Dear Editor,A hallmark of immune cells in response to inflammatory stimuli,both infectious and non-infectious,is the rapid and extensive change in metabolism.In addition to meet the energetic and biosynthetic need of ...Dear Editor,A hallmark of immune cells in response to inflammatory stimuli,both infectious and non-infectious,is the rapid and extensive change in metabolism.In addition to meet the energetic and biosynthetic need of the immune cell,research over the past decade has led to the appreciation of individual metabolites in cell signaling during metabolic reprogramming in immune response.One illustrative example is itaconate,a dicarboxylic acid derived from Kreb cycle metabolite,cis-aconitate,by the enzyme cis-aconitate decarboxylase(ACOD1).ACOD1 is encoded by immunoresponsive gene 1(IRG1),which is rapidly induced by various inflammatory stimuli in myeloid cells,leading to the prompt accumulation of itaconate to millimolar levels.Itaconate binds to multiple proteins to influence oxidative response,epigenetic modification,and gene expression intrinsically and to signal GPCR after secretion(Ye et al.,2024).These regulations on different pathways by a single metabolite concertedly modulate inflammatory responses.Beyond its role as an antimicrobial metabolite,itaconate has recently garnered attention in the research of cancer biology.Genetic and preclinical studies in animal models suggest that itaconate can create an immunosuppressive tumor microenvironment.The enhanced antitumor immunity and response to immune checkpoint inhibitors seen in Irg1-deficient mice,which otherwise exhibit normal development,underscore IRG1 as a compelling target for cancer immunotherapy(Chen et al.,2023;Gu et al.,2023;Zhao et al.,2022).However,current strategies to target IRG1/itaconate remain limited,emphasizing the need for therapeutic development to effectively blockade IRG1 in cancer treatment.展开更多
Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation,known as meta-inflammation.This state is associated with the development of metabolic disorders such as glucose intole...Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation,known as meta-inflammation.This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease.Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways.However,its role and molecular mechanism in obesity and associated complications are obscure.In this study,we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain,white adipose tissue inflammation,and metabolic dysregulation.To identify the target proteins of pyruvate,drug affinity responsive target stability was employed with proteomics,cellular thermal shift assay,and isothermal drug response to detect the interactions between pyruvate and its molecular targets.Consequently,we identified cytosolic phospholipase A2(cPLA2)as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity,white adipose tissue inflammation,and hepatic steatosis in a cPLA2-dependent manner.Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated,confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity.Overall,our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity but it also sheds light on the mechanism of its action.Pyruvate’s prior clinical use indicates that it can be considered a safe and viable alternative for obesity,whether consumed as a dietary supplement or as part of a regular diet.展开更多
Dear Editor,Tremendous efforts have been made globally to develop therapeutics and prophylactics against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)which has caused thousands of millions of infections ...Dear Editor,Tremendous efforts have been made globally to develop therapeutics and prophylactics against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)which has caused thousands of millions of infections and deaths worldwide.A series of potent neutralizing antibodies with defined epitopes targeting RBD have been recently identified with different strategies.However,being an RNA virus,the instability of the SARS-CoV-2 genome results in numerous S-protein variants with altered viral phenotypes.展开更多
Recent advances in genome editing,especially CRISPR-Cas nucleases,have revolutionized both laboratory research and clinical therapeutics.CRISPR-Cas nucleases,together with the DNA damage repair pathway in cells,enable...Recent advances in genome editing,especially CRISPR-Cas nucleases,have revolutionized both laboratory research and clinical therapeutics.CRISPR-Cas nucleases,together with the DNA damage repair pathway in cells,enable both genetic diversification by classical non-homologous end joining(c-NHEJ)and precise genome modification by homology-based repair(HBR).Genome editing in zygotes is a convenient way to edit the germline,paving the way for animal disease model generation,as well as human embryo genome editing therapy for some life-threatening and incurable diseases.HBR efficiency is highly dependent on the DNA donor that is utilized as a repair template.Here,we review recent progress in improving CRISPR-Cas nuclease-induced HBR in mammalian embryos by designing a suitable DNA donor.Moreover,we want to provide a guide for producing animal disease models and correcting genetic mutations through CRISPR-Cas nuclease-induced HBR in mammalian embryos.Finally,we discuss recent developments in precise genome-modification technology based on the CRISPR-Cas system.展开更多
