The rising prevalence of drug-resistant Gram-positive pathogens,particularly methicillin-resistant Staphy-lococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE),poses a substantial clinical challenge.Biofilm-a...The rising prevalence of drug-resistant Gram-positive pathogens,particularly methicillin-resistant Staphy-lococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE),poses a substantial clinical challenge.Biofilm-associated infections exacerbate this problem due to their inherent antibiotic resistance and complex structure.Current antibiotic treatments struggle to penetrate biofilms and eradicate persister cells,leading to prolonged antibiotic use and increased resistance.Host defense peptides(HDPs)have shown promise,but their clinical application is limited by factors such as enzymatic degradation and difficulty in largescale preparation.Synthetic HDP mimics,such as poly(2-oxazoline),have emerged as effective alter-natives.Herein,we found that the poly(2-oxazoline),Gly-POX_(20),demonstrated rapid and potent activity against clinically isolated multidrug-resistant Gram-positive strains.Gly-POX_(20) showed greater stability under physiological conditions compared to natural peptides,including resistance to protease degradation.Importantly,Gly-POX_(20) inhibited biofilm formation and eradicated mature biofilm and demonstrated superior in vivo therapeutic efficacy to vancomycin in a MRSA biofilm-associated mouse keratitis model,suggesting its potential as a novel antimicrobial agent against drug-resistant Gram-positive bacteria,especially biofilm-associated infections.展开更多
The mechanical,thermodynamic properties and electrical conductivities of L1_(2)-Al_(3)X(X=Zr,Sc,Er,Yb,Hf)structural phases in aluminum conductors were investigated through a first-principles study.The results demonstr...The mechanical,thermodynamic properties and electrical conductivities of L1_(2)-Al_(3)X(X=Zr,Sc,Er,Yb,Hf)structural phases in aluminum conductors were investigated through a first-principles study.The results demonstrate that all structural phases have good alloy-forming ability and structural stability,where Al_(3)Zr is the most superior.Al_(3)Zr,Al_(3)Hf and Al_(3)Sc have enhanced shear and deformation resistance in comparison to other phases.Within the temperature range of 200−600 K,Al_(3)Er and Al_(3)Yb possess the greatest thermodynamic stability,followed by Al_(3)Hf,Al_(3)Zr and Al_(3)Sc.Al_(3)Er and Al_(3)Yb have higher thermodynamic stability than Al_(3)Hf,Al_(3)Zr and Al_(3)Sc.All structural phases exhibit substantial metallic properties,indicating their good electrical conductivity.The electrical conductivities of Al_(3)Hf and Al_(3)Zr are higher than those of Al_(3)Er,Al_(3)Yb and Al_(3)Sc.The covalent bond properties in Al_(3)Sc,Al_(3)Er and Al_(3)Yb enhance the hardness,brittleness and thermodynamic stability of the structural phase.The thermodynamic stability of Al_(3)Sc is significantly reduced by ionic bonds.展开更多
Objectives:Progression to castration-resistant prostate cancer(CRPC)and metastasis are the greatest challenges to effective treatment.Anticancer strategies targeting the key kinases associated with the development of ...Objectives:Progression to castration-resistant prostate cancer(CRPC)and metastasis are the greatest challenges to effective treatment.Anticancer strategies targeting the key kinases associated with the development of CRPC may represent a breakthrough.The tyrosine kinase receptor Erythropoietin-producing hepatocellular(Eph)A2 receptor is highly expressed in CRPC cell lines and may be associated with tumor invasion and metastasis.However,the effects and exact mechanisms of EphA2 in CRPC are only partially understood.This study aimed to investigate the impact of EphA2 on CRPC cell behaviors and underlyingmolecular pathways.Methods:CRISPR/Cas9-mediated gene editing induced EphA2-disrupted in human-derived PC3 andDU145 cells.Single-guideRNAs(sgRNAs)targeting EphA2 were designed,and editing efficiency was validated.Optimal sgRNA sequences were selected to generate EphA2-knockdown(KD)and-overexpressing(OE)cell lines.Cell migration,proliferation,and apoptosis were assessed via functional assays.Transcriptomic analysis,quantitative PCR,and Western blotting were performed to identify downstream effectors.Bioinformatics analyses were used to correlate EphA2 and CDH1 expression with clinical parameters in prostate cancer patients.Results:Editing efficiency was found to vary among different sgRNAs targeting the EphA2 gene.EphA2-KD significantly inhibited CRPC cell migration but did not affect cell proliferation or apoptosis.Conversely,EphA2-OE significantly enhanced the migration of DU145 cells.Molecular analyses revealed that the expression of CDH1(an important marker of the epithelial-mesenchymal transition(EMT)in tumors)was significantly upregulated in PC3-EphA2-KD cells and downregulated in DU145-EphA2-OE cells,indicating that CDH1 is a downstream regulator of EphA2.Bioinformatic analysis revealed that higher EphA2 levels and lower CDH1 expression were both associated with an advanced tumor T stage,higher Gleason scores,and lymph nodemetastases in prostate cancer patients.More importantly,EphA2 was found to be an important predictor of lymph nodemetastasis,in addition to the Gleason score.Adding EphA2 to the Gleason score could significantly improve the detection of lymph node metastasis.Conclusion:CRISPR/Cas9-mediated EphA2-KD significantly suppressed the migration of CRPC cells through the inhibition of the EphA2-CDH1 axis.Strategies targeting the EphA2 genemay be promising for the treatment of CRPC.展开更多
基金financially supported by the National Key Research and Development Program of China(no.2022YFC2303100)National Natural Science Foundation of China(nos.T2325010,22305082,52203162,and 22075078)+1 种基金Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism(Shanghai Municipal Education Commission),the Fundamental Research Funds for the Central Universities(nos.JKVD1241029 and JKD01241701)Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry(Changchun Institute of Applied Chemistry,Chinese Academy of Sciences),the Open Project of Engineering Research Center of Dairy Quality and Safety Control Technology(Ministry of Education,no.R202201).
