138 results on '"Todd King"'
Search Results
2. Nutritional Ketosis as a Potential Treatment for Alcohol Use Disorder
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Vikrant R. Mahajan, Sophie K. Elvig, Leandro F. Vendruscolo, George F. Koob, Valerie L. Darcey, M. Todd King, Henry R. Kranzler, Nora D. Volkow, and Corinde E. Wiers
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alcoholism ,alcohol dependence ,alcohol withdrawal ,ketogenic diet ,ketone ester ,alcohol metabolism ,Psychiatry ,RC435-571 - Abstract
Alcohol use disorder (AUD) is a chronic, relapsing brain disorder, characterized by compulsive alcohol seeking and disrupted brain function. In individuals with AUD, abstinence from alcohol often precipitates withdrawal symptoms than can be life threatening. Here, we review evidence for nutritional ketosis as a potential means to reduce withdrawal and alcohol craving. We also review the underlying mechanisms of action of ketosis. Several findings suggest that during alcohol intoxication there is a shift from glucose to acetate metabolism that is enhanced in individuals with AUD. During withdrawal, there is a decline in acetate levels that can result in an energy deficit and could contribute to neurotoxicity. A ketogenic diet or ingestion of a ketone ester elevates ketone bodies (acetoacetate, β-hydroxybutyrate and acetone) in plasma and brain, resulting in nutritional ketosis. These effects have been shown to reduce alcohol withdrawal symptoms, alcohol craving, and alcohol consumption in both preclinical and clinical studies. Thus, nutritional ketosis may represent a unique treatment option for AUD: namely, a nutritional intervention that could be used alone or to augment the effects of medications.
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- 2021
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- View/download PDF
3. Ketone Ester D‐β‐Hydroxybutyrate‐(R)‐1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice
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Phung N. Thai, Charles V. Miller, M. Todd King, Saul Schaefer, Richard L. Veech, Nipavan Chiamvimonvat, Donald M. Bers, and Elena N. Dedkova
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cardiac function ,roGFP2‐GRX1 ,glutathione peroxidase 4 ,ketone bodies metabolism ,ketone ester ,mitochondrial permeability transition ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Heart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes mellitus. However, existing therapeutics for type 2 diabetes mellitus have limited success on the prevention of diabetic cardiomyopathy. The aim of this study was to determine whether moderate elevation in D‐β‐hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus. Methods and Results Type 2 diabetic (db/db) and their corresponding wild‐type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D‐β‐hydroxybutyrate‐(R)‐1,3 butanediol monoester (ketone ester [KE]). After 4 weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db/db mice. A KE diet increased expression of mitochondrial succinyl‐CoA:3‐oxoacid‐CoA transferase and restored decreased expression of mitochondrial β‐hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP‐mediated oxygen consumption in cardiac mitochondria from both wild‐type and db/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db/db mice on a KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin and glutathione peroxidase 4 and less permeability transition pore activity in mitochondria. Mitochondrial biogenesis, quality control, and elimination of dysfunctional mitochondria via mitophagy were significantly increased in cardiomyocytes from db/db mice on a KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 expression, which contributed to improved coupling between cytosolic E3 ubiquitin ligase translocation into mitochondria and microtubule‐associated protein 1 light chain 3–mediated autophagosome formation. Conclusions Moderate elevation in circulating D‐β‐hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control, and oxygen consumption and increases resistance to oxidative/redox stress and mPTP opening, thus resulting in improvement of cardiac function in animals with type 2 diabetes mellitus.
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- 2021
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4. HAPI: An API Standard for Accessing Heliophysics Time Series Data
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Robert S. Weigel, Jon Vandegriff, Jerry Faden, Todd King, D Aaron Roberts, Bernard T Harris, Robert Candey, Nand Lal, Scott Boardsen, Chris Lindholm, Doug Lindholm, Thomas Baltzer, Lawrence E. Brown, Eric W. Grimes, Baptiste Cecconi, Vincent Génot, Benjamin Renard, Arnaud Masson, and Beatriz Martinez
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Solar Physics - Abstract
Heliophysics data analysis often involves combining diverse science measurements, many of them captured as time series. Although there are now only a few commonly used data file formats, the diversity in mechanisms for automated access to and aggregation of such data holdings can make analysis that requires intercomparison of data from multiple data providers difficult. The Heliophysics Application Programmer's Interface (HAPI) is a recently developed standard for accessing distributed time series data to increase interoperability. The HAPI specification is based on the common elements of existing data services, and it standardizes the two main parts of a data service: the request interface and the response data structures. The interface is based on the REpresentational State Transfer (REST) or RESTful architecture style, and the HAPI specification defines five required REST endpoints. Data are returned via a streaming format that hides file boundaries; the metadata is detailed enough for the content to be scientifically useful, e.g., plotted with appropriate axes layout, units, and labels. Multiple mature HAPI-related open-source projects offer server-side implementation tools and client-side libraries for reading HAPI data in multiple languages (IDL, Java, MATLAB, and Python). Multiple data providers in the US and Europe have added HAPI access alongside their existing interfaces. Based on this experience, data can be served via HAPI with little or no information loss compared to similar existing web interfaces. Finally, HAPI has been recommended as a COSPAR standard for time series data delivery.
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- 2021
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5. The SPASE Data Model: A Metadata Standard for Registering, Finding, Accessing, and Using Heliophysics Data Obtained From Observations and Modeling
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D. Aaron Roberts, James Thieman, Vincent Génot, Todd King, Michel Gangloff, Chris Perry, Chiu Wiegand, Darren De Zeeuw, Shing F. Fung, Baptiste Cecconi, and Sébastien Hess
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- 2018
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6. MASER: A Science Ready Toolbox for Low Frequency Radio Astronomy.
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Baptiste Cecconi, Alan Loh, Pierre Le Sidaner, Renaud Savalle, Xavier Bonnin, Quynh Nhu Nguyen, Sonny Lion, Albert Shih, Stéphane Aicardi, Philippe Zarka, Corentin Louis, Andrée Coffre, Laurent Lamy, Laurent Denis, Jean-Mathias Grießmeier, Jeremy Faden, Chris Piker, Nicolas André, Vincent Génot, Stéphane Erard, Joseph N. Mafi, Todd King, Jim Sky, and Markus Demleitner
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- 2020
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7. Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice
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Vikrant R. Mahajan, Jacob A. Nadel, M. Todd King, Robert J. Pawlosky, Margaret I. Davis, Richard L. Veech, David M. Lovinger, and Armando G. Salinas
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BackgroundParkinson’s disease is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark mouse recapitulates several facets of Parkinson’s disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress.ObjectiveWe assessed whether administration of a ketone ester-enriched diet would improve motor and dopamine release deficits in MitoPark mice.MethodsMotor function (rotarod and open field tests), dopamine release (fast-scan cyclic voltammetry), tissue dopamine levels (GC-MS), and dopamine neurons and axons (immunofluorescence) were assessed in MitoPark and control mice fed either the standard or ketone ester-enriched diets.ResultsWhen started on the ketone diet before motor dysfunction onset, MitoPark mice had preserved motor function relative to standard diet MitoPark mice. While the ketone ester enriched diet did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MitoPark mice was greater than standard diet MitoPark mice but less than control mice. In a follow up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MitoPark mice relative to standard diet MitoPark mice.ConclusionThe improvement in motor dysfunction indicates that a ketone ester enriched diet or ketone supplement may represent a promising adjunct treatment for Parkinson’s disease.