The fall armyworm(FAW),Spodoptera frugiperda,is a destructive pest native to America and has recently become an invasive insect pest in China.Because of its rapid spread and great risks in China,understanding of FAW g...The fall armyworm(FAW),Spodoptera frugiperda,is a destructive pest native to America and has recently become an invasive insect pest in China.Because of its rapid spread and great risks in China,understanding of FAW genetic background and pesticide resistance is urgent and essential to develop effective management strategies.Here,we assembled a chromosome-level genome of a male FAW(SFynMstLFR)and compared re-sequencing results of the populations from America,Africa,and China.Strain identification of 163 individuals collected from America,Africa and China showed that both C and R strains were found in the American pop-ulations,while only C strain was found in the Chinese and African populations.Moreover,population geno-mics analysis showed that populations from Africa and China have close relationship with significantly genetic differentiation from American populations.Taken toge-ther,FAWs invaded into China were most likely origi-nated from Africa.Comparative genomics analysis displayed that the cytochrome p450 gene family is extremely expanded to 425 members in FAW,of which 283 genes are specific to FAW.Treatments of Chinese populations with twenty-three pesticides showed the variant patterns of transcriptome profiles,and several detoxification genes such as AOX,UGT and GST spe-cially responded to the pesticides.These findings will be useful in developing effective strategies for manage-ment of FAW in China and other invaded areas.展开更多
Inhibition of Mycobacterium tuberculosis(Mtb)cell wall assembly is an established strategy for anti-TB chemotherapy.Arabinosyltransferase EmbB,which catalyzes the transfer of arabinose from the donor decaprenyl-phosph...Inhibition of Mycobacterium tuberculosis(Mtb)cell wall assembly is an established strategy for anti-TB chemotherapy.Arabinosyltransferase EmbB,which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose(DPA)to its arabinosyl acceptor is an essential enzyme for Mtb cell wall synthesis.Analysis of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug,ethambutol.Herein,we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its"resting state"and DPA-bound"active state".EmbB is a fifteen-transmembrane-spanning protein,assembled as a dimer.Each protomer has an associated acyl-carrier-protein(AcpM)on their cytoplasmic surface.Confor-mational changes upon DPA binding indicate an asym-metric movement within the EmbB dimer during catalysis.Functional studies have identified critical residues in substrate recognition and catalysis,and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with DPA.The structures represent the first step directed towards a rational approach for anti-TB drug discovery.展开更多
In mammalian cells,long noncoding RNAs(lncRNAs)form complexes with proteins to execute various biological functions such as gene transcription,RNA processing and other signaling activities.However,methods to track end...In mammalian cells,long noncoding RNAs(lncRNAs)form complexes with proteins to execute various biological functions such as gene transcription,RNA processing and other signaling activities.However,methods to track endogenous lncRNA dynamics in live cells and screen for lncRNA interacting proteins are limited.Here,we report the development of CERTIS(CRISPR-mediated Endogenous lncRNA Tracking and Immunoprecipitation System)to visualize and isolate endogenous lncRNA,by precisely inserting a 24-repeat MS2 tag into the distal end of lncRNA locus through the CRISPR7Cas9 technology.In this study,we show that CERTIS effectively labeled the paraspeckle lncRNA NEAT1 without disturbing its physiological properties and could monitor the endogenous expression variation of NEAT1.In addition,CERTIS displayed superior performance on both short-and long-term tracking of NEAT1 dynamics in live cells.We found that NEAT1 and paraspeckles were sensitive to topoisomerase I specific inhibitors.Moreover,RNA Immunoprecipitation(RIP)of the MS2-tagged NEAT1 lncRNA successfully revealed several new protein components of paraspeckle.Our results support CERTIS as a tool suitable to track both spatial and temporal lncRNA regulation in live cells as well as study the lncRNA-protein interactomes.展开更多
Dear Editor,As of June,2020,more than ten million cases of COVID-19 have been reported worldwide.The causative pathogen of the disease is a novel coronavirus named severe acute respiratory syndrome coronavirus 2(SARS-...Dear Editor,As of June,2020,more than ten million cases of COVID-19 have been reported worldwide.The causative pathogen of the disease is a novel coronavirus named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)(World Health Organization,2020).Animal infection models are important to characterize the infection,pathogenesis,and immunology of SARS・CoV・2,as well as for the development of medications and vaccines against COVID-19.Mice are particularly attractive animal models for their identical genetic background,reliable reproducibility,well characterized biology,and the huge availability of research reagents and knockout animals.Models in inbreed mice such as BALB/c and C57BL/6J(C57),which are widely used in research,are highly desired.展开更多