文摘The rising prevalence of drug-resistant Gram-positive pathogens,particularly methicillin-resistant Staphy-lococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE),poses a substantial clinical challenge.Biofilm-associated infections exacerbate this problem due to their inherent antibiotic resistance and complex structure.Current antibiotic treatments struggle to penetrate biofilms and eradicate persister cells,leading to prolonged antibiotic use and increased resistance.Host defense peptides(HDPs)have shown promise,but their clinical application is limited by factors such as enzymatic degradation and difficulty in largescale preparation.Synthetic HDP mimics,such as poly(2-oxazoline),have emerged as effective alter-natives.Herein,we found that the poly(2-oxazoline),Gly-POX_(20),demonstrated rapid and potent activity against clinically isolated multidrug-resistant Gram-positive strains.Gly-POX_(20) showed greater stability under physiological conditions compared to natural peptides,including resistance to protease degradation.Importantly,Gly-POX_(20) inhibited biofilm formation and eradicated mature biofilm and demonstrated superior in vivo therapeutic efficacy to vancomycin in a MRSA biofilm-associated mouse keratitis model,suggesting its potential as a novel antimicrobial agent against drug-resistant Gram-positive bacteria,especially biofilm-associated infections.
基金National Natural Science Foundation of China (No. 52274403)。
文摘The mechanical,thermodynamic properties and electrical conductivities of L1_(2)-Al_(3)X(X=Zr,Sc,Er,Yb,Hf)structural phases in aluminum conductors were investigated through a first-principles study.The results demonstrate that all structural phases have good alloy-forming ability and structural stability,where Al_(3)Zr is the most superior.Al_(3)Zr,Al_(3)Hf and Al_(3)Sc have enhanced shear and deformation resistance in comparison to other phases.Within the temperature range of 200−600 K,Al_(3)Er and Al_(3)Yb possess the greatest thermodynamic stability,followed by Al_(3)Hf,Al_(3)Zr and Al_(3)Sc.Al_(3)Er and Al_(3)Yb have higher thermodynamic stability than Al_(3)Hf,Al_(3)Zr and Al_(3)Sc.All structural phases exhibit substantial metallic properties,indicating their good electrical conductivity.The electrical conductivities of Al_(3)Hf and Al_(3)Zr are higher than those of Al_(3)Er,Al_(3)Yb and Al_(3)Sc.The covalent bond properties in Al_(3)Sc,Al_(3)Er and Al_(3)Yb enhance the hardness,brittleness and thermodynamic stability of the structural phase.The thermodynamic stability of Al_(3)Sc is significantly reduced by ionic bonds.
基金funded by the National Natural Science Foundation of China(Grant No.81801754)the Suzhou Science and Technology Bureau Development Plan(Grant No.SYS2020147)the 26th Batch of Extra-Curricular Academic Research Fund Project of Soochow University(Grant No.KY2024235B).
文摘Objectives:Progression to castration-resistant prostate cancer(CRPC)and metastasis are the greatest challenges to effective treatment.Anticancer strategies targeting the key kinases associated with the development of CRPC may represent a breakthrough.The tyrosine kinase receptor Erythropoietin-producing hepatocellular(Eph)A2 receptor is highly expressed in CRPC cell lines and may be associated with tumor invasion and metastasis.However,the effects and exact mechanisms of EphA2 in CRPC are only partially understood.This study aimed to investigate the impact of EphA2 on CRPC cell behaviors and underlyingmolecular pathways.Methods:CRISPR/Cas9-mediated gene editing induced EphA2-disrupted in human-derived PC3 andDU145 cells.Single-guideRNAs(sgRNAs)targeting EphA2 were designed,and editing efficiency was validated.Optimal sgRNA sequences were selected to generate EphA2-knockdown(KD)and-overexpressing(OE)cell lines.Cell migration,proliferation,and apoptosis were assessed via functional assays.Transcriptomic analysis,quantitative PCR,and Western blotting were performed to identify downstream effectors.Bioinformatics analyses were used to correlate EphA2 and CDH1 expression with clinical parameters in prostate cancer patients.Results:Editing efficiency was found to vary among different sgRNAs targeting the EphA2 gene.EphA2-KD significantly inhibited CRPC cell migration but did not affect cell proliferation or apoptosis.Conversely,EphA2-OE significantly enhanced the migration of DU145 cells.Molecular analyses revealed that the expression of CDH1(an important marker of the epithelial-mesenchymal transition(EMT)in tumors)was significantly upregulated in PC3-EphA2-KD cells and downregulated in DU145-EphA2-OE cells,indicating that CDH1 is a downstream regulator of EphA2.Bioinformatic analysis revealed that higher EphA2 levels and lower CDH1 expression were both associated with an advanced tumor T stage,higher Gleason scores,and lymph nodemetastases in prostate cancer patients.More importantly,EphA2 was found to be an important predictor of lymph nodemetastasis,in addition to the Gleason score.Adding EphA2 to the Gleason score could significantly improve the detection of lymph node metastasis.Conclusion:CRISPR/Cas9-mediated EphA2-KD significantly suppressed the migration of CRPC cells through the inhibition of the EphA2-CDH1 axis.Strategies targeting the EphA2 genemay be promising for the treatment of CRPC.
