Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that requires long-term pharmacological management.Melittin,a peptide derived from bee venom,has shown promising therapeutic efficacy for RA by modulati...Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that requires long-term pharmacological management.Melittin,a peptide derived from bee venom,has shown promising therapeutic efficacy for RA by modulating immune balance.Given the critical role of the gut in immune regulation,oral administration of melittin could have significant clinical implications.However,this approach faces substantial challenges,including degradation by gastric fluids and off-target adverse effects,which compromise its efficacy and safety.To address these limitations,we developed an innovative orally administered,gut-targeted micro-nano system(SPM/AlgL)inspired by bacterial colonies.Herein,gas-shearing microfluidics is leveraged to monodisperse sialic acid-decorated peptide nanomedicines within calcium alginate microgels.These microspheres are then coated with probiotic biofilms,leveraging their acid resistance and intestinal adhesion properties.The biofilm coating effectively protects melittin from gastric degradation and enhances its accumulation in the mesenteric lymph nodes,thereby improving its targeting ability to inflammatory sites and reducing adverse effects.By modulating the Th1/Th2 and Th17/Treg ratios in the mesenteric lymph nodes and spleen tissues,this system successfully alleviates immune responses and efficiently mitigates the progression of arthritis.Overall,this oral therapeutic strategy demonstrates significant potential for advancing the immunotherapy of RA and other systemic autoimmune diseases.展开更多
Mutations in cytoplasmic DNA-degrading enzymes can lead to the accumulation of cytoplasmic DNA(cytoDNA),which excessively activates DNA-sensing pathways and exacerbates inflammatory aging.Reducing cytoDNA levels to su...Mutations in cytoplasmic DNA-degrading enzymes can lead to the accumulation of cytoplasmic DNA(cytoDNA),which excessively activates DNA-sensing pathways and exacerbates inflammatory aging.Reducing cytoDNA levels to suppress DNA-sensing mechanisms is therefore critical for treating elderly-onset rheumatoid arthritis(EORA).In this study,we constructed Trex1 mRNA loaded lipid nanoparticles(LNPs)via microfluidics and prepared DNase 1 loaded polydopamine(PDA)nanoparticles through oxidative polymerization.These two components were co-encapsulated into methacrylate hyaluronic acid(HAMA)microspheres using microfluidic photopolymerization.The LNPs incorporate cationic lipids to facilitate mRNA loading and promote endosomal escape,enabling efficient translation of TREX1 and subsequent recognition and degradation of cytoDNA.Meanwhile,cationic mesoporous poly-dopamine electrostatically adsorbs and degrades extracellular DNA.The microspheres function as a reservoir for sustained nanoparticles release,enabling synergistic inhibition of DNA sensing pathways.This microsphere based vaccine upregulates TREX1 expression in antigen presenting cells(APCs)and reduces cytoDNA levels,thereby suppressing overactivation of the cGAS-STING signaling axis and promoting immune tolerance.It also attenuates the differentiation of CD4^(+) T cells into Th1,Th2,Th17,and Treg subsets.In an aged rat model of rheumatoid arthritis,vaccination significantly attenuated soft tissue edema,synovial inflammation,and articular cartilage and bone destruction.By clearing excess cytoDNA and restraining DNA-sensing hyperactivation,this vaccine induces cellular immune tolerance and represents a promising therapeutic strategy for rheumatoid arthritis in the elderly.展开更多
This study aimed to comprehensively examine the association of gallstones,cholecystectomy,and cancer risk.Multivariable logistic regressions were performed to estimate the observational associations of gallstones and ...This study aimed to comprehensively examine the association of gallstones,cholecystectomy,and cancer risk.Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk,using data from a nationwide cohort involving 239799 participants.General and gender-specific two-sample Mendelian randomization(MR)analysis was further conducted to assess the causalities of the observed associations.Observationally,a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer(adjusted odds ratio(aOR)=2.54,95%confidence interval(CI)1.50–4.28),liver and bile duct cancer(aOR=2.46,95%CI 1.17–5.16),kidney cancer(aOR=2.04,95%CI 1.05–3.94),and bladder cancer(aOR=2.23,95%CI 1.01–5.13)in the general population,as well as cervical cancer(aOR=1.69,95%CI 1.12–2.56)in women.Moreover,cholecystectomy was associated with high odds of stomach cancer(aOR=2.41,95%CI 1.29–4.49),colorectal cancer(aOR=1.83,95%CI 1.18–2.85),and cancer of liver and bile duct(aOR=2.58,95%CI 1.11–6.02).MR analysis only supported the causal effect of gallstones on stomach,liver and bile duct,kidney,and bladder cancer.This study added evidence to the causal effect of gallstones on stomach,liver and bile duct,kidney,and bladder cancer,highlighting the importance of cancer screening in individuals with gallstones.展开更多
Introduction:Cognitive impairment poses a serious threat to the health of older adults.Understanding spatial distribution patterns and identifying high-risk areas are essential for developing targeted regional prevent...Introduction:Cognitive impairment poses a serious threat to the health of older adults.Understanding spatial distribution patterns and identifying high-risk areas are essential for developing targeted regional prevention and control strategies.This study examined the spatial distribution and clustering patterns of cognitive impairment in China in 2024.Methods:This study utilized data from the 2024 China Survey of Aging and Health.Rao-Scott chisquare tests were used to compare differences in prevalence across demographic subgroups.Global and local spatial autocorrelation analyses were conducted to examine the spatial distribution patterns and clustering characteristics.Results:In 2024,the prevalence of subjective cognitive decline(SCD)and mild cognitive impairment(MCI)among older adults≥65 years in China was 38.8%and 28.4%,respectively.The prevalence of SCD was highest in western China(45.1%),while MCI was highest in central China(31.0%).Global spatial autocorrelation analysis revealed that SCD(P=0.025)and MCI(P=0.015)distribution exhibited spatial clustering across China.Conclusions:The current burden of cognitive impairment in China’s older population is substantial and characterized by significant regional variations.Prevention and treatment measures should prioritize support for high-prevalence areas with limited resources and promote scientifically based,precise,and efficient cognitive impairment prevention and treatment strategies throughout China.展开更多
N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 h...N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells(Tregs).However,the role of m^(6)A methyltransferase in other subtypes of T cells remains unknown.T helper cells 17(Th17)play a pivotal role in host defense and autoimmunity.Here,we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation,and impeded the development of experimental autoimmune encephalomyelitis(EAE).We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system(CNS).Importantly,we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells,leading to disrupted Th17 cell differentiation and infiltration,and eventually attenuating the process of EAE.Collectively,our results highlight that m^(6)A modification sustains Th17 cell function,which provides new insights into the regulatory network of Th17 cells,and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.展开更多
Macrophage hyperactivation is a hallmark of inflammatory diseases,yet the role of alternative polyadenylation(APA)of mRNAs in regulating innate immunity remains unclear.In this study,we focused on 3’UTR-APA and demon...Macrophage hyperactivation is a hallmark of inflammatory diseases,yet the role of alternative polyadenylation(APA)of mRNAs in regulating innate immunity remains unclear.In this study,we focused on 3’UTR-APA and demonstrated that Nudt21,a crucial RNA-binding component of the 3’UTR-APA machinery,is significantly upregulated in various inflammatory conditions.By utilizing myeloid-specific Nudt21-deficient mice,we revealed a protective effect of Nudt21 depletion against colitis and severe hyperinflammation,primarily through diminished production of proinflammatory cytokines.Notably,Nudt21 regulates the mRNA stability of key autophagy-related genes,Map1lc3b and Ulk2,by mediating selective 3’UTR polyadenylation in activated macrophages.As a result,Nudt21-deficient macrophages display increased autophagic activity,which leads to reduced cytokine secretion.Our findings highlight an unexplored role of Nudt21-mediated 3’UTR-APA in modulating macrophage autophagy and offer new insights into the modulation of inflammation and disease progression.展开更多
