Robert A. Harris

Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, United States

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Publications (171)584.69 Total impact

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    ABSTRACT: Alterations in oxidative metabolism are considered to be one of the major contributors to Huntington's disease (HD) pathogenesis. However, existing data about oxidative metabolism in HD are contradictory. Here, we investigated the effect of mutant huntingtin (mHtt) on oxidative metabolism in YAC128 mice. Both mHtt and wild-type huntingtin (Htt) were associated with mitochondria and the amount of bound Htt was four-times higher than the amount of bound mHtt. Percoll gradient-purified brain synaptic and nonsynaptic mitochondria as well as unpurified brain, liver and heart mitochondria, isolated from 2- and 10-month old YAC128 mice and age-matched WT littermates had similar respiratory rates. There was no difference in mitochondrial membrane potential or ADP and ATP levels. Expression of selected nuclear-encoded mitochondrial proteins in 2-month and 10-month old YAC128 and WT mice was similar. Cultured striatal and cortical neurons from YAC128 and WT mice had similar respiratory and glycolytic activities as measured with Seahorse XF24 analyzer in medium containing 10 mM glucose and 15 mM pyruvate. In the medium with 2.5 mM glucose, YAC128 striatal neurons had similar respiration, but slightly lower glycolytic activity. Striatal neurons had lower maximal respiration compared to cortical neurons. In vivo experiments with YAC128 and WT mice showed similar O2 consumption, CO2 release, physical activity, food consumption, and fasted blood glucose. However, YAC128 mice were heavier and had more body fat compared to WT mice. Overall, our data argue against respiratory deficiency in YAC128 mice and, consequently, suggest that mitochondrial respiratory dysfunction is not essential for HD pathogenesis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 06/2015; DOI:10.1093/hmg/ddv209 · 6.68 Impact Factor
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    ABSTRACT: Reliance on glycolysis is a characteristic of malignancy, yet the development of resistance to BRAF inhibitors in melanoma is associated with gain of mitochondrial function. Concurrent attenuation of oxidative phosphorylation and HIF-1α/PKM2-dependent glycolysis promotes a non-apoptotic, iron- and oxygen-dependent cell death that we term ferroxitosis. The redox cycling agent menadione causes a robust increase in oxygen consumption, accompanied by significant loss of intracellular ATP and rapid cell death. Conversely, either hypoxic adaptation or iron chelation prevents menadione-induced ferroxitosis. Ectopic expression of K213Q HIF-1α mutant blunts the effects of menadione. However, knockdown of HIF-1α or PKM2 restores menadione-induced cytotoxicity in hypoxia. Similarly, exposure of melanoma cells to shikonin, a menadione analog and a potential PKM2 inhibitor, is sufficient to induce ferroxitosis under hypoxic conditions. Collectively, our findings reveal that ferroxitosis curtails metabolic plasticity in melanoma.
    Oncotarget 12/2014; 5(24):12694-12703. · 6.63 Impact Factor
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    ABSTRACT: The metabolism of glutamine and glucose is recognized as a promising therapeutic target for the treatment of cancer; however, targeted molecule that mediate glutamine and glucose metabolism in cancer cells has not been addressed. Here, we show that restricting the supply of glutamine in hepatoma cells, including HepG2 and Hep3B cells, markedly increased the expression of retinoic acid-related orphan receptor (ROR) α. Up-regulation of RORα in glutamine-deficient hepatoma cells resulted from an increase in the level of cellular reactive oxygen species and in the NADP+/NADPH ratio, which was consistent with a reduction in the GSH/GSSG ratio. Adenovirus-mediated overexpression of RORα (Ad-RORα) or treatment with the RORα activator, SR1078, reduced aerobic glycolysis and down-regulated biosynthetic pathways in hepatoma cells. Ad-RORα and SR1078 reduced the expression of pyruvate dehydrogenase kinase 2 (PDK2) and inhibited the phosphorylation of PDHe1α, subsequently shifted pyruvate to complete oxidation. The RORα-mediated decrease in PDK2 levels was caused by up-regulation of p21 rather than p53. Furthermore, RORα inhibited hepatoma growth both in vitro and in a xenograft model in vivo. We also found that suppression of PDK2 inhibited hepatoma growth in a xenograft model. These findings mimic the altered glucose utilization and hepatoma growth caused by glutamine deprivation. Finally, tumor tissue from 187 hepatocellular carcinoma patients expressed lower levels of RORα than adjacent non-tumor tissue, supporting a potential beneficial effect of RORα activation in the treatment of liver cancer. Conclusion: The data reported herein show that RORα mediates reprogramming of glucose metabolism in hepatoma cells in response to glutamine deficiency. The relationships established here between glutamine metabolism, RORα expression and signaling, and aerobic glycolysis have implications for therapeutic targeting of liver cancer metabolism. (Hepatology 2014)
