Objective:Considering that there are no effective biomarkers for the screening of cardia gastric cancer(CGC),we developed a noninvasive diagnostic approach,employing data-independent acquisition(DIA)proteomics to iden...Objective:Considering that there are no effective biomarkers for the screening of cardia gastric cancer(CGC),we developed a noninvasive diagnostic approach,employing data-independent acquisition(DIA)proteomics to identify candidate protein markers.Methods:Plasma samples were obtained from 40 subjects,10 each for CGC,cardia high-grade dysplasia(CHGD),cardia low-grade dysplasia(CLGD),and healthy controls.Proteomic profiles were obtained through liquid chromatography-mass spectrometry(LC-MS/MS-based DIA proteomics.Candidate plasma proteins were identified by weighted gene co-expression network analysis(WGCNA)combined with machine learning and further validated by the Human Protein Atlas(HPA)database.The area under the receiver operating characteristic curve(AUC)was used to evaluate the performance of the biomarker panel.Results:There was a clear distinction in proteomic features among CGC,CHGD,CLGD,and the healthy controls.According to the WGCNA,we found 42 positively associated and 164 inversely associated proteins related to CGC progression and demonstrated several canonical cancer-associated pathways.Combined with the results from random forests,LASSO regression,and immunohistochemical results from the HPA database,we identified three candidate proteins(GSTP1,CSRP1,and LY6G6F)that could together distinguish CLGD(AUC=0.91),CHGD(AUC=0.99)and CGC(AUC=0.98)from healthy controls with excellent accuracy.Conclusions:The panel of protein biomarkers showed promising diagnostic potential for CGC and precancerous lesions.Further validation and a larger-scale study are warranted to assess its potential clinical applications,suggesting a potential avenue for CGC prevention in the future.展开更多
By varying the intrinsic initial geometry,p/d/^(3)He+Au collisions at the Relativistic Heavy Ion Collider(RHIC)provide a unique opportunity to understand the collective behavior and probe possible sub-nucleon fluctuat...By varying the intrinsic initial geometry,p/d/^(3)He+Au collisions at the Relativistic Heavy Ion Collider(RHIC)provide a unique opportunity to understand the collective behavior and probe possible sub-nucleon fluctuations in small systems.In this study,we employed the hybrid model under TRENTo initial conditions to study the collective flow and fluid behavior in p/d/^(3)He+Au collisions.With fine-tuned parameters,iEBE-VISHNU can describe the v_(2)(pT) and v_(3)(pT) data from the PHENIX and STAR collaborations.However,for certain parameter sets with initial sub-nucleon fluctuations,the hydrodynamic simulations already go beyond their limits with an average Knudsen number <K_(n)> clearly larger than unity.Our calculations demonstrate that,for a meaningful evaluation of the fluid behavior in small systems,model simulations must also pay attention to the validity range of hydrodynamics.展开更多
Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for ge...Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.展开更多
SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that ...SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that SIRT7 expression declines during human mesenchymal stem cell(hMSC)aging and that SIRT7 deficiency accelerates senescence.Mechanistically,SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins,thus maintaining the repressive state of heterochromatin at nuclear periphery.Accordingly,deficiency of SIRT7 results in loss of heterochromatin,derepression of the LINE1 retrotransposon(LINE1),and activation of innate immune signaling via the cGAS-STING pathway.These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor.Together,these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.展开更多
progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated...progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in 14/RN gem）, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells （ESCs） with heterozygous （G608G/＋） or homozygous （G608G/G608G） LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells （ECs） did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells （MSCs） showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited iate-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.展开更多
The emergence of super-resolution(SR)fluorescence microscopy has rejuvenated the search for new cellular substructures.However,SR fluorescence microscopy achieves high contrast at the expense of a holistic view of the...The emergence of super-resolution(SR)fluorescence microscopy has rejuvenated the search for new cellular substructures.However,SR fluorescence microscopy achieves high contrast at the expense of a holistic view of the interacting partners and surrounding environment.Thus,we developed SR fluorescence-assisted diffraction computational tomography(SR-FACT),which combines label-free three-dimensional optical diffraction tomography(ODT)with two-dimensional fluorescence Hessian structured illumination microscopy.The ODT module is capable of resolving the mitochondria,lipid droplets,the nuclear membrane,chromosomes,the tubular endoplasmic reticulum,and lysosomes.Using dual-mode correlated live-cell imaging for a prolonged period of time,we observed novel subcellular structures named dark-vacuole bodies,the majority of which originate from densely populated perinuclear regions,and intensively interact with organelles such as the mitochondria and the nuclear membrane before ultimately collapsing into the plasma membrane.This work demonstrates the unique capabilities of SR-FACT,which suggests its wide applicability in cell biology in general.展开更多