Background:Abnormal alternative splicing is frequently associated with carcinogenesis.In B-cell acute lymphoblastic leukemia(B-ALL),double homeobox 4 fused with immunoglobulin heavy chain(DUX4/IGH)can lead to the aber...Background:Abnormal alternative splicing is frequently associated with carcinogenesis.In B-cell acute lymphoblastic leukemia(B-ALL),double homeobox 4 fused with immunoglobulin heavy chain(DUX4/IGH)can lead to the aberrant production of E-26 transformation-specific family related gene abnormal transcript(ERGalt)and other splicing variants.However,the molecular mechanism underpinning this process remains elusive.Here,we aimed to know how DUX4/IGH triggers abnormal splicing in leukemia.Methods:The differential intron retention analysis was conducted to identify novel DUX4/IGH-driven splicing in B-ALL patients.X-ray crystallography,small angle X-ray scattering(SAXS),and analytical ultracentrifugation were used to investigate how DUX4/IGH recognize double DUX4 responsive element(DRE)-DRE sites.The ERGalt biogenesis and B-cell differentiation assays were performed to characterize the DUX4/IGH crosslinking activity.To check whether recombination-activating gene 1/2(RAG1/2)was required for DUX4/IGH-driven splicing,the proximity ligation assay,co-immunoprecipitation,mammalian two hybrid characterizations,in vitro RAG1/2 cleavage,and shRNA knock-down assays were performed.Results:We reported previously unrecognized intron retention events in Ctype lectin domain family 12,member A abnormal transcript(CLEC12Aalt)and chromosome 6 open reading frame 89 abnormal transcript(C6orf89alt),where also harbored repetitive DRE-DRE sites.Supportively,X-ray crystallography and SAXS characterization revealed that DUX4 homeobox domain(HD)1-HD2 might dimerize into a dumbbell-shape trans configuration to crosslink two adjacent DRE sites.Impaired DUX4/IGH-mediated crosslinking abolishes ERGalt,CLEC12Aalt,and C6orf89alt biogenesis,resulting in marked alleviation of its inhibitory effect on B-cell differentiation.Furthermore,we also observed a rare RAG1/2-mediated recombination signal sequence-like DNA edition in DUX4/IGH target genes.Supportively,shRNA knock-down of RAG1/2 in leukemic Reh cells consistently impaired the biogenesis of ERGalt,CLEC12Aalt,and C6orf89alt.Conclusions:All these results suggest that DUX4/IGH-driven DNA crosslinking is required for RAG1/2 recruitment onto the double tandem DRE-DRE sites,catalyzing V(D)J-like recombination and oncogenic splicing in acute lymphoblastic leukemia.展开更多
Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human dise...Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.展开更多
Understanding sex disparities in modifiable risk factors across the lifespan is essential for crafting individualized intervention strategies.We aim to investigate age-related sex disparity in cardiometabolic phenotyp...Understanding sex disparities in modifiable risk factors across the lifespan is essential for crafting individualized intervention strategies.We aim to investigate age-related sex disparity in cardiometabolic phenotypes in a large nationwide Chinese cohort.A total of 254,670 adults aged 40 years or older were selected from a population-based cohort in China.Substantial sex disparities in the prevalence of metabolic diseases were observed across different age strata,particularly for dyslipidemia and its components.Generalized additive models were employed to characterize phenotype features,elucidating how gender differences evolve with advancing age.Half of the 16 phenotypes consistently exhibited no sex differences,while four(high-density lipoprotein[HDL]cholesterol,apolipoprotein A1,diastolic blood pressure,and fasting insulin)displayed significant sex differences across all age groups.Triglycerides,apolipoprotein B,non-HDL cholesterol,and total cholesterol demonstrated significant age-dependent sex disparities.Notably,premenopausal females exhibited significant age-related differences in lipid levels around the age of 40-50 years,contrasting with the relatively stable associations observed in males and postmenopausal females.Menopause played an important but not sole role in age-related sex differences in blood lipids.Sleep duration also had an age-and sex-dependent impact on lipids.Lipidomic analysis and K-means clustering further revealed that 58.6%of the 263 measured lipids varied with sex and age,with sphingomyelins,cholesteryl esters,and triacylglycerols being the most profoundly influenced lipid species by the combined effects of age,sex,and their interaction.These findings underscore the importance of age consideration when addressing gender disparities in metabolic diseases and advocate for personalized,age-specific prevention and management.展开更多
Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum...Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.展开更多
基金supported by grants from the National Natural Science Foundation of China(U23A20489 and 82372128)the Natural Science Foundation Distinguished Young Scholars grant of Guangdong Province(2023B1515020071,China)+1 种基金the Educational Commission of Guangdong Province of China key Project(2020ZDZX2001,China)the Postdoctoral Fellowship Program of CPSF(GZB20230444,China).
文摘Rheumatoid arthritis(RA)is a chronic systemic autoimmune disease that requires long-term pharmacological management.Melittin,a peptide derived from bee venom,has shown promising therapeutic efficacy for RA by modulating immune balance.Given the critical role of the gut in immune regulation,oral administration of melittin could have significant clinical implications.However,this approach faces substantial challenges,including degradation by gastric fluids and off-target adverse effects,which compromise its efficacy and safety.To address these limitations,we developed an innovative orally administered,gut-targeted micro-nano system(SPM/AlgL)inspired by bacterial colonies.Herein,gas-shearing microfluidics is leveraged to monodisperse sialic acid-decorated peptide nanomedicines within calcium alginate microgels.These microspheres are then coated with probiotic biofilms,leveraging their acid resistance and intestinal adhesion properties.The biofilm coating effectively protects melittin from gastric degradation and enhances its accumulation in the mesenteric lymph nodes,thereby improving its targeting ability to inflammatory sites and reducing adverse effects.By modulating the Th1/Th2 and Th17/Treg ratios in the mesenteric lymph nodes and spleen tissues,this system successfully alleviates immune responses and efficiently mitigates the progression of arthritis.Overall,this oral therapeutic strategy demonstrates significant potential for advancing the immunotherapy of RA and other systemic autoimmune diseases.
基金supported by the Leading Project of the Oriental Talent Program(Shanghai Leading Talent,No.039)the National Natural Science Foundation of China(W2411085 and 82502557)+2 种基金the Leading Project of the Oriental Talent Program(LJ2024012)the Postdoctoral Fellowship Program of CPSF(GZB20230444,China)the Shanghai Municipal Health Commission(2022XD055).
文摘Mutations in cytoplasmic DNA-degrading enzymes can lead to the accumulation of cytoplasmic DNA(cytoDNA),which excessively activates DNA-sensing pathways and exacerbates inflammatory aging.Reducing cytoDNA levels to suppress DNA-sensing mechanisms is therefore critical for treating elderly-onset rheumatoid arthritis(EORA).In this study,we constructed Trex1 mRNA loaded lipid nanoparticles(LNPs)via microfluidics and prepared DNase 1 loaded polydopamine(PDA)nanoparticles through oxidative polymerization.These two components were co-encapsulated into methacrylate hyaluronic acid(HAMA)microspheres using microfluidic photopolymerization.The LNPs incorporate cationic lipids to facilitate mRNA loading and promote endosomal escape,enabling efficient translation of TREX1 and subsequent recognition and degradation of cytoDNA.Meanwhile,cationic mesoporous poly-dopamine electrostatically adsorbs and degrades extracellular DNA.The microspheres function as a reservoir for sustained nanoparticles release,enabling synergistic inhibition of DNA sensing pathways.This microsphere based vaccine upregulates TREX1 expression in antigen presenting cells(APCs)and reduces cytoDNA levels,thereby suppressing overactivation of the cGAS-STING signaling axis and promoting immune tolerance.It also attenuates the differentiation of CD4^(+) T cells into Th1,Th2,Th17,and Treg subsets.In an aged rat model of rheumatoid arthritis,vaccination significantly attenuated soft tissue edema,synovial inflammation,and articular cartilage and bone destruction.By clearing excess cytoDNA and restraining DNA-sensing hyperactivation,this vaccine induces cellular immune tolerance and represents a promising therapeutic strategy for rheumatoid arthritis in the elderly.