    Hepatology 10/2014; 61(3). DOI:10.1002/hep.27577 · 11.19 Impact Factor
  • Jamie D Walls, Robert A Harris
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    ABSTRACT: Traditional nuclear magnetic resonance (NMR) experiments are "blind" to chirality since the spectra for left and right handed enantiomers are identical in an achiral medium. However, theoretical arguments have suggested that the effective Hamiltonian for spin-1/2 nuclei in the presence of electric and magnetic fields can be different for left and right handed enantiomers, thereby enabling NMR to be used to spectroscopically detect chirality even in an achiral medium. However, most proposals to detect the chiral NMR signature require measuring signals that are equivalent to picomolar concentrations for (1)H nuclei, which are outside current NMR detection limits. In this work, we propose to use an AC electric field that is resonantly modulated at the Larmor frequency, thereby enhancing the effect of the chiral term by four to six orders of magnitude. We predict that a steady-state transverse magnetization, whose direction will be opposite for different enantiomers, will build up during application of an AC electric field. We also propose an experimental setup that uses a solenoid coil with an AC current to generate the necessary periodic electric fields that can be used to generate chiral signals which are equivalent to the signal from a (1)H submicromolar concentration.
    The Journal of Chemical Physics 06/2014; 140(23):234201. DOI:10.1063/1.4882698 · 3.12 Impact Factor
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    ABSTRACT: Active metabolism regulates oocyte cell death via calcium/calmodulin-dependent protein kinase II (CaMKII)-mediated phosphorylation of caspase-2, but the link between metabolic activity and CaMKII is poorly understood. Here we identify coenzyme A (CoA) as the key metabolic signal that inhibits Xenopus laevis oocyte apoptosis by directly activating CaMKII. We found that CoA directly binds to the CaMKII regulatory domain in the absence of Ca(2+) to activate CaMKII in a calmodulin-dependent manner. Furthermore, we show that CoA inhibits apoptosis not only in X. laevis oocytes but also in Murine oocytes. These findings uncover a direct mechanism of CaMKII regulation by metabolism and further highlight the importance of metabolism in preserving oocyte viability.
    Molecular cell 10/2013; DOI:10.1016/j.molcel.2013.08.043 · 14.46 Impact Factor
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    ABSTRACT: Pyruvate dehydrogenase kinases (PDK1-4) play a critical role in the inhibition of the mitochondrial pyruvate dehydrogenase complex especially when blood glucose levels are low and pyruvate can be conserved for gluconeogenesis. Under diabetic conditions, the Pdk genes, particularly Pdk4, are often induced, and the elevation of the Pdk4 gene expression has been implicated in the increased gluconeogenesis in the liver and the decreased glucose utilization in the peripheral tissues. However, there is no direct evidence yet to show to what extent that the dysregulation of hepatic Pdk genes attributes to hyperglycemia and insulin resistance in vivo. To address this question, we crossed Pdk2 or Pdk4 null mice with a diabetic model that is deficient in hepatic insulin receptor substrates 1 and 2 (Irs1/2). Metabolic analyses reveal that deletion of the Pdk4 gene had better improvement in hyperglycemia and glucose tolerance than knockout of the Pdk2 gene whereas the Pdk2 gene deletion showed better insulin tolerance as compared to the Pdk4 gene inactivation on the Irs1/2 knockout genetic background. To examine the specific hepatic effects of Pdks on diabetes, we also knocked down the Pdk2 or Pdk4 gene using specific shRNAs. The data also indicate that the Pdk4 gene knockdown led to better glucose tolerance than the Pdk2 gene knockdown. In conclusion, our data suggest that hepatic Pdk4 may be critically involved in the pathogenesis of diabetes.
