Nmd Monitors Translational Fidelity 24/7, 2017 University of Massachusetts Medical School
Nmd Monitors Translational Fidelity 24/7, Alper Celik, Feng He, Allan Jacobson
Open Access Articles
Nonsense-mediated mRNA decay (NMD) is generally thought to be a eukaryotic mRNA surveillance pathway tasked with the elimination of transcripts harboring an in-frame premature termination codon (PTC). As presently conceived, NMD acting in this manner minimizes the likelihood that potentially toxic polypeptide fragments would accumulate in the cytoplasm. This notion is to be contrasted to the results of systematic RNA-Seq and microarray analyses of NMD substrates in multiple model systems, two different experimental approaches which have shown that many mRNAs identified as NMD substrates fail to contain a PTC. Our recent results provide insight into, as well as a possible ...
Defining Electron Bifurcation In The Electron-Transferring Flavoprotein Family, 2017 Montana State University
Defining Electron Bifurcation In The Electron-Transferring Flavoprotein Family, Amaya M. Garcia Costas, Saroj Poudel, Anne-Frances Miller, Gerrit J. Schut, Rhesa N. Ledbetter, Kathryn R. Fixen, Lance C. Seefeldt, Michael W. W. Adams, Caroline S. Harwood, Eric S. Boyd, John W. Peters
Chemistry Faculty Publications
Electron bifurcation is the coupling of exergonic and endergonic redox reactions to simultaneously generate (or utilize) low- and high-potential electrons. It is the third recognized form of energy conservation in biology and was recently described for select electron-transferring flavoproteins (Etfs). Etfs are flavin-containing heterodimers best known for donating electrons derived from fatty acid and amino acid oxidation to an electron transfer respiratory chain via Etf-quinone oxidoreductase. Canonical examples contain a flavin adenine dinucleotide (FAD) that is involved in electron transfer, as well as a non-redox-active AMP. However, Etfs demonstrated to bifurcate electrons contain a second FAD in place of the ...
Mitochondrial Reactive Oxygen Species In Lipotoxic Hearts Induces Post-Translational Modifications Of Akap121, Drp1 And Opa1 That Promote Mitochondrial Fission, Kensuke Tsushima, Heiko Bugger, Adam R. Wende, Jamie Soto, Gregory A. Jenson, Austin R. Tor, Rose Mcglauflin, Helena C. Kenny, Yuan Zhang, Rhonda Souvenir, Xiao X. Hu, Crystal L. Sloan, Renata O. Pereira, Vitor A. Lira, Kenneth W. Spitzer, Terry L. Sharp, Kooresh I. Shoghi, Genevieve C. Sparagna, Eva A. Rog-Zielinska, Peter Kohl, Oleh Khalimonchuk, Jean E. Schaffer, E. Dale Abel
Biochemistry -- Faculty Publications
Rationale: Cardiac lipotoxicity, characterized by increased uptake, oxidation and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood.
Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo.
Methods and Results: Using a transgenic mouse model of cardiac lipotoxicity overexpressing long-chain acyl-CoA synthetase 1 in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation ...
Inhibition Of Cholesterol Biosynthesis Through Rnf145-Dependent Ubiquitination Of Scap, 2017 University of California - Los Angeles
Inhibition Of Cholesterol Biosynthesis Through Rnf145-Dependent Ubiquitination Of Scap, Li Zhang, Prashant Rajbhandari, Christina Priest, Jaspreet Sandhu, Xiaohui Wu, Ryan E. Temel, Antonio Castrillo, Thomas Q. De Aguiar Vallim, Tamer Sallam, Peter Tontonoz
Saha Cardiovascular Research Center Faculty Publications
Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show ...
Age Drives Distortion Of Brain Metabolic, Vascular And Cognitive Functions, And The Gut Microbiome, 2017 University of Kentucky
Age Drives Distortion Of Brain Metabolic, Vascular And Cognitive Functions, And The Gut Microbiome, Jared D. Hoffman, Ishita Parikh, Stefan J. Green, George Chlipala, Robert P. Mohney, Mignon Keaton, Bjoern Bauer, Anika M. S. Hartz, Ai-Ling Lin
Sanders-Brown Center on Aging Faculty Publications
Advancing age is the top risk factor for the development of neurodegenerative disorders, including Alzheimer’s disease (AD). However, the contribution of aging processes to AD etiology remains unclear. Emerging evidence shows that reduced brain metabolic and vascular functions occur decades before the onset of cognitive impairments, and these reductions are highly associated with low-grade, chronic inflammation developed in the brain over time. Interestingly, recent findings suggest that the gut microbiota may also play a critical role in modulating immune responses in the brain via the brain-gut axis. In this study, our goal was to identify associations between deleterious changes ...