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- 2022
8. A Dietary Ketone Ester Normalizes Abnormal Behavior in a Mouse Model of Alzheimer’s Disease
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Robert J. Pawlosky, Yoshihero Kashiwaya, M. Todd King, and Richard L. Veech
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ketone bodies ,hippocampus ,tca cycle ,mitochondria ,pyruvate dehydrogenase ,anxiety ,n-acetyl-aspartate ,ketosis ,insulin ,glucose metabolism ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Because of a decreased sensitivity toward insulin, a key regulator of pyruvate dehydrogenase (PDH), Alzheimer’s patients have lower brain glucose utilization with reductions in Tricarboxylic Acid (TCA) cycle metabolites such as citrate, a precursor to n-acetyl-aspartate. In the 3xTgAd mouse model of Alzheimer’s disease (AD), aging mice also demonstrate low brain glucose metabolism. Ketone metabolism can overcome PDH inhibition and restore TCA cycle metabolites, thereby enhancing amino acid biosynthesis. A ketone ester of d-β-hydroxybutyrate was incorporated into a diet (Ket) and fed to 3xTgAd mice. A control group was fed a calorically matched diet (Cho). At 15 months of age, the exploratory and avoidance-related behavior patterns of the mice were evaluated. At 16.5 months of age, the animals were euthanized, and their hippocampi were analyzed for citrate, α-ketoglutarate, and amino acids. In the hippocampi of the Ket-fed mice, there were higher concentrations of citrate and α-ketoglutarate as well as higher concentrations of glutamate, aspartate and n-acetyl-aspartate compared with controls. There were positive associations between (1) concentrations of aspartate and n-acetyl-aspartate (n = 14, R = 0.9327), and (2) α-ketoglutarate and glutamate (n = 14, R = 0.8521) in animals maintained on either diet. Hippocampal n-acetyl-aspartate predicted the outcome of several exploratory and avoidance-related behaviors. Ketosis restored citrate and α-ketoglutarate in the hippocampi of aging mice. Higher concentrations of n-acetyl-aspartate corresponded with greater exploratory activity and reduced avoidance-related behavior.
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- 2020
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9. Lightweight Detection of Program Refactorings.
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Darren C. Atkinson and Todd King
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- 2005
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10. An Ester of β-Hydroxybutyrate Regulates Cholesterol Biosynthesis in Rats and a Cholesterol Biomarker in Humans
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Kemper, Martin F., Srivastava, Shireesh, Todd King, M., Clarke, Kieran, Veech, Richard L., and Pawlosky, Robert J.
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- 2015
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11. SPASE: The Connection along Solar and Space Physics Data Centers.
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James R. Thieman, D. Aaron Roberts, and Todd King
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- 2013
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12. Designing science web sites.
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Kica Worrilow, Todd King, Raymond Walker, Mark E. Rose, William Moore, and Steven Joy
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- 2010
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13. A registry framework and Rosetta attributes for distributed science.
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Todd King, Jan Merka, Thomas W. Narock, Raymond J. Walker, and Lee Bargatze
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- 2010
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14. SPASE 2.0: a standard data model for space physics.
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Todd King, James R. Thieman, and D. Aaron Roberts
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- 2010
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15. SPASE and the Heliophysics Virtual Observatories.
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James R. Thieman, D. Aaron Roberts, Todd King, Christopher C. Harvey, Christopher H. Perry, and Phil Richards
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- 2010
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16. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects
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Clarke, Kieran, Tchabanenko, Kirill, Pawlosky, Robert, Carter, Emma, Todd King, M., Musa-Veloso, Kathy, Ho, Manki, Roberts, Ashley, Robertson, Jeremy, VanItallie, Theodore B., and Veech, Richard L.
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- 2012
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17. A brave new (virtual) world: distributed searches, relevance scoring and facets.
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Todd King, Thomas W. Narock, Raymond J. Walker, Jan Merka, and Steven Joy
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- 2008
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18. The architecture of a multi-tiered virtual observatory.
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Todd King, Jan Merka, Raymond J. Walker, Steven Joy, and Thomas W. Narock
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- 2008
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19. Virtual observatories for space and solar physics research.
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Christopher C. Harvey, Michel Gangloff, Todd King, Christopher H. Perry, D. Aaron Roberts, and James R. Thieman
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- 2008
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20. Developing a SPASE Query Language.
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Thomas W. Narock and Todd King
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- 2008
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21. Relationship between inorganic ion distribution, resting membrane potential, and the ΔG ' of ATP hydrolysis: a new paradigm
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Richard L. Veech, Patrick C. Bradshaw, Robert J. Pawlosky, William Curtis, and M. Todd King
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0301 basic medicine ,Membrane potential ,Chemistry ,Diffusion ,Inorganic ions ,Kinetic energy ,Biochemistry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,ATP hydrolysis ,Genetics ,Biophysics ,Distribution (pharmacology) ,Na+/K+-ATPase ,Molecular Biology ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Cell membrane potential and inorganic ion distributions are currently viewed from a kinetic electric paradigm, which ignores thermodynamics. The resting membrane potential is viewed as a diffusion ...
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- 2019
22. Standardizing Access to Heliophysics Data - HAPI Specification Updates and Some New Usages for Cloud and Model Data
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Jon Vandegriff, Eric Winter, Alex Antunes, Brent Smith, Robert Weigel, Jeremy Faden, D Aaron Roberts, Robert Candey, Eric Grimes, Scott Boardsen, Bernard Harris, and Todd King
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- 2021
23. Nutritional Ketosis as a Potential Treatment for Alcohol Use Disorder
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Leandro F. Vendruscolo, Nora D. Volkow, Corinde E. Wiers, Sophie K. Elvig, Vikrant R. Mahajan, George F. Koob, Valerie L. Darcey, M. Todd King, and Henry R. Kranzler
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media_common.quotation_subject ,medicine.medical_treatment ,alcohol dependence ,RC435-571 ,Physiology ,Alcohol ,Alcohol use disorder ,Review ,chemistry.chemical_compound ,Alcohol intoxication ,mental disorders ,medicine ,alcohol withdrawal ,media_common ,ketone ester ,Psychiatry ,alcoholism ,business.industry ,Alcohol dependence ,Abstinence ,medicine.disease ,Psychiatry and Mental health ,chemistry ,ketogenic diet ,Ketone bodies ,alcohol metabolism ,Ketosis ,business ,Ketogenic diet - Abstract
Alcohol use disorder (AUD) is a chronic, relapsing brain disorder, characterized by compulsive alcohol seeking and disrupted brain function. In individuals with AUD, abstinence from alcohol often precipitates withdrawal symptoms than can be life threatening. Here, we review evidence for nutritional ketosis as a potential means to reduce withdrawal and alcohol craving. We also review the underlying mechanisms of action of ketosis. Several findings suggest that during alcohol intoxication there is a shift from glucose to acetate metabolism that is enhanced in individuals with AUD. During withdrawal, there is a decline in acetate levels that can result in an energy deficit and could contribute to neurotoxicity. A ketogenic diet or ingestion of a ketone ester elevates ketone bodies (acetoacetate, β-hydroxybutyrate and acetone) in plasma and brain, resulting in nutritional ketosis. These effects have been shown to reduce alcohol withdrawal symptoms, alcohol craving, and alcohol consumption in both preclinical and clinical studies. Thus, nutritional ketosis may represent a unique treatment option for AUD: namely, a nutritional intervention that could be used alone or to augment the effects of medications.
