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Search Results: 1 - 10 of 217297 matches for " Charles L. Hoppel "
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Aged rat heart: Modulation of age-related respiratory defects decreases ischemic-reflow injury  [PDF]
Edward J. Lesnefsky, Charles L. Hoppel
Health (Health) , 2013, DOI: 10.4236/health.2013.51001
Abstract:

Myocardial injury increases in the elderly heart during ischemia and reperfusion. Mitochondria, the key targets and sources of injury during ischemia and reperfusion, sustain ischemic damage to the electron transport chain that is superimposed upon age-related defects. In the adult heart, interventions to activate endogenous cytoprotective signaling systems meet in mitochondria to decrease cardiac injury. Unfortunately, these systems are largely ineffective in the aged heart. Thus, new treatment concepts are needed to reduce injury in the aged heart. Our group chose a strategy to directly treat the effector of cardiac injury in the aged heart, the mitochondria. We further utilized a novel approach to ask if the reversal of aging defects in cardiac mitochondria before ischemia could decrease ischemia-reperfusion injury in the heart. Three hours following treatment with the small molecule, nutriceutical acetylcarnitine (AcCN), oxidative phosphorylation as well as age-induced defects in electron transport chain complexes III and IV was corrected in the heart. When such hearts were then exposed to ischemia and reperfusion, cardiac injury was markedly reduced. Contraction during reperfusion improved and recovery became similar to that in adult hearts. Cardiac cell death was substantially reduced. Thus, age-related defects in electron transport are a key mechanism of the increased myocardial injury in the elderly heart during ischemia and reperfusion. Modulation of aging-induced defects in mitochondrial metabolism reduces cardiac injury from ischemia and reperfusion, and is a novel strategy to protect myocardium in the elderly patient at risk for an acute myocardial infarction.

Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women
Oliver Fiehn,W. Timothy Garvey,John W. Newman,Kerry H. Lok,Charles L. Hoppel,Sean H. Adams
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015234
Abstract: Insulin resistance progressing to type 2 diabetes mellitus (T2DM) is marked by a broad perturbation of macronutrient intermediary metabolism. Understanding the biochemical networks that underlie metabolic homeostasis and how they associate with insulin action will help unravel diabetes etiology and should foster discovery of new biomarkers of disease risk and severity. We examined differences in plasma concentrations of >350 metabolites in fasted obese T2DM vs. obese non-diabetic African-American women, and utilized principal components analysis to identify 158 metabolite components that strongly correlated with fasting HbA1c over a broad range of the latter (r = ?0.631; p<0.0001). In addition to many unidentified small molecules, specific metabolites that were increased significantly in T2DM subjects included certain amino acids and their derivatives (i.e., leucine, 2-ketoisocaproate, valine, cystine, histidine), 2-hydroxybutanoate, long-chain fatty acids, and carbohydrate derivatives. Leucine and valine concentrations rose with increasing HbA1c, and significantly correlated with plasma acetylcarnitine concentrations. It is hypothesized that this reflects a close link between abnormalities in glucose homeostasis, amino acid catabolism, and efficiency of fuel combustion in the tricarboxylic acid (TCA) cycle. It is speculated that a mechanism for potential TCA cycle inefficiency concurrent with insulin resistance is “anaplerotic stress” emanating from reduced amino acid-derived carbon flux to TCA cycle intermediates, which if coupled to perturbation in cataplerosis would lead to net reduction in TCA cycle capacity relative to fuel delivery.
