In-depth study of the components of polymyxins is the key to controlling the quality of this class of antibiotics.Similarities and variations of components present significant analytical challenges.A two-dimensional(2...In-depth study of the components of polymyxins is the key to controlling the quality of this class of antibiotics.Similarities and variations of components present significant analytical challenges.A two-dimensional(2D)liquid chromatography-mass spectrometry(LC-MS)method was established for screening and comprehensive profiling of compositions of the antibiotic colistimethate sodium(CMS).A high concentration of phosphate buffer mobile phase was used in the first-dimensional LC system to get the components well separated.For efficient and high-accuracy screening of CMS,a targeted method based on a self-constructed high resolution(HR)mass spectrum database of CMS components was established.The database was built based on the commercial MassHunter Personal Compound Database and Library(PCDL)software and its accuracy of the compound matching result was verified with six known components before being applied to genuine sample screening.On this basis,the unknown peaks in the CMS chromatograms were deduced and assigned.The molecular formula,group composition,and origins of a total of 99 compounds,of which the combined area percentage accounted for more than 95%of CMS components,were deduced by this 2D-LC-MS method combined with the MassHunter PCDL.This profiling method was highly efficient and could distinguish hundreds of components within 3 h,providing reliable results for quality control of this kind of complex drugs.展开更多
Ulcerative colitis(UC)is often accompanied by intestinal inflammation and disruption of intestinal epithelial structures,which are closely associated with changes in the intestinal microbiota.We previously revealed th...Ulcerative colitis(UC)is often accompanied by intestinal inflammation and disruption of intestinal epithelial structures,which are closely associated with changes in the intestinal microbiota.We previously revealed that Min pigs,a native Chinese breed,are more resistant to dextran sulfate sodium(DSS)-induced colitis than commercial Yorkshire pigs.Characterizing the microbiota in Min pigs would allow identification of the core microbes that confer colitis resistance.By analyzing the microbiota linked to the disease course in Min and Yorkshire pigs,we observed that Bacillus spp.were enriched in Min pigs and positively correlated with pathogen resistance.Using targeted screening,we identified and validated Bacillus siamensis MZ16 from Min pigs as a bacterial species with biofilm formation ability,superior salt and pH tolerance,and antimicrobial characteristics.Subsequently,we administered B.siamensis Mz16 to conventional or microbiota-deficient BALB/c mice with DSS-induced colitis to assess its efficacy in alleviating colitis.B.siamensis MZ16 partially counteracted DSS-induced colitis in conventional mice,but it did not mitigate DsS-induced colitis in microbiota-deficient mice.Further analysis revealed that B.siamensis MZ16 administration improved intestinal ecology and integrity and immunological barrier function in mice.Compared to the DSS-treated mice,mice preadministered B.siamensis MZ16 exhibited improved relative abundance of potentially beneficial microbes(Lactobacillus,Bacillus,Christensenellaceae R7,Ruminococcus,Clostridium,and Eubacterium),reduced relative abundance of pathogenic microbes(Escherichia-Shigella),and maintained colonic OCLN and ZO-1 levels and IgA and SlgA levels.Furthermore,B.siamensis MZ16 reduced proinflammatory cytokine levels by reversing NF-kB and MAPK pathway activation in the DSS group.Overall,B.siamensis MZ16 from Min pigs had beneficial effects on a colitis mouse model by enhancing intestinal barrier functions and reducing inflammation in a gut microbiotadependent manner.展开更多
Target-based and phenotype-based methods are the two main approaches for drug screening.Target-based drug screening focuses on specific targets CPA highly correlated with disease mechanisms,by detecting protein-ligand...Target-based and phenotype-based methods are the two main approaches for drug screening.Target-based drug screening focuses on specific targets CPA highly correlated with disease mechanisms,by detecting protein-ligand binding structure,dynamics and affinity.Currently,the four mainstream drug targets are G protein-coupled receptors(GPCRs),kinases,ion channels,and nuclear receptors,accounting for over 70%of effective drug targets,most of which are membrane proteins and enzymes.In recent years,various new drug targets have been continuously discovered,and the research focus has shifted from simple affinity analysis to high-throughput and high-content screening,as well as exploring drug-target interaction modes.These deepen reliance on the analytical techniques to have higher sensitivity,recognition specificity,and applicability to diversified target structures,which promoting the rapid development of novel screening methods.展开更多
