The prevalence of hepatocellular carcinoma(HCC)worldwide parallels that of persistent infection with the hepatitis B virus(HBV)and/or hepatitis C virus(HCV).According to recommendations by the World Health Organizatio...The prevalence of hepatocellular carcinoma(HCC)worldwide parallels that of persistent infection with the hepatitis B virus(HBV)and/or hepatitis C virus(HCV).According to recommendations by the World Health Organization guidelines for HBV/HCV,alpha-fetoprotein(AFP)testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients.These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades.In recent years,however,the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities.AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010,the European Association for the Study of the Liver in 2012,and the National Comprehensive Cancer Network in 2014.Other biomarkers,including the Lens culinaris agglutinin-reactive fraction of AFP(AFP-L3),des-γ-carboxyprothrombin,Dickkopf-1,midkine,and micro RNA,are being studied in this regard.Furthermore,increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors.Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC,determination of patient prognosis,and selection of appropriate treatment.However,further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.展开更多
Background:Tuberculosis infection still places a great burden on HIV-infected individuals in China and other developing countries.Knowledge of the survival of HIV-infected patients with pulmonary tuberculosis(PTB)woul...Background:Tuberculosis infection still places a great burden on HIV-infected individuals in China and other developing countries.Knowledge of the survival of HIV-infected patients with pulmonary tuberculosis(PTB)would provide important insights for the clinical management of this population,which remains to be well described in current China.Methods:HIV-infected patients with PTB admitted to Shanghai Public Health Clinical Center from January 2011 to December 2015 were retrospectively enrolled.In this cohort,the survival prognosis was estimated by the Kaplan-Meier method,while univariate and multivariate Cox proportional hazards models were used to determine the risk factors affecting mortality.Results:After reviewing 4914 admitted patients with HIV infection,359 PTB cases were identified.At the time of PTB diagnosis,the patients’median CD4+T cell count was 51/mm3(IQR:23-116),and 27.30%of patients(98/359)were on combination antiretroviral therapy(cART).For the 333 cases included in the survival analysis,the overall mortality was 15.92%(53/333)during a median 27-month follow-up.The risk factors,including age older than 60 years(HR:3.18;95%CI:1.66-6.10),complication with bacterial pneumonia(HR:2.64;95%CI:1.30-5.35),diagnosis delay(HR:2.60;95%CI:1.42-4.78),CD4+T cell count less than 50/mm3(HR:2.38;95%CI:1.27-4.43)and pulmonary atelectasis(HR:2.20;95%CI:1.05-4.60),might independently contribute to poor survival.Among patients without cART before anti-TB treatment,the later initiation of cART(more than 8 weeks after starting anti-TB treatment)was found to increase the mortality rate(OR:4.33;95%CI:1.22-15.36),while the initiation of cART within 4-8 weeks after starting anti-TB treatment was associated with the fewest deaths(0/14).Conclusions:The subjects in this study conducted in the cART era were still characterized by depressed immunological competence and low rates of cART administration,revealing possible intervention targets for preventing TB reactivation in HIV-infected individuals under current circumstances展开更多
BACKGROUND:Gastric lavage(GL)is one of the most critical early therapies for acute paraquat(PQ)poisoning;however,details of the treatment protocol remain to be established.METHODS:A rapid quantitative method involving...BACKGROUND:Gastric lavage(GL)is one of the most critical early therapies for acute paraquat(PQ)poisoning;however,details of the treatment protocol remain to be established.METHODS:A rapid quantitative method involving sodium dithionite testing was developed.It was validated for the determination of the PQ concentrations in gastric juice and eluate samples from a swine acute PQ poisoning model with early or delay GL,or without.The vital signs,laboratory testing,and PQ plasma concentrations were collected for therapeutic effect evaluation.RESULTS:The reaction conditions of the test were optimized for two types of samples.Early GL at one hour(H1)could improve the signs and symptoms after acute PQ poisoning at 24 hours(H24).In contrast,GL at 6 hours(H6)could only partially relieve the vital signs.The H1 GL group effectively reduced the peak of the plasma PQ concentration.In addition,the PQ concentrations in the plasma and the gastric juice were significantly decreased in both the GL groups as compared to the untreated group at H24.Moreover,there was no significant difference in the washing efficiencies calculated from the total eluates between the two GL groups.However,the washing efficiency of the first 10 L eluate is superior to that of the additional 10 L eluate.CONCLUSION:GL only at early stage may it benefit PQ poisoning in an animal model.The currently used 20 L GL volume may need to be reduced in view of the low washing efficiency in the later 10 L eluate.The rapid quantitative method can be used for gastric juice sample and has a certain value for clinical GL practices.展开更多
