D J Morré

Karolinska Institutet, Solna, Stockholm, Sweden

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Publications (512)1754.2 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Age-related NADH oxidase (arNOX), a cell surface-located hydroquinone oxidase capable of superoxide generation, appears at age 30 and increases with age thereafter. The ectodomain of arNOX is shed from the cell surface into body fluids including sera and saliva where its activity was measured spectrophotometrically using a reduction of ferricytochrome c as a measure of superoxide generation. The autofluorescence of advanced glycation end products correlates with epidermal arNOX activity as well. To demonstrate protein cross-linking, a fluorescence-labeled analog of tyrosine, tyramine, that would react with proteins carrying arNOX-generated tyrosyl radicals was used. The assay demonstrated the potential for arNOX-induced oxidative damage (dityrosine formation) to human collagen and elastin and to other surface proteins of intact human embryo fibroblasts and frozen sections from epidermal punch biopsies. The findings support a role for arNOX as a major source of oxidative damage leading to cross-linking of skin proteins.
    Archives for Dermatological Research 06/2014; · 2.71 Impact Factor
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    Claudia Hanau, D James Morré, Dorothy M Morré
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    ABSTRACT: Experts agree that one of the more promising strategies in cancer management is early detection coupled with early intervention. In this study, we evaluated an early cancer detection strategy of cancer presence based on serum levels of the cancer-specific transcript variants of ENOX2 in serum coupled with an ENOX2-targeted nutraceutical preparation of green tea concentrate plus Capsicum (Capsol-T(R)) as a strategy of Curative Prevention(R) involving early detection coupled with early intervention in early stage cancer when in its most susceptible and manageable stages.Experimental design: One hundred ten (110) subjects were tested for cancer presence using the ONCOblot(R) Tissue of Origin 2-D gel/western blot protocol for detection of serum presence of transcription variants of the ENOX2 protein. Subjects testing positive for ENOX2 received 350 mg of Capsol-T(R) in capsule form every 4 h including during the night for periods of at least 3 to 6 months or longer after which they were again tested for ENOX2 presence using the ONCOblot(R) Tissue of Origin Cancer Test protocol. Of the 110 subjects, both male and female, ages 40 to 84, with no evidence of clinical symptoms of cancer, 40% were positive for ENOX2 presence in the ONCOblot(R) Tissue of Origin Cancer Test. After completion of 3 to 17 months of Capsol-T(R) use, 94% of subjects subsequently tested negative for ENOX2 presence. Oral Capsol-T(R) is well tolerated and, for ENOX2 presence in serum in the absence of clinical cancer symptoms, is consistently effective in reducing the serum ENOX2 levels to below detectable limits.
    Clinical Proteomics 01/2014; 11(1):2.
  • World Journal of Cardiovascular Diseases 01/2014; 04(03):119-129.
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    ABSTRACT: ME-143 (NV-143), a synthetic isoflavone under clinical evaluation for efficacy in the management of ovarian and other forms of human cancer, blocked the activity of a cancer-specific and growth-related cell surface ECTO-NOX protein with both oxidative (hydroquinone) and protein disulfide-thiol interchange activity designated ENOX2 (tNOX) and inhibited the growth of cultured cancer cells with EC50s in the range of 20‐50 nM. Purified recombinant ENOX2 also bound ME-143 with a K d of 43 (40‐50) nM. Both the oxidative and protein disulfide-thiol interchange activities of ENOX proteins that alternate to generate a complex set of oscillations with a period length of 22 min compared to 24 min for the constitutive counterpart ENOX1 (CNOX) that characterizes ENOX proteins responded to ME-143. Oxidation of NADH or reduced coenzyme Q10 was rapidly blocked. In contrast, the protein disulfide-thiol interchange activity measured from the cleavage of dithiodipyridine (EC50 of ca. 50 nM) was inhibited progressively over an interval of 60 min that spanned three cycles of activity. Inhibition of the latter paralleled the inhibition of cell enlargement and the consequent inability of inhibited cells to initiate traverse of the cell cycle. Activities of constitutive ENOX1 (CNOX) forms of either cancer or noncancer cells were unaffected by ME-143 over the range of concentrations inhibiting ENOX2. Taken together, the findings show that ME-143 binds to ENOX2 with an affinity 4 to 10 times greater than that reported previously for the related anticancer isoflavone, phenoxodiol.
    Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 01/2014; 22(1). · 1.63 Impact Factor
  • Greg B Forney, D James Morré, Dorothy M Morré
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    ABSTRACT: ABSTRACT Reactive oxygen species that are produced by aerobic metabolism and signaling cascades have the potential to play important roles in maintaining homeostatic redox and cell proliferation. When the balance between the production and elimination of reactive oxygen species is perturbed toward production, the result is oxidative stress. High levels of oxidative stress are a general characteristic of cancer. The altered redox state within a tumor microenvironment confers a growth advantage through increased proliferation rates, evasion of apoptosis, and increased resistance to therapeutic compounds. We have tested a synergistic combination of green tea-Camellia sinensis-concentrate and powdered Capsicum powder (TeaFense™/Capsol-T™) as a dietary supplement to reduce oxidative stress as an approach to elimination of malignant cells. Here, we demonstrate that the green tea-powdered Capsicum mixture effectively reduces levels of oxidative stress in both cancer (HeLa) and noncancer (MCF-10A) cells as determined from measurements of levels of the oxidative stress indicator Nrf-2 by western blot analysis. Nrf-2 is a transcription factor that controls an antioxidant response element. Increased expression of Nrf-2 is linked to high levels of oxidative stress and vice versa. Based on levels of Nrf-2, the mixture of green tea concentrate plus powdered Capsicum reduced oxidative stress by more than 50% compared with 15% by the green tea concentrate alone.
    Journal of Dietary Supplements 12/2013; 10(4):318-24.
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    ABSTRACT: arNOX, an age-related NADH oxidase, has been shown to play a role in the formation of the autophagosome. The role of autophagy in tumorigenesis and tumor proliferation led to the hypothesis that abnormal arNOX levels might play a role in the pathology of cancer. Serum samples from cancer patients and age- and gender-matched healthy controls were assayed to measure arNOX activity by a standard assay involving measurements of superoxide production based on the reduction of ferricyanide c by superoxide monitored from the increase in absorbance at 550 nm with reference at 540 nm. Superoxide dismutase was added to the end of the assay to ensure return of the rate of ferricytochrome c reduction to the base line. Cancer and cardiovascular diseases are inversely correlated. Similarly, arNOX levels were decreased in cancer patients when compared to non-cancer control subjects while high arNOX levels have been implicated as an important cause of LDL oxidation and increased risk of cardiovascular disease. These findings may help further the understanding of the pathologies of cancer and cardiovascular disease and have implications for risk assessment for both diseases as well as for future therapeutic intervention strategies.
    Journal of medicine and life 07/2013; 1(2):38.
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    Hans Löw, Frederick L Crane, D James Morré
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    ABSTRACT: The observation that high cellular concentrations of NADH were associated with low adenylate cyclase activity led to a search for the mechanism of the effect. Since cyclase is in the plasma membrane, we considered the membrane might have a site for NADH action, and that NADH might be oxidized at that site. A test for NADH oxidase showed very low activity, which could be increased by adding growth factors. The plasma membrane oxidase was not inhibited by inhibitors of mitochondrial NADH oxidase such as cyanide, rotenone or antimycin. Stimulation of the plasma membrane oxidase by iso-proterenol or triiodothyronine was different from lack of stimulation in endoplasmic reticulum. After 25 years of research, three components of a trans membrane NADH oxidase have been discovered. Flavoprotein NADH coenzyme Q reductases (NADH cytochrome b reductase) on the inside, coenzyme Q in the middle, and a coenzyme Q oxidase on the outside as a terminal oxidase. The external oxidase segment is a copper protein with unique properties in timekeeping, protein disulfide isomerase and endogenous NADH oxidase activity, which affords a mechanism for control of cell growth by the overall NADH oxidase and the remarkable inhibition of oxidase activity and growth of cancer cells by a wide range of anti-tumor drugs. A second trans plasma membrane electron transport system has been found in voltage dependent anion channel (VDAC), which has NADH ferricyanide reductase activity. This activity must be considered in relation to ferricyanide stimulation of growth and increased VDAC antibodies in patients with autism.
    The international journal of biochemistry & cell biology 06/2012; 44(11):1834-8. · 4.89 Impact Factor
  • D James Morré, Dorothy M Morré
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    ABSTRACT: The key role of coenzyme Q (ubiquinone or Q) is in mitochondrial and prokaryotic energetics. Less well investigated is the basis for its presence in eukaryotic membrane locations other than mitochondria and in plasma where both antioxidant and potentially more targeted roles are indicated. Included in the latter is that of a lipid-soluble electron transfer intermediate that serves as the transmembrane component of plasma membrane and Golgi apparatus electron transport, which regulates cytosolic NAD(+) /NADH ratios and is involved in vectorial membrane displacements and in the regulation of cell growth. Important protective effects on circulating lipoproteins and in the prevention of coronary artery disease ensue not only from the antioxidant role of CoQ(10) but also from its ability to directly block protein oxidation and superoxide generation of the TM-9 family of membrane proteins known as age-related NADH oxidase or arNOX (ENOX3) and their shed forms that appear after age 30 and some of which associate specifically with low-density lipoprotein particles to catalyze protein oxidation and crosslinking.
