reproducibility and scalability.Moreover,given the natural characteristics of organoids,greater attention must be paid to ethical considerations.Here,we summarize recent advances in cancer organoid biobanking research,encompassing rectal,gastric,pancreatic,breast,and glioblastoma cancers.Living cancer biobanks that contain cancerous tissues and matched organoids with different genetic backgrounds,subtypes,and individualized characteristics will eventually contribute to the understanding of cancer and ultimately facilitate the development of innovative treatments.展开更多
Digital Pathology is becoming more and more important to achieve the goal of precision medicine.Advances in whole-slide imaging,software integration,and the accessibility of storage solutions have changed the patholog...Digital Pathology is becoming more and more important to achieve the goal of precision medicine.Advances in whole-slide imaging,software integration,and the accessibility of storage solutions have changed the pathologists’clinical practice,not only in terms of laboratory workflow but also for diagnosis and biomarkers analysis.In parallel with the pathology setting advancement,translational medicine is approaching the unprecedented opportunities unrevealed by artificial intelligence(AI).Indeed,the increased usage of biobanks’datasets in research provided new challenges for AI applications,such as advanced algorithms,and computer-aided techniques.In this scenario,machine learning-based approaches are being propose in order to improve biobanks from biospecimens collection repositories to computational datasets.To date,evidence on how to implement digital biobanks in translational medicine is still lacking.This viewpoint article summarizes the currently available literature that supports the biobanks’role in the digital pathology era,and to provide possible practical applications of digital biobanks.展开更多
The coronavirus disease 2019(COVID-19)pandemic has highlighted the practice of infectious diseases biobanking,as well as existing challenges and opportunities.Thus,the future of infectious diseases biobanking in the p...The coronavirus disease 2019(COVID-19)pandemic has highlighted the practice of infectious diseases biobanking,as well as existing challenges and opportunities.Thus,the future of infectious diseases biobanking in the post-pandemic era,shall not be an“entry-level version”of its counterpart in non-communicable diseases and large population cohorts,but incorporate the lessons learned.Biobanks constitute a critical research infrastructure supported by harmonized practices through the implementation of international standards,and perceived within the broader scope of healthcare's intersection with research.This perspective paper considers the barriers in biobanking and standardization of practices,as well as the emerging opportunities in the field.展开更多
目的分析甲基转移酶3(METTL3)抑制剂STM2457对人肝癌细胞系HepG2的影响,重点研究其对N6-甲基腺苷(m6A)表达的影响及其抗肿瘤机制。方法将HepG2细胞分为实验组(STM2457处理)和对照组(DMSO处理)。利用纳米孔(Nanopore)测序技术,结合m6Anet...目的分析甲基转移酶3(METTL3)抑制剂STM2457对人肝癌细胞系HepG2的影响,重点研究其对N6-甲基腺苷(m6A)表达的影响及其抗肿瘤机制。方法将HepG2细胞分为实验组(STM2457处理)和对照组(DMSO处理)。利用纳米孔(Nanopore)测序技术,结合m6Anet,NanoCount,xPore和GFOLD方法,分别对m6A修饰水平、转录组表达及差异基因进行分析。通过基因本体(GO)和京都基因与基因组百科(KEGG)对差异基因进行功能富集分析。结果STM2457降低HepG2细胞的m6A修饰位点数量(6446 vs 11549)及修饰水平(0.95±0.03 vs 0.98±0.03),差异具有统计学意义(Z=-19.915,P<0.01)。差异基因分析共筛选出109个上调基因和340个下调基因,其中与肝癌发生发展密切相关的基因PDLIM5、AZGP1和RNASET2,其m6A修饰水平降低,而基因表达水平升高。功能富集分析结果显示,差异基因主要富集在细胞黏附、凋亡、翻译调控及肝细胞癌相关通路。结论STM2457通过抑制METTL3活性,降低HepG2细胞的m6A修饰水平,上调基因PDLIM5,AZGP1和RNASET2的表达,促进HepG2细胞凋亡,为肝癌治疗提供潜在治疗靶点。展开更多
Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have rev...Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.展开更多
Background:Myeloid-derived suppressor cells(MDSCs)are important tumor microenvironment components in small cell lung cancer(SCLC).We successfully identified MDSCs expressing the surface marker CD33 in SCLC;nonetheless...Background:Myeloid-derived suppressor cells(MDSCs)are important tumor microenvironment components in small cell lung cancer(SCLC).We successfully identified MDSCs expressing the surface marker CD33 in SCLC;nonetheless,whether CD33^(+)MDSCs promote SCLC angiogenesis remains unclear.This study aims to explore the angiogenic effect and clinical significance of CD33^(+)MDSCs derived from SCLC.Method:Nineteen patients diagnosed with extensive-stage SCLC at Jilin Cancer Hospital were selected as the research subjects.CD33^(+)MDSCs were isolated from the peripheral blood of patients with SCLC using magnetic bead separation and CD33 