Leucine and Protein Metabolism in Obese Zucker Rats
Pengxiang She, Kristine C. Olson, Yoshihiro Kadota, Ayami Inukai, Yoshiharu Shimomura, Charles L. Hoppel, Sean H. Adams, Yasuko Kawamata, Hideki Matsumoto, Ryosei Sakai, Charles H. Lang, Christopher J. Lynch
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0059443
Abstract: Branched-chain amino acids (BCAAs) are circulating nutrient signals for protein accretion, however, they increase in obesity and elevations appear to be prognostic of diabetes. To understand the mechanisms whereby obesity affects BCAAs and protein metabolism, we employed metabolomics and measured rates of [1-14C]-leucine metabolism, tissue-specific protein synthesis and branched-chain keto-acid (BCKA) dehydrogenase complex (BCKDC) activities. Male obese Zucker rats (11-weeks old) had increased body weight (BW, 53%), liver (107%) and fat (~300%), but lower plantaris and gastrocnemius masses (?21–24%). Plasma BCAAs and BCKAs were elevated 45–69% and ~100%, respectively, in obese rats. Processes facilitating these rises appeared to include increased dietary intake (23%), leucine (Leu) turnover and proteolysis [35% per g fat free mass (FFM), urinary markers of proteolysis: 3-methylhistidine (183%) and 4-hydroxyproline (766%)] and decreased BCKDC per g kidney, heart, gastrocnemius and liver (?47–66%). A process disposing of circulating BCAAs, protein synthesis, was increased 23–29% by obesity in whole-body (FFM corrected), gastrocnemius and liver. Despite the observed decreases in BCKDC activities per gm tissue, rates of whole-body Leu oxidation in obese rats were 22% and 59% higher normalized to BW and FFM, respectively. Consistently, urinary concentrations of eight BCAA catabolism-derived acylcarnitines were also elevated. The unexpected increase in BCAA oxidation may be due to a substrate effect in liver. Supporting this idea, BCKAs were elevated more in liver (193–418%) than plasma or muscle, and per g losses of hepatic BCKDC activities were completely offset by increased liver mass, in contrast to other tissues. In summary, our results indicate that plasma BCKAs may represent a more sensitive metabolic signature for obesity than BCAAs. Processes supporting elevated BCAA]BCKAs in the obese Zucker rat include increased dietary intake, Leu and protein turnover along with impaired BCKDC activity. Elevated BCAAs/BCKAs may contribute to observed elevations in protein synthesis and BCAA oxidation.
Improved Mitochondrial Function with Diet-Induced Increase in Either Docosahexaenoic Acid or Arachidonic Acid in Membrane Phospholipids
Ramzi J. Khairallah, Junhwan Kim, Karen M. O'Shea, Kelly A. O'Connell, Bethany H. Brown, Tatiana Galvao, Caroline Daneault, Christine Des Rosiers, Brian M. Polster, Charles L. Hoppel, William C. Stanley
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034402
Abstract: Mitochondria can depolarize and trigger cell death through the opening of the mitochondrial permeability transition pore (MPTP). We recently showed that an increase in the long chain n3 polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA; 22:6n3) and depletion of the n6 PUFA arachidonic acid (ARA; 20:4n6) in mitochondrial membranes is associated with a greater Ca2+ load required to induce MPTP opening. Here we manipulated mitochondrial phospholipid composition by supplementing the diet with DHA, ARA or combined DHA+ARA in rats for 10 weeks. There were no effects on cardiac function, or respiration of isolated mitochondria. Analysis of mitochondrial phospholipids showed DHA supplementation increased DHA and displaced ARA in mitochondrial membranes, while supplementation with ARA or DHA+ARA increased ARA and depleted linoleic acid (18:2n6). Phospholipid analysis revealed a similar pattern, particularly in cardiolipin. Tetralinoleoyl cardiolipin was depleted by 80% with ARA or DHA+ARA supplementation, with linoleic acid side chains replaced by ARA. Both the DHA and ARA groups had delayed Ca2+-induced MPTP opening, but the DHA+ARA group was similar to the control diet. In conclusion, alterations in mitochondria membrane phospholipid fatty acid composition caused by dietary DHA or ARA was associated with a greater cumulative Ca2+ load required to induced MPTP opening. Further, high levels of tetralinoleoyl cardiolipin were not essential for normal mitochondrial function if replaced with very-long chain n3 or n6 PUFAs.