基金funded by the National Natural Science Foundation of China(Nos.82270859,82370819,and 82088102)the National Key R&D Program of China(No.2023YFC2506700)+1 种基金the Shanghai Municipal Government grant(No.22Y31900300)the Shanghai Clinical Research Center for Metabolic Diseases(No.19MC1910100).
文摘This study aimed to comprehensively examine the association of gallstones,cholecystectomy,and cancer risk.Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk,using data from a nationwide cohort involving 239799 participants.General and gender-specific two-sample Mendelian randomization(MR)analysis was further conducted to assess the causalities of the observed associations.Observationally,a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer(adjusted odds ratio(aOR)=2.54,95%confidence interval(CI)1.50–4.28),liver and bile duct cancer(aOR=2.46,95%CI 1.17–5.16),kidney cancer(aOR=2.04,95%CI 1.05–3.94),and bladder cancer(aOR=2.23,95%CI 1.01–5.13)in the general population,as well as cervical cancer(aOR=1.69,95%CI 1.12–2.56)in women.Moreover,cholecystectomy was associated with high odds of stomach cancer(aOR=2.41,95%CI 1.29–4.49),colorectal cancer(aOR=1.83,95%CI 1.18–2.85),and cancer of liver and bile duct(aOR=2.58,95%CI 1.11–6.02).MR analysis only supported the causal effect of gallstones on stomach,liver and bile duct,kidney,and bladder cancer.This study added evidence to the causal effect of gallstones on stomach,liver and bile duct,kidney,and bladder cancer,highlighting the importance of cancer screening in individuals with gallstones.
基金Supported by the National Key R&D Plan“Intergovernmental International Science and Technology Innovation Cooperation”Key Special Project(2021YFE0111800).
文摘Introduction:Cognitive impairment poses a serious threat to the health of older adults.Understanding spatial distribution patterns and identifying high-risk areas are essential for developing targeted regional prevention and control strategies.This study examined the spatial distribution and clustering patterns of cognitive impairment in China in 2024.Methods:This study utilized data from the 2024 China Survey of Aging and Health.Rao-Scott chisquare tests were used to compare differences in prevalence across demographic subgroups.Global and local spatial autocorrelation analyses were conducted to examine the spatial distribution patterns and clustering characteristics.Results:In 2024,the prevalence of subjective cognitive decline(SCD)and mild cognitive impairment(MCI)among older adults≥65 years in China was 38.8%and 28.4%,respectively.The prevalence of SCD was highest in western China(45.1%),while MCI was highest in central China(31.0%).Global spatial autocorrelation analysis revealed that SCD(P=0.025)and MCI(P=0.015)distribution exhibited spatial clustering across China.Conclusions:The current burden of cognitive impairment in China’s older population is substantial and characterized by significant regional variations.Prevention and treatment measures should prioritize support for high-prevalence areas with limited resources and promote scientifically based,precise,and efficient cognitive impairment prevention and treatment strategies throughout China.