expression was detected by flow cytometry.The angiogenic potential of CD33^(+)MDSCs derived from the peripheral blood of patients with SCLC and healthy individuals was assessed using human umbilical vein endothelial cell(HUVEC)angiogenesis assays,and the clinical significance of CD33^(+)MDSCs in promoting angiogenesis in patients with SCLC was analyzed using clinical data.Results:Compared to healthy individuals,the CD33^(+)MDSCs(CD14^(+)CD33^(+))isolated from the peripheral blood of SCLC patients exhibited a greater ability to promote HUVEC tubular growth(average vessel length:57.60 mm[47.78 mm]vs.39.07 mm[15.84 mm],p=0.000;vessel area:371,890 mm^(3)[699,927 mm^(3)]vs.334,652 mm^(3)[219,520 mm^(3)],p<0.000;total number of junctions:141[301]vs.120[94],p<0.005),and their angiogenic ability was associated with older age,female sex,high performance status scores,no systematic treatment,and treatment unresponsiveness(p<0.050).Furthermore,the enhanced angiogenic ability of CD33^(+)MDSCs may represent a risk factor for treatment unresponsiveness(average vessel length:Odds ratio=3.904,95%CI=1.812-8.409,p=0.001;vessel area:Odds ratio=2.501,95%CI=1.187-5.267,p=0.016;total number of junctions:Odds ratio=3.630,95%CI=1.686-7.815,p=0.001)and is associated with a poor SCLC prognosis(average vessel length:Hazard ratio=2.210,95%CI=1.299-3.758,p=0.003;vessel area:Hazard ratio=2.170,95%CI=1.274-3.693,p=0.004;total number of junctions:Hazard ratio=2.267,95%CI=1.333-3.853,p=0.003).Conclusion:CD33^(+)MDSCs derived from the peripheral blood of patients with SCLC promote angiogenesis,which is a risk factor for treatment unresponsiveness and is associated with poor prognosis.展开更多
Understanding spatial patterns of plant species diversity and the factors(e.g.,climate and human)that drive these patterns is essential for biodiversity conservation.We used data from 1700.1-ha forest plots in the She...Understanding spatial patterns of plant species diversity and the factors(e.g.,climate and human)that drive these patterns is essential for biodiversity conservation.We used data from 1700.1-ha forest plots in the Shettihalli tropical forest landscape of the Western Ghats biodiversity hotspot,India,to analyse tree community composition and the drivers of α-diversity(Shannon)andβ-diversity(LCBD).Compositional patterns were visualized using Non-Metric Multidimensional Scaling(NMDS),and hybrid feature selection with structural equation modeling(SEM)was employed to evaluate the direct and indirect effects of environmental variables on diversity.NMDS identified four distinct forest types in the Shettihalli landscape:semi-evergreen,dry deciduous,moist deciduous,and plantation forests,each with distinct plant composition.Shannon diversity and ecological uniqueness was significantly higher in semi-evergreen forest than in deciduous forest plots.The SEMs explained about 79%and 39–45%of the variation in α-diversity andβ-diversity.Our analysis indicated that current diversity patterns result from multiple processes,with structure,disturbance,and edaphic parameters exerting the strongest direct and indirect effects onα-diversity.β-diversity,in contrast,was largely influenced by climate,topography,stand structure,and edaphic factors.Overall,our findings indicate that various factors(e.g.,climate,topography,and human disturbance)interact to shape tree diversity patterns in tropical forests.These findings will help develop unique conservation and management strategies for distinct forest types in tropical forest ecosystems.展开更多
Circadian sensitivity significantly influences the severity of noise-induced hearing loss(NIHL),but the underlying mechanisms remain unclear.Here,we applied single-cell RNA sequencing to 97,043 cochlear cells,identify...Circadian sensitivity significantly influences the severity of noise-induced hearing loss(NIHL),but the underlying mechanisms remain unclear.Here,we applied single-cell RNA sequencing to 97,043 cochlear cells,identifying macrophages as the primary immune responders to acoustic trauma,with a notable increase in their proportion in the cochlea.Immunofluorescence confirmed significant recruitment and activation of cochlear macrophages following noise exposure,while in vivo macrophage depletion resulted in the recovery of hearing.Furthermore,analyses of differentially-expressed genes and pathways revealed pronounced activation of NLRP3 inflammasome signaling in macrophages during night-time noise exposure.Measurements of elevated IL-1βand IL-18 expression in cochlear macrophages by multiplex immunohistochemistry correlated with heightened inflammation in the night-time exposure group.These findings were further confirmed by the administration of the selective NLRP3 inhibitor CY-09,which mitigated inflammasome activation,preserved synaptic integrity,and protect against hearing loss.In conclusion,our findings underscore the role of macrophage-driven NLRP3 inflammasome activation in mediating circadian variations in cochlear damage,offering a potential therapeutic target for mitigating NIHL.展开更多
