Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome ...Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.展开更多
Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study ...Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly cancers.Methods:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in Drug Bank.We performed additional experimental validation for the dominant repurposed drugs in cancer.Results:The overall performance of the model was well supported by cross-validation and literature mining.Focusing on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments.Because of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative proteomics.Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA transport.Moreover,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model.Conclusions:Our predicted results,which have been released in a public database named The Predictive Database for Drug Repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.展开更多
This study presents an order exponential model for estimating road traffic safety in city clusters.The proposed model introduces the traffic flow intrinsic properties and uses the characteristics and regular patterns ...This study presents an order exponential model for estimating road traffic safety in city clusters.The proposed model introduces the traffic flow intrinsic properties and uses the characteristics and regular patterns of traffic development to identify road traffic safety levels in city clusters.Additionally,an evaluation index system of city cluster road traffic safety was constructed based on the spatial and temporal distribution.Then Order Exponential Evaluation Model(OEEM),a comprehensive model using order exponent function for road traffic safety evaluation,was put forward,which considers the main characteristics and the generation process of traffic accidents.The model effectively controlled the unsafe behavior of the traffic system.It could define the levels of city cluster road traffic safety and dynamically detect road safety risk.The proposed model was verified with statistical data from three Chinese city clusters by comparing the common model for road traffic safety with an ideal model.The results indicate that the order exponent approach undertaken in this study can be extended and applied to other research topics and fields.展开更多
Lysine post-translational modifications(PTMs)are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins.Dysr...Lysine post-translational modifications(PTMs)are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins.Dysregulation of lysine PTMs is implicated in many diseases,and targeting lysine PTM regulatory factors,including writers,erasers,and readers,has become an effective strategy for disease therapy.The continuing development of mass spectrometry(MS)technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs.The global characterization of lysine PTMs is crucial for deciphering the regulatory networks,molecular functions,and mechanisms of action of lysine PTMs.In this review,we focus on lysine PTMs,and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies.We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.展开更多
To address the shortcomings in decision-making methods for ground motion threshold warning models in high-speed rail earthquake early warning systems(HSREEWs),we propose a dual judgement method and corresponding early...To address the shortcomings in decision-making methods for ground motion threshold warning models in high-speed rail earthquake early warning systems(HSREEWs),we propose a dual judgement method and corresponding early warning process for earthquake early warning decisions based on joint peak ground acceleration(PGA)and complex earthquake environmental risk evaluation(ERE)values.First,we analyse the characteristics of four complex earthquake environments based on the characteristics of high-speed rail(HSR)operating environments.Second,we establish an earthquake environmental risk evaluation index system and propose an adversarial interpretive structure modelling method-based complex earthquake situation evaluation model(AISM-based ESEM).The AISM method firstly evaluates the proximity by the TOPSIS(technique for order preference by similarity to an ideal solution)method,then effectively rank targets with fuzzy attributes through opposite hierarchical extraction rules without sacrificing system functionality.Since PGA can reflect the current size of earthquake energy,combining PGA thresholds with ESEM-derived values of ERE can effectively determine the risk status of each train and make decisions on the most appropriate alarm form and control measures for that status.Finally,case analysis results under the background of Wenchuan Earthquake show that the new early warning decisionmaking method accurately assesses environmental risks in affected areas and provides corresponding warning levels as a supplement to existing HSREEWs warning models.展开更多