Dear Editor,Plant-specific WRKY transcription factors(TFs)are among the largest families of TFs in higher plants;they are also found in the unicellular eukaryote Giardia lamblia and the slime mold Dictyostelium discoi...Dear Editor,Plant-specific WRKY transcription factors(TFs)are among the largest families of TFs in higher plants;they are also found in the unicellular eukaryote Giardia lamblia and the slime mold Dictyostelium discoideum(Ulker and Somssich,2004),but not in animals.WRKY TFs participate in diverse developmental and physiological processes in plants,such as disease resistance,abiotic stress responses,senescence,seed and trichome development,as well as additional developmental and hormone-controlled processes(Agarwal et al.,2011).展开更多
Epigenetic modifications,including those on DNA and histones,have been shown to regulate cellular metabolism by controlling expression of enzymes involved in the corresponding metabolic pathways.In turn,metabolic flux...Epigenetic modifications,including those on DNA and histones,have been shown to regulate cellular metabolism by controlling expression of enzymes involved in the corresponding metabolic pathways.In turn,metabolic flux influences epigenetic regulation by affecting the biosynthetic balance of enzyme cofactors or donors for certain chromatin modifications.Recently,non-enzymatic covalent modifications(NECMs)by chemically reactive metabolites have been reported to manipulate chromatin architecture and gene transcription through multiple mechanisms.Here,we summarize these recent advances in the identification and characterization of NECMs on nucleic acids,histones,and transcription factors,providing an additional mechanistic link between metabolism and epigenetics.展开更多
In the original publication the Supplementary Material and Fig.2 are in correct.The correct versi on of Supplementary Material and Fig.2 are provided in this correction article.The text HBG2 appearing in the article s...In the original publication the Supplementary Material and Fig.2 are in correct.The correct versi on of Supplementary Material and Fig.2 are provided in this correction article.The text HBG2 appearing in the article should be read as HBG1.展开更多
Born in Dinghai County of Zhejiang province in June, 1926, Guan-Fu Zhu began to study at School of Medicine, Tongji University, in October, 1946 （Fig. 1）. Then he moved to the Department of Bacteriology and Immunolo...Born in Dinghai County of Zhejiang province in June, 1926, Guan-Fu Zhu began to study at School of Medicine, Tongji University, in October, 1946 （Fig. 1）. Then he moved to the Department of Bacteriology and Immunology of Peking Union Medical College in September, 1954, where he got his master degree under the supervision of Prof. Shao-Wen Xie, a renowned microbiologist and immunologist. In July, 1951, Mr. Zhu served as an assistant in teaching and research section of the Second Military Medical University of PLA. In January, 1958, he began to work at the Institute of Microbi- ology and Epidemiology, Academy of Military Medical Sci- ences, successively serving as a research assistant, assistant professor, associate professor and professor. Due to cardiovascular and cerebrovascular diseases, Mr. Guan- Fu Zhu unfortunately passed away on November 7th, 2015, at the age of 89.展开更多
Myocardial infarction afflicts close to three quarters of a million Americans annually, resulting in reduced heart function, arrhythmia, and frequently death. Cardiomy- ocyte death reduces the heart＇s pump capacity w...Myocardial infarction afflicts close to three quarters of a million Americans annually, resulting in reduced heart function, arrhythmia, and frequently death. Cardiomy- ocyte death reduces the heart＇s pump capacity while the deposition of a non-conductive scar incurs the risk of arrhythmia. Direct cardiac reprogramming emerged as a novel technology to simultaneously reduce scar tissue and generate new cardiomyocytes to restore cardiac function. This technology converts endogenous cardiac fibroblasts directly into induced cardiomyocyte-like cells using a variety of cocktails including transcription factors, microRNAs, and small molecules. Although promising, direct cardiac reprogramming is still in its fledging phase, and numerous barriers have to be overcome prior to its clinical application. This review discusses current findings to optimize reprogramming efficiency, including reprogramming factor cocktails and stoichiometry, epigenetic barriers to cell fate reprogramming, incomplete conversion and residual fibroblast identity, requisite growth factors, and environmental cues. Finally, we address the current challenges and future directions for the field.展开更多
