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Full-Text Articles in Medicine and Health Sciences

Autophagy And Protein Turnover Responses To Exercise-Nutrient Interactions In Human Skeletal Muscle, William J. Smiles Jun 2017

Autophagy And Protein Turnover Responses To Exercise-Nutrient Interactions In Human Skeletal Muscle, William J. Smiles

Theses

Skeletal muscle is a dynamic tissue comprising the largest protein reservoir of the human body with a rate of turnover of ~1-2% per day. Protein turnover is regulated by the coordination of intracellular systems regulating protein synthesis and breakdown that converge in a spatiotemporal manner on lysosomal organelles responsible for integrating a variety of contractile and nutritional stimuli. One such system, autophagy, which literally means to ‘self-eat,’ involves capturing of cellular material for deliver to, and disintegration by, the lysosome. The autophagic ‘cargo’ is subsequently recycled for use in synthetic reactions and thus maintenance of protein balance. As a dynamic ...


Individual And Combined Effects Of Cannabis And Tobacco On Drug Reward Processing In Non-Dependent Users, Chandni Hindocha, Will Lawn, Tom P. Freeman, H. Valerie Curran Jan 2017

Individual And Combined Effects Of Cannabis And Tobacco On Drug Reward Processing In Non-Dependent Users, Chandni Hindocha, Will Lawn, Tom P. Freeman, H. Valerie Curran

Faculty of Health Sciences Publications

Rationale: Cannabis and tobacco are often smoked simultaneously in joints, and this practice may increase the risks of developing tobacco and/or cannabis use disorders. Currently, there is no human experimental research on how these drugs interact on addiction-related measures. Objectives: This study aimed to investigate how cannabis and tobacco, each alone and combined together in joints, affected individuals’ demand for cannabis puffs and cigarettes, explicit liking of drug and non-drug-related stimuli and craving. Method: A double-blind, 2 (active cannabis, placebo cannabis) × 2 (active tobacco, placebo tobacco) crossover design was used with 24 non-dependent cannabis and tobacco smokers. They completed ...


Design, Synthesis, And Biological Activity Of 1,2,3-Triazolobenzodiazepine Bet Bromodomain Inhibitors [Accepted Manuscript], Phillip P. Sharp, Jean-Marc Garnier, Tamas Hatfaludi, Zhen Xu, David Segal, Kate E. Jarman, Hélène Jousset, Alexandra Garnham, John T. Feutrill, Anthony Cuzzupe, Peter Hall, Scott Taylor, Carl Walkley, Dean Tyler, Mark A. Dawson, Peter Czabotar, Andrew F. Wilks, Stefan Glaser, David C. S. Huang, Christopher J. Burns Jan 2017

Design, Synthesis, And Biological Activity Of 1,2,3-Triazolobenzodiazepine Bet Bromodomain Inhibitors [Accepted Manuscript], Phillip P. Sharp, Jean-Marc Garnier, Tamas Hatfaludi, Zhen Xu, David Segal, Kate E. Jarman, Hélène Jousset, Alexandra Garnham, John T. Feutrill, Anthony Cuzzupe, Peter Hall, Scott Taylor, Carl Walkley, Dean Tyler, Mark A. Dawson, Peter Czabotar, Andrew F. Wilks, Stefan Glaser, David C. S. Huang, Christopher J. Burns

Faculty of Health Sciences Publications

A number of diazepines are known to inhibit bromo- and extra-terminal domain (BET) proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c-MYC expression. These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors.


Rewriting The Transcriptome: Adenosine-To-Inosine Rna Editing By Adars, Carl Walkley, Jin Billy Li Jan 2017

Rewriting The Transcriptome: Adenosine-To-Inosine Rna Editing By Adars, Carl Walkley, Jin Billy Li

Faculty of Health Sciences Publications

One of the most prevalent forms of post-transcritpional RNA modification is the conversion of adenosine nucleosides to inosine (A-to-I), mediated by the ADAR family of enzymes. The functional requirement and regulatory landscape for the majority of A-to-I editing events are, at present, uncertain. Recent studies have identified key in vivo functions of ADAR enzymes, informing our understanding of the biological importance of A-to-I editing. Large-scale studies have revealed how editing is regulated both in cis and in trans. This review will explore these recent studies and how they broaden our understanding of the functions and regulation of ADAR-mediated RNA editing.


