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Autophagy and ethanol-induced liver injury

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World Journal of Gastroenterology 2009年第10期15卷 1178-1185页

作者： Terrence M donohue Jr Liver Study Unit The Omaha Veterans Affairs Medical Center Department of Internal Medicine University of Nebraska Medical Center Omaha Nebraska 68105 United States

The majority of ethanol metabolism occurs in the liver. Consequently, this organ sustains the greatest damage from ethanol abuse. Ethanol consumption disturbs the delicate balance of protein homeostasis in the liver, causing intracellular protein accumulation due to a disruption of hepatic protein catabolism. Evidence indicates that ethanol or its metabolism impairs trafficking events in the liver, including the process of macroautophagy, which is the engulfment and degradation of cytoplasmic constituents by the lysosomal system. Autophagy is an essential, ongoing cellular process that is highly regulated by nutrients, endocrine factors and signaling pathways. A great number of the genes and gene products that govern the autophagic response have been characterized and the major metabolic and signaling pathways that activate or suppress autophagy have been identified. This review describes the process of autophagy, its regulation and the possible mechanisms by which ethanol disrupts the process of autophagic degradation. The implications of autophagic suppression are discussed in relation to the pathogenesis of alcohol-induced liver injury.

关键词： Autophagy Autophagosome Ethanolmetabolism Hepatomegaly Lysosomes Signal transduction

Particle shape characterisation and its application to discrete element modelling

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Particuology 2014年第1期12卷 80-89页

作者： Kenneth C.Williams Wei Chen Sebastian Weeger Timothy J.donohue Centre for Bulk Solids and Particulate Technologies Newcastle Institute for Energy and Resources The University of Newcastle Georg-Simon-Ohm University Nuremberg TUNRA Bulk Solids Newcastle Institute for Energy and Resources The University of Newcastle

increasing importance has been placed on particle shape implementation within discrete element mod elling （DEM） in order to more accurately reflect the nonspherical behaviour of the bulk material being handled. As computational resources grow, complex particle shapes are increasingly being modelled as the associated simulation times become more realistic to provide timely solutions. The objective of this research is to assess particle shape descriptors through a digital image segmentation technique, and to further implement particle shape parameters into generation of corresponding irregular shaped DEM particles. Separated and lumped particle images were analysed and reconstructed through the devel opment of two distinct methodologies. Subsequently, various particle shape descriptors were obtained using combinations of image segmentation algorithms, including mathematical morphology processing, thresholding, edge detection, region growing, region splitting and region merging. DEM particles were subsequently created using particle shape results obtained above. Shape parameters of DEM particles were then examined and validated against the real particle shape parameters.

关键词： Particle shapesParticle morphologyimage segmentationDiscrete element modelling

Team-based stepped care in integrated delivery settings

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Family Medicine and Community Health 2015年第1期3卷 39-46页

作者： Cassandra Snipes Alexandros Maragakis William O’donohue Department of Psychology University of NevadaReno1664 N.Virginia StreetMail Stop 298RenoNVUSA 89557 Department of Psychiatry University of Maryland School of Medicine701 W.Pratt Street3rd FloorBaltimoreMD 21201

Fragmented health care delivery is recognized as increasingly *** care has been advanced as a reform that will improve quality of care and lower *** the application of integrated care systems in the United States,there has been a limited amount of empirical work explicating the most effective health care *** care has been proposed as a framework by which to implement coordinated team-based care and has gained preliminary empirical *** this manuscript a rationale for team-based stepped care is presented,tools for implementation are provided,and future research directions are suggested.