    PLoS ONE 08/2013; 8(8):e71997. DOI:10.1371/journal.pone.0071997 · 3.53 Impact Factor
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    ABSTRACT: Testosterone level is low in insulin-resistant type 2 diabetes (T2D). Whether this is due to negative effects of high level of insulin on the testes caused by insulin resistance has not been studied in detail. In this study, we found that insulin directly binds to insulin receptors in Leydig cell membranes and activates phospho-IR-β, phospho-IRS1, and phospho-AKT leading to up regulation of DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) gene expression in MA-10 mouse Leydig cell line. Insulin also inhibits cAMP-induced and liver receptor homolog-1 (LRH-1)-induced steroidogenic enzyme gene expression and steroidogenesis. In contrast, knockdown of DAX-1 reversed insulin-mediated inhibition of steroidogenesis. Whether insulin directly represses steroidogenesis through regulation of steroidogenic enzyme gene expression was assessed in insulin-injected mouse models and high-fat diet (HFD)-induced obesity (DIO). In insulin-injected mouse models, insulin receptor signal pathway was activated and subsequently inhibited steroidogenesis via induction of DAX-1 without significant change of LH or FSH level. Likewise, level of steroidogenic enzyme gene expression and steroidogenesis were low, but interestingly the level of DAX-1 was high in the testes of HFD-fed mice. These results represent a novel regulatory mechanism of steroidogenesis in Leydig cells. Insulin-mediated induction of DAX-1 in Leydig cells of testis may be a key regulatory step of serum sex hormone level in insulin-resistant states.
    Journal of Biological Chemistry 04/2013; 288(22). DOI:10.1074/jbc.M113.451773 · 4.60 Impact Factor
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    ABSTRACT: The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (Ang II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an Ang II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from Ang II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in Ang II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in Ang II-treated WT mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the Ang II-induced pathology and showed that deletion of PDK4 prevented Ang II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. Ang II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of PDH and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in Ang II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. Ang II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.
    AJP Heart and Circulatory Physiology 02/2013; 304(8). DOI:10.1152/ajpheart.00636.2012 · 4.01 Impact Factor
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    ABSTRACT: Cyclic AMP (cAMP) induces steroidogenic enzyme gene expression and stimulates testosterone production in Leydig cells. Phosphoenolpyruvate carboxykinase (PEPCK) is expressed in Leydig cells but its role has not been defined. In this study we found that PEPCK and glucose-6-phosphatase (G6Pase) are increased significantly following cAMP treatment of mouse Leydig cells. Moreover, cAMP treatment increased recruitment of the cAMP response element-binding transcription factor (CREB) and decreased recruitment of the corepressor DAX-1 on the pepck promoter. Furthermore, cAMP induced an increase in ATP which correlated with a decrease in phospho-AMPK. In contrast, knockdown or inhibition of PEPCK decreased ATP and increased phospho-AMPK. Treatment with an AMPK activator or overexpression of the constitutively active form of AMPK (CA-AMPK) inhibited cAMP-induced steroidogenic enzyme promoter activities and gene expression. Liver receptor homolog-1 (LRH-1) was involved in cAMP-induced steroidogenic enzyme gene expression but was inhibited by AMPK activation in Leydig cells. Additionally, inhibition or knockdown of PEPCK and G6Pase decreased cAMP-mediated induction of steroidogenic enzyme gene expression and steroidogenesis. Finally, pubertal mice (8-week-old) testis and hCG-induced prepubertal mouse testis showed increased PEPCK and G6Pase gene expression. Taken together, these results suggest that induction of PEPCK and G6Pase by cAMP plays an important role in Leydig cell steroidogenesis.