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- 2021
24. HAPI: An API Standard for Accessing Heliophysics Time Series Data
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Scott A. Boardsen, Thomas Baltzer, D. Aaron Roberts, B. Renard, Doug Lindholm, Robert S. Weigel, Vincent Génot, Lawrence D. Brown, Beatriz Martinez, Arnaud Masson, Robert M. Candey, Todd King, Chris Lindholm, Baptiste Cecconi, Nand Lal, B. T. Harris, Jeremy Faden, Eric Grimes, Jon Vandegriff, Laboratoire d'études spatiales et d'instrumentation en astrophysique = Laboratory of Space Studies and Instrumentation in Astrophysics (LESIA), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de recherche en astrophysique et planétologie (IRAP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)
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Geophysics ,Information retrieval ,Heliophysics ,data ,Series (mathematics) ,[SDU]Sciences of the Universe [physics] ,Space and Planetary Science ,Computer science ,API ,Data file ,time series ,Time series - Abstract
International audience; Heliophysics data analysis often involves combining diverse science measurements, many of them captured as time series. Although there are now only a few commonly used data file formats, the diversity in mechanisms for automated access to and aggregation of such data holdings can make analysis that requires intercomparison of data from multiple data providers difficult. The Heliophysics Application Programmer's Interface (HAPI) is a recently developed standard for accessing distributed time series data to increase interoperability. The HAPI specification is based on the common elements of existing data services, and it standardizes the two main parts of a data service: the request interface and the response data structures. The interface is based on the REpresentational State Transfer (REST) or RESTful architecture style, and the HAPI specification defines five required REST endpoints. Data are returned via a streaming format that hides file boundaries; the metadata is detailed enough for the content to be scientifically useful, e.g., plotted with appropriate axes layout, units, and labels. Multiple mature HAPI-related open-source projects offer server-side implementation tools and client-side libraries for reading HAPI data in multiple languages (IDL, Java, MATLAB, and Python). Multiple data providers in the US and Europe have added HAPI access alongside their existing interfaces. Based on this experience, data can be served via HAPI with little or no information loss compared to similar existing web interfaces. Finally, HAPI has been recommended as a COSPAR standard for time series data delivery.
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- 2021
25. The Design, Development and Operation of a Distributed Data Inventory System.
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Todd King, Steven Joy, and Raymond J. Walker
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- 1994
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26. Ketone Ester D-β-Hydroxybutyrate-(R)-1,3 Butanediol Prevents Decline in Cardiac Function in Type 2 Diabetic Mice
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Richard L. Veech, Elena N. Dedkova, Nipavan Chiamvimonvat, Charles Miller, M. Todd King, Phung N. Thai, Saul Schaefer, and Donald M. Bers
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Cardiac function curve ,medicine.medical_specialty ,Ketone ,Mice, Inbred Strains ,GPX4 ,Mitochondria, Heart ,Diabetes Mellitus, Experimental ,chemistry.chemical_compound ,Mice ,Internal medicine ,Medicine ,1,3-Butanediol ,Animals ,Humans ,Butylene Glycols ,chemistry.chemical_classification ,3-Hydroxybutyric Acid ,business.industry ,Type 2 Diabetes Mellitus ,Esters ,Ketones ,medicine.disease ,Endocrinology ,chemistry ,Mitochondrial permeability transition pore ,Diabetes Mellitus, Type 2 ,Heart failure ,Thioredoxin ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background Heart failure is responsible for approximately 65% of deaths in patients with type 2 diabetes mellitus. However, existing therapeutics for type 2 diabetes mellitus have limited success on the prevention of diabetic cardiomyopathy. The aim of this study was to determine whether moderate elevation in D‐β‐hydroxybutyrate improves cardiac function in animals with type 2 diabetes mellitus. Methods and Results Type 2 diabetic (db/db) and their corresponding wild‐type mice were fed a control diet or a diet where carbohydrates were equicalorically replaced by D‐β‐hydroxybutyrate‐(R)‐1,3 butanediol monoester (ketone ester [KE]). After 4 weeks, echocardiography demonstrated that a KE diet improved systolic and diastolic function in db/db mice. A KE diet increased expression of mitochondrial succinyl‐CoA:3‐oxoacid‐CoA transferase and restored decreased expression of mitochondrial β‐hydroxybutyrate dehydrogenase, key enzymes in cardiac ketone metabolism. A KE diet significantly enhanced both basal and ADP‐mediated oxygen consumption in cardiac mitochondria from both wild‐type and db/db animals; however, it did not result in the increased mitochondrial respiratory control ratio. Additionally, db/db mice on a KE diet had increased resistance to oxidative and redox stress, with evidence of restoration of decreased expression of thioredoxin and glutathione peroxidase 4 and less permeability transition pore activity in mitochondria. Mitochondrial biogenesis, quality control, and elimination of dysfunctional mitochondria via mitophagy were significantly increased in cardiomyocytes from db/db mice on a KE diet. The increase in mitophagy was correlated with restoration of mitofusin 2 expression, which contributed to improved coupling between cytosolic E3 ubiquitin ligase translocation into mitochondria and microtubule‐associated protein 1 light chain 3–mediated autophagosome formation. Conclusions Moderate elevation in circulating D‐β‐hydroxybutyrate levels via KE supplementation enhances mitochondrial biogenesis, quality control, and oxygen consumption and increases resistance to oxidative/redox stress and mPTP opening, thus resulting in improvement of cardiac function in animals with type 2 diabetes mellitus.
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- 2021
27. A Standard for Accessing Heliophysics Time Series Data
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Robert S Weigel, Jon Vandegriff, Jeremy B. Faden, Todd King, D Aaron Roberts, Bernard Harris, Robert M. Candey, Scott A. Boardsen, Doug Lindholm, Chris Lindholm, Thomas Baltzer, Lawrence Elwin Brown, E. W. Grimes, Baptiste Cecconi, Vincent Génot, Arnaud Masson, Beatriz Martinez, Benjamin Renard, and Nand Lal
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- 2021
28. Standardizing Time Series Data Access across Heliophysics and Planetary Data Centers using HAPI
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D. M. Lindholm, B. T. Harris, In Sook Moon, Todd King, Scott A. Boardsen, Nand Lal, Lawrence D. Brown, Jeremy Faden, Robert M. Candey, Christopher Lindholm, Robert S. Weigel, Eric Grimes, Jon Vandegriff, and D. Aaron Roberts
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Heliophysics ,Computer science ,Interoperability ,Time series ,Space weather ,Data science - Abstract
Interoperability between datasets in Heliophysics and Planetary archives is increasingly important to address complex science questions about space weather and planetary plasma environments. Yet fo...
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- 2020
29. Nutritional Modulation of Heart Failure in Mitochondrial Pyruvate Carrier-Deficient Mice
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Deborah M. Muoio, Timothy R. Koves, Carla J. Weinheimer, Richard L. Veech, Richard W. Gross, Attila Kovacs, Kelly D. Pyles, Trevor M. Shew, Kyle S. McCommis, M. Todd King, Olga Ilkayeva, Dakota R. Kamm, Brian N. Finck, and Brian J. DeBosch
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Cardiac function curve ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Anion Transport Proteins ,Citric Acid Cycle ,Down-Regulation ,Ketone Bodies ,Mitochondrion ,Mitochondrial Membrane Transport Proteins ,Article ,Mitochondria, Heart ,Mice ,Physiology (medical) ,Internal medicine ,Pyruvic Acid ,Internal Medicine ,medicine ,Animals ,Humans ,Metabolomics ,Heart metabolism ,Heart Failure ,Mice, Knockout ,business.industry ,Myocardium ,Dilated cardiomyopathy ,Cell Biology ,Fasting ,medicine.disease ,Lipid Metabolism ,Myocardial Contraction ,Mice, Inbred C57BL ,Endocrinology ,Heart failure ,Ketone bodies ,cardiovascular system ,Ketosis ,business ,Diet, Ketogenic ,Ketogenic diet - Abstract
The myocardium is metabolically flexible; however, impaired flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) complex, composed of MPC1 and MPC2, is required for pyruvate import into the mitochondria. Here we show that MPC1 and MPC2 expression is downregulated in failing human and mouse hearts. Mice with cardiac-specific deletion of Mpc2 (CS-MPC2−/−) exhibited normal cardiac size and function at 6 weeks old, but progressively developed cardiac dilation and contractile dysfunction, which was completely reversed by a high-fat, low-carbohydrate ketogenic diet. Diets with higher fat content, but enough carbohydrate to limit ketosis, also improved heart failure, while direct ketone body provisioning provided only minor improvements in cardiac remodelling in CS-MPC2−/− mice. An acute fast also improved cardiac remodelling. Together, our results reveal a critical role for mitochondrial pyruvate use in cardiac function, and highlight the potential of dietary interventions to enhance cardiac fat metabolism to prevent or reverse cardiac dysfunction and remodelling in the setting of MPC deficiency. Impaired myocardial metabolic flexibility is associated with cardiac dysfunction in diabetes and heart failure. McCommis et al. reveal a critical role for mitochondrial pyruvate use in cardiac function, and use dietary interventions to enhance cardiac fat metabolism in dilated cardiomyopathy.