Improved Metabolic Health Alters Host Metabolism in Parallel with Changes in Systemic Xeno-Metabolites of Gut Origin
Caitlin Campbell, Dmitry Grapov, Oliver Fiehn, Carol J. Chandler, Dustin J. Burnett, Elaine C. Souza, Gretchen A. Casazza, Mary B. Gustafson, Nancy L. Keim, John W. Newman, Gary R. Hunter, Jose R. Fernandez, W. Timothy Garvey, Mary-Ellen Harper, Charles L. Hoppel, John K. Meissen, Kohei Take, Sean H. Adams
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0084260
Abstract: Novel plasma metabolite patterns reflective of improved metabolic health (insulin sensitivity, fitness, reduced body weight) were identified before and after a 14–17 wk weight loss and exercise intervention in sedentary, obese insulin-resistant women. To control for potential confounding effects of diet- or microbiome-derived molecules on the systemic metabolome, sampling was during a tightly-controlled feeding test week paradigm. Pairwise and multivariate analysis revealed intervention- and insulin-sensitivity associated: (1) Changes in plasma xeno-metabolites (“non-self” metabolites of dietary or gut microbial origin) following an oral glucose tolerance test (e.g. higher post-OGTT propane-1,2,3-tricarboxylate [tricarballylic acid]) or in the overnight-fasted state (e.g., lower γ-tocopherol); (2) Increased indices of saturated very long chain fatty acid elongation capacity; (3) Increased post-OGTT α-ketoglutaric acid (α-KG), fasting α-KG inversely correlated with Matsuda index, and altered patterns of malate, pyruvate and glutamine hypothesized to stem from improved mitochondrial efficiency and more robust oxidation of glucose. The results support a working model in which improved metabolic health modifies host metabolism in parallel with altering systemic exposure to xeno-metabolites. This highlights that interpretations regarding the origins of peripheral blood or urinary “signatures” of insulin resistance and metabolic health must consider the potentially important contribution of gut-derived metabolites toward the host's metabolome.
Assimilation of stratospheric and mesospheric temperatures from MLS and SABER into a global NWP model
K. W. Hoppel,N. L. Baker,L. Coy,S. D. Eckermann
Atmospheric Chemistry and Physics Discussions , 2008,
Abstract: The forecast model and three-dimensional variational data assimilation components of the Navy Operational Global Atmospheric Prediction System (NOGAPS) have each been extended into the upper stratosphere and mesosphere to form an Advanced Level Physics High Altitude (ALPHA) version of NOGAPS extending to ~100 km. This NOGAPS-ALPHA NWP prototype is used to assimilate stratospheric and mesospheric temperature data from the Microwave Limb Sounder (MLS) and the Sounding of the Atmosphere using Broadband Radiometry (SABER) instruments. A 60-day analysis period in January and February, 2006, was chosen that includes a well documented stratospheric sudden warming. SABER temperatures indicate that the SSW caused the polar winter stratopause at ~40 km to disappear, then reform at ~80 km altitude and slowly descend during February. The NOGAPS-ALPHA analysis reproduces this observed stratospheric and mesospheric temperature structure, as well as realistic evolution of zonal winds, residual velocities, and Eliassen-Palm fluxes that aid interpretation of the vertically deep circulation and eddy flux anomalies that developed in response to this wave-breaking event. The observation minus forecast (O-F) standard deviations for MLS and SABER are ~2 K in the mid-stratosphere and increase monotonically to about 6 K in the upper mesosphere. Increasing O-F standard deviations in the mesosphere are expected due to increasing instrument error and increasing geophysical variance at small spatial scales in the forecast model. In the mid/high latitude winter regions, 10-day forecast skill is improved throughout the upper stratosphere and mesosphere when the model is initialized using the high-altitude analysis based on assimilation of both SABER and MLS data.