Bacillus subtilis strain NCD-2 is an excellent biocontrol agent for plant soil-borne diseases, and the lipopeptide fengycin is one of the active antifungal compounds in strain NCD-2. The regulator PhoP and its sensor ...Bacillus subtilis strain NCD-2 is an excellent biocontrol agent for plant soil-borne diseases, and the lipopeptide fengycin is one of the active antifungal compounds in strain NCD-2. The regulator PhoP and its sensor kinase PhoR compose a two-component system in B. subtilis. In this study, the phoR- and phoP-knockout mutants were constructed by in-frame deletion and the role of PhoR/PhoP on the production of fengycin was determined. Inactivation of phoR or phoP in B. subtilis decreased its inhibition ability against Botrytis cinerea growth in vitro compared to the strain NCD-2 wild type. The lipopeptides were extracted from strain NCD-2 wild type and its mutant strains by hydrochloric acid precipitate, and the lipopeptides from phoR-null mutant orphoP-null mutant almost lost the inhibition ability against B. cinerea growth compared to the lipopeptides from strain NCD-2 wild type. Fast protein liquid chromatography （FPLC） analysis of the lipopeptides showed that inactivation of phoR or phoP genes reduced the production of fengycin by strain NCD-2. The fengycin production abilities were compared for bacteria under low-phosphate medium （LPM） and high-phosphate medium （HPM）, respectively. Results indicated that the regulation of fengycin production by the PhoR/PhoP two-component system occurred in LPM but not in HPM. Reverse transcriptionaI-PCR confirmed that the fengycin synthetase gene fenC was positively regulated by phoP when cultured in LPM. All of these characteristics could be partially restored by complementation of intact phoR or phoP gene in the mutant. These data indicated that the PhoR/PhoP two-component system greatly regulated fengycin production and antifungal ability in B. subtilis NCD-2 mainly under low-phosphate conditions.展开更多
Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance ...Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance and differentiation,inhibiting canonical autophagy via deletion of core genes,such as Atg5,Atg16l1,and Atg7,or blockade of canonical interactions between FIP200 and ATG13(designated as FIP200-4A mutant or FIP200 KI)does not produce comparable detrimental effects.This highlights the likely critical involvement of the non-canonical functions of FIP200,the mechanisms of which have remained elusive.Here,utilizing genetic mouse models,we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1,primarily via TAX1BP1 in NSCs.Conditional deletion of Tax1bp1 in fip200hGFAP conditional knock-in(cKI)mice led to NSC deficiency,resembling the fip200hGFAP conditional knockout(cKO)mouse phenotype.Notably,reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation.Conversely,a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration.Furthermore,conditional deletion of Tax1bp1 in fip200hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200hGFAP cKO mice.Collectively,these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function,presenting novel therapeutic targets for neurodegenerative diseases.展开更多
BACKGROUND The pathogenicity of Helicobacter pylori is dependent on factors including the environment and the host.Although selenium is closely related to pathogenicity as an environmental factor,the specific correlat...BACKGROUND The pathogenicity of Helicobacter pylori is dependent on factors including the environment and the host.Although selenium is closely related to pathogenicity as an environmental factor,the specific correlation between them remains unclear.AIM To investigate how selenium acts on virulence factors and reduces their toxicity.METHODS H.pylori strains were induced by sodium selenite.The expression of cytotoxin-associated protein A(CagA)and vacuolating cytotoxin gene A(VacA)was determined by quantitative PCR and Western blotting.Transcriptomics was used to analyze CagA,CagM,CagE,Cag1,Cag3,and CagT.C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction,and H.pylori colonization,inflammatory reactions,and the cell adhesion ability of H.pylori were assessed.RESULTS CagA and VacA expression was upregulated at first and then downregulated in the H.pylori strains after sodium selenite treatment.Their expression was significantly and steadily downregulated after the 5th cycle(10 d).Transcriptome analysis revealed that sodium selenite altered the levels affect H.pylori virulence factors such as CagA,CagM,CagE,Cag1,Cag3,and CagT.Of these