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- 2020
30. MASER: A Science Ready Toolbox for Low Frequency Radio Astronomy
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Alan Loh, Baptiste Cecconi, J. Sky, Laurent Denis, Pierre Le Sidaner, Vincent Génot, Xavier Bonnin, Renaud Savalle, Joseph N. Mafi, Stéphane Erard, A. Coffre, Stéphane Aicardi, Corentin K. Louis, Chris Piker, Sonny Lion, Quynh Nhu Nguyen, P. Zarka, Jeremy Faden, Nicolas André, Markus Demleitner, Jean-Mathias Grießmeier, Laurent Lamy, Todd King, Albert Y. Shih, Laboratoire d'études spatiales et d'instrumentation en astrophysique (LESIA (UMR_8109)), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Unité Scientifique de la Station de Nançay (USN), Centre National de la Recherche Scientifique (CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire des Sciences de l'Univers en région Centre (OSUC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Observatoire de Paris, Université Paris sciences et lettres (PSL), Laboratoire de Physique et Chimie de l'Environnement et de l'Espace (LPC2E), Observatoire des Sciences de l'Univers en région Centre (OSUC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Centre National d’Études Spatiales [Paris] (CNES), Institut de recherche en astrophysique et planétologie (IRAP), Institut national des sciences de l'Univers (INSU - CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), CNRS-INSU : through ASOV., European Project: 871149,EPN2024-RI, European Project: 654208,H2020,H2020-INFRAIA-2014-2015,EPN2020-RI(2015), Laboratoire d'études spatiales et d'instrumentation en astrophysique = Laboratory of Space Studies and Instrumentation in Astrophysics (LESIA), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris sciences et lettres (PSL)-Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)
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010504 meteorology & atmospheric sciences ,Computer science ,[SDU.ASTR.EP]Sciences of the Universe [physics]/Astrophysics [astro-ph]/Earth and Planetary Astrophysics [astro-ph.EP] ,FOS: Physical sciences ,interoperability ,Low frequency ,radio astronomy ,7. Clean energy ,01 natural sciences ,law.invention ,Jupiter ,law ,Planet ,Saturn ,Computer Science (miscellaneous) ,Maser ,lcsh:Science (General) ,Instrumentation and Methods for Astrophysics (astro-ph.IM) ,0105 earth and related environmental sciences ,Earth and Planetary Astrophysics (astro-ph.EP) ,[SDU.ASTR]Sciences of the Universe [physics]/Astrophysics [astro-ph] ,Radio astronomy ,Tools ,Interoperability ,05 social sciences ,Astronomy ,Space physics ,Galaxy ,Computer Science Applications ,[SDU]Sciences of the Universe [physics] ,tools ,0509 other social sciences ,Ionosphere ,Astrophysics - Instrumentation and Methods for Astrophysics ,050904 information & library sciences ,Astrophysics - Earth and Planetary Astrophysics ,lcsh:Q1-390 - Abstract
MASER (Measurements, Analysis, and Simulation of Emission in the Radio range) is a comprehensive infrastructure dedicated to time-dependent low frequency radio astronomy (up to about 50 MHz). The main radio sources observed in this spectral range are the Sun, the magnetized planets (Earth, Jupiter, Saturn), and our Galaxy, which are observed either from ground or space. Ground observatories can capture high resolution data streams with a high sensitivity. Conversely, space-borne instruments can observe below the ionospheric cut-off (at about 10 MHz) and can be placed closer to the studied object. Several tools have been developed in the last decade for sharing space physics data. Data visualization tools developed by various institutes are available to share, display and analyse space physics time series and spectrograms. The MASER team has selected a sub-set of those tools and applied them to low frequency radio astronomy. MASER also includes a Python software library for reading raw data from agency archives., Submitted to Data Science Journal special issue after PV2018 conference
- Published
- 2020
31. Ketogenic Diet Prevents Heart Failure from Defective Mitochondrial Pyruvate Metabolism
- Author
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Attila Kovacs, Kelly D. Pyles, Olga Ilkayeva, Trevor M. Shew, M. Todd King, Carla J. Weinheimer, Richard L. Veech, Timothy R. Koves, Brian J. DeBosch, Dakota R. Kamm, Brian N. Finck, Richard W. Gross, Kyle S. McCommis, and Deborah M. Muoio
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2. Zero hunger ,chemistry.chemical_classification ,0303 health sciences ,medicine.medical_specialty ,Chemistry ,medicine.medical_treatment ,Dilated cardiomyopathy ,030204 cardiovascular system & hematology ,Carbohydrate ,medicine.disease ,Amino acid ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Heart failure ,Diabetes mellitus ,Internal medicine ,medicine ,Ketone bodies ,Ketosis ,030304 developmental biology ,Ketogenic diet - Abstract
The myocardium is metabolically flexible and can use fatty acids, glucose, lactate/pyruvate, ketones, or amino acids to fuel mechanical work. However, impaired metabolic flexibility is associated with cardiac dysfunction in conditions including diabetes and heart failure. The mitochondrial pyruvate carrier (MPC) is required for pyruvate metabolism and is composed of a hetero-oligomer of two proteins known as MPC1 and MPC2. Interestingly, MPC1 and MPC2 expression is downregulated in failing human hearts and in a mouse model of heart failure. Mice with cardiac-specific deletion of MPC2 (CS-MPC2-/-) exhibited loss of both MPC2 and MPC1 proteins and reduced pyruvate-stimulated mitochondrial respiration. CS-MPC2-/- mice exhibited normal cardiac size and function at 6-weeks old, but progressively developed cardiac dilation and contractile dysfunction thereafter. Feeding CS-MPC2-/- mice a ketogenic diet (KD) completely prevented or reversed the cardiac remodeling and dysfunction. Other diets with higher fat content and enough carbohydrate to limit ketosis also improved heart failure in CS-MPC2-/- mice, but direct ketone body provisioning provided only minor improvements in cardiac remodeling. Finally, KD was also able to prevent further remodeling in an ischemic, pressure-overload mouse model of heart failure. In conclusion, loss of mitochondrial pyruvate utilization leads to dilated cardiomyopathy that can be corrected by a ketogenic diet.