Dear Editor,Stem cell therapy holds enormous and revolutionary promise to treat various age-related diseases,such as diabetes,heart failure,and Parkinson’s disease.However,low retention and survival rate of delivered...Dear Editor,Stem cell therapy holds enormous and revolutionary promise to treat various age-related diseases,such as diabetes,heart failure,and Parkinson’s disease.However,low retention and survival rate of delivered stem cells,partially due to immunological rejection,constitute major hurdles for the clinical implementation of stem cell therapy(Lei et al.,2021a).Since mounting evidence showed that several types of stem cells mainly exert their therapeutic effects through the secretion of paracrine effects,exosomes,which are released by stem cells and execute most paracrine functions,have begun to draw attention in the field(Tran and Damaser,2015).Exosomes are membrane-enclosed vesicles with an average diameter of∼100 nanometers secreted by the cells,containing cytokines.展开更多
Dear Editor,The human body operates optimally at a core temperature of 37 degrees Celsius.Homeostasis at this temperature is essential for cellular and physiological functions(Cheshire,2016).However,infectious disease...Dear Editor,The human body operates optimally at a core temperature of 37 degrees Celsius.Homeostasis at this temperature is essential for cellular and physiological functions(Cheshire,2016).However,infectious diseases,inflammation,injury,neoplasia,and elevated climate temperature can cause a regulated rise in body core temperature,i.e.,fever(Pasi-khova et al,2017).Indeed,an acute or chronic increase in temperature leads to detrimental effects on vasculature by altering a number of indices of vascular structure and function(DuBose et al.,1998).展开更多
Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of ...Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem celis(hMSCs).Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration,increases mitochondrial reactive oxygen species(Ros)production,and accelerates cellular senescence.Mechanistically,the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes,especially several key subunits of complex III including UQCRC2.Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs.These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis,particularly for the mitochondrial respiration complex Il,thus providing a new potential target to counteract human stem cell senescence.展开更多
Dear Editor,The interventions that slow aging or promote healthy aging may provide preventative measures for age-related diseases(Zhang et al.,2015).Therefore,it is crucial to identify drugs that target aging-related ...Dear Editor,The interventions that slow aging or promote healthy aging may provide preventative measures for age-related diseases(Zhang et al.,2015).Therefore,it is crucial to identify drugs that target aging-related pathologies and improve health-span in geroscience research.Using model organisms such as C.elegans and rodents,several small molecules capable of alleviating the onset or progression of aging,including rapamycin,nicotinamide mononucleotide,and metformin,have been discovered(Partridge et al.,2020).However,the safety and efficacy of these chemicals still need in-depth evaluation before clinical applications(Partridge et al.,2020).As a result,it is necessary to identify additional compounds with geroprotective effects for human cells to counteract the general trend of populational aging.However,transforming a promising compound into an approved drug requires enormous resources.Alternatively,repurposing previously approved drugs for new clinical applications offers a more efficient and less costly path toward drug develop-ment.Therefore,testing U.S.Food and Drug Administration(FDA)-approved drugs for geroprotective effects may dis-covernew therapeutics that have already been stringently tested in humans for safety.展开更多
Dear Editor, N6-methyladenosine(m6A)is an abundant epitranscriptomic modification that regulates messenger RNA(mRNA)biology.The m6A modification regulates mRNA splicing,transport,stability,and translation through coor...Dear Editor, N6-methyladenosine(m6A)is an abundant epitranscriptomic modification that regulates messenger RNA(mRNA)biology.The m6A modification regulates mRNA splicing,transport,stability,and translation through coordinated activities by methyltransferases(writers),binding proteins(readers),and demethylases(erasers)(Huang et al.,2020;Wu et al.,2020).Among m6A regulators,fat mass of obesity-associ-ated protein(FTO),is the first discovered eraser with RNA m6A demethylation activity(Jia et al.,2011).Since then,FTO has been reported to play m6A-dependent roles in a variety of physiological processes including adipogenesis,neuro-genesis and tumorigenesis(Fischer et al.,2009;Li et al.,2017;Huang et al.,2020).Consequently,FTO deficiency in mice leads to dramatic phenotypes,such as decreased fat mass and impaired brain development(Fischer et al.,2009;Li et al.,2017).Similarly,inhibition of FTO reduces tumori-genesis in multiple types of cancer models,while FTO is highly expressed in many cancers(Huang et al.,2020).展开更多