The mitochondrial 3243A>G mutation(m.3243A>G)is associated with diverse clinical phenotypes.To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients,urine-derived stem ...The mitochondrial 3243A>G mutation(m.3243A>G)is associated with diverse clinical phenotypes.To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients,urine-derived stem cells(USCs)and a mitochondrial leucyl-tRNA synthetase gene(lars-2)deficient Caenorhabditis elegans(C.elegans)model are used to assess mitochondrial homeostasis and neuromuscular dysfunction.Patient-derived USCs with high levels of m.3243A>G heteroplasmy exhibit impaired mitochondrial function,disrupted mitochondrial dynamics,and inhibited mitophagy,which are reversed by MitoQ through suppression of OMA1 zinc metallopeptidase(OMA1)-induced mitochondrial phosphatase and tensin(PTEN)induced kinase 1(PINK1)degradation.Furthermore,lars-2 knockdown in C.elegans induces mitochondrial stress and mimics the loss of neural and muscle functions observed in patients with the m.3243A>G mutation.MitoQ treatment partially improves neurobehavioral function by promoting the PINK1 pathway.These findings suggest that MitoQ has therapeutic potential in the context of the m.3243A>G mutation.展开更多
Biobanks have emerged in the last two decades as foundational research infrastructures supporting scientific advancement.They are organized collections and providers of high-quality and research-ready biospecimens as ...Biobanks have emerged in the last two decades as foundational research infrastructures supporting scientific advancement.They are organized collections and providers of high-quality and research-ready biospecimens as they can authenticate,preserve,and offer independent access to biological materials,such as specimens and cultures of pathogenic microorganisms.In most cases,biospecimens will be standardized and prepared in multiple aliquots for long-term storage so that future researchers can use them as new technologies and knowledge evolve.展开更多
基金supported by the Program for Changjiang Scholars and Innovative Research Team in University in China(Grant No.IRT_14R40)National Key Research and Development Program of China(Grant No.2021YFC2500400)+4 种基金National Science and Technology Major Project(Grant No.2017ZX10203207)National Human Genetic Resources Sharing Service Platform(Grant No.2005DKA21300)National Key Research and Development Program of ChinaNet Construction of Human Genetic Resource Bio-bank in North China(Grant No.2016YFC1201703)and National Key R&D Program of China(Grant No.2017YFC0908300).
文摘Biobanks bridge the gap between basic and translational research.Traditional cancer biobanks typically contain normal and tumor tissues,and matched blood.However,biospecimens in traditional biobanks are usually nonrenewable.In recent years,increased interest has focused on establishing living biobanks,including organoid biobanks,for the collection and storage of viable and functional tissues for long periods of time.The organoid model is based on a 3D in vitro cell culture system,is highly similar to primary tissues and organs in vivo,and can recapitulate the phenotypic and genetic characteristics of target organs.Publications on cancer organoids have recently increased,and many types of cancer organoids have been used for modeling cancer processes,as well as for drug discovery and screening.On the basis of the current research status,more exploration of cancer organoids through technical advancements is required to improve reproducibility and scalability.Moreover,given the natural characteristics of organoids,greater attention must be paid to ethical considerations.Here,we summarize recent advances in cancer organoid biobanking research,encompassing rectal,gastric,pancreatic,breast,and glioblastoma cancers.Living cancer biobanks that contain cancerous tissues and matched organoids with different genetic backgrounds,subtypes,and individualized characteristics will eventually contribute to the understanding of cancer and ultimately facilitate the development of innovative treatments.
