Due to the low water-cement ratio of ultra-high-performance concrete(UHPC),fluidity and shrinkage cracking are key aspects determining the performance and durability of this type of concrete.In this study,the effects ...Due to the low water-cement ratio of ultra-high-performance concrete(UHPC),fluidity and shrinkage cracking are key aspects determining the performance and durability of this type of concrete.In this study,the effects of different types of cementitious materials,chemical shrinkage-reducing agents(SRA)and steel fiber(SF)were assessed.Compared with M2-UHPC and M3-UHPC,M1-UHPC was found to have better fluidity and shrinkage cracking performance.Moreover,different SRA incorporation methods,dosage and different SF types and aspect ratios were implemented.The incorporation of SRA and SF led to a decrease in the fluidity of UHPC.SRA internal content of 1%(NSRA-1%),SRA external content of 1%(WSRA-1%),STS-0.22 and STE-0.7 decreased the fluidity of UHPC by 3.3%,8.3%,9.2%and 25%,respectively.However,SRA and SF improved the UHPC shrinkage cracking performance.NSRA-1%and STE-0.7 reduced the shrinkage value of UHPC by 40%and 60%,respectively,and increased the crack resistance by 338%and 175%,respectively.In addition,the addition of SF was observed to make the microstructure of UHPC more compact,and the compressive strength and flexural strength of 28 d were increased by 26.9%and 19.9%,respectively.展开更多
To achieve higher strength and better durability,ultra-high performance concrete(UHPC)typically employs a relatively small water-binder ratio.However,this generally leads to an undesired increase in the paste viscosit...To achieve higher strength and better durability,ultra-high performance concrete(UHPC)typically employs a relatively small water-binder ratio.However,this generally leads to an undesired increase in the paste viscosity.In this study,the effects of liquid and powder polycarboxylate superplasticizers(PCE)on UHPC are compared and critically discussed.Moreover,the following influential factors are considered:air-entraining agents(AE),slump retaining agents(SA),and defoaming agents(DF)and the resulting flow characteristics,mechanical properties,and hydration properties are evaluated assuming UHPC containing 8‰powder PCE(PCE-based UHPC).It is found that the spread diameter of powder PCE is 5%higher than that of liquid PCE.Among the chemical admixtures studied,AEs have the best effect on improving UHPC workability,while DFs have the worst effect.When the addition of AE and SA is 1.25‰and 14.7%of PCE,paste viscosity reduces by 35%and 19%,respectively compared to the paste with only 8‰PCE.A low AE dosage(1.25‰)decreases compressive strength by 4.1%,while SA(8.1%)increases UHPC compressive strength by 9.1%.Both AE and SA significantly delay the UHPC hydration process,reducing the hydration heat release peaks by 76%and 27%,respectively.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
CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.H...CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.Here,we show that the palbociclibresistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis.Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib.Furthermore,PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells,leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation.Targeting PI3K/mTOR pathway with a specific PI3Kαinhibitor(BYL719)or an mTOR inhibitor(everolimus)reduced the protein levels of Cyclin D1 and CDK4,and restored the sensitivity to palbociclib.The tumor samples expressed significantly higher levels of Cyclin D1,CDK4,p-AKT and p-4E-BP1 after progression on palbociclib treatment.In conclusion,our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors,which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.展开更多
Metabolites of microorganisms have long been considered as potential sources for drug discovery.In this study,fve new depsidone derivatives,talaronins A-E(1-5)and three new xanthone derivatives,talaronins F-H(6-8),tog...Metabolites of microorganisms have long been considered as potential sources for drug discovery.In this study,fve new depsidone derivatives,talaronins A-E(1-5)and three new xanthone derivatives,talaronins F-H(6-8),together with 16 known compounds(9-24),were isolated from the ethyl acetate extract of the mangrove-derived fungus Talaromyces species WHUF0362.The structures were elucidated by analysis of spectroscopic data and chemical methods including alkaline hydrolysis and Mosher’s method.Compounds 1 and 2 each attached a dimethyl acetal group at the aromatic ring.A putative biogenetic relationship of the isolated metabolites was presented and suggested that the depsidones and the xanthones probably had the same biosynthetic precursors such as chrysophanol or rheochrysidin.The antimicrobial activity assay indicated that compounds 5,9,10,and 14 showed potent activity against Helicobacter pylori with minimum inhibitory concentration(MIC)values in the range of 2.42-36.04μmol/L.While secalonic acid D(19)demonstrated signifcant antimicrobial activity against four strains of H.pylori with MIC values in the range of 0.20 to 1.57μmol/L.Furthermore,secalonic acid D(19)exhibited cytotoxicity against cancer cell lines Bel-7402 and HCT-116 with IC_(50) values of 0.15 and 0.19μmol/L,respectively.The structure–activity relationship of depsidone derivatives revealed that the presence of the lactone ring and the hydroxyl at C-10 was crucial to the antimicrobial activity against H.pylori.The depsidone derivatives are promising leads to inhibit H.pylori and provide an avenue for further development of novel antibiotics.展开更多
基金the Key Research and Development Program of Hubei Province(2022BCA082 and 2022BCA077).