Dear Editor,As the most prevalent DNA methylation modification in prokaryotes,DNA N6 methyladenosine(6mA)in eukaryotic genomes has recently been observed in diverse species including Caenorhabditis elegans(Greer et al...Dear Editor,As the most prevalent DNA methylation modification in prokaryotes,DNA N6 methyladenosine(6mA)in eukaryotic genomes has recently been observed in diverse species including Caenorhabditis elegans(Greer et al.,2015),Dro-sophila melanogaster(Zhang et al,2015),mouse(Wu et al,2016)and human(Xiao et al,2018).6mA has been reported to associate with multiple physiological processes including embryonic development and tumorigenesis(Greer et al.,2015;Zhang et al.,2015;Xie et al.,2018),yet some con-troversies exist.In contrast to the findings showing that ALKBH1(alkB homolog 1)is a primary 6mA demethylase in mouse and human cells(Wu et al.,2016;Xiao et al.,2018;Xie et al..2018),other studies indicate that ALKBH1 is prone to demethylate 6mA on bubbled or bulged DNAs that are often featured by a locally unpairing region with flanking duplex,such as D-loop,R-loop as well as DNA or RNA stem-loop,and single-stranded DNAs at a lower efficiency.展开更多
Dear Editor,Cardiovascular diseases(CVDs)are the leading cause of death world-wide.Thus,diagnosing and treating CVD remains at the forefront for clinicians while identifying targetable disease mechanisms in preclinica...Dear Editor,Cardiovascular diseases(CVDs)are the leading cause of death world-wide.Thus,diagnosing and treating CVD remains at the forefront for clinicians while identifying targetable disease mechanisms in preclinical models are focus areas for researchers and drug developers(Cai et al.,2022a).The polymorphic protein apolipoprotein E(APOE),central to lipid transport and metabolism,is well-recognized for the role of its isoforms as important predictors for human cardiovascular disorders and neurodegenerative diseases(Tudorache et al.,2017).Plasma APOE is generated primarily from liver hepatocytes,accounting for around 75%of the APOE production from the whole body(Getz and Reardon,2009),and plays important functional roles in monocytes/macrophages,adipocytes,and the central nervous system(Kockx et al.,2018).However,despite the fact that APOE is widely expressed in different mammalian cells,studies on the functional roles of APOE mostly focus on its extracellular secreted form,and the specific effects of APOE,particularly intracellular form in cell types closely related to human cardiovascular diseases are therefore still poorly understood.展开更多
Dear Editor,Stem cells,including pluripotent stem cells and adult stem cells,possess the remarkable capability of being able to selfrenew while at the same time having potential to differentiate into different cell li...Dear Editor,Stem cells,including pluripotent stem cells and adult stem cells,possess the remarkable capability of being able to selfrenew while at the same time having potential to differentiate into different cell lineages and functionally distinct cell types.Human embryonic stem cells(hESCs)can differentiate into all adult stem cell types,including human mesenchymal stem cells(hMSCs)and human neural stem cells(hNSCs),but can also give rise to all terminally differentiated cell types(Wang et al.,2021a).Through the continuous replenishment of differentiated cells,stem cells support tissue homeostasis and respond to tissue injuries.Given the promising applications of stem cells in cell therapy and regenerative medicine,insights into molecular events underlying stem cell maintenance,self-renewal ability and pluripotency,continue to garner strong interest(Shan et al.,2021).Although metabolic pathways have been implicated in the reciprocal regulations of stem cell self-renewal and differentiation as well as organ homeostatic maintenance(Garcia-Prat et al.,2017),central aspects of how metabolic requirements differ and are regulated across the various types of human stem cells in our body remain enigmatic.展开更多
In a recent study published in Cell Metabolism,Thomas A.Rando and colleagues reported a critical role of dysregulated glutathione(GSH)metabolism in driving the aging process of skeletal muscle stem cells(MuSCs),uncove...In a recent study published in Cell Metabolism,Thomas A.Rando and colleagues reported a critical role of dysregulated glutathione(GSH)metabolism in driving the aging process of skeletal muscle stem cells(MuSCs),uncovering a novel mechanism underlying the divergent responses of quiescent stem cells to environmental stressors with age,thus providing a potentially accessible target to alleviate age-associated skeletal muscle degeneration.展开更多
基金supported by grants from the Beijing Nova Program(grant number:Z201100006820069)the Hope Star Talent Incentive Program of the Cancer Hospital of Chinese Academy of Medical Sci-ences,the National Natural Science Fund(grant number:81573224)+1 种基金the CAMS Innovation Fund for Medical Sciences(grant number:2021-I2M-1-023)the Shandong Province Natural Science Foundation Youth Branch(grant number:ZR202211080124).