基金supported by the National Natural Science Foundation of China(82230067,82061148013,91842105,81821001)Shanghai Science and Technology Committee(20JC1417400,201409005500)+3 种基金the National Key Research and Development Program of China(2018YFA0508000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29030101)the CAS Project for Young Scientists in Basic Research(YSBR-074)the Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment(2021B1212040004).
文摘N6-methyladenosine(m^(6)A),the most common and abundant epigenetic RNA modification,governs mRNA metabolism to determine cell differentiation,proliferation and response to stimulation.m^(6)A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells(Tregs).However,the role of m^(6)A methyltransferase in other subtypes of T cells remains unknown.T helper cells 17(Th17)play a pivotal role in host defense and autoimmunity.Here,we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation,and impeded the development of experimental autoimmune encephalomyelitis(EAE).We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system(CNS).Importantly,we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells,leading to disrupted Th17 cell differentiation and infiltration,and eventually attenuating the process of EAE.Collectively,our results highlight that m^(6)A modification sustains Th17 cell function,which provides new insights into the regulatory network of Th17 cells,and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.
基金supported by the National Natural Science Foundation of China(No.82325024,82341017,82350112,82030042 and 32070917 to H.-B.L.)the Ministry of Science and Technology of China(No.2021YFA1100800 to H.-B.L.)the Shanghai Municipal Health Commission(No.2022XD047 and 2022JC001 to H.-B.L.).
文摘Macrophage hyperactivation is a hallmark of inflammatory diseases,yet the role of alternative polyadenylation(APA)of mRNAs in regulating innate immunity remains unclear.In this study,we focused on 3’UTR-APA and demonstrated that Nudt21,a crucial RNA-binding component of the 3’UTR-APA machinery,is significantly upregulated in various inflammatory conditions.By utilizing myeloid-specific Nudt21-deficient mice,we revealed a protective effect of Nudt21 depletion against colitis and severe hyperinflammation,primarily through diminished production of proinflammatory cytokines.Notably,Nudt21 regulates the mRNA stability of key autophagy-related genes,Map1lc3b and Ulk2,by mediating selective 3’UTR polyadenylation in activated macrophages.As a result,Nudt21-deficient macrophages display increased autophagic activity,which leads to reduced cytokine secretion.Our findings highlight an unexplored role of Nudt21-mediated 3’UTR-APA in modulating macrophage autophagy and offer new insights into the modulation of inflammation and disease progression.
基金National Natural Science Foundation of China,Grant/Award Numbers:81970132,81770142,81800144,31800642Shanghai Science and Technology Committee,Grant/Award Number:20JC1410600+3 种基金Shanghai Guangci Translational Medical Research Development FoundationShanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support,Grant/Award Number:20152504The Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institute of Higher LearningSamuel Waxman Cancer Research Foundation。
文摘Background:Abnormal alternative splicing is frequently associated with carcinogenesis.In B-cell acute lymphoblastic leukemia(B-ALL),double homeobox 4 fused with immunoglobulin heavy chain(DUX4/IGH)can lead to the aberrant production of E-26 transformation-specific family related gene abnormal transcript(ERGalt)and other splicing variants.However,the molecular mechanism underpinning this process remains elusive.Here,we aimed to know how DUX4/IGH triggers abnormal splicing in leukemia.Methods:The differential intron retention analysis was conducted to identify novel DUX4/IGH-driven splicing in B-ALL patients.X-ray crystallography,small angle X-ray scattering(SAXS),and analytical ultracentrifugation were used to investigate how DUX4/IGH recognize double DUX4 responsive element(DRE)-DRE sites.The ERGalt biogenesis and B-cell differentiation assays were performed to characterize the DUX4/IGH crosslinking