文摘Due to the low water-cement ratio of ultra-high-performance concrete(UHPC),fluidity and shrinkage cracking are key aspects determining the performance and durability of this type of concrete.In this study,the effects of different types of cementitious materials,chemical shrinkage-reducing agents(SRA)and steel fiber(SF)were assessed.Compared with M2-UHPC and M3-UHPC,M1-UHPC was found to have better fluidity and shrinkage cracking performance.Moreover,different SRA incorporation methods,dosage and different SF types and aspect ratios were implemented.The incorporation of SRA and SF led to a decrease in the fluidity of UHPC.SRA internal content of 1%(NSRA-1%),SRA external content of 1%(WSRA-1%),STS-0.22 and STE-0.7 decreased the fluidity of UHPC by 3.3%,8.3%,9.2%and 25%,respectively.However,SRA and SF improved the UHPC shrinkage cracking performance.NSRA-1%and STE-0.7 reduced the shrinkage value of UHPC by 40%and 60%,respectively,and increased the crack resistance by 338%and 175%,respectively.In addition,the addition of SF was observed to make the microstructure of UHPC more compact,and the compressive strength and flexural strength of 28 d were increased by 26.9%and 19.9%,respectively.
基金Key Research and Development Program of Hubei Province(2022BCA082 and 2022BCA077).
文摘To achieve higher strength and better durability,ultra-high performance concrete(UHPC)typically employs a relatively small water-binder ratio.However,this generally leads to an undesired increase in the paste viscosity.In this study,the effects of liquid and powder polycarboxylate superplasticizers(PCE)on UHPC are compared and critically discussed.Moreover,the following influential factors are considered:air-entraining agents(AE),slump retaining agents(SA),and defoaming agents(DF)and the resulting flow characteristics,mechanical properties,and hydration properties are evaluated assuming UHPC containing 8‰powder PCE(PCE-based UHPC).It is found that the spread diameter of powder PCE is 5%higher than that of liquid PCE.Among the chemical admixtures studied,AEs have the best effect on improving UHPC workability,while DFs have the worst effect.When the addition of AE and SA is 1.25‰and 14.7%of PCE,paste viscosity reduces by 35%and 19%,respectively compared to the paste with only 8‰PCE.A low AE dosage(1.25‰)decreases compressive strength by 4.1%,while SA(8.1%)increases UHPC compressive strength by 9.1%.Both AE and SA significantly delay the UHPC hydration process,reducing the hydration heat release peaks by 76%and 27%,respectively.
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supported by the Notional Natural Science Foundation of China(82061148016,81630074,81872141,81702630,81672622)Guangzhou Science and Technology Plan Key Projects(201804020076)+2 种基金Natural Science Foundation of Guangdong(2019A1515010146)Beijing Medical Award Foundation(YXJL-20200941-0760)China Postdoctoral Science Foundation(2021TQ0384,2021M703731)。
文摘CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.Here,we show that the palbociclibresistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis.Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib.Furthermore,PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells,leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation.Targeting PI3K/mTOR pathway with a specific PI3Kαinhibitor(BYL719)or an mTOR inhibitor(everolimus)reduced the protein levels of Cyclin D1 and CDK4,and restored the sensitivity to palbociclib.The tumor samples expressed significantly higher levels of Cyclin D1,CDK4,p-AKT and p-4E-BP1 after progression on palbociclib treatment.In conclusion,our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors,which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.
基金This research was funded by grants from National Key Research and Development Program of China(2018YFC0311002)High-Level Talent Special Support Plan of Zhejiang Province(2019R52009).
文摘Metabolites of microorganisms have long been considered as potential sources for drug discovery.In this study,fve new depsidone derivatives,talaronins A-E(1-5)and three new xanthone derivatives,talaronins F-H(6-8),together with 16 known compounds(9-24),were isolated from the ethyl acetate extract of the mangrove-derived fungus Talaromyces species WHUF0362.The structures were elucidated by analysis of spectroscopic data and chemical methods including alkaline hydrolysis and Mosher’s method.Compounds 1 and 2 each attached a dimethyl acetal group at the aromatic ring.A putative biogenetic relationship of the isolated metabolites was presented and suggested that the depsidones and the xanthones probably had the same biosynthetic precursors such as chrysophanol or rheochrysidin.The antimicrobial activity assay indicated that compounds 5,9,10,and 14 showed potent activity against Helicobacter pylori with minimum inhibitory concentration(MIC)values in the range of 2.42-36.04μmol/L.While secalonic acid D(19)demonstrated signifcant antimicrobial activity against four strains of H.pylori with MIC values in the range of 0.20 to 1.57μmol/L.Furthermore,secalonic acid D(19)exhibited cytotoxicity against cancer cell lines Bel-7402 and HCT-116 with IC_(50) values of 0.15 and 0.19μmol/L,respectively.The structure–activity relationship of depsidone derivatives revealed that the presence of the lactone ring and the hydroxyl at C-10 was crucial to the antimicrobial activity against H.pylori.The depsidone derivatives are promising leads to inhibit H.pylori and provide an avenue for further development of novel antibiotics.
