Despite therapy with potent antiviral agents,chronic hepatitis B(CHB)patients remain at high risk of hepatocellular carcinoma(HCC).While metabolites have been rediscovered as active drivers of biological processes inc...Despite therapy with potent antiviral agents,chronic hepatitis B(CHB)patients remain at high risk of hepatocellular carcinoma(HCC).While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis,the specific metabolites modulating HCC risk in CHB patients are largely unknown.Here,we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale,prospective cohort.Metabolomics analysis reveals a reduction in long-chain acylcarnitines(LCACs)in the baseline plasma of patients with HCC development.LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity.Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A,which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway.Indeed,blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients.The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control.These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.展开更多
Background:The current outbreak of novel coronavirus disease 2019 has caused a seriousdisease burden worldwide.Vaccines are an important factor to sustain the epidemic.Although with a relatively high-vaccination world...Background:The current outbreak of novel coronavirus disease 2019 has caused a seriousdisease burden worldwide.Vaccines are an important factor to sustain the epidemic.Although with a relatively high-vaccination worldwide,the decay of vaccine efficacy andthe arising of new variants lead us to the challenge of maintaining a sufficient immunebarrier to protect the population.Method:A case-contact tracking data in Hunan,China,is used to estimate the contactpattern of cases for scenarios including school,workspace,etc,rather than ordinary susceptible population.Based on the estimated vaccine coverage and efficacy,a multi-groupvaccinated-exposed-presymptomatic-symptomatic-asymptomatic-removed model(VEFIAR)with 8 age groups,with each partitioned into 4 vaccination status groups isdeveloped.The optimal dose-wise vaccinating strategy is optimized based on the currentlyestimated immunity barrier of coverage and efficacy,using the greedy algorithm thatminimizes the cumulative cases,population size of hospitalization and fatality respectivelyin a certain future interval.Parameters of Delta and Omicron variants are used respectivelyin the optimization.Results:The estimated contact matrices of cases showed a concentration on middle ages,and has compatible magnitudes compared to estimations from contact surveys in otherstudies.The VEFIAR model is numerically stable.The optimal controled vaccination strategy requires immediate vaccination on the un-vaccinated high-contact population of age30e39 to reduce the cumulative cases,and is stable with different basic reproductionnumbers(R_(0)).As for minimizing hospitalization and fatality,the optimized strategy requires vaccination on the un-vaccinated of both aged 30e39 of high contact frequencyand the vulnerable older.Conclusion:The objective of reducing transmission requires vaccination in age groups ofthe highest contact frequency,with more priority for un-vaccinated than un-fully or fullyvaccinated.The objective of reducing total hospitalization and fatality requires not only toreduce transmission but also to protect the vulnerable older.The priority changes byvaccination progress.For any region,if the local contact pattern is available,then with thevaccination coverage,efficacy,and disease characteristics of relative risks in heterogeneouspopulations,the optimal dose-wise vaccinating process will be obtained and gives hintsfor decision-making.展开更多
Alcohol-associated liver disease(ALD)is a growing global health concern and its prevalence and severity are increasing steadily.While bacterial endotoxin translocation into the portal circulation is a well-established...Alcohol-associated liver disease(ALD)is a growing global health concern and its prevalence and severity are increasing steadily.While bacterial endotoxin translocation into the portal circulation is a well-established key factor,recent evidence highlights the critical role of sterile inflammation,triggered by diverse stimuli,in alcohol-induced liver injury.This review provides a comprehensive analysis of the complex interactions within the hepatic microenvironment in ALD.It examines the contributions of both parenchymal cells,like hepatocytes,and non-parenchymal cells,such as hepatic stellate cells,Kupffer cells,neutrophils,and liver sinusoidal endothelial cells,in driving the progression of the disease.Additionally,we explored the involvement of key mediators,including cytokines,chemokines and inflammasomes,which regulate inflammatory responses and promote liver injury and fibrosis.A particular focus has been placed on extracellular vesicles(EVs)as essential mediators of intercellular communication both within and beyond the liver.These vesicles facilitate the transfer of signalling molecules,such as microRNAs and proteins,which modulate immune responses,fibrogenesis and lipid metabolism,thereby influencing disease progression.Moreover,we underscore the importance of organ-to-organ crosstalk,particularly in the gut-liver axis,where dysbiosis and increased intestinal permeability lead to microbial translocation,exacerbating hepatic inflammation.The adipose-liver axis is also highlighted,particularly the impact of adipokines and free fatty acids from adipose tissue on hepatic steatosis and inflammation in the context of alcohol consumption.展开更多