Dear Editor,Targeted gene knock-out and knock-in mice are valuable tools for elucidating the function of genes in vivo （Capecchi, 2001）. Recently, the Cas9 endonuclease from Streptococcus pyogenes type Ⅱ CRISPR sys...Dear Editor,Targeted gene knock-out and knock-in mice are valuable tools for elucidating the function of genes in vivo （Capecchi, 2001）. Recently, the Cas9 endonuclease from Streptococcus pyogenes type Ⅱ CRISPR system has been demonstrated as a powerful tool for gene targeting.展开更多
Polyoxin is a group of structurally-related peptidyl nucleoside antibiotics bearing C-5 modifications on the nucleoside skeleton. Although the structural diversity and bioactivity preference of polyoxin are, to some e...Polyoxin is a group of structurally-related peptidyl nucleoside antibiotics bearing C-5 modifications on the nucleoside skeleton. Although the structural diversity and bioactivity preference of polyoxin are, to some extent, affected by such modifications, the biosynthetic logic for their occurence remains obscure. Here we report the identification of PolB in polyoxin pathway as an unusual UMP C-5 methylase with thymidylate syn- thase activity which is responsible for the C-5 methyla- tion of the nucleoside skeleton. To probe its molecular mechanism, we determined the crystal structures of PolB alone and in complexes with 5-Br UMP and 5-Br dUMP at 2.15 A, 1.76 A and 2.28 A resolutions, respec- tively. Loop 1 （residues 117-131）, Loop 2 （residues 192- 201） and the substrate recognition peptide （residues 94- 102） of PolB exhibit considerable conformational flexi-bility and adopt distinct structures upon binding to different substrate analogs. Consistent with the structural findings, a PolB homolog that harbors an identical function from Streptomyces viridochromogenes DSM 40736 was identified. The discovery of UMP C5-methy-lase opens the way to rational pathway engineering for polyoxin component optimization, and will also enrich the toolbox for natural nucleotide chemistry.展开更多
First-in-human clinical trial for age-related macular degen- eration using iPSC-derived retinal pigment epithelium （RPE） cells was conducted in 2014, showing no serious adverse effects to date, including tumor forma...First-in-human clinical trial for age-related macular degen- eration using iPSC-derived retinal pigment epithelium （RPE） cells was conducted in 2014, showing no serious adverse effects to date, including tumor formation. This appears to be attributable to relatively small number of transplanted cells, and distinct morphology of RPE cells; it might be relatively easy to minimize contamination of undifferentiated cells. However,展开更多
Initial skirmishes between the host and pathogen result in spillage of the contents of the bacterial cell.Amongst the spillage,the secondary messenger molecule,cyclic dimeric guanosine monophosphate(c di-GMP),was rece...Initial skirmishes between the host and pathogen result in spillage of the contents of the bacterial cell.Amongst the spillage,the secondary messenger molecule,cyclic dimeric guanosine monophosphate(c di-GMP),was recently shown to be bound by stimulator of interferon genes(STING).Binding of c di-GMP by STING activates the Tank Binding Kinase(TBK1)mediated signaling cascades that galvanize the body’s defenses for elimi-nation of the pathogen.In addition to c di-GMP,STING has also been shown to function in innate immune re-sponses against pathogen associated molecular pat-terns(PAMPs)originating from the DNA or RNA of pathogens.The pivotal role of STING in host defense is exemplified by the fact that STING-/-mice die upon infection by HSV-1.Thus,STING plays an essential role in innate immune responses against pathogens.This opens up an exciting possibility of targeting STING for development of adjuvant therapies to boost the im-mune defenses against invading microbes.Similarly,STING could be targeted for mitigating the inflamma-tory responses augmented by the innate immune sys-tem.This review summarizes and updates our current understanding of the role of STING in innate immune responses and discusses the future challenges in de-lineating the mechanism of STING-mediated responses.展开更多
Prostate cancer(PCa)is the second most frequently di-agnosed malignancy in men.Ge nome-wide association st udies(GWAS)has been highly successful in discover-ing susceptibility loci for prostate cancer.Currently,more t...Prostate cancer(PCa)is the second most frequently di-agnosed malignancy in men.Ge nome-wide association st udies(GWAS)has been highly successful in discover-ing susceptibility loci for prostate cancer.Currently,more than twenty GWAS have identified more than fifty com-mon variants associated with susceptibility with PCa.Yet with the increase in loci,voices from the scientifi c society are calling for more.In this review,we summarize current fi ndings,discuss the common problems troubling current studies and shed light upon possible breakthroughs in the future.GWAS is the beginning of something wonder-ful.Although we are quite near the end of the beginning,post-GWAS studies are just taking off and future studies are needed extensively.It is believed that in the future GWAS information will be helpful to build a comprehen-sive system intergraded with PCa prevention,diagnosis,molecular classifi cation,personalized therapy.展开更多