    Journal of Biological Chemistry 10/2012; DOI:10.1074/jbc.M112.421552 · 4.60 Impact Factor
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    ABSTRACT: Multiple cellular signaling pathways that control metabolism and survival are activated when cell are incubated under hypoxic conditions. Activation of the hypoxia inducible factor (HIF)-1 promotes expression of genes that increase the capacity to cope with the stress imposed by a reduced oxygen environment. Here we show that the orphan nuclear receptor estrogen related receptor γ (ERRγ) plays a critical role in hypoxia-mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) gene expression. ERRγ mRNA and protein levels were increased by hypoxia or desferrioxamine (DFO) treatment in hepatoma cell lines. Co-expression of HIF-1α and β increased ERRγ promoter activity as well as mRNA expression, while knockdown of endogenous HIF-1α reduced the hypoxia-mediated induction of ERRγ. In addition, hypoxia also increased the promoter activity and mRNA level of PDK4 in HepG2 cells. Adenovirus mediated-overexpression of ERRγ specifically increased PDK4 gene expression, while ablation of endogenous ERRγ significantly decreased hypoxia-mediated induction of PDK4 gene expression. Finally, GSK5182, an inverse agonist of ERRγ, strongly inhibited the hypoxia-mediated induction of PDK4 protein and promoter activity. Regulation of the transcriptional activity of ERRγ may provide a therapeutic approach for the regulation of PDK4 gene expression under hypoxia.
    PLoS ONE 09/2012; 7(9):e46324. DOI:10.1371/journal.pone.0046324 · 3.53 Impact Factor
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    ABSTRACT: Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.
    Science 09/2012; 338(6105):394-7. DOI:10.1126/science.1224631 · 31.48 Impact Factor
  • Graham R Fleming, Robert A Harris
    Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences 08/2012; 370(1972):3618-9. DOI:10.1098/rsta.2012.0193 · 2.86 Impact Factor
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    ABSTRACT: Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wild-type but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP-dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.
    Diabetes 06/2012; 61(10):2484-94. DOI:10.2337/db11-1665 · 8.47 Impact Factor
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    ABSTRACT: During reperfusion of the ischaemic myocardium, fatty acid oxidation rates quickly recover, while glucose oxidation rates remain depressed. Direct stimulation of glucose oxidation via activation of pyruvate dehydrogenase (PDH), or secondary to an inhibition of malonyl CoA decarboxylase (MCD), improves cardiac functional recovery during reperfusion following ischaemia. However, the effects of such interventions on the evolution of myocardial infarction are unknown. The purpose of this study was to determine whether infarct size is decreased in response to increased glucose oxidation. In vivo, direct stimulation of PDH in mice with the PDH kinase (PDHK) inhibitor, dichloroacetate, significantly decreased infarct size following temporary ligation of the left anterior descending coronary artery. These results were recapitulated in PDHK 4-deficient (PDHK4-/-) mice, which have enhanced myocardial PDH activity. These interventions also protected against ischaemia/reperfusion injury in the working heart, and dichloroacetate failed to protect in PDHK4-/- mice. In addition, there was a dramatic reduction in the infarct size in malonyl CoA decarboxylase-deficient (MCD-/-) mice, in which glucose oxidation rates are enhanced (secondary to an inhibition of fatty acid oxidation) relative to their wild-type littermates (10.8 ± 3.8 vs. 39.5 ± 4.7%). This cardioprotective effect in MCD-/- mice was associated with increased PDH activity in the ischaemic area at risk (1.89 ± 0.18 vs. 1.52 ± 0.05 μmol/g wet weight/min). These findings demonstrate that stimulating glucose oxidation via targeting either PDH or MCD decreases the infarct size, validating the concept that optimizing myocardial metabolism is a novel therapy for ischaemic heart disease.