Non-coding RNAs(ncRNAs),encompassing microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),have emerged as critical regulators of gene expression and cellular function.In alcohol-associated liver...Non-coding RNAs(ncRNAs),encompassing microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),have emerged as critical regulators of gene expression and cellular function.In alcohol-associated liver disease(ALD),chronic alcohol consumption disrupts the expression and function of ncRNAs in the liver and circulation,contributing to the disease's pathogenesis and progression.Dysregulated ncRNAs influence key pathways involved in hepatocyte injury,lipid metabolism,inflammation,and hepatic stellate cell(HSC)activation,thereby exacerbating steatosis,inflammation,and fibrosis.Furthermore,extracellular vesicles play a pivotal role in mediating ncRNA-driven intercellular communication,amplifying liver damage and fibrosis.This review provides a comprehensive overview of the multifaceted roles of ncRNAs in ALD,with a focus on their mechanistic contributions to disease development and progression.Additionally,we discuss the potential of ncRNAs as diagnostic biomarkers and therapeutic targets,emphasizing their translational relevance in addressing the burden of ALD.展开更多
Chronic hepatitis B virus(HBV)infection remains a global health burden.Timely and effective antiviral therapy is beneficial for patients with HBV infection.With existing antiviral drugs,including nucleos(t)ide analogs...Chronic hepatitis B virus(HBV)infection remains a global health burden.Timely and effective antiviral therapy is beneficial for patients with HBV infection.With existing antiviral drugs,including nucleos(t)ide analogs and interferon-alfa,patients can achieve viral suppression with improved prognosis.However,the rate of hepatitis B surface antigen loss is low.To achieve a functional cure and even complete cure in chronic hepatitis B patients,new antivirals need to be developed.In this review,we summarized the advantages and disadvantages of existing antiviral drugs and focused on new antivirals including direct-acting antiviral drugs and immunotherapeutic approaches.展开更多
Introduction:The objective of this paper was to assess the epidemiology of rabies in Hunan Province,analyze the associated factors,understand the status of prevention and treatment after rabies exposure,evaluate the e...Introduction:The objective of this paper was to assess the epidemiology of rabies in Hunan Province,analyze the associated factors,understand the status of prevention and treatment after rabies exposure,evaluate the effectiveness of prevention and treatment,and provide a scientific basis for formulating effective prevention and control measures.Methods:The surveillance data of rabies in Hunan Province in 2020 were collected and analyzed by descriptive epidemiological method.Results:In 2020,a total of 59 cases of rabies were reported in Hunan Province,with an incidence rate of 0.09/100,000.Overall,42 cases(71.19%)were due to animal bites and 43 cases(72.88%)were of grade III.The proportion of hand and combined injury of hand was the highest(40.68%).A total of 603,261 cases of rabies exposure were reported from the rabies post-exposure prophylaxis(PEP)clinic in Hunan Province.Dogs were the main animal causing injuries,accounting for 74.21%.Only 83,418(13.84%)of the animals had a clear immune history,and a total of 11 dog attacks were reported in Hunan Province.The average immunity rate of dogs in the whole province was 30.98%.In 2020,554 dogs were sampled in the whole province;20 of them were positive for a positivity rate of 3.61%.Conclusions:Rabies in Hunan Province in 2020 had a relatively low prevalence.Failure to treat wounds,immunoglobulin injections,and vaccination after exposure were the main causes of rabies.Therefore,post-exposure management of rabies should be further strengthened to reduce the risk of rabies for high-risk populations.展开更多
基金supported by National Key Research and Development Program of China(2022YFC2304800)National Natural Science Foundation of China(U22A20274 and 82203305)+1 种基金Guangdong Basic and Applied Basic Research Foundation of Guangzhou Joint Fund(2022B1515120039,China)Science and Technology Projects in Guangzhou(2024B03J0326,China).
文摘Despite therapy with potent antiviral agents,chronic hepatitis B(CHB)patients remain at high risk of hepatocellular carcinoma(HCC).While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis,the specific metabolites modulating HCC risk in CHB patients are largely unknown.Here,we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale,prospective cohort.Metabolomics analysis reveals a reduction in long-chain acylcarnitines(LCACs)in the baseline plasma of patients with HCC development.LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity.Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A,which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway.Indeed,blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients.The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control.These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.