文摘Objective:Considering that there are no effective biomarkers for the screening of cardia gastric cancer(CGC),we developed a noninvasive diagnostic approach,employing data-independent acquisition(DIA)proteomics to identify candidate protein markers.Methods:Plasma samples were obtained from 40 subjects,10 each for CGC,cardia high-grade dysplasia(CHGD),cardia low-grade dysplasia(CLGD),and healthy controls.Proteomic profiles were obtained through liquid chromatography-mass spectrometry(LC-MS/MS-based DIA proteomics.Candidate plasma proteins were identified by weighted gene co-expression network analysis(WGCNA)combined with machine learning and further validated by the Human Protein Atlas(HPA)database.The area under the receiver operating characteristic curve(AUC)was used to evaluate the performance of the biomarker panel.Results:There was a clear distinction in proteomic features among CGC,CHGD,CLGD,and the healthy controls.According to the WGCNA,we found 42 positively associated and 164 inversely associated proteins related to CGC progression and demonstrated several canonical cancer-associated pathways.Combined with the results from random forests,LASSO regression,and immunohistochemical results from the HPA database,we identified three candidate proteins(GSTP1,CSRP1,and LY6G6F)that could together distinguish CLGD(AUC=0.91),CHGD(AUC=0.99)and CGC(AUC=0.98)from healthy controls with excellent accuracy.Conclusions:The panel of protein biomarkers showed promising diagnostic potential for CGC and precancerous lesions.Further validation and a larger-scale study are warranted to assess its potential clinical applications,suggesting a potential avenue for CGC prevention in the future.
基金Supported in part by the National Natural Science Foundation of China(12247107,12075007,12147173(Baochi Fu))。
文摘By varying the intrinsic initial geometry,p/d/^(3)He+Au collisions at the Relativistic Heavy Ion Collider(RHIC)provide a unique opportunity to understand the collective behavior and probe possible sub-nucleon fluctuations in small systems.In this study,we employed the hybrid model under TRENTo initial conditions to study the collective flow and fluid behavior in p/d/^(3)He+Au collisions.With fine-tuned parameters,iEBE-VISHNU can describe the v_(2)(pT) and v_(3)(pT) data from the PHENIX and STAR collaborations.However,for certain parameter sets with initial sub-nucleon fluctuations,the hydrodynamic simulations already go beyond their limits with an average Knudsen number <K_(n)> clearly larger than unity.Our calculations demonstrate that,for a meaningful evaluation of the fluid behavior in small systems,model simulations must also pay attention to the validity range of hydrodynamics.
基金supported by the National Key Research and Development Program of China(2017YFA0103304)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100)+5 种基金the National Key Research and Development Program of China(2015CB964800,2017YFA0102802,2014CB910503 and 2018YFA0107203)the National High Tech no logy Research and Development Program of China(2015AA020307)the National Natural Science Foundation of China(Grant Nos.31671429,91749202,91749123,81625009,81330008,81371342,81471414,81422017,81601233,81671377,31601109,31601158,81771515 and 81701388)Program of Beijing Municipal Science and Technology Commission(Z151100003 915072)Key Research Program of the Chinese Academy of Sciences(KJZDEW-TZ-L05),Beijing Municipal Commission of Health and Family Planning(PXM2018_026283_000002)Advanced Innovation Center for Human Brain Protection(117212).