Protein Recoding By Adar1-Mediated Rna Editing Is Not Essential For Normal Development And Homeostasis, Jacki E. Heraud-Farlow, Alistair M. Chalk, Sandra Linder, Qin Li, Scott Taylor, Joshua M. White, Lokman Pang, Brian J. Liddicoat, Ankita Gupte, Jin Billy Li, Carl Walkley Jan 2017

Protein Recoding By Adar1-Mediated Rna Editing Is Not Essential For Normal Development And Homeostasis, Jacki E. Heraud-Farlow, Alistair M. Chalk, Sandra Linder, Qin Li, Scott Taylor, Joshua M. White, Lokman Pang, Brian J. Liddicoat, Ankita Gupte, Jin Billy Li, Carl Walkley

Faculty of Health Sciences Publications

Background
Adenosine-to-inosine (A-to-I) editing of dsRNA by ADAR proteins is a pervasive epitranscriptome feature. Tens of thousands of A-to-I editing events are defined in the mouse, yet the functional impact of most is unknown. Editing causing protein recoding is the essential function of ADAR2, but an essential role for recoding by ADAR1 has not been demonstrated. ADAR1 has been proposed to have editing-dependent and editing-independent functions. The relative contribution of these in vivo has not been clearly defined. A critical function of ADAR1 is editing of endogenous RNA to prevent activation of the dsRNA sensor MDA5 (Ifih1). Outside of this ...


Psilocybin For Treatment-Resistant Depression: Fmri-Measured Brain Mechanisms, Robin L. Carhart-Harris, Leor Roseman, Mark Bolstridge, Lysia Demetriou, J. Nienke Pannekoek, Matthew B. Wall, Mark Tanner, Mendel Kaelen, John Mcgonigle, Kevin Murphy, Robert Leech, H. Valerie Curran, David J. Nutt Jan 2017

Psilocybin For Treatment-Resistant Depression: Fmri-Measured Brain Mechanisms, Robin L. Carhart-Harris, Leor Roseman, Mark Bolstridge, Lysia Demetriou, J. Nienke Pannekoek, Matthew B. Wall, Mark Tanner, Mendel Kaelen, John Mcgonigle, Kevin Murphy, Robert Leech, H. Valerie Curran, David J. Nutt

Faculty of Health Sciences Publications

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex ...


Sulfonylurea Drug Pretreatment And Functional Outcome In Diabetic Patients With Acute Intracerebral Hemorrhage [Accepted Manuscript], Jason J. Chang, Yasser Khorchid, Ali Kerro, L. Goodwin Burgess, Nitin Goyal, Anne W. Alexandrov, Andrei V. Alexandrov, Georgios Tsivgoulis Jan 2017

Sulfonylurea Drug Pretreatment And Functional Outcome In Diabetic Patients With Acute Intracerebral Hemorrhage [Accepted Manuscript], Jason J. Chang, Yasser Khorchid, Ali Kerro, L. Goodwin Burgess, Nitin Goyal, Anne W. Alexandrov, Andrei V. Alexandrov, Georgios Tsivgoulis

Faculty of Health Sciences Publications

Purpose: Intracerebral hemorrhage (ICH) is associated with poor clinical outcome and high mortality. Sulfonylurea (SFU) use may be a viable therapy for inhibiting sulfonylurea receptor-1 and NCCa-ATP channels and reducing perihematomal edema and blood-brain barrierdisruption. We sought to evaluate the effects of prehospital SFU use with outcomes in diabetic patients with acute ICH. Methods: We retrospectively analyzed a cohort of diabetic patients presenting with acute ICH at a tertiary care center. Study inclusion criteria included spontaneous ICH etiology and age > 18 years. Baseline clinical severity was documented using ICH-score. Hematoma volumes (HV) on admission were calculated using ABC/2 formula ...