基金supported by the National Key Research and Development Program of China(2021YFC2301604)the Research Project on Education and Teaching Reform of Undergraduate Universities of Fujian Province,China(FBJG20210260)+2 种基金the Self-supporting Program of Guangzhou Laboratory(Grant No.SRPG22-007)the Bill&Melinda Gates Foundation(Grant INV-005834 to T.C.)the Research on the Precise Prevention and Control System of SARS-Cov-2(Grant No.35022022YJ07,Topic No.2022YJ-3).
文摘Background:The current outbreak of novel coronavirus disease 2019 has caused a seriousdisease burden worldwide.Vaccines are an important factor to sustain the epidemic.Although with a relatively high-vaccination worldwide,the decay of vaccine efficacy andthe arising of new variants lead us to the challenge of maintaining a sufficient immunebarrier to protect the population.Method:A case-contact tracking data in Hunan,China,is used to estimate the contactpattern of cases for scenarios including school,workspace,etc,rather than ordinary susceptible population.Based on the estimated vaccine coverage and efficacy,a multi-groupvaccinated-exposed-presymptomatic-symptomatic-asymptomatic-removed model(VEFIAR)with 8 age groups,with each partitioned into 4 vaccination status groups isdeveloped.The optimal dose-wise vaccinating strategy is optimized based on the currentlyestimated immunity barrier of coverage and efficacy,using the greedy algorithm thatminimizes the cumulative cases,population size of hospitalization and fatality respectivelyin a certain future interval.Parameters of Delta and Omicron variants are used respectivelyin the optimization.Results:The estimated contact matrices of cases showed a concentration on middle ages,and has compatible magnitudes compared to estimations from contact surveys in otherstudies.The VEFIAR model is numerically stable.The optimal controled vaccination strategy requires immediate vaccination on the un-vaccinated high-contact population of age30e39 to reduce the cumulative cases,and is stable with different basic reproductionnumbers(R_(0)).As for minimizing hospitalization and fatality,the optimized strategy requires vaccination on the un-vaccinated of both aged 30e39 of high contact frequencyand the vulnerable older.Conclusion:The objective of reducing transmission requires vaccination in age groups ofthe highest contact frequency,with more priority for un-vaccinated than un-fully or fullyvaccinated.The objective of reducing total hospitalization and fatality requires not only toreduce transmission but also to protect the vulnerable older.The priority changes byvaccination progress.For any region,if the local contact pattern is available,then with thevaccination coverage,efficacy,and disease characteristics of relative risks in heterogeneouspopulations,the optimal dose-wise vaccinating process will be obtained and gives hintsfor decision-making.
基金supported by NIH grants K01AA26385,R01AA030993,Indiana University Research Support Fund Grant(IU RSFG),Indiana Institute for Medical Research(IIMR),the Ralph W.and Grace M.Showalter Research Trust and the Indiana University School of Medicine and the Central Society for Clinical and Translational Research(CSCTR)Early Career Development AwardJM is supported in part by NIH grant K99AA031067,the Indiana Clinical and Translational Sciences Institute grant UM1TR004402 and the CSCTR Early Career Development Award+2 种基金GZ is supported by Southern Medical UniversityTT is supported in part by the American Liver Foundation Postdoctoral awardSL is supported in part by NIH/NIAAA grants U01AA026917,UH2/UH3 AA026903,R01AA030312,Department of Veterans Affairs Merit Awards 1I01CX000361 and I01 BX006202 and Dean’s Scholar from the Indiana University School of Medicine.
文摘Alcohol-associated liver disease(ALD)is a growing global health concern and its prevalence and severity are increasing steadily.While bacterial endotoxin translocation into the portal circulation is a well-established key factor,recent evidence highlights the critical role of sterile inflammation,triggered by diverse stimuli,in alcohol-induced liver injury.This review provides a comprehensive analysis of the complex interactions within the hepatic microenvironment in ALD.It examines the contributions of both parenchymal cells,like hepatocytes,and non-parenchymal cells,such as hepatic stellate cells,Kupffer cells,neutrophils,and liver sinusoidal endothelial cells,in driving the progression of the disease.Additionally,we explored the involvement of key mediators,including cytokines,chemokines and inflammasomes,which regulate inflammatory responses and promote liver injury and fibrosis.A particular focus has been placed on extracellular vesicles(EVs)as essential mediators of intercellular communication both within and beyond the liver.These vesicles facilitate the transfer of signalling molecules,such as microRNAs and proteins,which modulate immune responses,fibrogenesis and lipid metabolism,thereby influencing disease progression.Moreover,we underscore the importance of organ-to-organ crosstalk,particularly in the gut-liver axis,where dysbiosis and increased intestinal permeability lead to microbial translocation,exacerbating hepatic inflammation.The adipose-liver axis is also highlighted,particularly the impact of adipokines and free fatty acids from adipose tissue on hepatic steatosis and inflammation in the context of alcohol consumption.