文摘Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.
文摘SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that SIRT7 expression declines during human mesenchymal stem cell(hMSC)aging and that SIRT7 deficiency accelerates senescence.Mechanistically,SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins,thus maintaining the repressive state of heterochromatin at nuclear periphery.Accordingly,deficiency of SIRT7 results in loss of heterochromatin,derepression of the LINE1 retrotransposon(LINE1),and activation of innate immune signaling via the cGAS-STING pathway.These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor.Together,these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.
文摘progeria syndrome （HGPS） and Wemer syndrome （WS） are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A （LMNA） gene, resulting in the production of a truncated protein product-progerin. WS is caused by mutations in 14/RN gem）, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells （ESCs） with heterozygous （G608G/＋） or homozygous （G608G/G608G） LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells （ECs） did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells （MSCs） showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited iate-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
基金supported by grants from the National Natural Science Foundation of China(91750203,91854112,81925022,31521062,91850111,31901061,and 31327901)the National Science and Technology Major Project Programme(2016YFA0500400,2017YFC0110203,and SQ2016YFJC040028)+3 种基金the Beijing Natural Science Foundation(L172003,7152079,and 5194026)the National Postdoctoral Program for Innovative Talents(BX201800008)the China Postdoctoral Science Foundation(2019M650329)the High-performance Computing Platform of Peking University.
文摘The emergence of super-resolution(SR)fluorescence microscopy has rejuvenated the search for new cellular substructures.However,SR fluorescence microscopy achieves high contrast at the expense of a holistic view of the interacting partners and surrounding environment.Thus,we developed SR fluorescence-assisted diffraction computational tomography(SR-FACT),which combines label-free three-dimensional optical diffraction tomography(ODT)with two-dimensional fluorescence Hessian structured illumination microscopy.The ODT module is capable of resolving the mitochondria,lipid droplets,the nuclear membrane,chromosomes,the tubular endoplasmic reticulum,and lysosomes.Using dual-mode correlated live-cell imaging for a prolonged period of time,we observed novel subcellular structures named dark-vacuole bodies,the majority of which originate from densely populated perinuclear regions,and intensively interact with organelles such as the mitochondria and the nuclear membrane before ultimately collapsing into the plasma membrane.This work demonstrates the unique capabilities of SR-FACT,which suggests its wide applicability in cell biology in general.
基金This work was supported by the National Key Research and Development Program of China(2020YFA0804000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)+9 种基金the National Key Research and Development Program of China(2018YFC2000100,2020YFA0112201,2017YFA0103304,2017YFA0102802,2018YFA0107203,2020YFA0803401,and 2019YFA0802202)the National Natural Science Foundation of China(Grant Nos.81921006,81625009,91749202,81861168034,91949209,92049304,81822018,82071588,92049116,81801370,31801010,31970597,31901058 and U20A20403)the Program of the Beijing Municipal Science and Technology Commission(Z191100001519005)Beijing Natural Science Foundation(Z190019)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)China Postdoctoral Science Foundation(2018M640154)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-JKCS011)the Youth Innovation Promotion Association of CAS(2021078,E1CAZW0401)the State Key Laboratory of Stem Cell and Reproductive Biology,the State Key Laboratory of Membrane Biology,and the Milky Way Research Foundation(MWRF).
文摘Dear Editor,Stem cell therapy holds enormous and revolutionary promise to treat various age-related diseases,such as diabetes,heart failure,and Parkinson’s disease.However,low retention and survival rate of delivered stem cells,partially due to immunological rejection,constitute major hurdles for the clinical implementation of stem cell therapy(Lei et al.,2021a).Since mounting evidence showed that several types of stem cells mainly exert their therapeutic effects through the secretion of paracrine effects,exosomes,which are released by stem cells and execute most paracrine functions,have begun to draw attention in the field(Tran and Damaser,2015).Exosomes are membrane-enclosed vesicles with an average diameter of∼100 nanometers secreted by the cells,containing cytokines.
文摘Dear Editor,The human body operates optimally at a core temperature of 37 degrees Celsius.Homeostasis at this temperature is essential for cellular and physiological functions(Cheshire,2016).However,infectious diseases,inflammation,injury,neoplasia,and elevated climate temperature can cause a regulated rise in body core temperature,i.e.,fever(Pasi-khova et al,2017).Indeed,an acute or chronic increase in temperature leads to detrimental effects on vasculature by altering a number of indices of vascular structure and function(DuBose et al.,1998).
