The initial cluster of severe pneumonia cases that triggered the COVID-19 epidemic was identified inWuhan,China in December 2019.While early cases of the disease were linked to a wet market,human-to-human transmission...The initial cluster of severe pneumonia cases that triggered the COVID-19 epidemic was identified inWuhan,China in December 2019.While early cases of the disease were linked to a wet market,human-to-human transmission has driven the rapid spread of the virus throughout China.The Chinese government has implemented containment strategies of city-wide lockdowns,screening at airports and train stations,and isolation of suspected patients;however,the cumulative case count keeps growing every day.The ongoing outbreak presents a challenge for modelers,as limited data are available on the early growth trajectory,and the epidemiological characteristics of the novel coronavirus are yet to be fully elucidated.We use phenomenological models that have been validated during previous outbreaks to generate and assess short-term forecasts of the cumulative number of confirmed reported cases in Hubei province,the epicenter of the epidemic,and for the overall trajectory in China,excluding the province of Hubei.We collect daily reported cumulative confirmed cases for the 2019-nCoV outbreak for each Chinese province from the National Health Commission of China.Here,we provide 5,10,and 15 day forecasts for five consecutive days,February 5th through February 9th,with quantified uncertainty based on a generalized logistic growth model,the Richards growth model,and a sub-epidemic wave model.Our most recent forecasts reported here,based on data up until February 9,2020,largely agree across the three models presented and suggest an average range of 7409e7496 additional confirmed cases in Hubei and 1128e1929 additional cases in other provinces within the next five days.Models also predict an average total cumulative case count between 37,415 and 38,028 in Hubei and 11,588e13,499 in other provinces by February 24,2020.Mean estimates and uncertainty bounds for both Hubei and other provinces have remained relatively stable in the last three reporting dates(February 7th e 9th).We also observe that each of the models predicts that the epidemic h展开更多
It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular ...It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular molecules thereby maintaining cellular hemostasis. Alcohol exposure significantly alters several of these post-translational modifications leading to impairments of many essential physiological processes. Here, we present new insights into novel modifications following ethanol exposure and their role in the initiation and progression of liver injury. This critical review condenses the proceedings of a symposium at the European Society for the Biomedical Research on Alcoholism Meeting held September 12-15, 2015, in Valencia, Spain.展开更多
Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at ma...Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at many levels including nutrient intake,absorption,utilization,and excretion,and can lead to many nutritional disturbances and deficiencies.Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease(ALD).There is growing interest regarding epigenetic changes,including histone modifications that regulate gene expression during disease pathogenesis.Notably,modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation,and control gene transcription.This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD.The review is focused on four critical metabolites,namely,acetate,S-adenosylmethionine,nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD.展开更多
Alcohol-associated liver disease(ALD)is a common chronic liver disease and major contributor to liver disease-related deaths worldwide.Despite its prevalence,there are few effective pharmacological options for the sev...Alcohol-associated liver disease(ALD)is a common chronic liver disease and major contributor to liver disease-related deaths worldwide.Despite its prevalence,there are few effective pharmacological options for the severe stages of this disease.While much pre-clinical research attention is paid to drug development in ALD,many of these experimental therapeutics have limitations such as poor pharmacokinetics,poor efficacy,or off-target side effects due to systemic administration.One means of addressing these limitations is through liver-targeted drug delivery,which can be accomplished with different platforms including liposomes,polymeric nanoparticles,exosomes,bacteria,and adenoassociated viruses,among others.These platforms allow drugs to target the liver passively or actively,thereby reducing systemic circulation and increasing the‘effective dose’in the liver.While many studies,some clinical,have applied targeted delivery systems to other liver diseases such as viral hepatitis or hepatocellular carcinoma,only few have investigated their efficacy in ALD.This review provides basic information on these liver-targeting drug delivery platforms,including their benefits and limitations,and summarizes the current research efforts to apply them to the treatment of ALD in rodent models.We also discuss gaps in knowledge in the field,which when addressed,may help to increase the efficacy of novel therapies and better translate them to humans.展开更多
