Influenza A virus(IAV)shows an extensive host range and rapid genomic variations,leading to continuous emergence of novel viruses with significant antigenic variations and the potential for cross-species transmission....Influenza A virus(IAV)shows an extensive host range and rapid genomic variations,leading to continuous emergence of novel viruses with significant antigenic variations and the potential for cross-species transmission.This causes global pandemics and seasonal flu outbreaks,posing sustained threats worldwide.Thus,studying all IAVs'evolutionary patterns and underlying mechanisms is crucial for effective prevention and control.We developed FluTyping to identify IAV genotypes,to explore overall genetic diversity patterns and their restriction factors.FluTyping groups isolates based on genetic distance and phylogenetic relationships using whole genomes,enabling identification of each isolate's genotype.Three distinct genetic diversity patterns were observed:one genotype domination pattern comprising only H1N1 and H3N2 seasonal influenza subtypes,multi-genotypes cocirculation pattern including majority avian influenza subtypes and swine influenza H1N2,and hybrid-circulation pattern involving H7N9 and three H5 subtypes of influenza viruses.Furthermore,the IAVs in multi-genotypes cocirculation pattern showed region-specific dominant genotypes,implying the restriction of virus transmission is a key factor contributing to distinct genetic diversity patterns,and the genomic evolution underlying different patterns was more influenced by host-specific factors.In summary,a comprehensive picture of the evolutionary patterns of overall IAVs is provided by the FluTyping's identified genotypes,offering important theoretical foundations for future prevention and control of these viruses.展开更多
Most genome-wide association studies(GWAS)of Venous Thromboembolism(VTE)have used data from individuals of European descent,however,genetic factors for VTE have not been fully identified in Chinese populations,which c...Most genome-wide association studies(GWAS)of Venous Thromboembolism(VTE)have used data from individuals of European descent,however,genetic factors for VTE have not been fully identified in Chinese populations,which causes the limited use of existing polygenic risk scores(PRS)to identify subpopulations at high risk of VTE for prevention.We,therefore,aimed to curate all the potential VTE-related single-nucleotide polymorphisms(SNPs)for the construction of a new improved PRS model based on the self-adapting method,and then evaluate its utility and effectiveness in the stratification of VTE risk in Chinese populations.We comprehensively analyzed the mutation spectrum of VTE-associated SNPs in the Chinese cohort,and ranked their individual risk effects independently using risk ratio,logistic regression coefficient,and penalty regression coefficient as evaluation criteria.By integrating various algorithms and evaluating their performance,we trained the optimal prediction model of VTE risk in the Chinese population with the least SNP features,established an adaptive PRS model with progressive SNP overlay,and tested it on an independent Chinese population cohort.Self-adaptive polygenic risk score model based on all 318 SNPs or on the 44 most strongly associated SNPs performed similarly(areas under receiver-operating characteristic curves(AUCs)of 0.739 and 0.709,respectively)on the testing dataset of the Chinese VTE cohort,and that achieve the overall best level of the AUC from a conventional PRS model based on known genetic risk factors(0.620–0.718).In addition,we observed the self-adaptive PRS model was an independent effective risk stratification indicator beyond other clinical characteristics including age and smoking status.Our data revealed that only 44 SNPs-derived PRS model can be effectively used in discriminating subpopulations at high risk of VTE.To become clinically useful,our model could benefit from a practically feasible VTE screening program for precision prevention in Chinese populations.展开更多