文摘Digital Pathology is becoming more and more important to achieve the goal of precision medicine.Advances in whole-slide imaging,software integration,and the accessibility of storage solutions have changed the pathologists’clinical practice,not only in terms of laboratory workflow but also for diagnosis and biomarkers analysis.In parallel with the pathology setting advancement,translational medicine is approaching the unprecedented opportunities unrevealed by artificial intelligence(AI).Indeed,the increased usage of biobanks’datasets in research provided new challenges for AI applications,such as advanced algorithms,and computer-aided techniques.In this scenario,machine learning-based approaches are being propose in order to improve biobanks from biospecimens collection repositories to computational datasets.To date,evidence on how to implement digital biobanks in translational medicine is still lacking.This viewpoint article summarizes the currently available literature that supports the biobanks’role in the digital pathology era,and to provide possible practical applications of digital biobanks.
文摘The coronavirus disease 2019(COVID-19)pandemic has highlighted the practice of infectious diseases biobanking,as well as existing challenges and opportunities.Thus,the future of infectious diseases biobanking in the post-pandemic era,shall not be an“entry-level version”of its counterpart in non-communicable diseases and large population cohorts,but incorporate the lessons learned.Biobanks constitute a critical research infrastructure supported by harmonized practices through the implementation of international standards,and perceived within the broader scope of healthcare's intersection with research.This perspective paper considers the barriers in biobanking and standardization of practices,as well as the emerging opportunities in the field.
文摘目的分析甲基转移酶3(METTL3)抑制剂STM2457对人肝癌细胞系HepG2的影响,重点研究其对N6-甲基腺苷(m6A)表达的影响及其抗肿瘤机制。方法将HepG2细胞分为实验组(STM2457处理)和对照组(DMSO处理)。利用纳米孔(Nanopore)测序技术,结合m6Anet,NanoCount,xPore和GFOLD方法,分别对m6A修饰水平、转录组表达及差异基因进行分析。通过基因本体(GO)和京都基因与基因组百科(KEGG)对差异基因进行功能富集分析。结果STM2457降低HepG2细胞的m6A修饰位点数量(6446 vs 11549)及修饰水平(0.95±0.03 vs 0.98±0.03),差异具有统计学意义(Z=-19.915,P<0.01)。差异基因分析共筛选出109个上调基因和340个下调基因,其中与肝癌发生发展密切相关的基因PDLIM5、AZGP1和RNASET2,其m6A修饰水平降低,而基因表达水平升高。功能富集分析结果显示,差异基因主要富集在细胞黏附、凋亡、翻译调控及肝细胞癌相关通路。结论STM2457通过抑制METTL3活性,降低HepG2细胞的m6A修饰水平,上调基因PDLIM5,AZGP1和RNASET2的表达,促进HepG2细胞凋亡,为肝癌治疗提供潜在治疗靶点。
基金supported by the Guangdong Basic and Applied Basic Research Foundation,No.2023A1515030045(to HS)Presidential Foundation of Zhujiang Hospital of Southern Medical University,No.yzjj2022ms4(to HS)。
文摘Intracerebral hemorrhage is the most dangerous subtype of stroke,characterized by high mortality and morbidity rates,and frequently leads to significant secondary white matter injury.In recent decades,studies have revealed that gut microbiota can communicate bidirectionally with the brain through the gut microbiota–brain axis.This axis indicates that gut microbiota is closely related to the development and prognosis of intracerebral hemorrhage and its associated secondary white matter injury.The NACHT,LRR,and pyrin domain-containing protein 3(NLRP3)inflammasome plays a crucial role in this context.This review summarizes the dysbiosis of gut microbiota following intracerebral hemorrhage and explores the mechanisms by which this imbalance may promote the activation of the NLRP3 inflammasome.These mechanisms include metabolic pathways(involving short-chain fatty acids,lipopolysaccharides,lactic acid,bile acids,trimethylamine-N-oxide,and tryptophan),neural pathways(such as the vagus nerve and sympathetic nerve),and immune pathways(involving microglia and T cells).We then discuss the relationship between the activated NLRP3 inflammasome and secondary white matter injury after intracerebral hemorrhage.The activation of the NLRP3 inflammasome can exacerbate secondary white matter injury by disrupting the blood–brain barrier,inducing neuroinflammation,and interfering with nerve regeneration.Finally,we outline potential treatment strategies for intracerebral hemorrhage and its secondary white matter injury.Our review highlights the critical role of the gut microbiota–brain axis and the NLRP3 inflammasome in white matter injury following intracerebral hemorrhage,paving the way for exploring potential therapeutic approaches.