Limitations of wind extraction from 4D-Var assimilation of ozone
D. R. Allen, K. W. Hoppel, G. E. Nedoluha, D. D. Kuhl, N. L. Baker, L. Xu,T. E. Rosmond
Atmospheric Chemistry and Physics (ACP) & Discussions (ACPD) , 2013,
Abstract: Time-dependent variational data assimilation allows the possibility of extracting wind information from observations of ozone or other trace gases. Since trace gas observations are not available at sufficient resolution for deriving feature-track winds, they must be combined with model background information to produce an analysis. If done with time-dependent variational assimilation, wind information may be extracted via the adjoint of the linearized tracer continuity equation. This paper presents idealized experiments that illustrate the mechanics of tracer–wind extraction and demonstrate some of the limitations of this procedure. We first examine tracer–wind extraction using a simple one-dimensional advection equation. The analytic solution for a single trace gas observation is discussed along with numerical solutions for multiple observations. The limitations of tracer–wind extraction are then explored using highly idealized ozone experiments performed with a development version of the Navy Global Environmental Model (NAVGEM) in which globally distributed hourly stratospheric ozone profiles are assimilated in a single 6 h update cycle in January 2009. Starting with perfect background ozone conditions, but imperfect dynamical conditions, ozone errors develop over the 6 h background window. Wind increments are introduced in the analysis in order to reduce the differences between background ozone and ozone observations. For "perfect" observations (unbiased and no random error), this results in root-mean-square (RMS) vector wind error reductions of up to ~4 m s 1 in the winter hemisphere and tropics. Wind extraction is more difficult in the summer hemisphere due to weak ozone gradients and smaller background wind errors. The limitations of wind extraction are also explored for observations with imposed random errors and for limited sampling patterns. As expected, the amount of wind information extracted degrades as observation errors or data voids increase. In the case of poorly specified observation error covariances, assimilation of ozone data with imposed errors may result in increased RMS wind error, since the assimilation is constrained too tightly to the noisy observations.
Assimilation of stratospheric and mesospheric temperatures from MLS and SABER into a global NWP model
K. W. Hoppel, N. L. Baker, L. Coy, S. D. Eckermann, J. P. McCormack, G. E. Nedoluha,D. E. Siskind
Atmospheric Chemistry and Physics (ACP) & Discussions (ACPD) , 2008,
Abstract: The forecast model and three-dimensional variational data assimilation components of the Navy Operational Global Atmospheric Prediction System (NOGAPS) have each been extended into the upper stratosphere and mesosphere to form an Advanced Level Physics High Altitude (ALPHA) version of NOGAPS extending to ~100 km. This NOGAPS-ALPHA NWP prototype is used to assimilate stratospheric and mesospheric temperature data from the Microwave Limb Sounder (MLS) and the Sounding of the Atmosphere using Broadband Emission Radiometry (SABER) instruments. A 60-day analysis period in January and February 2006, was chosen that includes a well documented stratospheric sudden warming. SABER and MLS temperatures indicate that the SSW caused the polar winter stratopause at ~40 km to disappear, then reform at ~80 km altitude and slowly descend during February. The NOGAPS-ALPHA analysis reproduces this observed stratospheric and mesospheric temperature structure, as well as realistic evolution of zonal winds, residual velocities, and Eliassen-Palm fluxes that aid interpretation of the vertically deep circulation and eddy flux anomalies that developed in response to this wave-breaking event. The observation minus forecast (O-F) standard deviations for MLS and SABER are ~2 K in the mid-stratosphere and increase monotonically to about 6 K in the upper mesosphere. Increasing O-F standard deviations in the mesosphere are expected due to increasing instrument error and increasing geophysical variance at small spatial scales in the forecast model. In the mid/high latitude winter regions, 10-day forecast skill is improved throughout the upper stratosphere and mesosphere when the model is initialized using the high-altitude analysis based on assimilation of both SABER and MLS data.
Semi-classical properties of geometric quantization with metaplectic correction
L. Charles
Mathematics , 2006, DOI: 10.1007/s00220-006-0155-5
Abstract: The geometric quantization of a symplectic manifold endowed with a prequantum bundle and a metaplectic structure is defined by means of an integrable complex structure. We prove that its semi-classical limit does not depend on the choice of the complex structure. We show this in two ways. First, by introducing unitary identifications between the quantum spaces associated to the various complex polarizations and second, by defining an asymptotically flat connection in the bundle of quantum spaces over the space of complex structures. Furthermore Berezin-Toeplitz operators are intertwined by these identifications and have principal and subprincipal symbols defined independently of the complex structure. The relation with Schrodinger equation and the group of prequantum bundle automorphisms is considered as well.
Symbolic calculus for Toeplitz operators with half-forms
L. Charles
Mathematics , 2006,
Abstract: This paper is devoted to the use of half-form bundles in the symbolic calculus of Berezin-Toeplitz operators on Kahler manifolds. We state the Bohr-Sommerfeld conditions and relate them to the functional calculus of Toeplitz operators, a trace formula and the characteristic classes in deformation quantization. We also develop the symbolic calculus of Lagrangian sections, with the crucial estimate of the subprincipal terms.
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