- Published
- 2020
- Full Text
- View/download PDF
32. Interoperability for Heliophysics and Planetary Time Series Data via HAPI
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B. T. Harris, D. Aaron Roberts, Nand Lal, Scott A. Boardsen, Robert S. Weigel, Todd King, Jeremy Faden, Eric Grimes, Jon Vandegriff, Lawrence D. Brown, and Robert M. Candey
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business.industry ,Computer science ,Interoperability ,Python (programming language) ,Data structure ,Data access ,Software ,Heliophysics ,Server ,Software engineering ,business ,Implementation ,computer ,computer.programming_language - Abstract
The Heliophysics Application Programmer’s Interface (HAPI) represents a grass-roots effort to develop a common interface that data providers can use to offer time series data for computer-to-computer data access. Multiple data centers with Heliophysics and Planetary data are adopting this emerging standard. Several scientific analysis packages (Autoplot, SPEDAS) seamlessly pull from HAPI servers, and we have created and are enhancing Python libraries that can be used to read HAPI data into useful data structures within personalized analysis code. The HAPI specification and supporting software are available on GitHub. We will discuss the latest developments of the HAPI specification, current server and client implementations, all in the context of the push for increased interoperability within Heliophysics and Planetary data analysis. https://hapi-server.github.io/
- Published
- 2020
33. A Dietary Ketone Ester Normalizes Abnormal Behavior in a Mouse Model of Alzheimer's Disease
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Richard L. Veech, Yoshihero Kashiwaya, M. Todd King, and Robert J. Pawlosky
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0301 basic medicine ,Male ,hippocampus ,medicine.medical_treatment ,Ketone Bodies ,lcsh:Chemistry ,Mice ,0302 clinical medicine ,lcsh:QH301-705.5 ,Spectroscopy ,n-acetyl-aspartate ,chemistry.chemical_classification ,Communication ,Glutamate receptor ,Brain ,Esters ,General Medicine ,Ketones ,Pyruvate dehydrogenase complex ,anxiety ,Computer Science Applications ,Amino acid ,mitochondria ,Ketone bodies ,medicine.medical_specialty ,insulin ,ketosis ,glucose metabolism ,Citric Acid Cycle ,Glutamic Acid ,Carbohydrate metabolism ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,pyruvate dehydrogenase ,Alzheimer Disease ,Internal medicine ,medicine ,Animals ,Physical and Theoretical Chemistry ,Molecular Biology ,TCA cycle ,Aspartic Acid ,Insulin ,Organic Chemistry ,medicine.disease ,Diet ,Citric acid cycle ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Glucose ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Ketosis ,030217 neurology & neurosurgery - Abstract
Because of a decreased sensitivity toward insulin, a key regulator of pyruvate dehydrogenase (PDH), Alzheimer’s patients have lower brain glucose utilization with reductions in Tricarboxylic Acid (TCA) cycle metabolites such as citrate, a precursor to n-acetyl-aspartate. In the 3xTgAd mouse model of Alzheimer’s disease (AD), aging mice also demonstrate low brain glucose metabolism. Ketone metabolism can overcome PDH inhibition and restore TCA cycle metabolites, thereby enhancing amino acid biosynthesis. A ketone ester of d-β-hydroxybutyrate was incorporated into a diet (Ket) and fed to 3xTgAd mice. A control group was fed a calorically matched diet (Cho). At 15 months of age, the exploratory and avoidance-related behavior patterns of the mice were evaluated. At 16.5 months of age, the animals were euthanized, and their hippocampi were analyzed for citrate, α-ketoglutarate, and amino acids. In the hippocampi of the Ket-fed mice, there were higher concentrations of citrate and α-ketoglutarate as well as higher concentrations of glutamate, aspartate and n-acetyl-aspartate compared with controls. There were positive associations between (1) concentrations of aspartate and n-acetyl-aspartate (n = 14, R = 0.9327), and (2) α-ketoglutarate and glutamate (n = 14, R = 0.8521) in animals maintained on either diet. Hippocampal n-acetyl-aspartate predicted the outcome of several exploratory and avoidance-related behaviors. Ketosis restored citrate and α-ketoglutarate in the hippocampi of aging mice. Higher concentrations of n-acetyl-aspartate corresponded with greater exploratory activity and reduced avoidance-related behavior.
- Published
- 2019
34. Ketone bodies mimic the life span extending properties of caloric restriction
- Author
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Kieran Clarke, William Curtis, M. Todd King, Robert J. Pawlosky, Richard L. Veech, and Patrick C. Bradshaw
- Subjects
0301 basic medicine ,Clinical Biochemistry ,Calorie restriction ,Cell Biology ,Metabolism ,Biology ,medicine.disease ,Biochemistry ,Superoxide dismutase ,03 medical and health sciences ,030104 developmental biology ,Genetics ,Ketone bodies ,medicine ,biology.protein ,Ketosis ,Molecular Biology ,Transcription factor ,PI3K/AKT/mTOR pathway ,Free-radical theory of aging - Abstract
The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3 ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. © 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5):305-314, 2017.
- Published
- 2017
35. Changing Gears in the Motor City: A Case Study on Great Lakes Water Authority’s Shift to Proactive Pipe Management
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Susan Donnally, Bryon Wood, Todd King, and Jody Caldwell
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Water authority ,Business ,Environmental planning - Published
- 2019
36. SIRT3 Haploinsufficiency Aggravates Loss of GABAergic Interneurons and Neuronal Network Hyperexcitability in an Alzheimer's Disease Model
- Author
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Qijin Zhao, Jing Wang, Myriam Gorospe, Ruiqian Wan, Richard L. Veech, M. Todd King, Nathaniel Ghena, Aiwu Cheng, Mark P. Mattson, and Isabella Perone
- Subjects
0301 basic medicine ,Male ,SIRT3 ,Mice, Transgenic ,Neuroprotection ,03 medical and health sciences ,Amyloid beta-Protein Precursor ,Mice ,0302 clinical medicine ,Alzheimer Disease ,Interneurons ,Seizures ,Sirtuin 3 ,medicine ,Premovement neuronal activity ,Animals ,Humans ,gamma-Aminobutyric Acid ,Cerebral Cortex ,Epilepsy ,biology ,General Neuroscience ,Electroencephalography ,Ketones ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Cerebral cortex ,Nerve Degeneration ,biology.protein ,GABAergic ,Female ,Alzheimer's disease ,Calretinin ,Nerve Net ,Diet, Ketogenic ,Neuroscience ,030217 neurology & neurosurgery ,Parvalbumin - Abstract
Impaired mitochondrial function and aberrant neuronal network activity are believed to be early events in the pathogenesis of Alzheimer's disease (AD), but how mitochondrial alterations contribute to aberrant activity in neuronal circuits is unknown. In this study, we examined the function of mitochondrial protein deacetylase sirtuin 3 (SIRT3) in the pathogenesis of AD. Compared with AppPs1 mice, Sirt3-haploinsufficient AppPs1 mice (Sirt3+/−AppPs1) exhibit early epileptiform EEG activity and seizure. Both male and female Sirt3+/−AppPs1 mice were observed to die prematurely before 5 months of age. When comparing male mice among different genotypes, Sirt3 haploinsufficiency renders GABAergic interneurons in the cerebral cortex vulnerable to degeneration and associated neuronal network hyperexcitability. Feeding Sirt3+/−AppPs1 AD mice with a ketone ester-rich diet increases SIRT3 expression and prevents seizure-related death and the degeneration of GABAergic neurons, indicating that the aggravated GABAergic neuron loss and neuronal network hyperexcitability in Sirt3+/−AppPs1 mice are caused by SIRT3 reduction and can be rescued by increase of SIRT3 expression. Consistent with a protective role in AD, SIRT3 levels are reduced in association with cerebral cortical Aβ pathology in AD patients. In summary, SIRT3 preserves GABAergic interneurons and protects cerebral circuits against hyperexcitability, and this neuroprotective mechanism can be bolstered by dietary ketone esters.SIGNIFICANCE STATEMENTGABAergic neurons provide the main inhibitory control of neuronal activity in the brain. By preserving mitochondrial function, SIRT3 protects parvalbumin and calretinin interneurons against Aβ-associated dysfunction and degeneration in AppPs1 Alzheimer's disease mice, thus restraining neuronal network hyperactivity. The neuronal network dysfunction that occurs in Alzheimer's disease can be partially reversed by physiological, dietary, and pharmacological interventions to increase SIRT3 expression and enhance the functionality of GABAergic interneurons.