基金supported by the National Key Research and Development Program of China(2018YFC2000100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16000000)+9 种基金the National Natural Science Foundation of China(8190143281921006,82125011,92149301,92168201,91949209,92049304,92049116,32121001,82192863,82122024,82071588,81861168034,81922027,81870228,32100937,31900524,82201727)the National Key Research and Development Program of China(2020YFA0804000,2020YFA0113400,2020YFA0112200,2018YFA0107203,the STI2030-Major Projects-2021ZD0202400,2021YFF1201005,2022YFA1103700,2022YFA1103800)CAS Project for Young Scientists in Basic Research(YSBR-076,YSBR-012)the Program of the Beijing Natural Science Foundation(Z190019,JQ20031)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)Young Elite Scientists Sponsorship Program by CAST(YESS20200012)Youth Innovation Promotion Association of CAS(EiCAZW0401)the Pilot Project for Public Welfare Development and Reform of Beijing-affliated Medical Research Institutes(11000022T000000461062)the Informatization Plan of Chinese Academy of Sciences(CAS-WX2021SF-0301,CASWX2022SDC-XK14)CAS Special Research Assistant(SRA)Program,and the Tencent Foundation(2021-1045).
文摘Although the mTOR-4E-BP1 signaling pathway is implicated in aging and aging-related disorders,the role of 4E-BP1 in regulating human stem cell homeostasis remains largely unknown.Here,we report that the expression of 4E-BP1 decreases along with the senescence of human mesenchymal stem celis(hMSCs).Genetic inactivation of 4E-BP1 in hMSCs compromises mitochondrial respiration,increases mitochondrial reactive oxygen species(Ros)production,and accelerates cellular senescence.Mechanistically,the absence of 4E-BP1 destabilizes proteins in mitochondrial respiration complexes,especially several key subunits of complex III including UQCRC2.Ectopic expression of 4E-BP1 attenuates mitochondrial abnormalities and alleviates cellular senescence in 4E-BP1-deficient hMSCs as well as in physiologically aged hMSCs.These findings together demonstrate that 4E-BP1 functions as a geroprotector to mitigate human stem cell senescence and maintain mitochondrial homeostasis,particularly for the mitochondrial respiration complex Il,thus providing a new potential target to counteract human stem cell senescence.
基金This work was supported by the National Key Research and Development Program of China(2020YFA0804000)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)+8 种基金the Program of Beijing Municipal Science and Technology Commission(Z191100001519005)the National Key Research and Developme nt Program of China(2018YFC2000100,2020YFA0112201,2017YFA0103304,2017YFA0102802,2018YFA0107203,2020YFA0113400)the National Natural Science Foundation of China(Grant Nos.81921006,81625009,91749202,81861168034,91949209,92049304,81822018,82071588,92049116,81922027,81870228,82125011,82122024,32100937)the Program of the Beijing Natural Science Foundation(Z190019,JQ20031)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)Beijing Hospitals Authority Youth Programme(QML20200802)Youth Innovation Promotion Association of CAS(2021078,E1CAZW0401)the State Key Laboratory of Stem Cell and Reproductive Biology,the State Key Laboratory of Membrane Biology,and the Milky Way Research Foundation(MWRF).
文摘Dear Editor,The interventions that slow aging or promote healthy aging may provide preventative measures for age-related diseases(Zhang et al.,2015).Therefore,it is crucial to identify drugs that target aging-related pathologies and improve health-span in geroscience research.Using model organisms such as C.elegans and rodents,several small molecules capable of alleviating the onset or progression of aging,including rapamycin,nicotinamide mononucleotide,and metformin,have been discovered(Partridge et al.,2020).However,the safety and efficacy of these chemicals still need in-depth evaluation before clinical applications(Partridge et al.,2020).As a result,it is necessary to identify additional compounds with geroprotective effects for human cells to counteract the general trend of populational aging.However,transforming a promising compound into an approved drug requires enormous resources.Alternatively,repurposing previously approved drugs for new clinical applications offers a more efficient and less costly path toward drug develop-ment.Therefore,testing U.S.Food and Drug Administration(FDA)-approved drugs for geroprotective effects may dis-covernew therapeutics that have already been stringently tested in humans for safety.