activity.To check whether recombination-activating gene 1/2(RAG1/2)was required for DUX4/IGH-driven splicing,the proximity ligation assay,co-immunoprecipitation,mammalian two hybrid characterizations,in vitro RAG1/2 cleavage,and shRNA knock-down assays were performed.Results:We reported previously unrecognized intron retention events in Ctype lectin domain family 12,member A abnormal transcript(CLEC12Aalt)and chromosome 6 open reading frame 89 abnormal transcript(C6orf89alt),where also harbored repetitive DRE-DRE sites.Supportively,X-ray crystallography and SAXS characterization revealed that DUX4 homeobox domain(HD)1-HD2 might dimerize into a dumbbell-shape trans configuration to crosslink two adjacent DRE sites.Impaired DUX4/IGH-mediated crosslinking abolishes ERGalt,CLEC12Aalt,and C6orf89alt biogenesis,resulting in marked alleviation of its inhibitory effect on B-cell differentiation.Furthermore,we also observed a rare RAG1/2-mediated recombination signal sequence-like DNA edition in DUX4/IGH target genes.Supportively,shRNA knock-down of RAG1/2 in leukemic Reh cells consistently impaired the biogenesis of ERGalt,CLEC12Aalt,and C6orf89alt.Conclusions:All these results suggest that DUX4/IGH-driven DNA crosslinking is required for RAG1/2 recruitment onto the double tandem DRE-DRE sites,catalyzing V(D)J-like recombination and oncogenic splicing in acute lymphoblastic leukemia.
基金supported by the National Natural Science Foundation of China(31871380,32000500,32070730,32170756,32170804,81330008,81671377,81725010,81725010,81872874,81921006,81922027,81971312,81991512,82030041,82103167,82122024,82125009,82125011,82130044,91749126,91949101,91949207,92049302)the National Key Research and Development Program of China(2017YFA0506400,2018YFA0800200,2018YFA0800700,2018YFA0900200,2018YFC2000100,2018YFC2000400,2018YFE-0203700,20192ACB70002,2019YFA0802202,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002800,2020YFC-2002900,2021ZD0202401)+11 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100,XDA16010603,XDA16020400,XDB29020000,XDB39000000,XDB39000000,XDB39030300)the China Association for Science and Technology(2021QNRC001)the Beijing Municipal Science and Technology Commission(Z200022)the Natural Science Foundation of Shanghai(21JC1406400)the Key Programs of the Jiangxi ProvinceChina(20192ACB70002)the“Shu Guang”Project supported by the Shanghai Municipal Education Commission and Shanghai Education Development Foundation(19SG18)the Shanghai Sailing Program(22YF1434300)the Research Project of Joint Laboratory of University of Science and Technology of China and Anhui Mental Health Center(2019LH03)the Fundamental Research Funds for the Central Universities(WK2070210004)the Young Elite Scientists Sponsorship Program by China Association for Science and Technology(YESS20210002)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2022083)。
文摘Aging is characterized by a progressive deterioration of physiological integrity,leading to impaired functional ability and ultimately increased susceptibility to death.It is a major risk factor for chronic human diseases,including cardiovascular disease,diabetes,neurological degeneration,and cancer.Therefore,the growing emphasis on “healthy aging” raises a series of important questions in life and social sciences.In recent years,there has been unprecedented progress in aging research,particularly the discovery that the rate of aging is at least partly controlled by evolutionarily conserved genetic pathways and biological processes.In an attempt to bring full-fledged understanding to both the aging process and age-associated diseases,we review the descriptive,conceptual,and interventive aspects of the landscape of aging composed of a number of layers at the cellular,tissue,organ,organ system,and organismal levels.
基金supported by the National Natural Science Foundation of China(82170819,82370810,91857205,82088102,and 82200998)the National Key Research and Development Program of China(2022YFC2505202 and 2021YFA1301103)+1 种基金the Science and Technology Commission of Shanghai Municipality(23JS1400900,23Y11908400,and 23XD1422400)the Innovative research team of high-level local universities in Shanghai.