A Cross-Sectional Study Of Dietary And Genetic Predictors Of Blood Folate Levels In Healthy Young Adults, Daniel Cummings, Kevin F. Dowling, Noah J. Silverstein, Alexandra S. Tanner, Hamdi Eryilmaz, Jordan W. Smoller, Joshua L. Roffman
Open Access Articles
Since 1998, the U.S. has mandated folic acid (FA) fortification of certain grain products to reduce the risk of neural tube defects. Folate intake and red blood cell (RBC) folate concentrations increased substantially post-intervention, although recent studies raise concerns about the level of ongoing benefit. This study investigated blood folate level determinants in healthy young adults, including intake of naturally occurring food folate, synthetic FA, and the interaction of naturally occurring food folate with a common missense variant in the FOLH1 gene thought to affect absorption. Participants (n = 265) completed the Diet History Questionnaire II, RBC folate testing, and ...
Probing The Metabolic Phenotype Of Breast Cancer Cells By Multiple Tracer Stable Isotope Resolved Metabolomics, 2017 University of Kentucky
Probing The Metabolic Phenotype Of Breast Cancer Cells By Multiple Tracer Stable Isotope Resolved Metabolomics, Andrew N. Lane, Julie Tan, Yali Wang, Jun Yan, Richard M. Higashi, Teresa W. -M. Fan
Center for Environmental and Systems Biochemistry Faculty Publications
Breast cancers vary by their origin and specific set of genetic lesions, which gives rise to distinct phenotypes and differential response to targeted and untargeted chemotherapies. To explore the functional differences of different breast cell types, we performed Stable Isotope Resolved Metabolomics (SIRM) studies of one primary breast (HMEC) and three breast cancer cells (MCF-7, MDAMB-231, and ZR75-1) having distinct genotypes and growth characteristics, using 13C6-glucose, 13C-1+2-glucose, 13C5,15N2-Gln, 13C3-glycerol, and 13C8-octanoate as tracers. These tracers were designed to probe the central energy producing ...
Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, 2017 University of Massachusetts Medical School
Intergenerational Effects Of Nicotine In An Animal Model Of Paternal Nicotine Exposure, Markus Parzival Vallaster
GSBS Dissertations and Theses
Environmental conditions imposed onto organisms during certain phases of their life cycles such as embryogenesis or puberty can not only impact the organisms’ own health, but also affect subsequent generations. The underlying mechanisms causing intergenerational phenotypes are not encoded in the genome, but the result of reversible epigenetic modifications. This work investigates in a mouse model the impact of paternal nicotine exposure on the next generation regarding addictive behavior modulation, metabolic changes, and molecular mechanisms. It provides evidence that male offspring from nicotine-exposed fathers (NIC offspring) is more resistant to lethal doses of nicotine. This phenotype is gender-specific and depends ...
Activin Receptor Type 2a (Acvr2a) Functions Directly In Osteoblasts As A Negative Regulator Of Bone Mass, 2017 Johns Hopkins University
Activin Receptor Type 2a (Acvr2a) Functions Directly In Osteoblasts As A Negative Regulator Of Bone Mass, Brian C. Goh, Vandana Singhal, Angelica J. Herrera, Ryan E. Tomlinson, Soohyun Kim, Marie-Claude Faugere, Emily L. Germain-Lee, Thomas L. Clemens, Se-Jin Lee, Douglas J. Digirolamo
Internal Medicine Faculty Publications
Bone and skeletal muscle mass are highly correlated in mammals, suggesting the existence of common anabolic signaling networks that coordinate the development of these two anatomically adjacent tissues. The activin signaling pathway is an attractive candidate to fulfill such a role. Here, we generated mice with conditional deletion of activin receptor (ACVR) type 2A, ACVR2B, or both, in osteoblasts, to determine the contribution of activin receptor signaling in regulating bone mass. Immunohistochemistry localized ACVR2A and ACVR2B to osteoblasts and osteocytes. Primary osteoblasts expressed activin signaling components, including ACVR2A, ACVR2B, and ACVR1B (ALK4) and demonstrated increased levels of phosphorylated Smad2/3 ...