Abdominal Aortic Aneurysm(AAA)is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta,which has no effective therapeutic approaches due to unclear molecular mechanis...Abdominal Aortic Aneurysm(AAA)is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta,which has no effective therapeutic approaches due to unclear molecular mechanisms.Using single-cell RNA sequencing,we analyzed the molecular profile of individual cells within control and AAA abdominal aortas.We found cellular heterogeneity,with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells(VSMCs)in AAA.Up-regulated genes in AAA were associated with muscle tissue development and apoptosis.Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA.Additionally,VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation.Similar observations were made in a mouse model of AAA induced by Angiotensin II,further affirming the relevance of our findings to human AAA.The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention.Nicotinamide phosphoribosyltransferase(NAMPT,also named VISFATIN)signaling emerged as a signature event in AAA.NAMPT was significantly downregulated in AAA.NAMPT-extracellular vesicles(EVs)derived from mesenchymal stem cells restored NAMPT levels,and offered protection against AAA.Furthermore,NAMPT-EVs not only repressed injuries,such as cell senescence and DNA damage,but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models,suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment.These findings shed light on the cellular heterogeneity and injuries in AAA,and offered promising therapeutic intervention for AAA treatment.展开更多
Idiopathic pulmonary fibrosis(IPF)is a chronic interstitial lung disease with a high mortality rate and limited therapeutic options.Dysregulated macrophage polarization as a driver of fibroblast activation and epithel...Idiopathic pulmonary fibrosis(IPF)is a chronic interstitial lung disease with a high mortality rate and limited therapeutic options.Dysregulated macrophage polarization as a driver of fibroblast activation and epithelial-mesenchymal transition(EMT)is the key to IPF evolution,but lacks an effective management approach.Herein,we develop a novel inhalable methane nanocapsule(MNC)which is able to spatiotemporally control methane release in the lung to locally remodel fibrogenic microenvironment in IPF.MNC is formulated through self-assembly of biodegradable poly(lactic-co-glycolic acid)-polyethylene glycol(PLGA-PEG)copolymer and a new acid-responsive methane prodrug Fe(BPY)_(2)(CH_(3))_(2) to enhance the efficacy of pulmonary methane delivery by facilitating mucosal penetration and sustained methane release in response to the acidic inflammatory niche.In a bleomycin(BLM)-induced pulmonary fibrosis model,MNC inhalation achieves efficient MNC deposition and sustained methane release in the lung,significantly reducing inflammation progression,ameliorating fibrosis formation,and improving lung function without systemic side effects.Mechanistically,MNC not only rebalances macrophage polarization by inhibiting M2 phenotype overexpression but also downregulates the ratio of MMP9/TIMP-1 to suppress myofibroblast proliferation and EMT,synergistically suspending the fibrotic progression of IPF.The developed inhalable methane nanocapsule offers a promising strategy to remodel pulmonary fibrogenic microenvironment for safe and effective treatment of IPF.展开更多
CONSPECTUS:Hydrogen medicine materials are defined as a new concept of biomedical materials specifically engineered to overcome critical challenges in hydrogen medicine,including exploration of biological effects and ...CONSPECTUS:Hydrogen medicine materials are defined as a new concept of biomedical materials specifically engineered to overcome critical challenges in hydrogen medicine,including exploration of biological effects and mechanisms of H2 by in vivo monitoring of H2 transportation,metabolism and transformation,enhancement of H2 therapeutic efficacy against various oxidative stress-related diseases by high-efficiency and site-specific delivery and controlled release of H2,etc.As the smallest and weakly reductive molecule,H2 exhibits some unique biological characteristics,including high tissue permeability,antioxidative stress(OS),anti-inflammation,antiapoptosis,antisenescence,pro-regeneration/pro-self-repairing,anticancer,antibiofilm,high bio-compatibility,and biosafety,holding a high value of biomedical applications.However,the related biological mechanisms are not very clear.Typically,multifaceted biological behaviors of H2 in varied pathological microenvironments,such as inflammation,cancer,and injured tissue,have not been well elucidated.Moreover,as a therapeutic agent,the pharmacokinetics of H2,involving absorption,biodistribution,metabolism,and excretion,has to be clarified before clinical application,which needs the development of hydrogen bioprobes to resolve.Based on high biosafety and therapeutic validity of H2,both hydrogen gas inhalator and hydrogen-rich water generator have been clinically approved for adjuvant therapy of some respiratory and digestive system diseases including chronic obstructive pulmonary disease(COPD),hyperuricemia,hyperlipemia,gastrelcosis and coprostasis,but they hardly realize effective