基金supported by the National Key Research and Development Program of China(No.2022YFC2304800 to Ge Zeng)NIH K99AA031067,the CSCTR Early Career Development Award,and Indiana Clinical and Translational Sciences Institute grant UM1TR004402(in part to Jing Ma)+3 种基金the National Institutes of Health(NIH R01AA030993 to Zhihong Yang)the American Liver Foundation Postdoctoral Award(in part to Themis Thoudam)NIH grant R01AA030312,Department of Veterans Affairs Merit Awards 1I01CX000361 and I01BX006202the Indiana University School of Medicine Dean's Scholar Award(in part to Suthat Liangpunsakul)。
文摘Non-coding RNAs(ncRNAs),encompassing microRNAs(miRNAs),long non-coding RNAs(lncRNAs),and circular RNAs(circRNAs),have emerged as critical regulators of gene expression and cellular function.In alcohol-associated liver disease(ALD),chronic alcohol consumption disrupts the expression and function of ncRNAs in the liver and circulation,contributing to the disease's pathogenesis and progression.Dysregulated ncRNAs influence key pathways involved in hepatocyte injury,lipid metabolism,inflammation,and hepatic stellate cell(HSC)activation,thereby exacerbating steatosis,inflammation,and fibrosis.Furthermore,extracellular vesicles play a pivotal role in mediating ncRNA-driven intercellular communication,amplifying liver damage and fibrosis.This review provides a comprehensive overview of the multifaceted roles of ncRNAs in ALD,with a focus on their mechanistic contributions to disease development and progression.Additionally,we discuss the potential of ncRNAs as diagnostic biomarkers and therapeutic targets,emphasizing their translational relevance in addressing the burden of ALD.
基金National Natural Science Foundation of China(Nos.81871668,82070614,and 82100637)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(No.2017BT01S131)。
文摘Chronic hepatitis B virus(HBV)infection remains a global health burden.Timely and effective antiviral therapy is beneficial for patients with HBV infection.With existing antiviral drugs,including nucleos(t)ide analogs and interferon-alfa,patients can achieve viral suppression with improved prognosis.However,the rate of hepatitis B surface antigen loss is low.To achieve a functional cure and even complete cure in chronic hepatitis B patients,new antivirals need to be developed.In this review,we summarized the advantages and disadvantages of existing antiviral drugs and focused on new antivirals including direct-acting antiviral drugs and immunotherapeutic approaches.
文摘Introduction:The objective of this paper was to assess the epidemiology of rabies in Hunan Province,analyze the associated factors,understand the status of prevention and treatment after rabies exposure,evaluate the effectiveness of prevention and treatment,and provide a scientific basis for formulating effective prevention and control measures.Methods:The surveillance data of rabies in Hunan Province in 2020 were collected and analyzed by descriptive epidemiological method.Results:In 2020,a total of 59 cases of rabies were reported in Hunan Province,with an incidence rate of 0.09/100,000.Overall,42 cases(71.19%)were due to animal bites and 43 cases(72.88%)were of grade III.The proportion of hand and combined injury of hand was the highest(40.68%).A total of 603,261 cases of rabies exposure were reported from the rabies post-exposure prophylaxis(PEP)clinic in Hunan Province.Dogs were the main animal causing injuries,accounting for 74.21%.Only 83,418(13.84%)of the animals had a clear immune history,and a total of 11 dog attacks were reported in Hunan Province.The average immunity rate of dogs in the whole province was 30.98%.In 2020,554 dogs were sampled in the whole province;20 of them were positive for a positivity rate of 3.61%.Conclusions:Rabies in Hunan Province in 2020 had a relatively low prevalence.Failure to treat wounds,immunoglobulin injections,and vaccination after exposure were the main causes of rabies.Therefore,post-exposure management of rabies should be further strengthened to reduce the risk of rabies for high-risk populations.