factors,CagM and CagE expression was continuously downregulated and further downregulated after 2 h of induction with sodium selenite.Moreover,CagT expression was upregulated before the 3rd cycle(6 d)and significantly downregulated after the 5th cycle.Cag1 and Cag3 expression was upregulated and downregulated,respectively,but no significant change was observed by the 5th cycle.C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction.The extent of H.pylori colonization in the stomach increased;however,sodium selenite also induced a mild inflammatory reaction in the gastric mucosa of H.pylori-infected mice,and the cell adhesion ability of H.pylori was significantly weakened.CONCLUSION These results demonstrate that H.pylori displayed virulence attenuation after the 10th d of sodium selenite treatment.Sodium s展开更多
基金Supported by Grants-in-Aid from the Ministry of Education,Science,Sports,and Culture of Japan
文摘The prevalence of hepatocellular carcinoma(HCC)worldwide parallels that of persistent infection with the hepatitis B virus(HBV)and/or hepatitis C virus(HCV).According to recommendations by the World Health Organization guidelines for HBV/HCV,alpha-fetoprotein(AFP)testing and abdominal ultrasound should be performed in routine surveillance of HCC every 6 mo for high-risk patients.These examinations have also been recommended worldwide by many other HCC guidelines over the past few decades.In recent years,however,the role of AFP in HCC surveillance and diagnosis has diminished due to advances in imaging modalities.AFP was excluded from the surveillance and/or diagnostic criteria in the HCC guidelines published by the American Association for the Study of Liver Diseases in 2010,the European Association for the Study of the Liver in 2012,and the National Comprehensive Cancer Network in 2014.Other biomarkers,including the Lens culinaris agglutinin-reactive fraction of AFP(AFP-L3),des-γ-carboxyprothrombin,Dickkopf-1,midkine,and micro RNA,are being studied in this regard.Furthermore,increasing attention has focused on the clinical utility of biomarkers as pre-treatment predictors for tumor recurrence and as post-treatment monitors.Serum and tissue-based biomarkers and genomics may aid in the diagnosis of HCC,determination of patient prognosis,and selection of appropriate treatment.However,further studies are needed to better characterize the accuracy and potential role of these approaches in clinical practice.
基金This study was supported by the National Natural Science Foundation of China(NSFC No.81571977 and No.31500697)Medical Science Support Program by Shanghai Science and Technology Committee(No.16411960400).
文摘Background:Tuberculosis infection still places a great burden on HIV-infected individuals in China and other developing countries.Knowledge of the survival of HIV-infected patients with pulmonary tuberculosis(PTB)would provide important insights for the clinical management of this population,which remains to be well described in current China.Methods:HIV-infected patients with PTB admitted to Shanghai Public Health Clinical Center from January 2011 to December 2015 were retrospectively enrolled.In this cohort,the survival prognosis was estimated by the Kaplan-Meier method,while univariate and multivariate Cox proportional hazards models were used to determine the risk factors affecting mortality.Results:After reviewing 4914 admitted patients with HIV infection,359 PTB cases were identified.At the time of PTB diagnosis,the patients’median CD4+T cell count was 51/mm3(IQR:23-116),and 27.30%of patients(98/359)were on combination antiretroviral therapy(cART).For the 333 cases included in the survival analysis,the overall mortality was 15.92%(53/333)during a median 27-month follow-up.The risk factors,including age older than 60 years(HR:3.18;95%CI:1.66-6.10),complication with bacterial pneumonia(HR:2.64;95%CI:1.30-5.35),diagnosis delay(HR:2.60;95%CI:1.42-4.78),CD4+T cell count less than 50/mm3(HR:2.38;95%CI:1.27-4.43)and pulmonary atelectasis(HR:2.20;95%CI:1.05-4.60),might independently contribute to poor survival.Among patients without cART before anti-TB treatment,the later initiation of cART(more than 8 weeks after starting anti-TB treatment)was found to increase the mortality rate(OR:4.33;95%CI:1.22-15.36),while the initiation of cART within 4-8 weeks after starting anti-TB treatment was associated with the fewest deaths(0/14).Conclusions:The subjects in this study conducted in the cART era were still characterized by depressed immunological competence and low rates of cART administration,revealing possible intervention targets for preventing TB reactivation in HIV-infected individuals under current circumstances
基金Natural Science Found of Jiangsu Province(BK20171500,16KJB320003)Program for Key disease of Jiangsu Province Science and Technology Department(BL2014088)+1 种基金Program for Innovative Medical Research Team of Jiangsu Province(CXTDA2017007)Jiangsu Province’s key provincial talents program(QNRC2016597).