基金supported by the National Key Research and Development Program of China(2019YFA0110100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)+6 种基金the National Natural Science Foundation of China(Grant Nos.31900524,31970597,81921006,81625009,91749202,81861168034,91949209,92049304,82125011,81822018,92049116,82071588,82122024,32100937,92149301,and 92168201)the National Key Research and Development Program of China(2018YFC2000100,2020YFA0804000,2017YFA0103300,2017YFA0102800,2018YFA0107200,2019YFA0110900,2020YFA0112200,2020YFA0803401,and 2019YFA0802202)Beijing Natural Science Foundation(Z190019)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)the 14th Five-year Network Security and Informatization Plan of Chinese Academy of Sciences(WX145XQ07-18)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)Youth Innovation Promotion Association of CAS(E1CAZW0401)。
文摘Dear Editor, N6-methyladenosine(m6A)is an abundant epitranscriptomic modification that regulates messenger RNA(mRNA)biology.The m6A modification regulates mRNA splicing,transport,stability,and translation through coordinated activities by methyltransferases(writers),binding proteins(readers),and demethylases(erasers)(Huang et al.,2020;Wu et al.,2020).Among m6A regulators,fat mass of obesity-associ-ated protein(FTO),is the first discovered eraser with RNA m6A demethylation activity(Jia et al.,2011).Since then,FTO has been reported to play m6A-dependent roles in a variety of physiological processes including adipogenesis,neuro-genesis and tumorigenesis(Fischer et al.,2009;Li et al.,2017;Huang et al.,2020).Consequently,FTO deficiency in mice leads to dramatic phenotypes,such as decreased fat mass and impaired brain development(Fischer et al.,2009;Li et al.,2017).Similarly,inhibition of FTO reduces tumori-genesis in multiple types of cancer models,while FTO is highly expressed in many cancers(Huang et al.,2020).
基金This work was supported by the National Key Research and Development Program of China(2017YFA0102802)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010100)+9 种基金the National Key Research and Development(2018YFC2000100,2017YFA0103304,National Natural Science Foundation 81625009,91749202,81861168034,91949209,91749123,81671377,Program of China 2018YFA0107203)the of China(Grant Nos.81921006,31671429,81822018,81870228,81922027,31900524,81701388,31770900,and 31730054)the Program of the Beijing Municipal Science and Technology Commission(Z191100001519005)Beijing Natural Science Foundation(Z190019)Beijing Municipal Commission of Health and Family Planning(PXM2018_026283_000002)Advanced Innovation Center for Human Brain Protection(3500-1192012)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)Young Elite Scientists Sponsorship Program by CAST,Youth Innovation Promotion Association of CASthe State Key Laboratory of Stem Cell and Reproductive Biology and the State Key Laboratory of Membrane Biology.
文摘Dear Editor,As the most prevalent DNA methylation modification in prokaryotes,DNA N6 methyladenosine(6mA)in eukaryotic genomes has recently been observed in diverse species including Caenorhabditis elegans(Greer et al.,2015),Dro-sophila melanogaster(Zhang et al,2015),mouse(Wu et al,2016)and human(Xiao et al,2018).6mA has been reported to associate with multiple physiological processes including embryonic development and tumorigenesis(Greer et al.,2015;Zhang et al.,2015;Xie et al.,2018),yet some con-troversies exist.In contrast to the findings showing that ALKBH1(alkB homolog 1)is a primary 6mA demethylase in mouse and human cells(Wu et al.,2016;Xiao et al.,2018;Xie et al..2018),other studies indicate that ALKBH1 is prone to demethylate 6mA on bubbled or bulged DNAs that are often featured by a locally unpairing region with flanking duplex,such as D-loop,R-loop as well as DNA or RNA stem-loop,and single-stranded DNAs at a lower efficiency.