基金supported by grants from Noncommunicable Chronic Diseases-National Science and Technology Major Program(No.2023ZD0500400 to D.Y.and Y.L.)the National Key R&D Program of China(No.2020YFA 0803202 to D.Y.and No.2019YFA 0802900 to Y.L.)+2 种基金the Fundamental Research Funds for the Central Universities(No.2024300408 to Y.L.)the Jiangsu Provincial Science and Technology Plan Special Fund(No.BK20232018 to Y.L.)NSFC grants(Nos.82225036,31821002,and 31871431 to D.Y.,Nos.82103366 and 32370823 to L-L.C.,Nos.32122035 and 32471000 to Y.L.)。
文摘Dear Editor,A hallmark of immune cells in response to inflammatory stimuli,both infectious and non-infectious,is the rapid and extensive change in metabolism.In addition to meet the energetic and biosynthetic need of the immune cell,research over the past decade has led to the appreciation of individual metabolites in cell signaling during metabolic reprogramming in immune response.One illustrative example is itaconate,a dicarboxylic acid derived from Kreb cycle metabolite,cis-aconitate,by the enzyme cis-aconitate decarboxylase(ACOD1).ACOD1 is encoded by immunoresponsive gene 1(IRG1),which is rapidly induced by various inflammatory stimuli in myeloid cells,leading to the prompt accumulation of itaconate to millimolar levels.Itaconate binds to multiple proteins to influence oxidative response,epigenetic modification,and gene expression intrinsically and to signal GPCR after secretion(Ye et al.,2024).These regulations on different pathways by a single metabolite concertedly modulate inflammatory responses.Beyond its role as an antimicrobial metabolite,itaconate has recently garnered attention in the research of cancer biology.Genetic and preclinical studies in animal models suggest that itaconate can create an immunosuppressive tumor microenvironment.The enhanced antitumor immunity and response to immune checkpoint inhibitors seen in Irg1-deficient mice,which otherwise exhibit normal development,underscore IRG1 as a compelling target for cancer immunotherapy(Chen et al.,2023;Gu et al.,2023;Zhao et al.,2022).However,current strategies to target IRG1/itaconate remain limited,emphasizing the need for therapeutic development to effectively blockade IRG1 in cancer treatment.
基金supported by National Institutes of Health(NIH)research grants R01AR062207,R01AR061484,R01AR076900,R01AR078035 and R01NS070328.
文摘Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation,known as meta-inflammation.This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease.Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways.However,its role and molecular mechanism in obesity and associated complications are obscure.In this study,we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain,white adipose tissue inflammation,and metabolic dysregulation.To identify the target proteins of pyruvate,drug affinity responsive target stability was employed with proteomics,cellular thermal shift assay,and isothermal drug response to detect the interactions between pyruvate and its molecular targets.Consequently,we identified cytosolic phospholipase A2(cPLA2)as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity,white adipose tissue inflammation,and hepatic steatosis in a cPLA2-dependent manner.Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated,confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity.Overall,our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity but it also sheds light on the mechanism of its action.Pyruvate’s prior clinical use indicates that it can be considered a safe and viable alternative for obesity,whether consumed as a dietary supplement or as part of a regular diet.
基金supported by ShanghaiTech,Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at ShanghaiTech University(G.Z.),and grants from the National Key Research and Development Program of China[Grant Nos.2017YFC1001301(G.Z.),2019YFA0111001(H.W.)]the National Natural Science Foundation of China[Nos.31670919(H.W.),81822045(L.L.)]+1 种基金Lingang Laboratory(No.LG202101-01-07 to X.Y.),Program of Shanghai Academic/Technology Research Leader[20XD1420300(L.L.)]Emergency response to new coronavirus infection scientific and technological project[YD9110002004(J.W.)],and Shanghai Sailing Program[20YF1430900(S.-M.Z.)].
文摘Dear Editor,Tremendous efforts have been made globally to develop therapeutics and prophylactics against severe acute respiratory syndrome coronavirus-2(SARS-CoV-2)which has caused thousands of millions of infections and deaths worldwide.A series of potent neutralizing antibodies with defined epitopes targeting RBD have been recently identified with different strategies.However,being an RNA virus,the instability of the SARS-CoV-2 genome results in numerous S-protein variants with altered viral phenotypes.
基金the Key Technologies Research and Development Program(2017YFC1001901)the Guangdong Special Support Program(2019BT02Y276)+2 种基金Guangdong Basic and Applied Basic Research Foundation(2018A030313370 and 2021A1515010759)the National Natural Science Foundation of China(31971365)the Guangzhou Science and Technology Project(201803010020).