Alcoholic liver disease(ALD)comprises a spectrum of liver pathology,including steatosis,steatohepatitis,and cirrhosis.Previous work from our group and others suggests that dietary fat,both the amount and composition,p...Alcoholic liver disease(ALD)comprises a spectrum of liver pathology,including steatosis,steatohepatitis,and cirrhosis.Previous work from our group and others suggests that dietary fat,both the amount and composition,plays a pivotal role in ALD development and progression;however,the impact of specific dietary fatty acids on ALD pathogenesis is not fully elucidated.Preclinical rodent models of ALD revealed the deleterious effects of omega-6 polyunsaturated fatty acids(n-6 PUFAs),specifically linoleic acid(LA),and this may be partially attributed to the increased levels of pro-inflammatory oxidized LA metabolites.There is limited understanding regarding the role of omega-3 polyunsaturated fatty acids(n-3 PUFAs,such as alpha-linolenic acid,eicosapentaenoic acid,and docosahexaenoic acid),and bioactive n-3 PUFAderived lipid molecules in ALD.Given that majority of n-6 and n-3 PUFAs-derived metabolites are potent endogenous signaling molecules,knowledge regarding the changes in these lipid mediators may shed new light on the mechanisms contributing to ALD pathogenesis and reveal novel therapeutic targets and biomarkers of this disease.The current review summarizes relevant scientific literature regarding the role of dietary fat,distinct fatty acids,and bioactive fatty acid metabolites in ALD,and highlights recent advances in the field.展开更多
基金GC is supported by NSF grants 1610429 and 1633381.
文摘The initial cluster of severe pneumonia cases that triggered the COVID-19 epidemic was identified inWuhan,China in December 2019.While early cases of the disease were linked to a wet market,human-to-human transmission has driven the rapid spread of the virus throughout China.The Chinese government has implemented containment strategies of city-wide lockdowns,screening at airports and train stations,and isolation of suspected patients;however,the cumulative case count keeps growing every day.The ongoing outbreak presents a challenge for modelers,as limited data are available on the early growth trajectory,and the epidemiological characteristics of the novel coronavirus are yet to be fully elucidated.We use phenomenological models that have been validated during previous outbreaks to generate and assess short-term forecasts of the cumulative number of confirmed reported cases in Hubei province,the epicenter of the epidemic,and for the overall trajectory in China,excluding the province of Hubei.We collect daily reported cumulative confirmed cases for the 2019-nCoV outbreak for each Chinese province from the National Health Commission of China.Here,we provide 5,10,and 15 day forecasts for five consecutive days,February 5th through February 9th,with quantified uncertainty based on a generalized logistic growth model,the Richards growth model,and a sub-epidemic wave model.Our most recent forecasts reported here,based on data up until February 9,2020,largely agree across the three models presented and suggest an average range of 7409e7496 additional confirmed cases in Hubei and 1128e1929 additional cases in other provinces within the next five days.Models also predict an average total cumulative case count between 37,415 and 38,028 in Hubei and 11,588e13,499 in other provinces by February 24,2020.Mean estimates and uncertainty bounds for both Hubei and other provinces have remained relatively stable in the last three reporting dates(February 7th e 9th).We also observe that each of the models predicts that the epidemic h
文摘It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular molecules thereby maintaining cellular hemostasis. Alcohol exposure significantly alters several of these post-translational modifications leading to impairments of many essential physiological processes. Here, we present new insights into novel modifications following ethanol exposure and their role in the initiation and progression of liver injury. This critical review condenses the proceedings of a symposium at the European Society for the Biomedical Research on Alcoholism Meeting held September 12-15, 2015, in Valencia, Spain.