Regulation Of Iron-Related Molecules In The Rat Hippocampus: Sex- And Age-Associated Differences, 2017 Marshall University
Regulation Of Iron-Related Molecules In The Rat Hippocampus: Sex- And Age-Associated Differences, Srinivasarao Thulluri, Miaozong Wu, Eric R. Blough, Nandini D.P.K. Manne, Ashley B. Litchfield, Bin Wang
Iron accumulation, especially that of free oxidized ferrous iron, has been shown to induce tissue oxidative damage and contribute to brain aging and the development of neurodegenerative disease. Here we examine whether sex and advanced age affect the expression of iron-related molecules that participate in regulating free iron levels (heme oxygenase I (HOI), iron-regulatory protein I (IRPI), and ferritin heavy chain (FTH)) and whether changes in the expression of these molecules are associated with differences in the expression of alpha-synuclein (ASN) which is thought to be a critical regulator in the pathogenesis of neurodegeneration. Using a well-established aging animal model ...
Autophagy And Protein Turnover Responses To Exercise-Nutrient Interactions In Human Skeletal Muscle, 2017 Australian Catholic University
Autophagy And Protein Turnover Responses To Exercise-Nutrient Interactions In Human Skeletal Muscle, William J. Smiles
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 ...
Glycolytic Reliance Promotes Anabolism In Photoreceptors, 2017 Harvard Medical School
Glycolytic Reliance Promotes Anabolism In Photoreceptors, Yashodhan Chinchore, Tedi Begaj, David Wu, Eugene Drokhlyansky, Constance L. Cepko
Senior Scholars Program
Vertebrate photoreceptors are among the most metabolically active cells, exhibiting a high rate of ATP consumption. This is coupled with a high anabolic demand, necessitated by the diurnal turnover of a specialized membrane-rich organelle, the outer segment, which is the primary site of phototransduction. How photoreceptors balance their catabolic and anabolic demands is poorly understood. Here, we show that rod photoreceptors in mice rely on glycolysis for their outer segment biogenesis. Genetic perturbations targeting allostery or key regulatory nodes in the glycolytic pathway impacted the size of the outer segments. Fibroblast growth factor signaling was found to regulate glycolysis, with ...
Obesity, Metabolic Factors And Risk Of Different Histological Types Of Lung Cancer: A Mendelian Randomization Study, 2017 International Agency for Research on Cancer (IARC), France
Obesity, Metabolic Factors And Risk Of Different Histological Types Of Lung Cancer: A Mendelian Randomization Study, Robert Carreras-Torres, Mattias Johansson, Philip C. Haycock, Kaitlin H. Wade, Caroline L. Relton, Richard M. Martin, George Davey Smith, Demetrius Albanes, Melinda C. Aldrich, Angeline Andrew, Susanne M. Arnold, Heike Bickeböller, Stig E. Bojesen, Hans Brunnström, Jonas Manjer, Irene Brüske, Neil E. Caporaso, Chu Chen, David C. Christiani, Warren Jay Christian, Jennifer A. Doherty, Eric J. Duell, John K. Field, Michael P. A. Davies, Michael W. Marcus, Gary E. Goodman, Kjell Grankvist, Aage Haugen, Yun-Chul Hong, Lambertus A. Kiemeney
Markey Cancer Center Faculty Publications
Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer.
Methods and findings
We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung ...
Exploring Cancer Metabolism Using Stable Isotope-Resolved Metabolomics (Sirm), 2017 University of Kentucky
Exploring Cancer Metabolism Using Stable Isotope-Resolved Metabolomics (Sirm), Ronald C. Bruntz, Andrew N. Lane, Richard M. Higashi, Teresa W. -M. Fan
Center for Environmental and Systems Biochemistry Faculty Publications
Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions.
Genome- And Cd4+ T-Cell Methylome-Wide Association Study Of Circulating Trimethylamine-N-Oxide In The Genetics Of Lipid Lowering Drugs And Diet Network (Goldn), 2017 The University of Alabama at Birmingham
Genome- And Cd4+ T-Cell Methylome-Wide Association Study Of Circulating Trimethylamine-N-Oxide In The Genetics Of Lipid Lowering Drugs And Diet Network (Goldn), Stella Aslibekyan, Marguerite R. Irvin, Bertha A. Hidalgo, Rodney T. Perry, Elias J. Jeyarajah, Erwin Garcia, Irina Shalaurova, Paul N. Hopkins, Michael A. Province, Hemant K. Tiwari, Jose M. Ordovas, Devin M. Absher, Donna K. Arnett
Epidemiology Faculty Publications
Background: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels.
Methods and results: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease ...