- Published
- 2019
37. MASER (Measuring Analyzing & Simulating Emissions in Radio frequencies), a Toolbox for Low Frequency Radio Astronomy
- Author
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Sonny Lion, A. Loh, J. Sky, Vincent Génot, Albert Y. Shih, Patrick Canu, Xavier Bonnin, Jean-Mathias Greißmeier, Markus Demleitner, Quynh Nhu Nguyen, Nicolas André, Baptiste Cecconi, Pierre Le Sidaner, Todd King, Corentin Louis, A. Coffre, Stéphane Aicardi, C. Piker, Stéphane Erard, Mark Sharlow, Laurent Denis, Renaud Savalle, Jeremy Faden, Joseph N. Mafi, Jean-Louis Pinçon, Laurent Lamy, and Philippe Zarka
- Subjects
law ,Astrophysics::High Energy Astrophysical Phenomena ,Environmental science ,Astrophysics::Cosmology and Extragalactic Astrophysics ,Radio frequency ,Low frequency ,Maser ,Astrophysics::Galaxy Astrophysics ,Toolbox ,Remote sensing ,Radio astronomy ,law.invention - Abstract
The MASER (Measuring, Analysing and Simulating Radio Emissions) project provides a comprehensive infrastructure dedicated to low frequency radio emissions (typically < 50 to 100 MHz). The four main...
- Published
- 2018
38. Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes
- Author
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Alan Smith, Tom Ashmore, Andrew J. Murray, Julian L. Griffin, Brianna J. Stubbs, Scott Drawer, Rhys D. Evans, Stefan Neubauer, Tom Kirk, Pete J. Cox, Kieran Clarke, Richard L. Veech, Stewart W. McLure, James A. West, Cameron J. Holloway, Kristof Willerton, M. Todd King, Michael S. Dodd, Murray, Andrew [0000-0002-0929-9315], West, James [0000-0002-1535-7737], Griffin, Julian [0000-0003-1336-7744], and Apollo - University of Cambridge Repository
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,Rest ,Carbohydrates ,Ketone Bodies ,Oxidative phosphorylation ,0601 Biochemistry and Cell Biology ,Endocrinology & Metabolism ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Carnitine ,Internal medicine ,medicine ,Humans ,Glycolysis ,Exercise physiology ,Muscle, Skeletal ,Exercise ,Molecular Biology ,Adiposity ,Glycogen ,Chemistry ,Ketosis ,030229 sport sciences ,Cell Biology ,Metabolism ,Carbohydrate ,medicine.disease ,Diet ,030104 developmental biology ,Endocrinology ,1101 Medical Biochemistry and Metabolomics ,Athletes ,Physical Endurance ,Ketone bodies ,Female ,Energy Metabolism - Abstract
Ketosis, the metabolic response to energy crisis, is a mechanism to sustain life by altering oxidative fuel selection. Often overlooked for its metabolic potential, ketosis is poorly understood outside of starvation or diabetic crisis. Thus, we studied the biochemical advantages of ketosis in humans using a ketone ester-based form of nutrition without the unwanted milieu of endogenous ketone body production by caloric or carbohydrate restriction. In five separate studies of 39 high-performance athletes, we show how this unique metabolic state improves physical endurance by altering fuel competition for oxidative respiration. Ketosis decreased muscle glycolysis and plasma lactate concentrations, while providing an alternative substrate for oxidative phosphorylation. Ketosis increased intramuscular triacylglycerol oxidation during exercise, even in the presence of normal muscle glycogen, co-ingested carbohydrate and elevated insulin. These findings may hold clues to greater human potential and a better understanding of fuel metabolism in health and disease.
- Published
- 2016
39. A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate
- Author
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Hee-Woong Lim, Nathaniel W. Snyder, Kyoung-Jae Won, Mary T. Doan, Wenshan Wang, Joseph A. Baur, Sean O'Connor, Sophie Trefely, Alexis J. Cowan, Alexander P. Sakers, Rana K. Gupta, Paul Cohen, Richard L. Veech, Patrick Seale, Joshua D. Rabinowitz, M. Todd King, Mengle Shao, and Jeff Ishibashi
- Subjects
0301 basic medicine ,Male ,Physiology ,Blotting, Western ,Adipose tissue ,In Vitro Techniques ,Mass Spectrometry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Fibrosis ,Adipocyte ,Precursor cell ,medicine ,Adipocytes ,Animals ,Humans ,Molecular Biology ,Transcription factor ,PRDM16 ,Adipogenesis ,3-Hydroxybutyric Acid ,Catabolism ,Chemistry ,Cell Biology ,Adipose Tissue, Beige ,medicine.disease ,Flow Cytometry ,Cell biology ,DNA-Binding Proteins ,030104 developmental biology ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. This adipogenic versus fibrogenic fate decision is poorly understood. Cold exposure or β3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice reduced fibrosis and restored beige adipogenesis. PRDM16-expressing adipose cells secreted the metabolite β-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and enhanced beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and restored beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling.
- Published
- 2018
40. Ketone Bodies and their Polymers in Heart Failure and Type 2 Diabetes: Lessons Learned from the Ketone Ester Diet
- Author
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Phung N. Thai, Eleonora Zakharian, Elena N. Dedkova, Richard L. Veech, Donald M. Bers, M. Todd King, Saul Schaefer, and Lusine Demirkhanyan
- Subjects
chemistry.chemical_classification ,medicine.medical_specialty ,Endocrinology ,Ketone ,chemistry ,Internal medicine ,Heart failure ,Biophysics ,medicine ,Ketone bodies ,Type 2 diabetes ,medicine.disease - Published
- 2019
41. The “great” controlling nucleotide coenzymes
- Author
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Veech, Richard L., primary, Todd King, Michael, additional, Pawlosky, Robert, additional, Kashiwaya, Yoshihiro, additional, Bradshaw, Patrick C., additional, and Curtis, William, additional
- Published
- 2019
- Full Text
- View/download PDF
42. Effectiveness of a sediment time critical removal action-PCB reduction in fish tissue, surface water, and sediment via wet excavation
- Author
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John W Kern, Andrew D Santini, Todd King, and Keith Krawczyk
- Subjects
location.dated_location ,geography ,geography.geographical_feature_category ,Floodplain ,Environmental remediation ,Geography, Planning and Development ,Environmental engineering ,Sediment ,Polychlorinated biphenyl ,General Medicine ,Portage Creek ,Contamination ,chemistry.chemical_compound ,location ,chemistry ,Environmental science ,Surface water ,General Environmental Science ,Catfish - Abstract
Documenting successful remediation of polychlorinated biphenyl (PCB)-contaminated sediments is limited; potentially due to inadequate monitoring methods, complexities associated with the environment, and selected remedial techniques. At some sites, absence of appropriate baseline and postremoval monitoring limits proper evaluation of remedial efficacy. Accurate interpretation of interactions between media, space, time, species, lipid content, and remedial technique requires robust study design and data. This article presents baseline and postremoval data documenting reduced PCB concentrations in fish tissue, surface water, and sediment in response to the US Environmental Protection Agency (USEPA) time-critical removal action (TCRA) that was conducted at the former Bryant Mill Pond (BMP) on Portage Creek in Kalamazoo, Michigan. The BMP is part of an operable unit (OU) within the Allied Paper, Inc./Portage Creek/Kalamazoo River Superfund Site. PCBs discharged to the creek as a byproduct of carbonless copy paper recycling are the primary contaminant of concern. Paper waste residuals commonly appear as gray to light gray clays in river sediments and floodplain soils. The cleanup criterion was 10 mg/kg, with a residual PCB concentration goal of 1 mg/kg. Because the PCB-containing waste is (generally) associated with readily visible light gray clay, excavation of all visibly contaminated current or formerly impounded sediment served as a surrogate for the cleanup criteria and goal. Sediment was wet excavated and backfilled after diversion of the creek. After confirmation that PCB concentrations met cleanup criteria, the stream was diverted to the excavated side, and excavation and backfilling were completed. Overall, 146 000 cubic yards of material including PCB-contaminated sediments were removed from the BMP. The long-term monitoring (LTM) program implemented by the Michigan Department of Environmental Quality (MDEQ), and historic data from a variety of sources (federal, state, and local