Diabetic kidney disease(DKD)is a major microvascular complication of type 2 diabetes mellitus(T2DM).Monitoring the early diagnostic period and disease progression plays a crucial role in treating DKD.In this study,to ...Diabetic kidney disease(DKD)is a major microvascular complication of type 2 diabetes mellitus(T2DM).Monitoring the early diagnostic period and disease progression plays a crucial role in treating DKD.In this study,to comprehensively elucidate the molecular characteristics of urinary proteins and urinary exosome proteins in type 2 DKD,we performed large-scale urinary proteomics(n=144)and urinary exosome proteomics(n=44)analyses on T2DM patients with albuminuria in varying degrees.The dynamics analysis of the urinary and exosome proteomes in our study provides a valuable resource for discovering potential urinary biomarkers in patients with DKD.A series of potential biomarkers,such as SERPINA1 and transferrin(TF),were detected and validated to be used for DKD diagnosis or disease monitoring.The results of our study comprehensively elucidated the changes in the urinary proteome and revealed several potential biomarkers reflecting the progression of DKD,which provide a reference for DKD biomarker screening.展开更多
AMP-activated protein kinase(AMPK)is a conserved energy sensor that plays roles in diverse biological processes via phosphorylating various substrates.Emerging studies have demonstrated the regulatory roles of AMPK in...AMP-activated protein kinase(AMPK)is a conserved energy sensor that plays roles in diverse biological processes via phosphorylating various substrates.Emerging studies have demonstrated the regulatory roles of AMPK in DNA repair,but the underlying mechanisms remain to be fully understood.Herein,using mass spectrometry-based proteomic technologies,we systematically investigate the regulatory network of AMPK in DNA damage response(DDR).Our system-wide phosphoproteome study uncovers a variety of newly-identified potential substrates involved in diverse biological processes,whereas our system-wide histone modification analysis reveals a link between AMPK and histone acetylation.Together with these findings,we discover that AMPK promotes apoptosis by phosphorylating apoptosis-stimulating of p53 protein 2(ASPP2)in an irradiation(IR)-dependent manner and regulates histone acetylation by phosphorylating histone deacetylase 9(HDAC9)in an IR-independent manner.Besides,we reveal that disrupting the histone acetylation by the bromodomain BRD4 inhibitor JQ-1 enhances the sensitivity of AMPKdeficient cells to IR.Therefore,our study has provided a resource to investigate the interplay between phosphorylation and histone acetylation underlying the regulatory network of AMPK,which could be beneficial to understand the exact role of AMPK in DDR.展开更多
Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Here...Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Herein,we establish 35 Chinese PCa primary cell models to capture specific characteristics among PCa patients,including gene mutations,mRNA/protein/surface protein distributions,and pharmaceutical responses.The multi-omics analyses identify Anterior Gradient 2(AGR2)as a pre-operative prognostic biomarker in PCa.Through the drug library screening,we describe crizotinib as a selective compound for malignant PCa primary cells.We further perform the pharmacoproteome analysis and identify 14,372 significant protein-drug correlations.Surprisingly,the diminished AGR2 enhances the inhibition activity of crizotinib via ALK/c-MET-AKT axis activation which is validated by PC3 and xenograft model.Our integrated multi-omics approach yields a comprehensive understanding of PCa biomarkers and pharmacological responses,allowing for more precise diagnosis and therapies.展开更多
Dear Editor,Obesity is caused by an imbalance between energy intake and expenditure,and has become a global epidemic with over 650 million adults affected.Adipose tissues in mammals are composed of white adipose tissu...Dear Editor,Obesity is caused by an imbalance between energy intake and expenditure,and has become a global epidemic with over 650 million adults affected.Adipose tissues in mammals are composed of white adipose tissue(WAT)and classical brown adipose tissue(BAT),and their balance is highly related to the occurrence of obesity.The browning of white adipocytes results in“beige”or“brite”adipocytes,which appear functionally similar to classical brown adipocytes,and can be detected in WAT deposits of animals that have been exposed to cold or other inducers(Fu et al.,2015).展开更多
With the development of mass spectrometry(MS)-based proteomics technologies,patient-derived xenograft(PDX),which is generated from the primary tumor of a patient,is widely used for the proteome-wide analysis of cancer...With the development of mass spectrometry(MS)-based proteomics technologies,patient-derived xenograft(PDX),which is generated from the primary tumor of a patient,is widely used for the proteome-wide analysis of cancer mechanism and biomarker identification of a drug.However,the proteomics data interpretation is still challenging due to complex data deconvolution from the PDX sample that is a cross-species mixture of human cancerous tissues and immunodeficient mouse tissues.In this study,by using the lab-assembled mixture of human and mouse cells with different mixing ratios as a benchmark,we developed and evaluated a new method,SPA(shared peptide allocation),for protein quantitation by considering the unique and shared peptides of both species.The results showed that SPA could provide more convenient and accurate protein quantitation in human–mouse mixed samples.Further validation on a pair of gastric PDX samples(one bearing FGFR2 amplification while the other one not)showed that our new method not only significantly improved the overall protein identification,but also detected the differential phosphorylation of FGFR2 and its downstream mediators(such as RAS and ERK)exclusively.The tool pdx SPA is freely available at https://github.com/LiLab-Proteomics/pdx SPA.展开更多