文摘Understanding sex disparities in modifiable risk factors across the lifespan is essential for crafting individualized intervention strategies.We aim to investigate age-related sex disparity in cardiometabolic phenotypes in a large nationwide Chinese cohort.A total of 254,670 adults aged 40 years or older were selected from a population-based cohort in China.Substantial sex disparities in the prevalence of metabolic diseases were observed across different age strata,particularly for dyslipidemia and its components.Generalized additive models were employed to characterize phenotype features,elucidating how gender differences evolve with advancing age.Half of the 16 phenotypes consistently exhibited no sex differences,while four(high-density lipoprotein[HDL]cholesterol,apolipoprotein A1,diastolic blood pressure,and fasting insulin)displayed significant sex differences across all age groups.Triglycerides,apolipoprotein B,non-HDL cholesterol,and total cholesterol demonstrated significant age-dependent sex disparities.Notably,premenopausal females exhibited significant age-related differences in lipid levels around the age of 40-50 years,contrasting with the relatively stable associations observed in males and postmenopausal females.Menopause played an important but not sole role in age-related sex differences in blood lipids.Sleep duration also had an age-and sex-dependent impact on lipids.Lipidomic analysis and K-means clustering further revealed that 58.6%of the 263 measured lipids varied with sex and age,with sphingomyelins,cholesteryl esters,and triacylglycerols being the most profoundly influenced lipid species by the combined effects of age,sex,and their interaction.These findings underscore the importance of age consideration when addressing gender disparities in metabolic diseases and advocate for personalized,age-specific prevention and management.
基金supported by the National Natural Science Foundation of China(31730036,31871380,31871382,31930055,31930058,32000500,32022034,32030033,32070730,32130046,3217050247,32150005,32200595,32222024,81730019,81730022,81830014,81921006,81925005,81970426,81971301,81971312,82030041,82061160495,82070805,82071595,82090020,82100841,82120108009,82122024,82125002,82125011,82125012,82130045,82171284,82173061,82173398,82225007,82225015,82225017,82225018,82230047,82230088,82271600,91949106,91949201,92049116,92049302,92049304,92149303,92149306,92157202,92168201,92169102,92249301,92268201)the National Key Research and Development Program of China(2018YFA0800700,2018YFC2000100,2018YFC2000102,2018YFC2002003,2019YFA0110900,2019YFA0801703,2019YFA0801903,2019YFA0802202,2019YFA0904800,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002900,2020YFC2008000,2020YFE0202200,2021YFA0804900,2021YFA1100103,2021YFA1100900,2021YFE0114200,2021ZD0202400,2022YFA0806001,2022YFA0806002,2022YFA0806600,2022YFA1103200,2022YFA1103601,2022YFA1103701,2022YFA1103800,2022YFA1103801,2022YFA1104100,2022YFA1104904,2022YFA1303000,2022YFC2009900,2022YFC2502401,2022YFC3602400,2022YFE0118000,2022ZD0213200)+14 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030302,XDB39000000,XDB39030600)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2020085,2021080)CAS Project for Young Scientists in Basic Research(YSBR-076)the Program of the Beijing Natural Science Foundation(JQ20031)Clinical Research Operating Fund of Central High level hospitals(2022-PUMCHE-001)CAMS Innovation Fund for Medical Sciences(CIFMS)(2022-I2M1-004)Talent Program of the Chinese Academy of Medical Science(2022RC310-10)Research Funds from Health@Inno HK Program launched by Innovation Technology Commission of the Hong Kong Special Administrative Region,Guangdong Basic and Applied Basic Research Foundation(2020B1515020044)Guangzhou Planned Project of Science and Technology(202002020039)the Major Technology Innovation of Hubei Province(2019ACA141)the Science and Technology Major Project of Hunan Provincial Science and Technology Department(2021SK1010)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Natural Science Foundation of Sichuan Province(2023NSFSC0003)Yunnan Fundamental Research Project(202201AS070080)the State Key Laboratory of Membrane Biology。
文摘Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.