delivery toward remote diseased focuses.Therefore,efficient,site-specific and controlled/sustained H2-delivering materials with high biosafety urgently need to be developed for improving the outcome of hydrogen therapy.Based on these unique advantages and unsolved key issues in hydrogen medicine,hydrogen medicine materials as an emerging interdisciplinary field have attracted increasing attention in recent years.In this Account,we present a brief overview of the recent advances of hydrogen medicine materials including hydrogen bioprobes and hydrogen-delivering materials(hydrogen carriers,hydrolytic hydrogen-generating materials,and catalytic hydrogen-generating materials),as well as their typical biomedical applications including targeted inflammation therapy,targeted tumor therapy,and local tissue repair/regeneration.Finally,a forward-looking perspective on hydrogen medicine materials is demonstrated,which attempts to address the current clinical challenges in the field of hydrogen medicine.Especially,the development of small molecular bioprobes for in vivo H2 detection,the understanding of H2 pharmacokinetics and potential bioeffects,the exploration of the profound mechanisms underlying multifaceted biological behaviors of H2,the development of versatile hydrogen-delivering materials for the treatment of various intractable diseases,and the evaluation of potential long-term toxicity risk of both high-dose H2 and hydrogen〓〓delivering materials are highlighted.This Account is expected to illuminate the way for exploration of hydrogen medicine materials.展开更多
Main text Fibrillar aggregates ofα-synuclein(αSyn)play a key role in the pathogenesis of Parkinson’s disease(PD)and other synucleinopathies,making them critical targets for diagnostic approaches.In this context,see...Main text Fibrillar aggregates ofα-synuclein(αSyn)play a key role in the pathogenesis of Parkinson’s disease(PD)and other synucleinopathies,making them critical targets for diagnostic approaches.In this context,seed amplification assays(SAAs)have emerged as a promising diagnostic technique by exploiting the self-propagating nature of misfoldedαSyn aggregates.SAAs have been successfully used to detectαSyn in various biological samples,including cerebrospinal fluid(CSF),skin,and blood[1].Among these,blood-based diagnostics are particularly suitable for early detection and disease monitoring due to their non-invasive nature.However,the presence of numerous components,such as albumin and other inhibitory proteins,complicates the implementation of SAA in blood samples[2].展开更多
基金supported by the National Key Plan for Scientific Research and Development of China(2021YFC2301305 and 2021YFC2302001)the National Natural Science Foundation of China(32370703,92169106,9216910042 and 32070678)+2 种基金the CAMS Innovation Fund for Medical Science(2022-I2M-1-021,2021-I2M-1-051)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2021-PT180-001)the Emergency Key Program of Guangzhou Laboratory(grant EKPG21-12).
文摘Influenza A virus(IAV)shows an extensive host range and rapid genomic variations,leading to continuous emergence of novel viruses with significant antigenic variations and the potential for cross-species transmission.This causes global pandemics and seasonal flu outbreaks,posing sustained threats worldwide.Thus,studying all IAVs'evolutionary patterns and underlying mechanisms is crucial for effective prevention and control.We developed FluTyping to identify IAV genotypes,to explore overall genetic diversity patterns and their restriction factors.FluTyping groups isolates based on genetic distance and phylogenetic relationships using whole genomes,enabling identification of each isolate's genotype.Three distinct genetic diversity patterns were observed:one genotype domination pattern comprising only H1N1 and H3N2 seasonal influenza subtypes,multi-genotypes cocirculation pattern including majority avian influenza subtypes and swine influenza H1N2,and hybrid-circulation pattern involving H7N9 and three H5 subtypes of influenza viruses.Furthermore,the IAVs in multi-genotypes cocirculation pattern showed region-specific dominant genotypes,implying the restriction of virus transmission is a key factor contributing to distinct genetic diversity patterns,and the genomic evolution underlying different patterns was more influenced by host-specific factors.In summary,a comprehensive picture of the evolutionary patterns of overall IAVs is provided by the FluTyping's identified genotypes,offering important theoretical foundations for future prevention and control of these viruses.
基金National High Level Hospital Clinical Research Funding 2023-NHLHCRF-YGJH-03.