Increased Cortical Porosity Is Associated With Daily, Not Weekly, Administration Of Equivalent Doses Of Teriparatide, Roger Zebaze, Ryoko Takao-Kawabata, Yu Peng, Ali Ghasem Zadeh, Kyoko Hirano, Hiroshi Yamane, Aya Takakura, Yukihiro Isogai, Toshinori Ishizuya, Ego Seeman Jan 2017

Increased Cortical Porosity Is Associated With Daily, Not Weekly, Administration Of Equivalent Doses Of Teriparatide, Roger Zebaze, Ryoko Takao-Kawabata, Yu Peng, Ali Ghasem Zadeh, Kyoko Hirano, Hiroshi Yamane, Aya Takakura, Yukihiro Isogai, Toshinori Ishizuya, Ego Seeman

Faculty of Health Sciences Publications

Introduction: The pharmacokinetic profile of parathyroid hormone (PTH) determines its effects on bone resorption and formation. When administered intermittently, anabolic effects are favored in comparison with the continuous treatment. Among the intermittent treatment regimens, lower frequency of administration may have a lower effect on bone remodeling. We therefore hypothesized that weekly administration of teriparatide will produce less increase in intracortical remodeling and porosity than reported using daily treatment. Methods: We treated 17 female New Zealand white rabbits aged 6 months for 1 month with teriparatide [human PTH(1-34)] as follows. (i) Vehicle-treated Control (n = 4); (ii) 20 μg/kg daily ...


Effects Of Acarbose On Cardiovascular And Diabetes Outcomes In Patients With Coronary Heart Disease And Impaired Glucose Tolerance (Ace): A Randomised, Double-Blind, Placebo-Controlled Trial [Accepted Manuscript], Rury R. Holman, Ruth L. Coleman, Juliana C. N. Chan, Jean-Louis Chiasson, Huimei Feng, Junbo Ge, Hertzel C. Gerstein, Richard Gray, Yong Huo, Zhihui Lang, John J. Mcmurray, Lars Rydén, Stefan Schröder, Yihong Sun, Michael J. Theodorakis, Michal Tendera, Lynne Tucker, Jaakko Tuomilehto, Yidong Wei, Wenying Yang, Duolao Wang, Dayi Hu, Changyu Pan Jan 2017

Effects Of Acarbose On Cardiovascular And Diabetes Outcomes In Patients With Coronary Heart Disease And Impaired Glucose Tolerance (Ace): A Randomised, Double-Blind, Placebo-Controlled Trial [Accepted Manuscript], Rury R. Holman, Ruth L. Coleman, Juliana C. N. Chan, Jean-Louis Chiasson, Huimei Feng, Junbo Ge, Hertzel C. Gerstein, Richard Gray, Yong Huo, Zhihui Lang, John J. Mcmurray, Lars Rydén, Stefan Schröder, Yihong Sun, Michael J. Theodorakis, Michal Tendera, Lynne Tucker, Jaakko Tuomilehto, Yidong Wei, Wenying Yang, Duolao Wang, Dayi Hu, Changyu Pan

Faculty of Health Sciences Publications

Background: The effect of the α-glucosidase inhibitor acarbose on cardiovascular outcomes in patients with coronary heart disease and impaired glucose tolerance is unknown. We aimed to assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced. Methods: The Acarbose Cardiovascular Evaluation (ACE) trial was a randomised, double-blind, placebo-controlled, phase 4 trial, with patients recruited from 176 hospital outpatient clinics in China. Chinese patients with coronary heart disease and impaired glucose tolerance were randomly assigned (1:1), in ...


Practical Issues In Evidence-Based Use Of Performance Supplements: Supplement Interactions, Repeated Use And Individual Responses, Louise M. Burke Jan 2017

Practical Issues In Evidence-Based Use Of Performance Supplements: Supplement Interactions, Repeated Use And Individual Responses, Louise M. Burke

Faculty of Health Sciences Publications

Current sports nutrition guidelines recommend that athletes only take supplements following an evidence-based analysis of their value in supporting training outcomes or competition performance in their specific event. While there is sound evidence to support the use of a few performance supplements under specific scenarios (creatine, beta-alanine, bicarbonate, caffeine, nitrate/beetroot juice and, perhaps, phosphate), there is a lack of information around several issues needed to guide the practical use of these products in competitive sport. First, there is limited knowledge around the strategy of combining the intake of several products in events in which performance benefits are seen with ...