BACKGROUND The World Health Organization recommends testing all human immunodeficiency virus(HIV)patients for hepatitis C virus(HCV).In resource-constrained contexts with low-to-intermediate HCV prevalence among HIV p...BACKGROUND The World Health Organization recommends testing all human immunodeficiency virus(HIV)patients for hepatitis C virus(HCV).In resource-constrained contexts with low-to-intermediate HCV prevalence among HIV patients,as in Cambodia,targeted testing is,in the short-term,potentially more feasible and cost-effective.AIM To develop a clinical prediction score(CPS)to risk-stratify HIV patients for HCV coinfection(HCV RNA detected),and derive a decision rule to guide prioritization of HCV testing in settings where‘testing all’is not feasible or unaffordable in the short term.METHODS We used data of a cross-sectional HCV diagnostic study in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh.Key populations were very rare in this cohort.Score development relied on the Spiegelhalter and Knill-Jones method.Predictors with an adjusted likelihood ratio≥1.5 or≤0.67 were retained,transformed to natural logarithms,and rounded to integers as score items.CPS performance was evaluated by the area-under-the-ROC curve(AUROC)with 95% confidence intervals(CI),and diagnostic accuracy at the different cut-offs.For the decision rule,HCV coinfection probability≥1% was agreed as test-threshold.RESULTS Among the 3045 enrolled HIV patients,106 had an HCV coinfection.Of the 11 candidate predictors(from history-taking,laboratory testing),seven had an adjusted likelihood ratio≥1.5 or≤0.67:≥50 years(+1 point),diabetes mellitus(+1),partner/household member with liver disease(+1),generalized pruritus(+1),platelets<200×10^(9)/L(+1),aspartate transaminase(AST)<30 IU/L(-1),AST-to-platelet ratio index(APRI)≥0.45(+1),and APRI<0.45(-1).The AUROC was 0.84(95%CI:0.80-0.89),indicating good discrimination of HCV/HIV coinfection and HIV mono-infection.The CPS result≥0 best fits the test-threshold(negative predictive value:99.2%,95%CI:98.8-99.6).Applying this threshold,30%(n=926)would be tested.Sixteen coinfections(15%)would have been missed,none with advanced fibrosis.CONCLUSION The CPS performed well in the derivation cohort,and bears potential for other contexts of low-to-intermediate prevalence and little onward risk of transmission(i.e.cohorts without major risk factors as injecting drug use,men having sex with men),and where available resources do not allow to test all HIV patients as recommended by WHO.However,the score requires external validation in other patient cohorts before any wider use can be considered.展开更多
Humans are exposed daily to diverse synthetic chemicals through a variety of routes,including diet,inhalation,skin contact,and even through the umbilical cord to the fetus.Numerous chemicals(e.g.,per-and polyfluoroalk...Humans are exposed daily to diverse synthetic chemicals through a variety of routes,including diet,inhalation,skin contact,and even through the umbilical cord to the fetus.Numerous chemicals(e.g.,per-and polyfluoroalkyl substances,polycyclic aromatic hydrocarbons,triazine pesticides,benzotriazole UV stabilizers,synthetic phenolic antioxidants)have been definitively documented as developmental neurotoxicants,endocrine disruptors,and carcinogens.Chemical exposure is an important cause of many noncommunicable diseases such as cancer,miscarriage,birth defects,obesity,asthma,pneumonia,diabetes mellitus,and depression.1−3 Despite progress in exploring associations between certain chemicals and diseases,some significant scientific issues still remain unresolved,including identifying chemicals currently used in commerce that are capable of jeopardizing human health,and accurately estimating the contribution of chemical pollution to disease or death.展开更多
基金support from the Science Research Program Project for Drug Regulation,Jiangsu Medical Products Administration,China(Grant No.:202207)the National Drug Standards Revision Project,China(Grant No.:2023Y41)+1 种基金the National Natural Science Foundation of China(Grant No.:22276080)the Foreign Expert Project,China(Grant No.:G2022014096L).