基金Science and Technology Agency of Jilin Provincial Project(Grant/Award Number:20230203075SF)Youth Project of Jilin Provincial Health Commission(Grant/Award Number:2024A123)。
文摘Background:Myeloid-derived suppressor cells(MDSCs)are important tumor microenvironment components in small cell lung cancer(SCLC).We successfully identified MDSCs expressing the surface marker CD33 in SCLC;nonetheless,whether CD33^(+)MDSCs promote SCLC angiogenesis remains unclear.This study aims to explore the angiogenic effect and clinical significance of CD33^(+)MDSCs derived from SCLC.Method:Nineteen patients diagnosed with extensive-stage SCLC at Jilin Cancer Hospital were selected as the research subjects.CD33^(+)MDSCs were isolated from the peripheral blood of patients with SCLC using magnetic bead separation and CD33 expression was detected by flow cytometry.The angiogenic potential of CD33^(+)MDSCs derived from the peripheral blood of patients with SCLC and healthy individuals was assessed using human umbilical vein endothelial cell(HUVEC)angiogenesis assays,and the clinical significance of CD33^(+)MDSCs in promoting angiogenesis in patients with SCLC was analyzed using clinical data.Results:Compared to healthy individuals,the CD33^(+)MDSCs(CD14^(+)CD33^(+))isolated from the peripheral blood of SCLC patients exhibited a greater ability to promote HUVEC tubular growth(average vessel length:57.60 mm[47.78 mm]vs.39.07 mm[15.84 mm],p=0.000;vessel area:371,890 mm^(3)[699,927 mm^(3)]vs.334,652 mm^(3)[219,520 mm^(3)],p<0.000;total number of junctions:141[301]vs.120[94],p<0.005),and their angiogenic ability was associated with older age,female sex,high performance status scores,no systematic treatment,and treatment unresponsiveness(p<0.050).Furthermore,the enhanced angiogenic ability of CD33^(+)MDSCs may represent a risk factor for treatment unresponsiveness(average vessel length:Odds ratio=3.904,95%CI=1.812-8.409,p=0.001;vessel area:Odds ratio=2.501,95%CI=1.187-5.267,p=0.016;total number of junctions:Odds ratio=3.630,95%CI=1.686-7.815,p=0.001)and is associated with a poor SCLC prognosis(average vessel length:Hazard ratio=2.210,95%CI=1.299-3.758,p=0.003;vessel area:Hazard ratio=2.170,95%CI=1.274-3.693,p=0.004;total number of junctions:Hazard ratio=2.267,95%CI=1.333-3.853,p=0.003).Conclusion:CD33^(+)MDSCs derived from the peripheral blood of patients with SCLC promote angiogenesis,which is a risk factor for treatment unresponsiveness and is associated with poor prognosis.
基金supported by the Department of Biotechnology,Ministry of Science and Technology,Govt.India,under grant No.BT/Coord.Ⅱ/10/02/2016/22.03.2018the Indian Council of Social Science Research,New Delhi,India,for providing a short-term doctoral fellowship(RFD/Short-Term/2022-23/ENV/ST/66)。
文摘Understanding spatial patterns of plant species diversity and the factors(e.g.,climate and human)that drive these patterns is essential for biodiversity conservation.We used data from 1700.1-ha forest plots in the Shettihalli tropical forest landscape of the Western Ghats biodiversity hotspot,India,to analyse tree community composition and the drivers of α-diversity(Shannon)andβ-diversity(LCBD).Compositional patterns were visualized using Non-Metric Multidimensional Scaling(NMDS),and hybrid feature selection with structural equation modeling(SEM)was employed to evaluate the direct and indirect effects of environmental variables on diversity.NMDS identified four distinct forest types in the Shettihalli landscape:semi-evergreen,dry deciduous,moist deciduous,and plantation forests,each with distinct plant composition.Shannon diversity and ecological uniqueness was significantly higher in semi-evergreen forest than in deciduous forest plots.The SEMs explained about 79%and 39–45%of the variation in α-diversity andβ-diversity.Our analysis indicated that current diversity patterns result from multiple processes,with structure,disturbance,and edaphic parameters exerting the strongest direct and indirect effects onα-diversity.β-diversity,in contrast,was largely influenced by climate,topography,stand structure,and edaphic factors.Overall,our findings indicate that various factors(e.g.,climate,topography,and human disturbance)interact to shape tree diversity patterns in tropical forests.These findings will help develop unique conservation and management strategies for distinct forest types in tropical forest ecosystems.