文摘BACKGROUND:Gastric lavage(GL)is one of the most critical early therapies for acute paraquat(PQ)poisoning;however,details of the treatment protocol remain to be established.METHODS:A rapid quantitative method involving sodium dithionite testing was developed.It was validated for the determination of the PQ concentrations in gastric juice and eluate samples from a swine acute PQ poisoning model with early or delay GL,or without.The vital signs,laboratory testing,and PQ plasma concentrations were collected for therapeutic effect evaluation.RESULTS:The reaction conditions of the test were optimized for two types of samples.Early GL at one hour(H1)could improve the signs and symptoms after acute PQ poisoning at 24 hours(H24).In contrast,GL at 6 hours(H6)could only partially relieve the vital signs.The H1 GL group effectively reduced the peak of the plasma PQ concentration.In addition,the PQ concentrations in the plasma and the gastric juice were significantly decreased in both the GL groups as compared to the untreated group at H24.Moreover,there was no significant difference in the washing efficiencies calculated from the total eluates between the two GL groups.However,the washing efficiency of the first 10 L eluate is superior to that of the additional 10 L eluate.CONCLUSION:GL only at early stage may it benefit PQ poisoning in an animal model.The currently used 20 L GL volume may need to be reduced in view of the low washing efficiency in the later 10 L eluate.The rapid quantitative method can be used for gastric juice sample and has a certain value for clinical GL practices.
基金funded by the earmarked fund for the China Agriculture Research System (CARS-18-15)the National Natural Science Foundation of China (31272085,31572051)the Special Fund for Agro-scientific Research in the Public Interest,China (201503109)
文摘Bacillus subtilis strain NCD-2 is an excellent biocontrol agent for plant soil-borne diseases, and the lipopeptide fengycin is one of the active antifungal compounds in strain NCD-2. The regulator PhoP and its sensor kinase PhoR compose a two-component system in B. subtilis. In this study, the phoR- and phoP-knockout mutants were constructed by in-frame deletion and the role of PhoR/PhoP on the production of fengycin was determined. Inactivation of phoR or phoP in B. subtilis decreased its inhibition ability against Botrytis cinerea growth in vitro compared to the strain NCD-2 wild type. The lipopeptides were extracted from strain NCD-2 wild type and its mutant strains by hydrochloric acid precipitate, and the lipopeptides from phoR-null mutant orphoP-null mutant almost lost the inhibition ability against B. cinerea growth compared to the lipopeptides from strain NCD-2 wild type. Fast protein liquid chromatography （FPLC） analysis of the lipopeptides showed that inactivation of phoR or phoP genes reduced the production of fengycin by strain NCD-2. The fengycin production abilities were compared for bacteria under low-phosphate medium （LPM） and high-phosphate medium （HPM）, respectively. Results indicated that the regulation of fengycin production by the PhoR/PhoP two-component system occurred in LPM but not in HPM. Reverse transcriptionaI-PCR confirmed that the fengycin synthetase gene fenC was positively regulated by phoP when cultured in LPM. All of these characteristics could be partially restored by complementation of intact phoR or phoP gene in the mutant. These data indicated that the PhoR/PhoP two-component system greatly regulated fengycin production and antifungal ability in B. subtilis NCD-2 mainly under low-phosphate conditions.