The CRISPR/Cas9 system,originally derived from the prokaryotic adaptive immune system,has been developed as efficient genome editing tools.It enables precise gene manipulation on chromosomal DNA through the specific b...The CRISPR/Cas9 system,originally derived from the prokaryotic adaptive immune system,has been developed as efficient genome editing tools.It enables precise gene manipulation on chromosomal DNA through the specific binding of programmable sgRNA to target DNA,and the Cas9 protein,which has endonuclease activity,will cut a double strand break at specific locus.However,Cas9 is a foreign protein in mammalian cells,and the potential risks associated with its introduction into mammalian cells are not fully understood.In this study,we performed pull-down and mass spectrometry(MS)analysis of Streptococcus pyogenes Cas9(SpyCas9)interacting proteins in HEK293T cells and showed that the majority of Cas9-associated proteins identified by MS were localized in the nucleolus.Interestingly,we further discovered that the Cas9 protein contains a sequence encoding a nucleolus detention signal(NoDS).Compared with wild-type(WT)Cas9,NoDS-mutated variants of Cas9(mCas9)are less stable,although their gene editing activity is minimally affected.Overexpression of WT Cas9,but not mCas9,causes general effects on transcription and protein translation in the host cell.Overall,identification of NoDS in Cas9 will improve the understanding of Cas9's biological function in vivo,and the removal of NoDS in Cas9 may enhance its safety for future clinical use.展开更多
基金supported by the Natural Science Foundation of China(Grant Nos.:22225702 and 32322048)the National Key R&D Program of China(Grant No.:2020YFE0202200)+8 种基金the Shanghai Academic/Technology Research Leader Program,China(Grant No.:22XD1420900)Guangdong High-level New R&D Institute,China(Grant No.:2019B090904008)Guangdong High-level Innovative Research Institute,China(Grant No.:2021B0909050003)the Shanghai Rising-Star Program,China(Grant No.:22QA1411100)the Youth Innovation Promotion Association of the Chinese Academy of Sciences(Grant No.:2021276)the Young Elite Scientists Sponsorship Program by China Association for Science and Technology,China(Grant No.:2022QNRC001)the open fund of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,China(Grant No.:KF-202201)We also thank the support of the Innovative Research Team of High-Level Local Universities in Shanghai,China(Grant No.:SHSMU-ZDCX20212700)Sanofi scholarship program.
文摘Pharmacological perturbation studies based on protein-level signatures are fundamental for drug discovery. In the present study, we used a mass spectrometry (MS)-based proteomic platform to profile the whole proteome of the breast cancer MCF7 cell line under stress induced by 78 bioactive compounds. The integrated analysis of perturbed signal abundance revealed the connectivity between phenotypic behaviors and molecular features in cancer cells. Our data showed functional relevance in exploring the novel pharmacological activity of phenolic xanthohumol, as well as the noncanonical targets of clinically approved tamoxifen, lovastatin, and their derivatives. Furthermore, the rational design of synergistic inhibition using a combination of histone methyltransferase and topoisomerase was identified based on their complementary drug fingerprints. This study provides rich resources for the proteomic landscape of drug responses for precision therapeutic medicine.
基金supported by the National Natural Science Foundation of China(Grant Nos.31871329,1670066,81872888,and 81821005)Shanghai Municipal Science and Technology Major Project(Grant No.2017SHZDZX01)+2 种基金the Key New Drug Creation and Manufacturing Program of China(Grant No.2018ZX09711002-004)the Special Project on Precision Medicine under the National Key R&D Program(Grant No.SQ2017YFSF090210)the K.C.Wong Education Foundation。
文摘Objective:Drug repurposing,the application of existing therapeutics to new indications,holds promise in achieving rapid clinical effects at a much lower cost than that of de novo drug development.The aim of our study was to perform a more comprehensive drug repurposing prediction of diseases,particularly cancers.Methods:Here,by targeting 4,096 human diseases,including 384 cancers,we propose a greedy computational model based on a heterogeneous multilayer network for the repurposing of 1,419 existing drugs in Drug Bank.We performed additional experimental validation for the dominant repurposed drugs in cancer.Results:The overall performance of the model was well supported by cross-validation and literature mining.Focusing on the top-ranked repurposed drugs in cancers,we verified the anticancer effects of 5 repurposed drugs widely used clinically in drug sensitivity experiments.Because of the distinctive antitumor effects of nifedipine(an antihypertensive agent)and nortriptyline(an antidepressant drug)in prostate cancer,we further explored their underlying mechanisms by using quantitative proteomics.Our analysis revealed that both nifedipine and nortriptyline affected the cancer-related pathways of DNA replication,the cell cycle,and RNA transport.Moreover,in vivo experiments demonstrated that nifedipine and nortriptyline significantly inhibited the growth of prostate tumors in a xenograft model.Conclusions:Our predicted results,which have been released in a public database named The Predictive Database for Drug Repurposing(PAD),provide an informative resource for discovering and ranking drugs that may potentially be repurposed for cancer treatment and determining new therapeutic effects of existing drugs.