    BioFactors 06/2011; 37(5):355-60. · 3.09 Impact Factor
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    ABSTRACT: HUVEC or mouse 3T3 cells infected with SV-40 generate within 3 to 5 days post-infection an ENOX2 species corresponding to the exon-4 minus splice variant of a tumor-associated NADH oxidase (ENOX2 or tNOX) expressed at the cancer cell surface. This study was to seek evidence for splicing factors that might direct formation of the exon 4 minus ENOX2 splice variant. To determine if silencing of ENOX2 exon 4 occurs because of motifs located in exon 4, transfections were performed on MCF-10A (mammary non-cancer), BT-20 (mammary cancer), and HeLa (cervical cancer) cells using a GFP minigene construct containing either a constitutively spliced exon (albumin exon 2) or the alternatively spliced ENOX2 exon 4 between the two GFP halves. Removal of exon 4 from the processed RNA of the GFP minigene construct occurred with HeLa and to a lesser extent with BT-20 but not in non-cancer MCF-10A cells. The Splicing Rainbow Program was used to identify all of the possible hnRNPs binding sites of exon 4 of ENOX2. There are 8 Exonic Splicing Silencers (ESSs) for hnRNP binding in the exon 4 sequences. Each of these sites were mutated by site-directed mutagenesis to test if any were responsible for the splicing skip. Results showed MutG75 ESS mutation changed the GFP expression which is a sign of splicing silence, while other mutations did not. As MutG75 changed the ESS binding site for hnRNP F, this result suggests that hnRNP F directs formation of the exon 4 minus variant of ENOX2.
    Molecular and Cellular Biochemistry 05/2011; 357(1-2):55-63. · 2.33 Impact Factor
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    ABSTRACT: Constituents and inhibitors of intermediary metabolism resulting in alterations in levels of cytosolic NADH, stimulation of sphingomyelinase and inhibition of sphingosine kinase were evaluated for effects on growth inhibition and induction of apoptosis by the ENOX2 inhibitors EGCG, the principal catechin of green tea, and phenoxodiol, a naturally occurring isoflavone. Responses were evaluated from dose-response curves of the metabolites and metabolic inhibitors in which growth of HeLa cells, apoptosis based on DAPI fluorescence and cytosolic NADH levels were correlated with sphingomyelinase and spingosine kinase activities and levels of ceramide and sphingosine1-phosphate. Growth inhibition correlated with the modulation of localized cytosolic NADH levels by metabolites and metabolic inhibitors, the response of sphingomyelinase and sphingosine kinase located near the inner surface of the plasma membrane, and apoptosis. Based on findings with metabolites, we conclude that apoptosis in cancer cell lines caused by ENOX2 inhibitors such as EGCG and phenoxodiol is a direct response to elevated levels of cytosolic NADH that result from ENOX2 inhibition. The findings help to explain why increased NADH levels resulting from ENOX2 inhibition result in decreased prosurvival sphingosine-1-phosphate and increased proapoptotic ceramide, both of which may be important to initiation of the ENOX2 inhibitor-induced apoptotic cascade.
    Biochimica et Biophysica Acta 05/2011; 1810(8):784-9. · 4.66 Impact Factor
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    ABSTRACT: ECTO-NOX proteins are growth-related cell surface proteins that catalyze both hydroquinone or NADH oxidation and protein disulfide interchange and exhibit time-keeping and prion-like properties. A bacterially expressed truncated recombinant 46 kDa ENOX2 with full ENOX2 activity bound ca 2 moles copper and 2 moles of zinc per mole of protein. Unfolding of the protein in trifluoroacetic acid in the presence of the copper chelator bathocuproine resulted in reversible loss of both enzymatic activities and of a characteristic pattern in the Amide I to Amide II ratios determined by FTIR with restoration by added copper. The H546-V-H together with His 562 form one copper binding site and H582 represents a second copper site as determined from site-directed mutagenesis. Bound copper emerges as having an essential role in ENOX2 both for enzymatic activity and for the structural changes that underly the periodic alternations in activity that define the time-keeping cycle of the protein.