关键词： integrated care team-based care behavioral health in primary care

Treating Adult Substance Abuse Using Family Behavior Therapy: A Step-by-Step Approach 1

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implications of the gene balance hypothesis for dosage compensation

2011年

作者： Brad donohue Daniel N. Allen

ISBN: (纸本)0470621931;9780470621936

Family Behavior Therapy (FBT) is an evidence-based treatment that helps adult patients address substance abuse as well as coexisting problem behaviors, including family dysfunction, employment, and mood disorders. donohue and Allen are the premier researchers and practitioners of FBT, and their book is the first to provide the practical, step-by-step guidance needed to use this cost-effective inte

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Frontiers in Biology 2011年第2期6卷 118-124页

作者： James A.BiRCHLER Lin SUN Ryan donohue Abhijit SANYAL Weiwu XiE Division of Biological Sciences University of Missouri ColumbiaMO 65211USA

Dosage compensation refers to the equal expression between the sexes despite the fact that the dosage of the X chromosome is different in males and *** Drosophila there is a twofold upregulation of the single male *** triple X metafemales,there is also dosage compensation,which occurs by a two-thirds *** is a concomitant reduction in expression of many autosomal genes in *** male specific lethal(MSL)complex is present on the male X *** is discussed showing that the MSL complex sequesters a histone acetyltransferase to the X chromosome to mute an otherwise increased expression by diminishing the histone acetylation on the *** lines of evidence indicate that a constraining activity occurs from the MSL complex to prevent overcompensation on the X that might otherwise occur from the high level of acetylation ***,the evidence suggests that dosage compensation is a modification of a regulatory inverse dosage effect that is a reflection of intrinsic gene regulatory mechanisms and that the MSL complex has evolved in reaction in order to equalize the expression on both the X and autosomes of males and females.

关键词： inverse dosage effect male specific lethal complex histone acetylation metafemales

Alcohol-induced steatosis in liver cells

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World Journal of Gastroenterology 2007年第37期13卷 4974-4978页

作者： Terrence M donohue Jr Liver Study Unit The Omaha Veterans Affairs Medical Center the Department of Internal Medicine University of Nebraska Medical Center Omaha Nebraska 68105 United States

Alcohol-induced fatty liver (steatosis) was believed to result from excessive generation of reducing equivalents from ethanol metabolism, thereby enhancing fat accumulation. Recent findings have revealed a more complex picture in which ethanol oxidation is still required, but specific transcription as well as humoral factors also have important roles. Transcription factors involved include the sterol regulatory element binding protein 1 (SREBP-1) which is activated to induce genes that regulate lipid biosynthesis. Conversely, ethanol consumption causes a general down-regulation of lipid (fatty acid) oxidation, a reflection of inactivation of the peroxisome proliferator- activated receptor-alpha (PPAR-α) that regulates genes involved in fatty acid oxidation. A third transcription factor is the early growth response-1 (Egr-1), which is strongly induced prior to the onset of steatosis. The activities of all these factors are governed by that of the principal regulatory enzyme, AMP kinase. important humoral factors, including adiponectin, and tumor necrosis factor-α (TNF-α), also regulate alcohol-induced steatosis. Their levels are affected by alcohol consumption and by each other. This review will summarize the actions of these proteins in ethanol-elicited fatty liver. Because steatosis is now regarded as a significant risk factor for advanced liver pathology, an understanding of the molecular mechanisms in its etiology is essential for development of effective therapies.

关键词： Ethanol metabolism Fatty liver Sterolregulatory element binding protein Peroxisomeproliferator activated receptor Early growth response-i Fatty acid toxicity Triglycerides Acetaldehyde Reactiveoxygen species

implication of altered proteasome function in alcoholic liverinjury

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World Journal of Gastroenterology 2007年第37期13卷 4931-4937页

作者： Natalia A Osna Terrence M donohue Jr Liver Study Unit The Omaha Veterans Affairs Medical Center the Department of Internal Medicine University of Nebraska Medical Center Omaha Nebraska 68105 United States