agencies and responsible parties) provided data demonstrating TCRA effectiveness. Before TCRA, surface sediment PCB concentration in instream and formerly inundated sediment combined was 83 mg/kg (with a maximum of 700 mg/kg). Instream sediments that are more representative of fish exposures had a pre-TCRA surface weighted average concentration (SWAC) of 27 mg/kg. The post-TCRA SWAC for instream and floodplain sediments combined was 0.26 mg/kg. Average surface water concentrations at the downstream end of the BMP were reduced from 0.11 µg/L pre-TCRA to 0.0025 µg/L post-TCRA. Tissue samples for adult carp fillets decreased from 4 mg/kg pre-TCRA to 0.26 mg/kg post-TCRA; whole body white suckers from 3 mg/kg pre-TCRA to 0.1 mg/kg post-TCRA; whole body channel catfish from 39 mg/kg-L pre-TCRA to 2.6 mg/kg-L post-TCRA. Concentrations of PCBs in 2 species of resident fish (carp and white suckers), caged channel catfish, surface water, and sediment were reduced by over 1 order of magnitude within 1 year of completion, substantively accelerating natural recovery processes. A slight increase in PCB concentration was observed in both whole body suckers and adult carp fillets in the second monitoring period post-TCRA; however, these concentrations are still near an order of magnitude less than pre-TCRA concentrations and appear to be currently stable or on a slight downward trend. Integr Environ Assess Manag 2015;11:161–170. © 2014 SETAC
- Published
- 2014
43. Ketone bodies mimic the life span extending properties of caloric restriction
- Author
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Richard L, Veech, Patrick C, Bradshaw, Kieran, Clarke, William, Curtis, Robert, Pawlosky, and M Todd, King
- Subjects
Aging ,Oxidative Stress ,Longevity ,Animals ,Humans ,Pyruvate Dehydrogenase Complex ,Ketone Bodies ,Caenorhabditis elegans ,Telomere Shortening ,Caloric Restriction - Abstract
The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP
- Published
- 2017
44. The Neutral Gas and Ion Mass Spectrometer on the Mars Atmosphere and Volatile Evolution Mission
- Author
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Cynthia Gundersen, Ryan M. Miller, E. Raaen, Marvin Noriega, Patrick Kimvilakani, J. Thomas Nolan, Ferzan Jaeger, Todd King, Charles Edmonson, Ken Arnett, James W. Kellogg, Robert Arvey, Florence Tan, Edwin Weidner, Steven Battel, Kiran Patel, Felix Noreiga, Curt Cooper, B. D. Prats, Anthony Melak, Christopher S. Johnson, Therese Errigo, Mehdi Benna, Paul R. Mahaffy, Jerome Hengemihle, Matthew Lefavor, Vincent Holmes, Daniel Carrigan, Eric Lyness, John Maurer, Bruce P. Block, Michael Barciniak, D. N. Harpold, and Mirl Bendt
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Atmospheric escape ,Astronomy and Astrophysics ,Atmosphere of Mars ,Mars Exploration Program ,Atmospheric sciences ,Ion source ,Astrobiology ,Atmosphere ,Solar wind ,Planetary science ,Space and Planetary Science ,Physics::Space Physics ,Astrophysics::Solar and Stellar Astrophysics ,Environmental science ,Astrophysics::Earth and Planetary Astrophysics ,Ionosphere ,Physics::Atmospheric and Oceanic Physics - Abstract
The Neutral Gas and Ion Mass Spectrometer (NGIMS) of the Mars Atmosphere and Volatile Evolution Mission (MAVEN) is designed to measure the composition, struc- ture, and variability of the upper atmosphere of Mars. The NGIMS complements two other instrument packages on the MAVEN spacecraft designed to characterize the neutral upper atmosphere and ionosphere of Mars and the solar wind input to this region of the atmo- sphere. The combined measurement set is designed to quantify atmosphere escape rates and provide input to models of the evolution of the martian atmosphere. The NGIMS is designed to measure both surface reactive and inert neutral species and ambient ions along the space- craft track over the 125-500 km altitude region utilizing a dual ion source and a quadrupole analyzer.
- Published
- 2014
45. Mitigation of Damage from Reactive Oxygen Species and Ionizing Radiation by Ketone Body Esters
- Author
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William Curtis, Martin Kemper, Alexandra Miller, Robert Pawlosky, M. Todd King, and Richard L. Veech
- Abstract
Reactive oxygen and nitrogen species, ROS and RNS, are ubiquitous in living cells. They have beneficial effects but are also the cause of a wide variety of diseases. However adding excessive amounts of reducing agents has a long history of clinical failure. This problem can be overcome by providing a novel ester of D-beta-hydroxybutyrate–R-1,3-butanediol, which is rapidly hydrolyzed to ketone bodies, the metabolism of which leads to the production of NADPH. The free cytosolic [NADP+]/[NADPH] redox potential is the most negative in the cell and sets the potential of the glutathione and ascorbic acid couples. Ketone bodies also act by inhibiting histone deacetylases, activating the transcription factor FOXO3 and increasing the transcription of enzymes involved in the destruction of ROS. Ketone esters would be effective in the treatment of a variety of disparate diseases where ROS play a role, ranging from Parkinson’s disease to radiation sickness and aging.
- Published
- 2016
46. Alzheimer’s Disease
- Author
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Richard L. Veech and M. Todd King
- Abstract
Deficits in cerebral glucose utilization in Alzheimer’s disease (AD) arise decades before cognitive impairment and accumulation of amyloid plaques and neurofibrillary tangles in brain. Addressing this metabolic deficit has greater potential in treating AD than targeting later disease processes – an approach that has failed consistently in the clinic. Cerebral glucose utilization requires numerous enzymes, many of which have been shown to decline in AD. Perhaps the most important is pyruvate dehydrogenase (PDH), which links glycolysis with the Krebs cycle and aerobic metabolism, and whose activity is greatly suppressed in AD. The unique metabolism of ketone bodies allows them to bypass the block at pyruvate dehydrogenase and restore brain metabolism. Recent studies in mouse genetic models of AD and in a human Alzheimer’s patient showed the potential of ketones in maintaining brain energetics and function. Oral ketone bodies might be a promising avenue for treatment of Alzheimer’s disease.
- Published
- 2016
47. The energetics of ion distribution: the origin of the resting electric potential of cells
- Author
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Kieran Clarke, Richard L. Veech, D Gates, Yoshihiro Kashiwaya, and M. Todd King
- Subjects
Male ,ATPase ,Clinical Biochemistry ,Analytical chemistry ,Inorganic ions ,Biochemistry ,Ion ,Membrane Potentials ,symbols.namesake ,Adenosine Triphosphate ,ATP hydrolysis ,Cations ,Genetics ,Animals ,Nernst equation ,Rats, Wistar ,Molecular Biology ,Membrane potential ,Ions ,biology ,Chemistry ,Hydrolysis ,Myocardium ,Sodium ,Water ,Cell Biology ,Hydrogen-Ion Concentration ,Resting potential ,Rats ,Electrophysiology ,Liver ,symbols ,biology.protein ,Potassium ,Thermodynamics ,Electric potential - Abstract
The relation between the energies of ion movement and ATP hydrolysis is unknown in tissues with widely varying electric potentials. Consequently, we measured the concentration of the nine major inorganic ions in the extra- and intracellular phases in heart, liver, and red cells with resting electrical potentials, E(N), of -86, -28, and -6 mV, respectively, under six different physiological conditions. We calculated the Nernst electric potential and the energy of ion movement between the phases. We found that the energy of ATP hydrolysis was essentially constant, between -54 and -58 kJ/mol, in all tissues and conditions. In contrast, as E(N) decreased, the energies of the Na+ and K+ gradients decreased, with slopes approximating their valence. The difference between the energies of Na+ and K+ gradients remained constant at 17 kJ/mol, which is approximately one third of the energy of ATP hydrolysis, demonstrating near-equilibrium of the Na+/K+ ATPase in all tissues under all conditions. All cations, except K+, were pumped out of cells and all anions, except Cl- in liver and red cell, were pumped into cells. We conclude that the energy of ATP was expressed in Na+/K+ ATPase and its linked inorganic ion transporters to create a Gibbs-Donnan near-equilibrium system, an inherent part of which was the electric potential.