基金Supported by The National Institute of Alcohol Abuse and Alcoholism grants AA014371 (to Joshi-Barve S),AA015970 (to McClain CJ), and Office of Dietary Supplements, NIH
文摘Alcoholism is a major health problem in the United States and worldwide,and alcohol remains the single most significant cause of liver-related diseases and deaths.Alcohol is known to influence nutritional status at many levels including nutrient intake,absorption,utilization,and excretion,and can lead to many nutritional disturbances and deficiencies.Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease(ALD).There is growing interest regarding epigenetic changes,including histone modifications that regulate gene expression during disease pathogenesis.Notably,modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation,and control gene transcription.This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD.The review is focused on four critical metabolites,namely,acetate,S-adenosylmethionine,nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD.
基金Supported by National Institutes of Health,No. R01AA028905-01A1 (to Kirpich IA),No. 1F31AA028423-01A1 (to Warner JB),No. F32AA027950-01A1 (to Hardesty JE) and No. U01AA026934 (to McClain CJ)Jewish Heritage Fund for Excellence Research Enhancement Grant Program at the University of Louisville+1 种基金an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health,No. P20GM113226 (to McClain CJ)National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health,No. P50AA024337 (to McClain CJ)
文摘Alcohol-associated liver disease(ALD)is a common chronic liver disease and major contributor to liver disease-related deaths worldwide.Despite its prevalence,there are few effective pharmacological options for the severe stages of this disease.While much pre-clinical research attention is paid to drug development in ALD,many of these experimental therapeutics have limitations such as poor pharmacokinetics,poor efficacy,or off-target side effects due to systemic administration.One means of addressing these limitations is through liver-targeted drug delivery,which can be accomplished with different platforms including liposomes,polymeric nanoparticles,exosomes,bacteria,and adenoassociated viruses,among others.These platforms allow drugs to target the liver passively or actively,thereby reducing systemic circulation and increasing the‘effective dose’in the liver.While many studies,some clinical,have applied targeted delivery systems to other liver diseases such as viral hepatitis or hepatocellular carcinoma,only few have investigated their efficacy in ALD.This review provides basic information on these liver-targeting drug delivery platforms,including their benefits and limitations,and summarizes the current research efforts to apply them to the treatment of ALD in rodent models.We also discuss gaps in knowledge in the field,which when addressed,may help to increase the efficacy of novel therapies and better translate them to humans.
基金supported by National Institutes of Health(NIH)grants R01 AA024102-01A1(I.A.Kirpich),U01AA022489(C.J.McClain),1U01AA021901-01(C.J.McClain),1U01AA021893-01(C.J.McClain),R01AA023681(C.J.McClain)the Department of Veterans Affairs I01BX000350(C.J.McClain).Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number T35ES014559(K.H.Zirnheld)+1 种基金an Institutional Development Award(IDeA)from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM113226(C.J.McClain)the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under Award Number P50AA024337(C.J.McClain).
文摘Alcoholic liver disease(ALD)comprises a spectrum of liver pathology,including steatosis,steatohepatitis,and cirrhosis.Previous work from our group and others suggests that dietary fat,both the amount and composition,plays a pivotal role in ALD development and progression;however,the impact of specific dietary fatty acids on ALD pathogenesis is not fully elucidated.Preclinical rodent models of ALD revealed the deleterious effects of omega-6 polyunsaturated fatty acids(n-6 PUFAs),specifically linoleic acid(LA),and this may be partially attributed to the increased levels of pro-inflammatory oxidized LA metabolites.There is limited understanding regarding the role of omega-3 polyunsaturated fatty acids(n-3 PUFAs,such as alpha-linolenic acid,eicosapentaenoic acid,and docosahexaenoic acid),and bioactive n-3 PUFAderived lipid molecules in ALD.Given that majority of n-6 and n-3 PUFAs-derived metabolites are potent endogenous signaling molecules,knowledge regarding the changes in these lipid mediators may shed new light on the mechanisms contributing to ALD pathogenesis and reveal novel therapeutic targets and biomarkers of this disease.The current review summarizes relevant scientific literature regarding the role of dietary fat,distinct fatty acids,and bioactive fatty acid metabolites in ALD,and highlights recent advances in the field.