基金Sponsored by the National Natural Science Foundation of China(Grant No.51178157)the High-level Project of the Top Six Talents in Jiangsu Province(Grant No.JXQC-021)+1 种基金the Key Science and Technology Program in Henan Province(Grant No.182102310004)the Humanities and Social Science Research Programs Foundation of Ministry of Education of China(Grant No.18YJAZH028).
文摘This study presents an order exponential model for estimating road traffic safety in city clusters.The proposed model introduces the traffic flow intrinsic properties and uses the characteristics and regular patterns of traffic development to identify road traffic safety levels in city clusters.Additionally,an evaluation index system of city cluster road traffic safety was constructed based on the spatial and temporal distribution.Then Order Exponential Evaluation Model(OEEM),a comprehensive model using order exponent function for road traffic safety evaluation,was put forward,which considers the main characteristics and the generation process of traffic accidents.The model effectively controlled the unsafe behavior of the traffic system.It could define the levels of city cluster road traffic safety and dynamically detect road safety risk.The proposed model was verified with statistical data from three Chinese city clusters by comparing the common model for road traffic safety with an ideal model.The results indicate that the order exponent approach undertaken in this study can be extended and applied to other research topics and fields.
基金supported by grants from the Program of Shanghai Academic Research Leader(Grant No.22XD1420900)the National Natural Science Foundation of China(Grant Nos.22225702,32071432,32171434,and 81821005)+3 种基金the Youth Science and Technology Talents in Shanghai Sail Plan of China(Grant No.21YF1456000)the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,China(Grant No.KF-202201)the Guangdong High-level New R&D Institute,China(Grant No.2019B090904008)the Guangdong High-level Innovative Research Institute,China(Grant No.2021B0909050003).
文摘Lysine post-translational modifications(PTMs)are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins.Dysregulation of lysine PTMs is implicated in many diseases,and targeting lysine PTM regulatory factors,including writers,erasers,and readers,has become an effective strategy for disease therapy.The continuing development of mass spectrometry(MS)technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs.The global characterization of lysine PTMs is crucial for deciphering the regulatory networks,molecular functions,and mechanisms of action of lysine PTMs.In this review,we focus on lysine PTMs,and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies.We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy.
基金supported in part by the Key Scientific and Technological projects of Henan Province(Grant No.182102310004)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(Grant No.KYCX19_0304)the scholarship of China Scholarship Council(Grant No.201906840033,202006840084).
文摘To address the shortcomings in decision-making methods for ground motion threshold warning models in high-speed rail earthquake early warning systems(HSREEWs),we propose a dual judgement method and corresponding early warning process for earthquake early warning decisions based on joint peak ground acceleration(PGA)and complex earthquake environmental risk evaluation(ERE)values.First,we analyse the characteristics of four complex earthquake environments based on the characteristics of high-speed rail(HSR)operating environments.Second,we establish an earthquake environmental risk evaluation index system and propose an adversarial interpretive structure modelling method-based complex earthquake situation evaluation model(AISM-based ESEM).The AISM method firstly evaluates the proximity by the TOPSIS(technique for order preference by similarity to an ideal solution)method,then effectively rank targets with fuzzy attributes through opposite hierarchical extraction rules without sacrificing system functionality.Since PGA can reflect the current size of earthquake energy,combining PGA thresholds with ESEM-derived values of ERE can effectively determine the risk status of each train and make decisions on the most appropriate alarm form and control measures for that status.Finally,case analysis results under the background of Wenchuan Earthquake show that the new early warning decisionmaking method accurately assesses environmental risks in affected areas and provides corresponding warning levels as a supplement to existing HSREEWs warning models.