- Published
- 2016
48. Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects
- Author
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Theodore B. VanItallie, Richard L. Veech, Kathy Musa-Veloso, Kirill Tchabanenko, M. Todd King, Kieran Clarke, Emma Carter, Manki Ho, Robert J. Pawlosky, Jeremy Robertson, and Ashley Roberts
- Subjects
Adult ,Male ,medicine.medical_specialty ,Ketone ,Meal replacement ,Adolescent ,medicine.medical_treatment ,Kinetics ,Hydroxybutyrates ,Toxicology ,Body weight ,Article ,Young Adult ,Internal medicine ,medicine ,Ingestion ,Humans ,chemistry.chemical_classification ,General Medicine ,Plasma levels ,Ketones ,Middle Aged ,Endocrinology ,chemistry ,Biochemistry ,Tolerability ,Dietary Supplements ,Female ,Ketogenic diet - Abstract
Induction of mild states of hyperketonemia may improve physical and cognitive performance. In this study, we determined the kinetic parameters, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, a ketone monoester administered in the form of a meal replacement drink to healthy human volunteers. Plasma levels of β-hydroxybutyrate and acetoacetate were elevated following administration of a single dose of the ketone monoester, whether at 140, 357, or 714 mg/kg body weight, while the intact ester was not detected. Maximum plasma levels of ketones were attained within 1–2 h, reaching 3.30 mM and 1.19 mM for β-hydroxybutyrate and acetoacetate, respectively, at the highest dose tested. The elimination half-life ranged from 0.8–3.1 h for β-hydroxybutyrate and 8–14 h for acetoacetate. The ketone monoester was also administered at 140, 357, and 714 mg/kg body weight, three times daily, over 5 days (equivalent to 0.42, 1.07, and 2.14 g/kg/d). The ketone ester was generally well-tolerated, although some gastrointestinal effects were reported, when large volumes of milk-based drink were consumed, at the highest ketone monoester dose. Together, these results suggest ingestion of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate is a safe and simple method to elevate blood ketone levels, compared with the inconvenience of preparing and consuming a ketogenic diet.
- Published
- 2016
49. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer's disease
- Author
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Mohamed R. Mughal, Yoshihiro Kashiwaya, Kieran Clarke, Ruiqian Wan, Mark P. Mattson, Eitan Okun, M. Todd King, Jong Hwan Lee, Richard L. Veech, and Christian Bergman
- Subjects
Male ,Aging ,medicine.medical_specialty ,Amyloid ,medicine.drug_class ,medicine.medical_treatment ,Hippocampus ,Mice, Transgenic ,tau Proteins ,Anxiety ,Anxiolytic ,Amygdala ,Article ,Mice ,Random Allocation ,Alzheimer Disease ,Internal medicine ,medicine ,Animals ,Maze Learning ,Amyloid beta-Peptides ,Chemistry ,General Neuroscience ,Subiculum ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Ketone bodies ,Neurology (clinical) ,Geriatrics and Gerontology ,Alzheimer's disease ,Cognition Disorders ,Diet, Ketogenic ,Neuroscience ,Developmental Biology ,Ketogenic diet - Abstract
Alzheimer's disease (AD) involves progressive accumulation of amyloid β-peptide (Aβ) and neurofibrillary pathologies, and glucose hypometabolism in brain regions critical for memory. The 3xTgAD mouse model was used to test the hypothesis that a ketone ester-based diet can ameliorate AD pathogenesis. Beginning at a presymptomatic age, 2 groups of male 3xTgAD mice were fed a diet containing a physiological enantiomeric precursor of ketone bodies (KET) or an isocaloric carbohydrate diet. The results of behavioral tests performed at 4 and 7 months after diet initiation revealed that KET-fed mice exhibited significantly less anxiety in 2 different tests. 3xTgAD mice on the KET diet also exhibited significant, albeit relatively subtle, improvements in performance on learning and memory tests. Immunohistochemical analyses revealed that KET-fed mice exhibited decreased Aβ deposition in the subiculum, CA1 and CA3 regions of the hippocampus, and the amygdala. KET-fed mice exhibited reduced levels of hyperphosphorylated tau deposition in the same regions of the hippocampus, amygdala, and cortex. Thus, a novel ketone ester can ameliorate proteopathic and behavioral deficits in a mouse AD model. © 2013 .
- Published
- 2016
50. Mitochondrial Biogenesis and Increased Uncoupling Protein 1 in Brown Adipose Tissue of Mice Fed a Ketone Ester Diet
- Author
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Joseph Tam, Richard L. Veech, M. Todd King, Gang Niu, Kieran Clarke, Shireesh Srivastava, Xiaoyuan Chen, Yoshihiro Kashiwaya, and Ulrich Baxa
- Subjects
Leptin ,Male ,medicine.medical_specialty ,Adipose tissue ,Hydroxybutyrates ,Ketone Bodies ,Biology ,Biochemistry ,Ion Channels ,Research Communications ,Mitochondrial Proteins ,Eating ,Mice ,Adipose Tissue, Brown ,Microscopy, Electron, Transmission ,Fluorodeoxyglucose F18 ,Internal medicine ,Brown adipose tissue ,Genetics ,medicine ,Animals ,Resting energy expenditure ,Molecular Biology ,Uncoupling Protein 1 ,3-Hydroxybutyric Acid ,KE diet ,Thermogenin ,Diet ,Mitochondria ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,Mitochondrial biogenesis ,Electron Transport Chain Complex Proteins ,Ketone bodies ,Insulin Resistance ,Biotechnology - Abstract
We measured the effects of a diet in which d-β-hydroxybutyrate-(R)-1,3 butanediol monoester [ketone ester (KE)] replaced equicaloric amounts of carbohydrate on 8-wk-old male C57BL/6J mice. Diets contained equal amounts of fat, protein, and micronutrients. The KE group was fed ad libitum, whereas the control (Ctrl) mice were pair-fed to the KE group. Blood d-β-hydroxybutyrate levels in the KE group were 3-5 times those reported with high-fat ketogenic diets. Voluntary food intake was reduced dose dependently with the KE diet. Feeding the KE diet for up to 1 mo increased the number of mitochondria and doubled the electron transport chain proteins, uncoupling protein 1, and mitochondrial biogenesis-regulating proteins in the interscapular brown adipose tissue (IBAT). [18F]-Fluorodeoxyglucose uptake in IBAT of the KE group was twice that in IBAT of the Ctrl group. Plasma leptin levels of the KE group were more than 2-fold those of the Ctrl group and were associated with increased sympathetic nervous system activity to IBAT. The KE group exhibited 14% greater resting energy expenditure, but the total energy expenditure measured over a 24-h period or body weights was not different. The quantitative insulin-sensitivity check index was 73% higher in the KE group. These results identify KE as a potential antiobesity supplement.—Srivastava, S., Kashiwaya, Y., King, M. T. Baxa, U., Tam, J., Niu, G., Chen, X., Clarke, K., Veech, R. L. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet.
- Published
- 2016
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