A National Perspective On Childhood Obesity Medical Education: Do Medical Students In Canada Perceive That They Are Prepared To Treat Children With Obesity?, 2017 The University of Western Ontario
A National Perspective On Childhood Obesity Medical Education: Do Medical Students In Canada Perceive That They Are Prepared To Treat Children With Obesity?, Dr. Dalia Hasan
Electronic Thesis and Dissertation Repository
The purposes of this survey-based, mixed-methods study were to investigate medical students’ perceptions of: (1) the overall level of medical school training acquired in relation to childhood obesity treatment; (2) the medical school training acquired in relation to specific competencies associated with the treatment of children with obesity and their caregiver(s); and (3) additional training needed. Results showed that of the 507 students who provided complete data, approximately 60% (n = 303) disagreed or strongly disagreed that their medical training related to childhood obesity was adequate. With regard to specific competencies and additional training needed, quantitative and qualitative data revealed ...
Temperature Induces Significant Changes In Both Glycolytic Reserve And Mitochondrial Spare Respiratory Capacity In Colorectal Cancer Cell Lines, Mihail I. Mitov, Jennifer W. Harris, Michael Alstott, Yekaterina Y. Zaytseva, B. Mark Evers, D. Allan Butterfield
Markey Cancer Center Faculty Publications
Thermotherapy, as a method of treating cancer, has recently attracted considerable attention from basic and clinical investigators. A number of studies and clinical trials have shown that thermotherapy can be successfully used as a therapeutic approach for various cancers. However, the effects of temperature on cancer bioenergetics have not been studied in detail with a real time, in a microplate, label-free detection approach.
This study investigate how changes in temperature affect the bioenergetics characteristics (mitochondrial function and glycolysis) of three colorectal cancer (CRC) cell lines utilizing the Seahorse XF96 technology. Experiments were performed at 32°C, 37°C and 42 ...
Dynamics Of Maternal And Infant Vitamin E Tocopherols During Nicu Hospitalization, 2017 University of Nebraska Medical Center
Dynamics Of Maternal And Infant Vitamin E Tocopherols During Nicu Hospitalization, Jana K. Wells
Theses & Dissertations
OBJECTIVE: The main objective of this prospective cohort is to investigate serum levels of vitamin E tocopherol isoforms (specifically alpha and gamma) in mothers and infants admitted to the Neonatal Intensive Care Unit (NICU) in relation to infant feeding modality.
METHODS: This was a prospective cohort of 34 mothers and their infants admitted to the neonatal intensive care unit (NICU). Samples of maternal and cord blood were collected at the time of delivery, and a food frequency questionnaire (FFQ) was administered to the mother to measure maternal vitamin E tocopherol intake. After nutrition treatment of each feeding modality had been ...
Effect Of Obesity And Exercise On The Expression Of The Novel Myokines, Myonectin And Fibronectin Type Iii Domain Containing 5, 2017 East Tennessee State University
Effect Of Obesity And Exercise On The Expression Of The Novel Myokines, Myonectin And Fibronectin Type Iii Domain Containing 5, Jonathan M. Peterson, Ryan Mart, Cherie E. Bond
Metabolic dysfunction in skeletal muscle is a major contributor to the development of type 2 diabetes. Endurance exercise training has long been established as an effective means to directly restore skeletal muscle glucose and lipid uptake and metabolism. However, in addition to the direct effects of skeletal muscle on glucose and lipids, there is renewed interest in the ability of skeletal muscle to coordinate metabolic activity of other tissues, such as adipose tissue and liver. The purpose of this study was to examine the effects of endurance exercise on the expression level of two novel muscle-derived secreted factors, or myokines ...
Investigating The Mechanism Of Novel Anticancer Agent, As1411 : Does Metabolism To Guanine Play A Role?, 2017 University of Louisville
Investigating The Mechanism Of Novel Anticancer Agent, As1411 : Does Metabolism To Guanine Play A Role?, Parker T Howard
College of Arts & Sciences Senior Honors Theses
AS1411 is an oligonucleotide that has shown promising results in lab experiments and clinical trials as an anti-cancer drug, Likewise, treatments with guanine based purine compounds (GBPCs) have demonstrated similar anti-proliferative effects in vitro. This activity is dependent on the HGPRT enzyme. Similarities in activity and physical structure has led us to believe that AS1411 and GBPCs operate by a similar mechanism. To test this, we compare the activity of both in the presence of HGPRT siRNAs and HGPRT deficient cells. While siRNA treatment was unable to alter the activity of GBPCs or AS1411 in our cell lines, HGPRT deficient ...