文摘Recent advances in genome editing,especially CRISPR-Cas nucleases,have revolutionized both laboratory research and clinical therapeutics.CRISPR-Cas nucleases,together with the DNA damage repair pathway in cells,enable both genetic diversification by classical non-homologous end joining(c-NHEJ)and precise genome modification by homology-based repair(HBR).Genome editing in zygotes is a convenient way to edit the germline,paving the way for animal disease model generation,as well as human embryo genome editing therapy for some life-threatening and incurable diseases.HBR efficiency is highly dependent on the DNA donor that is utilized as a repair template.Here,we review recent progress in improving CRISPR-Cas nuclease-induced HBR in mammalian embryos by designing a suitable DNA donor.Moreover,we want to provide a guide for producing animal disease models and correcting genetic mutations through CRISPR-Cas nuclease-induced HBR in mammalian embryos.Finally,we discuss recent developments in precise genome-modification technology based on the CRISPR-Cas system.
基金This study was financially supported by the Yunnan Eco-friendly Food International Cooperation Research Center(YEFICRC)Project of Yunnan Provincial Key Programs(Grant No.2019ZG009)the National Key R&D Program of China(Grant No.2019YFD0300101)+3 种基金the Guangdong Provincial Key Laboratory of Genome Read and Write(Grant No.2017B030301011)the Key Research Program of the Chinese Academy of Sciences(KJZD-SW-L07)the Youth Innovation Promotion Association,CAS(No.2016080)Key-Area Research and Development Program of Guangdong Province(No.2020B020224002)。
文摘The fall armyworm(FAW),Spodoptera frugiperda,is a destructive pest native to America and has recently become an invasive insect pest in China.Because of its rapid spread and great risks in China,understanding of FAW genetic background and pesticide resistance is urgent and essential to develop effective management strategies.Here,we assembled a chromosome-level genome of a male FAW(SFynMstLFR)and compared re-sequencing results of the populations from America,Africa,and China.Strain identification of 163 individuals collected from America,Africa and China showed that both C and R strains were found in the American pop-ulations,while only C strain was found in the Chinese and African populations.Moreover,population geno-mics analysis showed that populations from Africa and China have close relationship with significantly genetic differentiation from American populations.Taken toge-ther,FAWs invaded into China were most likely origi-nated from Africa.Comparative genomics analysis displayed that the cytochrome p450 gene family is extremely expanded to 425 members in FAW,of which 283 genes are specific to FAW.Treatments of Chinese populations with twenty-three pesticides showed the variant patterns of transcriptome profiles,and several detoxification genes such as AOX,UGT and GST spe-cially responded to the pesticides.These findings will be useful in developing effective strategies for manage-ment of FAW in China and other invaded areas.
文摘Inhibition of Mycobacterium tuberculosis(Mtb)cell wall assembly is an established strategy for anti-TB chemotherapy.Arabinosyltransferase EmbB,which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose(DPA)to its arabinosyl acceptor is an essential enzyme for Mtb cell wall synthesis.Analysis of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug,ethambutol.Herein,we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its"resting state"and DPA-bound"active state".EmbB is a fifteen-transmembrane-spanning protein,assembled as a dimer.Each protomer has an associated acyl-carrier-protein(AcpM)on their cytoplasmic surface.Confor-mational changes upon DPA binding indicate an asym-metric movement within the EmbB dimer during catalysis.Functional studies have identified critical residues in substrate recognition and catalysis,and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with DPA.The structures represent the first step directed towards a rational approach for anti-TB drug discovery.
基金This work was supported by the National Key Research and Development Program of China(2017YFA0102801,2018YFA0107003)National Natural Science Foundation of China(91640119,91749113,31570827,31871479 and 31930058)+1 种基金Natural Science Foundation of Guangdong Province(2017A030313116)the China Postdoctoral Science Foundation(2018M631021).
文摘In mammalian cells,long noncoding RNAs(lncRNAs)form complexes with proteins to execute various biological functions such as gene transcription,RNA processing and other signaling activities.However,methods to track endogenous lncRNA dynamics in live cells and screen for lncRNA interacting proteins are limited.Here,we report the development of CERTIS(CRISPR-mediated Endogenous lncRNA Tracking and Immunoprecipitation System)to visualize and isolate endogenous lncRNA,by precisely inserting a 24-repeat MS2 tag into the distal end of lncRNA locus through the CRISPR7Cas9 technology.In this study,we show that CERTIS effectively labeled the paraspeckle lncRNA NEAT1 without disturbing its physiological properties and could monitor the endogenous expression variation of NEAT1.In addition,CERTIS displayed superior performance on both short-and long-term tracking of NEAT1 dynamics in live cells.We found that NEAT1 and paraspeckles were sensitive to topoisomerase I specific inhibitors.Moreover,RNA Immunoprecipitation(RIP)of the MS2-tagged NEAT1 lncRNA successfully revealed several new protein components of paraspeckle.Our results support CERTIS as a tool suitable to track both spatial and temporal lncRNA regulation in live cells as well as study the lncRNA-protein interactomes.