基金supported by the National Key Research and Development Program of China(nos.2020YFA0804000,2022YFA1103700,2020YFA0112200,2021YFF1201005,2022YFA1103800,the STI2030-Major Projects-2021ZD0202400)the National Natural Science Foundation of China(nos.81921006,82125011,92149301,92168201,91949209,92049304,92049116,32121001,82192863,82122024,82071588,32000500,82271600,32100937)+7 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(no.XDA16000000)the Program of the Beijing Natural Science Foundation(no.Z190019)CAS Project for Young Scientists in Basic Research(nos.YSBR-076,YSBR-012)The Pilot Project for Public Welfare Development and Reform of Beijing-affliated Medical Research Institutes(no.11000022T000000461062)Youth Innovation Promotion Association of CAS(nos.E1CAZW0401,2022083)Young Elite Scientists Sponsorship Program by CAST(nos.YESS20200012,YESS20210002)the Informatization Plan of Chinese Academy of Sciences(nos.CAS-WX2021SF-0301,CAS-WX2022SDC-XK14,CASWx2021SF-0101)the Tencent Foundation(no.2021-1045).
文摘Dear Editor,Cardiovascular diseases(CVDs)are the leading cause of death world-wide.Thus,diagnosing and treating CVD remains at the forefront for clinicians while identifying targetable disease mechanisms in preclinical models are focus areas for researchers and drug developers(Cai et al.,2022a).The polymorphic protein apolipoprotein E(APOE),central to lipid transport and metabolism,is well-recognized for the role of its isoforms as important predictors for human cardiovascular disorders and neurodegenerative diseases(Tudorache et al.,2017).Plasma APOE is generated primarily from liver hepatocytes,accounting for around 75%of the APOE production from the whole body(Getz and Reardon,2009),and plays important functional roles in monocytes/macrophages,adipocytes,and the central nervous system(Kockx et al.,2018).However,despite the fact that APOE is widely expressed in different mammalian cells,studies on the functional roles of APOE mostly focus on its extracellular secreted form,and the specific effects of APOE,particularly intracellular form in cell types closely related to human cardiovascular diseases are therefore still poorly understood.
基金the National Key Research and Development Program of China(2018YFA0107203)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)+10 种基金the National Key Research and Development Program of China(2020YFA0804000,2018YFC2000100,2020YFA0112201,2017YFA0103304,2017YFA0102802,2020YFA0113400,2019YFA0110100)the National Natural Science Foundation of China(Grant Nos.81901433,81921006,81625009,91749202,81861168034,91949209,92049304,81822018,92049116,82071588,32000500,81922027,81870228,82125011,82122024,32100937,92149301,92168201)the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)the Program of Beijing Municipal Science and Technology Commission(Z191100001519005)the Program of the Beijing Natural Science Foundation(Z190019,JQ20031)K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)Beijing Hospitals Authority Youth Programme(QML20200802)Youth Innovation Promotion Association of CAS(2021078,E1CAZW0401)the 14th Five-year Network Security and Informatization Plan of Chinese Academy of Sciences(WX145XQ07-18)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-JKCS-011)the State Key Laboratory of Stem Cell and Reproductive Biology,the State Key Laboratory of Membrane Biology,and the Milky Way Research Foundation(MWRF).
文摘Dear Editor,Stem cells,including pluripotent stem cells and adult stem cells,possess the remarkable capability of being able to selfrenew while at the same time having potential to differentiate into different cell lineages and functionally distinct cell types.Human embryonic stem cells(hESCs)can differentiate into all adult stem cell types,including human mesenchymal stem cells(hMSCs)and human neural stem cells(hNSCs),but can also give rise to all terminally differentiated cell types(Wang et al.,2021a).Through the continuous replenishment of differentiated cells,stem cells support tissue homeostasis and respond to tissue injuries.Given the promising applications of stem cells in cell therapy and regenerative medicine,insights into molecular events underlying stem cell maintenance,self-renewal ability and pluripotency,continue to garner strong interest(Shan et al.,2021).Although metabolic pathways have been implicated in the reciprocal regulations of stem cell self-renewal and differentiation as well as organ homeostatic maintenance(Garcia-Prat et al.,2017),central aspects of how metabolic requirements differ and are regulated across the various types of human stem cells in our body remain enigmatic.
文摘In a recent study published in Cell Metabolism,Thomas A.Rando and colleagues reported a critical role of dysregulated glutathione(GSH)metabolism in driving the aging process of skeletal muscle stem cells(MuSCs),uncovering a novel mechanism underlying the divergent responses of quiescent stem cells to environmental stressors with age,thus providing a potentially accessible target to alleviate age-associated skeletal muscle degeneration.