文摘In-depth study of the components of polymyxins is the key to controlling the quality of this class of antibiotics.Similarities and variations of components present significant analytical challenges.A two-dimensional(2D)liquid chromatography-mass spectrometry(LC-MS)method was established for screening and comprehensive profiling of compositions of the antibiotic colistimethate sodium(CMS).A high concentration of phosphate buffer mobile phase was used in the first-dimensional LC system to get the components well separated.For efficient and high-accuracy screening of CMS,a targeted method based on a self-constructed high resolution(HR)mass spectrum database of CMS components was established.The database was built based on the commercial MassHunter Personal Compound Database and Library(PCDL)software and its accuracy of the compound matching result was verified with six known components before being applied to genuine sample screening.On this basis,the unknown peaks in the CMS chromatograms were deduced and assigned.The molecular formula,group composition,and origins of a total of 99 compounds,of which the combined area percentage accounted for more than 95%of CMS components,were deduced by this 2D-LC-MS method combined with the MassHunter PCDL.This profiling method was highly efficient and could distinguish hundreds of components within 3 h,providing reliable results for quality control of this kind of complex drugs.
基金supported by the National Natural Science Foundation of China(32372924 and 32302759)Fundamental Research Funds for the Central Universities(SWU-KQ23012).
文摘Ulcerative colitis(UC)is often accompanied by intestinal inflammation and disruption of intestinal epithelial structures,which are closely associated with changes in the intestinal microbiota.We previously revealed that Min pigs,a native Chinese breed,are more resistant to dextran sulfate sodium(DSS)-induced colitis than commercial Yorkshire pigs.Characterizing the microbiota in Min pigs would allow identification of the core microbes that confer colitis resistance.By analyzing the microbiota linked to the disease course in Min and Yorkshire pigs,we observed that Bacillus spp.were enriched in Min pigs and positively correlated with pathogen resistance.Using targeted screening,we identified and validated Bacillus siamensis MZ16 from Min pigs as a bacterial species with biofilm formation ability,superior salt and pH tolerance,and antimicrobial characteristics.Subsequently,we administered B.siamensis Mz16 to conventional or microbiota-deficient BALB/c mice with DSS-induced colitis to assess its efficacy in alleviating colitis.B.siamensis MZ16 partially counteracted DSS-induced colitis in conventional mice,but it did not mitigate DsS-induced colitis in microbiota-deficient mice.Further analysis revealed that B.siamensis MZ16 administration improved intestinal ecology and integrity and immunological barrier function in mice.Compared to the DSS-treated mice,mice preadministered B.siamensis MZ16 exhibited improved relative abundance of potentially beneficial microbes(Lactobacillus,Bacillus,Christensenellaceae R7,Ruminococcus,Clostridium,and Eubacterium),reduced relative abundance of pathogenic microbes(Escherichia-Shigella),and maintained colonic OCLN and ZO-1 levels and IgA and SlgA levels.Furthermore,B.siamensis MZ16 reduced proinflammatory cytokine levels by reversing NF-kB and MAPK pathway activation in the DSS group.Overall,B.siamensis MZ16 from Min pigs had beneficial effects on a colitis mouse model by enhancing intestinal barrier functions and reducing inflammation in a gut microbiotadependent manner.