文摘Dear Editor,As of June,2020,more than ten million cases of COVID-19 have been reported worldwide.The causative pathogen of the disease is a novel coronavirus named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)(World Health Organization,2020).Animal infection models are important to characterize the infection,pathogenesis,and immunology of SARS・CoV・2,as well as for the development of medications and vaccines against COVID-19.Mice are particularly attractive animal models for their identical genetic background,reliable reproducibility,well characterized biology,and the huge availability of research reagents and knockout animals.Models in inbreed mice such as BALB/c and C57BL/6J(C57),which are widely used in research,are highly desired.
基金supported by grants 31670740 and 31270803 from NSFC(the National Science Foundation of China).
文摘Dear Editor,Plant-specific WRKY transcription factors(TFs)are among the largest families of TFs in higher plants;they are also found in the unicellular eukaryote Giardia lamblia and the slime mold Dictyostelium discoideum(Ulker and Somssich,2004),but not in animals.WRKY TFs participate in diverse developmental and physiological processes in plants,such as disease resistance,abiotic stress responses,senescence,seed and trichome development,as well as additional developmental and hormone-controlled processes(Agarwal et al.,2011).
基金Work in the David lab is supported by R21 DA044767,CCSG core grant P30 CA008748,and SPORE P50-CA192937 from the National Institutes of Health.In addition,work in the lab is supported by the Tri-institutional Therapeutic Discovery Institute,the Mr.William H.Goodwin and Mrs.Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Center for Experimental Therapeutics at MSKCC,the Pershing Square Sohn Cancer Research Alliance,and Cycle for Survival.Y.D.is a Josie Robertson Young Investigator.Additionally,YD is supported by the Parker Institute for Cancer Immunotherapy and the Anna Fuller Cancer Research Foundation.
文摘Epigenetic modifications,including those on DNA and histones,have been shown to regulate cellular metabolism by controlling expression of enzymes involved in the corresponding metabolic pathways.In turn,metabolic flux influences epigenetic regulation by affecting the biosynthetic balance of enzyme cofactors or donors for certain chromatin modifications.Recently,non-enzymatic covalent modifications(NECMs)by chemically reactive metabolites have been reported to manipulate chromatin architecture and gene transcription through multiple mechanisms.Here,we summarize these recent advances in the identification and characterization of NECMs on nucleic acids,histones,and transcription factors,providing an additional mechanistic link between metabolism and epigenetics.
文摘In the original publication the Supplementary Material and Fig.2 are in correct.The correct versi on of Supplementary Material and Fig.2 are provided in this correction article.The text HBG2 appearing in the article should be read as HBG1.
文摘Born in Dinghai County of Zhejiang province in June, 1926, Guan-Fu Zhu began to study at School of Medicine, Tongji University, in October, 1946 （Fig. 1）. Then he moved to the Department of Bacteriology and Immunology of Peking Union Medical College in September, 1954, where he got his master degree under the supervision of Prof. Shao-Wen Xie, a renowned microbiologist and immunologist. In July, 1951, Mr. Zhu served as an assistant in teaching and research section of the Second Military Medical University of PLA. In January, 1958, he began to work at the Institute of Microbi- ology and Epidemiology, Academy of Military Medical Sci- ences, successively serving as a research assistant, assistant professor, associate professor and professor. Due to cardiovascular and cerebrovascular diseases, Mr. Guan- Fu Zhu unfortunately passed away on November 7th, 2015, at the age of 89.
基金the National Natural Science Foundation for General and Key Programs (C81530049,C81130055,C31470860,Y.Z.)Knowledge Innovation Program of Chinese Academy of Sciences (XDA04020202-19,Y.Z.).