基金supported by the National Key Research and Development Program of China(2020YFE0202200)the National Natural Science Foundation of China(22225702,32071432,32171434,81600702)+4 种基金the Program of Shanghai Academic Research Leader(22XD1420900)the State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,China(KF-202201)the Innovative Research Team of High-Level Local Universities in Shanghai(SHSMU-ZDCX20212700)the Guangdong High-level New R&D Institute(2019B090904008)the Guangdong High-level Innovative Research Institute(2021B0909050003).
文摘Diabetic kidney disease(DKD)is a major microvascular complication of type 2 diabetes mellitus(T2DM).Monitoring the early diagnostic period and disease progression plays a crucial role in treating DKD.In this study,to comprehensively elucidate the molecular characteristics of urinary proteins and urinary exosome proteins in type 2 DKD,we performed large-scale urinary proteomics(n=144)and urinary exosome proteomics(n=44)analyses on T2DM patients with albuminuria in varying degrees.The dynamics analysis of the urinary and exosome proteomes in our study provides a valuable resource for discovering potential urinary biomarkers in patients with DKD.A series of potential biomarkers,such as SERPINA1 and transferrin(TF),were detected and validated to be used for DKD diagnosis or disease monitoring.The results of our study comprehensively elucidated the changes in the urinary proteome and revealed several potential biomarkers reflecting the progression of DKD,which provide a reference for DKD biomarker screening.
基金supported by the National Natural Science Foundation of China(Grant Nos.81872888,81821005,81673489,and 31871414)the Special Project on Precision Medicine under the National Key R&D Program(Grant No.2017YFC0906600)+2 种基金the Shanghai Science and Technology Development Funds,China(Grant No.19JC1416300)the Key New Drug Creation and Manufacturing Program of China(Grant Nos.2018ZX09711002-004 and 2018ZX09711002-007)the KC Wong Education Foundation。
文摘AMP-activated protein kinase(AMPK)is a conserved energy sensor that plays roles in diverse biological processes via phosphorylating various substrates.Emerging studies have demonstrated the regulatory roles of AMPK in DNA repair,but the underlying mechanisms remain to be fully understood.Herein,using mass spectrometry-based proteomic technologies,we systematically investigate the regulatory network of AMPK in DNA damage response(DDR).Our system-wide phosphoproteome study uncovers a variety of newly-identified potential substrates involved in diverse biological processes,whereas our system-wide histone modification analysis reveals a link between AMPK and histone acetylation.Together with these findings,we discover that AMPK promotes apoptosis by phosphorylating apoptosis-stimulating of p53 protein 2(ASPP2)in an irradiation(IR)-dependent manner and regulates histone acetylation by phosphorylating histone deacetylase 9(HDAC9)in an IR-independent manner.Besides,we reveal that disrupting the histone acetylation by the bromodomain BRD4 inhibitor JQ-1 enhances the sensitivity of AMPKdeficient cells to IR.Therefore,our study has provided a resource to investigate the interplay between phosphorylation and histone acetylation underlying the regulatory network of AMPK,which could be beneficial to understand the exact role of AMPK in DDR.
基金supported by National Natural Science Foundation of China(22137002[Y.D.],32071432[M.T.],81872102[H.J.])University Innovation Research Group Project of Chongqing(CXQT21016[Y.D.])+3 种基金High-Level Innovation Platform Project of Chongqing[Y.D.]Talent Program of Chongqing(CQYC202003053[Y.D.])The collaborative project of Chinese Academy of Sciences institutions and universities in Chongqing(HZ2021006[Y.D.])Innovative Research Team of High-Level Local Universities in Shanghai(SSMU-ZDCX20181202[M.T.]).