The proteasome is a major protein-degrading enzyme, which catalyzes degradation of oxidized and aged proteins, signal transduction factors and cleaves peptides for antigen presentation. Proteasome exists in the equilibrium of 26S and 20S particles. Proteasome function is altered by ethanol metabolism, depending on oxidative stress levels： low oxidative stress induces proteasome activity, while high oxidative stress reduces it. The proposed mechanisms for modulation of proteasome activity are related to oxidative modification of proteasomal proteins with primary and secondary products derived from ethanol oxidation. Decreased proteolysis by the proteasome results in the accumulation of insoluble protein aggregates, which cannot be degraded by proteasome and which further inhibit proteasome function. Mallory bodies, a common signature of alcoholic liver diseases, are formed by liver cells, when proteasome is unable to remove cytokeratins. Proteasome inhibition by ethanol also promotes the accumulation of pro-apoptotic factors in mitochondria of ethanol-metabolizing liver cells that are normally degraded by proteasome. in addition, decreased proteasome function also induces accumulation of the negative regulators of cytokine signaling （i-~B and SOCS）, thereby blocking cytokine signal transduction. Finally, ethanol-elicited blockade of interferon type 2 and 2 signaling and decreased proteasome function impairs generation of peptides for MHC class Ⅰ-restricted antigen presentation.

关键词： 20S proteasome 26S proteasome, PA28, CYP2E1, Apoptosis, Liver

involvement of autophagy in alcoholic liver injury and hepatitis C pathogenesis

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World Journal of Gastroenterology 2011年第20期17卷 2507-2514页

作者： Natalia A Osna Paul G Thomes Terrence M donohue University of Nebraska Medical Center VA Medical Center

This review describes the principal pathways of macroautophagy (i.e. autophagy), microautophagy and chaperone-mediated autophagy as they are currently known to occur in mammalian cells. Because of its crucial role as an accessory digestive organ, the liver has a particularly robust autophagic activity that is sensitive to changes in plasma and dietary components. Ethanol consumption causes major changes in hepatic protein and lipid metabolism and both are regulated by autophagy, which is significantly affected by hepatic ethanol metabolism. Ethanol exposure enhances autophagosome formation in liver cells, but suppresses lysosome function. Excessive ethanol consumption synergizes with hepatitis C virus (HCV) to exacerbate liver injury, as alcohol-consuming HCV patients frequently have a longer course of infection and more severe manifestations of chronic hepatitis than abstinent HCV patients. Alcohol-elicited exacerbation of HCV infection pathogenesis is related to modulation by ethanol metabolism of HCV replication. Additionally, as part of this mechanism, autophagic proteins have been shown to regulate viral (HCV) replication and their intracel-lular accumulation. Because ethanol induces autophagosome expression, enhanced levels of autophagic proteins may enhance HCV infectivity in liver cells of alcoholics and heavy drinkers.

关键词： Autophagy iysosome Autophagosome Hepatitis C virus Hepatitis C virus replication cycle Ethanol

Re-evaluation of the function of the male specific lethal complex in Drosophila

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Journal of Genetics and Genomics 2011年第8期38卷 327-332页

作者： James Birchler Harvey Fernandez Ryan donohue Abhijit Sanyal Division of Biological Sciences 311 Tucker HallUniversity of MissouriColumbiaMO 65211USA

A set of proteins and noncoding RNAs, referred to as the male specific lethal （MSL） complex, is present on the male X chromosome in Drosophila and has been postulated to be responsible for dosage compensation of this chromosome -- the up-regulation of its expression to be equal to that of two X chromosomes in females. This hypothesis is evaluated in view of lesser known aspects of dosage compensation such as the fact that metafemales with three X chromosomes also have equal expression to normal females, which would require a down-regulation of each gene copy Moreover, when this complex is ectopically expressed in females or specifically targeted to a reporter in males, there is no increase in expression of the genes or targets with which it is associated. These observations are not consistent with the hypothesis that the MSL complex conditions dosage compensation. A synthesis is described that can account for these observations.

关键词： Dosage compensation MSL Aneuploidy Gene balance hypothesis X chromosome