文摘Myocardial infarction afflicts close to three quarters of a million Americans annually, resulting in reduced heart function, arrhythmia, and frequently death. Cardiomy- ocyte death reduces the heart＇s pump capacity while the deposition of a non-conductive scar incurs the risk of arrhythmia. Direct cardiac reprogramming emerged as a novel technology to simultaneously reduce scar tissue and generate new cardiomyocytes to restore cardiac function. This technology converts endogenous cardiac fibroblasts directly into induced cardiomyocyte-like cells using a variety of cocktails including transcription factors, microRNAs, and small molecules. Although promising, direct cardiac reprogramming is still in its fledging phase, and numerous barriers have to be overcome prior to its clinical application. This review discusses current findings to optimize reprogramming efficiency, including reprogramming factor cocktails and stoichiometry, epigenetic barriers to cell fate reprogramming, incomplete conversion and residual fibroblast identity, requisite growth factors, and environmental cues. Finally, we address the current challenges and future directions for the field.
文摘Dear Editor,Targeted gene knock-out and knock-in mice are valuable tools for elucidating the function of genes in vivo （Capecchi, 2001）. Recently, the Cas9 endonuclease from Streptococcus pyogenes type Ⅱ CRISPR system has been demonstrated as a powerful tool for gene targeting.
文摘Polyoxin is a group of structurally-related peptidyl nucleoside antibiotics bearing C-5 modifications on the nucleoside skeleton. Although the structural diversity and bioactivity preference of polyoxin are, to some extent, affected by such modifications, the biosynthetic logic for their occurence remains obscure. Here we report the identification of PolB in polyoxin pathway as an unusual UMP C-5 methylase with thymidylate syn- thase activity which is responsible for the C-5 methyla- tion of the nucleoside skeleton. To probe its molecular mechanism, we determined the crystal structures of PolB alone and in complexes with 5-Br UMP and 5-Br dUMP at 2.15 A, 1.76 A and 2.28 A resolutions, respec- tively. Loop 1 （residues 117-131）, Loop 2 （residues 192- 201） and the substrate recognition peptide （residues 94- 102） of PolB exhibit considerable conformational flexi-bility and adopt distinct structures upon binding to different substrate analogs. Consistent with the structural findings, a PolB homolog that harbors an identical function from Streptomyces viridochromogenes DSM 40736 was identified. The discovery of UMP C5-methy-lase opens the way to rational pathway engineering for polyoxin component optimization, and will also enrich the toolbox for natural nucleotide chemistry.
文摘First-in-human clinical trial for age-related macular degen- eration using iPSC-derived retinal pigment epithelium （RPE） cells was conducted in 2014, showing no serious adverse effects to date, including tumor formation. This appears to be attributable to relatively small number of transplanted cells, and distinct morphology of RPE cells; it might be relatively easy to minimize contamination of undifferentiated cells. However,
基金supported by the National Natural Science Foundation of China(Grant No.31070660)the Ministry of Science and Technology of China(No.2009DFB30310).
文摘Initial skirmishes between the host and pathogen result in spillage of the contents of the bacterial cell.Amongst the spillage,the secondary messenger molecule,cyclic dimeric guanosine monophosphate(c di-GMP),was recently shown to be bound by stimulator of interferon genes(STING).Binding of c di-GMP by STING activates the Tank Binding Kinase(TBK1)mediated signaling cascades that galvanize the body’s defenses for elimi-nation of the pathogen.In addition to c di-GMP,STING has also been shown to function in innate immune re-sponses against pathogen associated molecular pat-terns(PAMPs)originating from the DNA or RNA of pathogens.The pivotal role of STING in host defense is exemplified by the fact that STING-/-mice die upon infection by HSV-1.Thus,STING plays an essential role in innate immune responses against pathogens.This opens up an exciting possibility of targeting STING for development of adjuvant therapies to boost the im-mune defenses against invading microbes.Similarly,STING could be targeted for mitigating the inflamma-tory responses augmented by the innate immune sys-tem.This review summarizes and updates our current understanding of the role of STING in innate immune responses and discusses the future challenges in de-lineating the mechanism of STING-mediated responses.
文摘Prostate cancer(PCa)is the second most frequently di-agnosed malignancy in men.Ge nome-wide association st udies(GWAS)has been highly successful in discover-ing susceptibility loci for prostate cancer.Currently,more than twenty GWAS have identified more than fifty com-mon variants associated with susceptibility with PCa.Yet with the increase in loci,voices from the scientifi c society are calling for more.In this review,we summarize current fi ndings,discuss the common problems troubling current studies and shed light upon possible breakthroughs in the future.GWAS is the beginning of something wonder-ful.Although we are quite near the end of the beginning,post-GWAS studies are just taking off and future studies are needed extensively.It is believed that in the future GWAS information will be helpful to build a comprehen-sive system intergraded with PCa prevention,diagnosis,molecular classifi cation,personalized therapy.