文摘Target-based and phenotype-based methods are the two main approaches for drug screening.Target-based drug screening focuses on specific targets CPA highly correlated with disease mechanisms,by detecting protein-ligand binding structure,dynamics and affinity.Currently,the four mainstream drug targets are G protein-coupled receptors(GPCRs),kinases,ion channels,and nuclear receptors,accounting for over 70%of effective drug targets,most of which are membrane proteins and enzymes.In recent years,various new drug targets have been continuously discovered,and the research focus has shifted from simple affinity analysis to high-throughput and high-content screening,as well as exploring drug-target interaction modes.These deepen reliance on the analytical techniques to have higher sensitivity,recognition specificity,and applicability to diversified target structures,which promoting the rapid development of novel screening methods.
文摘BACKGROUND The World Health Organization recommends testing all human immunodeficiency virus(HIV)patients for hepatitis C virus(HCV).In resource-constrained contexts with low-to-intermediate HCV prevalence among HIV patients,as in Cambodia,targeted testing is,in the short-term,potentially more feasible and cost-effective.AIM To develop a clinical prediction score(CPS)to risk-stratify HIV patients for HCV coinfection(HCV RNA detected),and derive a decision rule to guide prioritization of HCV testing in settings where‘testing all’is not feasible or unaffordable in the short term.METHODS We used data of a cross-sectional HCV diagnostic study in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh.Key populations were very rare in this cohort.Score development relied on the Spiegelhalter and Knill-Jones method.Predictors with an adjusted likelihood ratio≥1.5 or≤0.67 were retained,transformed to natural logarithms,and rounded to integers as score items.CPS performance was evaluated by the area-under-the-ROC curve(AUROC)with 95% confidence intervals(CI),and diagnostic accuracy at the different cut-offs.For the decision rule,HCV coinfection probability≥1% was agreed as test-threshold.RESULTS Among the 3045 enrolled HIV patients,106 had an HCV coinfection.Of the 11 candidate predictors(from history-taking,laboratory testing),seven had an adjusted likelihood ratio≥1.5 or≤0.67:≥50 years(+1 point),diabetes mellitus(+1),partner/household member with liver disease(+1),generalized pruritus(+1),platelets<200×10^(9)/L(+1),aspartate transaminase(AST)<30 IU/L(-1),AST-to-platelet ratio index(APRI)≥0.45(+1),and APRI<0.45(-1).The AUROC was 0.84(95%CI:0.80-0.89),indicating good discrimination of HCV/HIV coinfection and HIV mono-infection.The CPS result≥0 best fits the test-threshold(negative predictive value:99.2%,95%CI:98.8-99.6).Applying this threshold,30%(n=926)would be tested.Sixteen coinfections(15%)would have been missed,none with advanced fibrosis.CONCLUSION The CPS performed well in the derivation cohort,and bears potential for other contexts of low-to-intermediate prevalence and little onward risk of transmission(i.e.cohorts without major risk factors as injecting drug use,men having sex with men),and where available resources do not allow to test all HIV patients as recommended by WHO.However,the score requires external validation in other patient cohorts before any wider use can be considered.
基金the National Natural Science Foundation of China(22206197,22376044,22322602the Research Funds of Hangzhou Institute for Advanced Study,UCAS(2023HIASY012,2023HIAS-P005)+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0750100)the Youth Innovation Promotion Association CAS(2022022)for joint financial support.
文摘Humans are exposed daily to diverse synthetic chemicals through a variety of routes,including diet,inhalation,skin contact,and even through the umbilical cord to the fetus.Numerous chemicals(e.g.,per-and polyfluoroalkyl substances,polycyclic aromatic hydrocarbons,triazine pesticides,benzotriazole UV stabilizers,synthetic phenolic antioxidants)have been definitively documented as developmental neurotoxicants,endocrine disruptors,and carcinogens.Chemical exposure is an important cause of many noncommunicable diseases such as cancer,miscarriage,birth defects,obesity,asthma,pneumonia,diabetes mellitus,and depression.1−3 Despite progress in exploring associations between certain chemicals and diseases,some significant scientific issues still remain unresolved,including identifying chemicals currently used in commerce that are capable of jeopardizing human health,and accurately estimating the contribution of chemical pollution to disease or death.