文摘Most genome-wide association studies(GWAS)of Venous Thromboembolism(VTE)have used data from individuals of European descent,however,genetic factors for VTE have not been fully identified in Chinese populations,which causes the limited use of existing polygenic risk scores(PRS)to identify subpopulations at high risk of VTE for prevention.We,therefore,aimed to curate all the potential VTE-related single-nucleotide polymorphisms(SNPs)for the construction of a new improved PRS model based on the self-adapting method,and then evaluate its utility and effectiveness in the stratification of VTE risk in Chinese populations.We comprehensively analyzed the mutation spectrum of VTE-associated SNPs in the Chinese cohort,and ranked their individual risk effects independently using risk ratio,logistic regression coefficient,and penalty regression coefficient as evaluation criteria.By integrating various algorithms and evaluating their performance,we trained the optimal prediction model of VTE risk in the Chinese population with the least SNP features,established an adaptive PRS model with progressive SNP overlay,and tested it on an independent Chinese population cohort.Self-adaptive polygenic risk score model based on all 318 SNPs or on the 44 most strongly associated SNPs performed similarly(areas under receiver-operating characteristic curves(AUCs)of 0.739 and 0.709,respectively)on the testing dataset of the Chinese VTE cohort,and that achieve the overall best level of the AUC from a conventional PRS model based on known genetic risk factors(0.620–0.718).In addition,we observed the self-adaptive PRS model was an independent effective risk stratification indicator beyond other clinical characteristics including age and smoking status.Our data revealed that only 44 SNPs-derived PRS model can be effectively used in discriminating subpopulations at high risk of VTE.To become clinically useful,our model could benefit from a practically feasible VTE screening program for precision prevention in Chinese populations.
基金funded by the National Natural Science Grant of China(No.82072225,82272246)High-level Hospital Construction Project of Guangdong Provincial People’s Hospital(No.DFJHBF202104,No.DFJH201918)+1 种基金Science and Technology Program of Guangzhou,China(No.202206010044)Guangdong Basic and Applied Basic Research Foundation(2021B1515120062).
文摘Abdominal Aortic Aneurysm(AAA)is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta,which has no effective therapeutic approaches due to unclear molecular mechanisms.Using single-cell RNA sequencing,we analyzed the molecular profile of individual cells within control and AAA abdominal aortas.We found cellular heterogeneity,with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells(VSMCs)in AAA.Up-regulated genes in AAA were associated with muscle tissue development and apoptosis.Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA.Additionally,VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation.Similar observations were made in a mouse model of AAA induced by Angiotensin II,further affirming the relevance of our findings to human AAA.The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention.Nicotinamide phosphoribosyltransferase(NAMPT,also named VISFATIN)signaling emerged as a signature event in AAA.NAMPT was significantly downregulated in AAA.NAMPT-extracellular vesicles(EVs)derived from mesenchymal stem cells restored NAMPT levels,and offered protection against AAA.Furthermore,NAMPT-EVs not only repressed injuries,such as cell senescence and DNA damage,but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models,suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment.These findings shed light on the cellular heterogeneity and injuries in AAA,and offered promising therapeutic intervention for AAA treatment.
基金supported by the National Natural Science Foundation of China(82372104,82172078,and U23A20690)Guangdong Basic and Applied Basic Research Foundation(2024A1515030203)+1 种基金Shenzhen Science and Technology Program(RCJC20210706092010008)Guangzhou Science and Technology Bureau Basic Research Program City School Enterprise Joint Funding Project(2025A03J4530)。
文摘Idiopathic pulmonary fibrosis(IPF)is a chronic interstitial lung disease with a high mortality rate and limited therapeutic options.Dysregulated macrophage polarization as a driver of fibroblast activation and epithelial-mesenchymal transition(EMT)is the key to IPF evolution,but lacks an effective management approach.Herein,we develop a novel inhalable methane nanocapsule(MNC)which is able to spatiotemporally control methane release in the lung to locally remodel fibrogenic microenvironment in IPF.MNC is formulated through self-assembly of biodegradable poly(lactic-co-glycolic acid)-polyethylene glycol(PLGA-PEG)copolymer and a new acid-responsive methane prodrug Fe(BPY)_(2)(CH_(3))_(2) to enhance the efficacy of pulmonary methane delivery by facilitating mucosal penetration and sustained methane release in response to the acidic inflammatory niche.In a bleomycin(BLM)-induced pulmonary fibrosis model,MNC inhalation achieves efficient MNC deposition and sustained methane release in the lung,significantly reducing inflammation progression,ameliorating fibrosis formation,and improving lung function without systemic side effects.Mechanistically,MNC not only rebalances macrophage polarization by inhibiting M2 phenotype overexpression but also downregulates the ratio of MMP9/TIMP-1 to suppress myofibroblast proliferation and EMT,synergistically suspending the fibrotic progression of IPF.The developed inhalable methane nanocapsule offers a promising strategy to remodel pulmonary fibrogenic microenvironment for safe and effective treatment of IPF.