基金National Natural Science Foundation of China(U2004138,81773132,81820108021)University Excellent Teaching Team of“Qinglan Project”in Jiangsu Province(2022-25)+1 种基金Henan Province Key Research and Development Project(232102521028)Excellent Youth Foundation of Henan Scientific Committee(21230040016)。
文摘Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance and differentiation,inhibiting canonical autophagy via deletion of core genes,such as Atg5,Atg16l1,and Atg7,or blockade of canonical interactions between FIP200 and ATG13(designated as FIP200-4A mutant or FIP200 KI)does not produce comparable detrimental effects.This highlights the likely critical involvement of the non-canonical functions of FIP200,the mechanisms of which have remained elusive.Here,utilizing genetic mouse models,we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1,primarily via TAX1BP1 in NSCs.Conditional deletion of Tax1bp1 in fip200hGFAP conditional knock-in(cKI)mice led to NSC deficiency,resembling the fip200hGFAP conditional knockout(cKO)mouse phenotype.Notably,reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation.Conversely,a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration.Furthermore,conditional deletion of Tax1bp1 in fip200hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200hGFAP cKO mice.Collectively,these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function,presenting novel therapeutic targets for neurodegenerative diseases.
基金National Natural Science Foundation of China,No.32060018 and No.32360035Through Special Fund Projects for Guide Local Science and Technology Development by the China Government,No.GUIKEZY20198004+2 种基金Anhui Provincial Natural Science Foundation,No.2308085QH245the Natural Science Foundation of the Anhui Higher Education Institutions of China,No.2023AH040261Changzhou Science and Technology Project Fund,No.CJ20210012.
文摘BACKGROUND The pathogenicity of Helicobacter pylori is dependent on factors including the environment and the host.Although selenium is closely related to pathogenicity as an environmental factor,the specific correlation between them remains unclear.AIM To investigate how selenium acts on virulence factors and reduces their toxicity.METHODS H.pylori strains were induced by sodium selenite.The expression of cytotoxin-associated protein A(CagA)and vacuolating cytotoxin gene A(VacA)was determined by quantitative PCR and Western blotting.Transcriptomics was used to analyze CagA,CagM,CagE,Cag1,Cag3,and CagT.C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction,and H.pylori colonization,inflammatory reactions,and the cell adhesion ability of H.pylori were assessed.RESULTS CagA and VacA expression was upregulated at first and then downregulated in the H.pylori strains after sodium selenite treatment.Their expression was significantly and steadily downregulated after the 5th cycle(10 d).Transcriptome analysis revealed that sodium selenite altered the levels affect H.pylori virulence factors such as CagA,CagM,CagE,Cag1,Cag3,and CagT.Of these factors,CagM and CagE expression was continuously downregulated and further downregulated after 2 h of induction with sodium selenite.Moreover,CagT expression was upregulated before the 3rd cycle(6 d)and significantly downregulated after the 5th cycle.Cag1 and Cag3 expression was upregulated and downregulated,respectively,but no significant change was observed by the 5th cycle.C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction.The extent of H.pylori colonization in the stomach increased;however,sodium selenite also induced a mild inflammatory reaction in the gastric mucosa of H.pylori-infected mice,and the cell adhesion ability of H.pylori was significantly weakened.CONCLUSION These results demonstrate that H.pylori displayed virulence attenuation after the 10th d of sodium selenite treatment.Sodium s
基金supported by the Qinghai Special Project of Innovation Platform for Basic Conditions of Scientific Research(No.2020-ZJ-T05)the National Natural Science Foundation of China(No.82174052)+1 种基金Function Development and Technical Innovation Project of Instrument of Chinese Academy of Sciences(No.2022gl09)the Development Project of Qinghai Provincial Key Laboratory(No.2021-ZJ-Y14)。