基金supported by the Scientific and Innovative Action Plan of Shanghai(CN)(22Y11902000)the National Natural Science Foundation of China(82371144 and 82201273)+2 种基金the Cross-Disciplinary Research Fund of Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine(JYJC202231)the Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases(14DZ2260300)We extend our gratitude to Prof.Hao Wu and the Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases for providing essential resources and laboratory facilities,and to Prof.Lei Song and Prof.Zhiyong Liu for valuable insights and guidance.
文摘Circadian sensitivity significantly influences the severity of noise-induced hearing loss(NIHL),but the underlying mechanisms remain unclear.Here,we applied single-cell RNA sequencing to 97,043 cochlear cells,identifying macrophages as the primary immune responders to acoustic trauma,with a notable increase in their proportion in the cochlea.Immunofluorescence confirmed significant recruitment and activation of cochlear macrophages following noise exposure,while in vivo macrophage depletion resulted in the recovery of hearing.Furthermore,analyses of differentially-expressed genes and pathways revealed pronounced activation of NLRP3 inflammasome signaling in macrophages during night-time noise exposure.Measurements of elevated IL-1βand IL-18 expression in cochlear macrophages by multiplex immunohistochemistry correlated with heightened inflammation in the night-time exposure group.These findings were further confirmed by the administration of the selective NLRP3 inhibitor CY-09,which mitigated inflammasome activation,preserved synaptic integrity,and protect against hearing loss.In conclusion,our findings underscore the role of macrophage-driven NLRP3 inflammasome activation in mediating circadian variations in cochlear damage,offering a potential therapeutic target for mitigating NIHL.
基金funded by the NIH Office of Research Infrastructure Programs(P40 OD010440)supported by the National Natural Science Foundation of China(82471893 and 82070913)+2 种基金Key discipline project of Hongkou District Health Commission(HKLCFC202403)Tongji Hospital Start-up Funding for Scientific Research(RCQD2301)Research fund from Shanghai Fourth People's Hospital(sykyqd01801,SYXKZT-2021-1001).
文摘The mitochondrial 3243A>G mutation(m.3243A>G)is associated with diverse clinical phenotypes.To elucidate the underlying mechanisms and explore intervention strategies in m.3243A>G patients,urine-derived stem cells(USCs)and a mitochondrial leucyl-tRNA synthetase gene(lars-2)deficient Caenorhabditis elegans(C.elegans)model are used to assess mitochondrial homeostasis and neuromuscular dysfunction.Patient-derived USCs with high levels of m.3243A>G heteroplasmy exhibit impaired mitochondrial function,disrupted mitochondrial dynamics,and inhibited mitophagy,which are reversed by MitoQ through suppression of OMA1 zinc metallopeptidase(OMA1)-induced mitochondrial phosphatase and tensin(PTEN)induced kinase 1(PINK1)degradation.Furthermore,lars-2 knockdown in C.elegans induces mitochondrial stress and mimics the loss of neural and muscle functions observed in patients with the m.3243A>G mutation.MitoQ treatment partially improves neurobehavioral function by promoting the PINK1 pathway.These findings suggest that MitoQ has therapeutic potential in the context of the m.3243A>G mutation.
文摘Biobanks have emerged in the last two decades as foundational research infrastructures supporting scientific advancement.They are organized collections and providers of high-quality and research-ready biospecimens as they can authenticate,preserve,and offer independent access to biological materials,such as specimens and cultures of pathogenic microorganisms.In most cases,biospecimens will be standardized and prepared in multiple aliquots for long-term storage so that future researchers can use them as new technologies and knowledge evolve.