基金support from the National Natural Science Foundation of China(52425309,82172078,U23A20690,82372104)Guang Dong Basic and Applied Basic Research Foundation(2024A1515030203)+2 种基金Shenzhen Science and Technology Program(RCJC20210706092010008,JCYJ20230807113918038)National Key Research and Development Program of China(2022YFB3804500)Natural Science Foundation of Top Talent of SZTU(GDRC202338).
文摘CONSPECTUS:Hydrogen medicine materials are defined as a new concept of biomedical materials specifically engineered to overcome critical challenges in hydrogen medicine,including exploration of biological effects and mechanisms of H2 by in vivo monitoring of H2 transportation,metabolism and transformation,enhancement of H2 therapeutic efficacy against various oxidative stress-related diseases by high-efficiency and site-specific delivery and controlled release of H2,etc.As the smallest and weakly reductive molecule,H2 exhibits some unique biological characteristics,including high tissue permeability,antioxidative stress(OS),anti-inflammation,antiapoptosis,antisenescence,pro-regeneration/pro-self-repairing,anticancer,antibiofilm,high bio-compatibility,and biosafety,holding a high value of biomedical applications.However,the related biological mechanisms are not very clear.Typically,multifaceted biological behaviors of H2 in varied pathological microenvironments,such as inflammation,cancer,and injured tissue,have not been well elucidated.Moreover,as a therapeutic agent,the pharmacokinetics of H2,involving absorption,biodistribution,metabolism,and excretion,has to be clarified before clinical application,which needs the development of hydrogen bioprobes to resolve.Based on high biosafety and therapeutic validity of H2,both hydrogen gas inhalator and hydrogen-rich water generator have been clinically approved for adjuvant therapy of some respiratory and digestive system diseases including chronic obstructive pulmonary disease(COPD),hyperuricemia,hyperlipemia,gastrelcosis and coprostasis,but they hardly realize effective delivery toward remote diseased focuses.Therefore,efficient,site-specific and controlled/sustained H2-delivering materials with high biosafety urgently need to be developed for improving the outcome of hydrogen therapy.Based on these unique advantages and unsolved key issues in hydrogen medicine,hydrogen medicine materials as an emerging interdisciplinary field have attracted increasing attention in recent years.In this Account,we present a brief overview of the recent advances of hydrogen medicine materials including hydrogen bioprobes and hydrogen-delivering materials(hydrogen carriers,hydrolytic hydrogen-generating materials,and catalytic hydrogen-generating materials),as well as their typical biomedical applications including targeted inflammation therapy,targeted tumor therapy,and local tissue repair/regeneration.Finally,a forward-looking perspective on hydrogen medicine materials is demonstrated,which attempts to address the current clinical challenges in the field of hydrogen medicine.Especially,the development of small molecular bioprobes for in vivo H2 detection,the understanding of H2 pharmacokinetics and potential bioeffects,the exploration of the profound mechanisms underlying multifaceted biological behaviors of H2,the development of versatile hydrogen-delivering materials for the treatment of various intractable diseases,and the evaluation of potential long-term toxicity risk of both high-dose H2 and hydrogen〓〓delivering materials are highlighted.This Account is expected to illuminate the way for exploration of hydrogen medicine materials.
基金supported by grants from the Key Research and Development Program of Guangzhou(2023B03 J0631)Guangdong Basic and Applied Basic Research Foundation(2022B1515230004)+1 种基金Guangzhou Municipal Science and Technology Bureau’s Basic Research Program for the year 2024 jointly funded by the city and universities(2023 A03 J01331)Xinjiang Uyghur Autonomous Region Key Research and Development Project(2023B03003).
文摘Main text Fibrillar aggregates ofα-synuclein(αSyn)play a key role in the pathogenesis of Parkinson’s disease(PD)and other synucleinopathies,making them critical targets for diagnostic approaches.In this context,seed amplification assays(SAAs)have emerged as a promising diagnostic technique by exploiting the self-propagating nature of misfoldedαSyn aggregates.SAAs have been successfully used to detectαSyn in various biological samples,including cerebrospinal fluid(CSF),skin,and blood[1].Among these,blood-based diagnostics are particularly suitable for early detection and disease monitoring due to their non-invasive nature.However,the presence of numerous components,such as albumin and other inhibitory proteins,complicates the implementation of SAA in blood samples[2].