文摘Prostate cancer(PCa)is the second most prevalent malignancy in males across the world.A greater knowledge of the relationship between protein abundance and drug responses would benefit precision treatment for PCa.Herein,we establish 35 Chinese PCa primary cell models to capture specific characteristics among PCa patients,including gene mutations,mRNA/protein/surface protein distributions,and pharmaceutical responses.The multi-omics analyses identify Anterior Gradient 2(AGR2)as a pre-operative prognostic biomarker in PCa.Through the drug library screening,we describe crizotinib as a selective compound for malignant PCa primary cells.We further perform the pharmacoproteome analysis and identify 14,372 significant protein-drug correlations.Surprisingly,the diminished AGR2 enhances the inhibition activity of crizotinib via ALK/c-MET-AKT axis activation which is validated by PC3 and xenograft model.Our integrated multi-omics approach yields a comprehensive understanding of PCa biomarkers and pharmacological responses,allowing for more precise diagnosis and therapies.
文摘Dear Editor,Obesity is caused by an imbalance between energy intake and expenditure,and has become a global epidemic with over 650 million adults affected.Adipose tissues in mammals are composed of white adipose tissue(WAT)and classical brown adipose tissue(BAT),and their balance is highly related to the occurrence of obesity.The browning of white adipocytes results in“beige”or“brite”adipocytes,which appear functionally similar to classical brown adipocytes,and can be detected in WAT deposits of animals that have been exposed to cold or other inducers(Fu et al.,2015).
基金supported by the Special Project on Precision Medicine under the National Key R&D Program of China(Grant No.2017YFC09066600)the National Natural Science Foundation of China(Grant Nos.31871329,31670066,and 31271416)+1 种基金the National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”,China(Grant No.2018ZX09711002007)the Natural Science Foundation of Shanghai,China(Grant No.17ZR1413900)。
文摘With the development of mass spectrometry(MS)-based proteomics technologies,patient-derived xenograft(PDX),which is generated from the primary tumor of a patient,is widely used for the proteome-wide analysis of cancer mechanism and biomarker identification of a drug.However,the proteomics data interpretation is still challenging due to complex data deconvolution from the PDX sample that is a cross-species mixture of human cancerous tissues and immunodeficient mouse tissues.In this study,by using the lab-assembled mixture of human and mouse cells with different mixing ratios as a benchmark,we developed and evaluated a new method,SPA(shared peptide allocation),for protein quantitation by considering the unique and shared peptides of both species.The results showed that SPA could provide more convenient and accurate protein quantitation in human–mouse mixed samples.Further validation on a pair of gastric PDX samples(one bearing FGFR2 amplification while the other one not)showed that our new method not only significantly improved the overall protein identification,but also detected the differential phosphorylation of FGFR2 and its downstream mediators(such as RAS and ERK)exclusively.The tool pdx SPA is freely available at https://github.com/LiLab-Proteomics/pdx SPA.
基金This work was supported by the National Key Research and Development Program of China(No.2018YFC0310900)the National Natural Science Foundation of China grants(No.31270830,21572038,21877016 to Y.D,No.31671386 to Q.H,81972621 to W.J)+1 种基金the Development Fund for Shanghai Talents,Fund of State Key Laboratory of Bioorganic and Natural Products Chemistry,Fund of State Key Laboratory of Drug Research,Chinese Academy of Science(No.SIMM1601KF-08)Hehai University Graduate Student Research Grant.
文摘The CRISPR/Cas9 system,originally derived from the prokaryotic adaptive immune system,has been developed as efficient genome editing tools.It enables precise gene manipulation on chromosomal DNA through the specific binding of programmable sgRNA to target DNA,and the Cas9 protein,which has endonuclease activity,will cut a double strand break at specific locus.However,Cas9 is a foreign protein in mammalian cells,and the potential risks associated with its introduction into mammalian cells are not fully understood.In this study,we performed pull-down and mass spectrometry(MS)analysis of Streptococcus pyogenes Cas9(SpyCas9)interacting proteins in HEK293T cells and showed that the majority of Cas9-associated proteins identified by MS were localized in the nucleolus.Interestingly,we further discovered that the Cas9 protein contains a sequence encoding a nucleolus detention signal(NoDS).Compared with wild-type(WT)Cas9,NoDS-mutated variants of Cas9(mCas9)are less stable,although their gene editing activity is minimally affected.Overexpression of WT Cas9,but not mCas9,causes general effects on transcription and protein translation in the host cell.Overall,identification of NoDS in Cas9 will improve the understanding of Cas9's biological function in vivo,and the removal of NoDS in Cas9 may enhance its safety for future clinical use.