    Cardiovascular Research 03/2012; 94(2):359-69. DOI:10.1093/cvr/cvs129 · 5.81 Impact Factor
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    Ki-Up Lee, Robert A Harris
    Experimental Diabetes Research 03/2012; 2012:985075. DOI:10.1155/2012/985075 · 3.54 Impact Factor
  • Graham R. Fleming, Robert A. Harris
    Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences 01/2012; 370(1972):3618-3619. DOI:10.2307/41582521 · 2.86 Impact Factor
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    ABSTRACT: Sulforaphane (SFN) is a dietary isothiocyanate that exerts chemopreventive effects via NF-E2-related factor 2 (Nrf2)-mediated induction of antioxidant/phase II enzymes, such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). This work was undertaken to evaluate the effects of SFN on hepatic fibrosis and profibrotic transforming growth factor (TGF)-β/Smad signaling, which are closely associated with oxidative stress. SFN suppressed TGF-β-enhanced expression of α-smooth muscle actin (α-SMA), a marker of hepatic stellate cell (HSC) activation, and profibrogenic genes such as type I collagen, fibronectin, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and plasminogen activator inhibitor (PAI)-1 in hTERT, an immortalized human HSC line. SFN inhibited TGF-β-stimulated activity of a PAI-1 promoter construct and (CAGA)(9) MLP-Luc, an artificial Smad3/4-specific reporter, in addition to reducing phosphorylation and nuclear translocation of Smad3. Nrf2 overexpression was sufficient to inhibit the TGF-β/Smad signaling and PAI-1 expression. Conversely, knockdown of Nrf2, but not inhibition of HO-1 or NQO1 activity, significantly abolished the inhibitory effect of SFN on (CAGA)(9) MLP-Luc activity. However, inhibition of NQO1 activity reversed repression of TGF-β-stimulated expression of type I collagen by SFN, suggesting the involvement of antioxidant activity of SFN in the suppression of Smad-independent fibrogenic gene expression. Finally, SFN treatment attenuated the development and progression of early stage hepatic fibrosis induced by bile duct ligation in mice, accompanied by reduced expression of type I collagen and α-SMA. Collectively, these results show that SFN elicits an antifibrotic effect on hepatic fibrosis through Nrf2-mediated inhibition of the TGF-β/Smad signaling and subsequent suppression of HSC activation and fibrogenic gene expression.
    Free Radical Biology and Medicine 12/2011; 52(3):671-82. DOI:10.1016/j.freeradbiomed.2011.11.012 · 5.71 Impact Factor
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    Gary G. Hoffman, Robert A. Harris, Lawrence R. Pratt
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    ABSTRACT: This paper derives the finite temperature optimized Thomas–Fermi theory applicable to the electronic structure of atoms, molecules, and ions under conditions where both the bulk electron density and the electron temperature are substantial. The derivation provides a simple rule for transcribing the finite temperature case from the previous ground-state statistical electron-density functional theories. Keywords: plasma simulation, plasma chemistry, statistical theory of electron densities, Thomas–Fermi theory, optimized Thomas–Fermi theory.
    Canadian Journal of Chemistry 02/2011; 70(2):478-481. DOI:10.1139/v92-068 · 1.01 Impact Factor
  • Robert A Harris
    The Journal of Physical Chemistry B 10/2010; 114(43):13922. DOI:10.1021/jp1079422 · 3.38 Impact Factor

Publication Stats

3k Citations
584.69 Total Impact Points

Institutions

  • 2012–2015
    • Richard L. Roudebush VA Medical Center
      Indianapolis, Indiana, United States
  • 2007–2014
    • Indiana University-Purdue University School of Medicine
      • Department of Biochemistry and Molecular Biology
      Indianapolis, Indiana, United States
  • 1972–2014
    • Indiana University-Purdue University Indianapolis
      • • Department of Biochemistry and Molecular Biology
      • • Department of Chemistry and Chemical Biology
      Indianapolis, Indiana, United States
  • 1965–2014
    • University of California, Berkeley
      • • Department of Chemistry
      • • Department of Physics
      Berkeley, California, United States
  • 2012–2013
    • Chonnam National University
      • School of Biological Sciences and Technology
      Yeoju, Gyeonggi, South Korea
  • 2011
    • Kyungpook National University
      Daikyū, Daegu, South Korea
  • 1999
    • Ochanomizu University
      • Department of Nutrition and Food Science
      Tōkyō, Japan
  • 1996
    • Nagoya Institute of Technology
      • Department of Materials Science and Engineering
      Nagoya, Aichi, Japan
  • 1992
    • Wayne State University
      • Department of Chemistry
      Detroit, MI, United States
  • 1982
    • National Institute on Alcohol Abuse and Alcoholism
      Maryland, United States
  • 1967
    • University of Chicago
      • James Franck Institute
      Chicago, Illinois, United States