    Journal of Bioenergetics 10/2010; 42(5):355-60. · 1.60 Impact Factor
  • Thomas De Luca, Dorothy M Morré, D James Morré
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    ABSTRACT: ENOX2 (tNOX), a tumor-associated cell surface ubiquinol (NADH) oxidase, functions as an alternative terminal oxidase for plasma membrane electron transport. Ubiquitous in all cancer cell lines studied thus far, ENOX2 expression correlates with the abnormal growth and division associated with the malignant phenotype. ENOX2 has been proposed as the cellular target for various quinone site inhibitors that demonstrate anticancer activity such as the green tea constituent epigallocatechin-3-gallate (EGCg) and the isoflavone phenoxodiol (PXD). Here we present a possible mechanism that explains how these substances result in apoptosis in cancer cells by ENOX2-mediated alterations of cytosolic amounts of NAD(+) and NADH. When ENOX2 is inhibited, plasma membrane electron transport is diminished, and cytosolic NADH accumulates. We show in HeLa cells that NADH levels modulate the activities of two pivotal enzymes of sphingolipid metabolism: sphingosine kinase 1 (SK1) and neutral sphingomyelinase (nSMase). Their respective products sphingosine 1-phosphate (S1P) and ceramide (Cer) are key determinants of cell fate. S1P promotes cell survival and Cer promotes apoptosis. Using plasma membranes isolated from cervical adenocarcinoma (HeLa) cells as well as purified proteins of both bacterial and human origin, we demonstrate that NADH inhibits SK1 and stimulates nSMase, while NAD(+) inhibits nSMase and has no effect on SK1. Additionally, intact HeLa cells treated with ENOX2 inhibitors exhibit an increase in Cer and a decrease in S1P. Treatments that stimulate cytosolic NADH production potentiate the antiproliferative effects of ENOX2 inhibitors while those that attenuate NADH production or stimulate plasma membrane electron transport confer a survival advantage.
    Journal of Cellular Biochemistry 08/2010; 110(6):1504-11. · 3.06 Impact Factor
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    ABSTRACT: An aging-related cell-surface oxidase (aging-related NADH oxidase, arNOX) generating superoxide and other reactive oxygen species is shed from the cell surface and is found in saliva, urine, perspiration, and interstitial fluids that surround the collagen and elastin matrix underlying dermis. arNOX activity correlates with age and reaches a maximum at about age 65 in males and 55 in females. arNOX activities are highly correlated with values of human skin where a causal relationship is indicated. Ongoing efforts focus on cloning arNOX proteins and development of antiaging formulas based on arNOX inhibition (intervention).
    Rejuvenation Research 03/2010; 13(2-3):162-4. · 2.92 Impact Factor
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    ABSTRACT: Golgi apparatus from rat liver contain an ascorbate free radical oxidoreductase that oxidizes NADH at neutral pH with monodehydroascorbate as acceptor to generate a membrane potential. At pH 5.0, the reverse reaction occurs from NAD(+). The electron spin resonance signal of the ascorbate-free radical and its disappearance upon the addition of NADH (pH 7) or NAD(+) (pH 5.0) confirms monodehydroascorbate involvement. Location of monodehydroascorbate both external to and within Golgi apparatus compartments is suggested from energization provided by inward or outward flux of electrons across the Golgi apparatus membranes. The isolated membranes are sealed, oriented cytoplasmic side out and impermeable to NAD(+) and ascorbate. NAD(+) derived through the action of Golgi apparatus beta-NADP phosphohydrolase is simultaneously reduced to NADH with monodehydroascorbate present. The response of the NADH- (NAD(+)-) ascorbate free radical oxidoreductase system to pH in Golgi apparatus provides a simple regulatory mechanism to control vesicle acidification.
    Journal of Bioenergetics 03/2010; 42(2):181-7. · 1.60 Impact Factor
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    ABSTRACT: Aging-related cell-surface NADH oxidase (arNOX)-specific activities increase with age between age 30 and ages 50-65. The protein is shed and circulates. Activity correlates with a number of aging-related disorders including low-density lipoprotein (LDL) oxidation as a precondition to atherosclerosis as well as oxidation of collagen and elastin as a major contributor to skin aging. arNOX inhibitors formulated for sustained release are capable of maintaining circulating arNOX at low levels with regular use as food supplements formulated with natural compounds. Among the best sources are certain culinary seasonings, all of which are ingredients used extensively in the French kitchen. Their regular use may contribute to an understanding of the nutritional basis for the French Paradox.
    Rejuvenation Research 12/2009; 13(2-3):159-61. · 2.92 Impact Factor
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    ABSTRACT: Activity of an age-related, superoxide-forming, cell-surface oxidase (arNOX) comparing dermis, epidermis, serum, and saliva from female and male subjects ages 28-72 years measured spectrophotometrically using reduction of ferricytochrome c correlated with oxidative skin damage as estimated from autofluoresence of skin using an Advanced Glycation End products Reader (AGE-Reader; DiagnOptics B.V., Netherlands). By reducing arNOX activity in skin with arNOX-inhibitory ingredients (NuSkin's ageLOC technology), skin appearance was improved through decreased protein cross-linking and an accelerated increase in collagen.
    Rejuvenation Research 12/2009; 13(2-3):165-7. · 2.92 Impact Factor
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    ABSTRACT: The Purdue-UAB Botanicals Research Center for Age Related Disease uses multidisciplinary and innovative technologies to investigate the bioavailability of bioactive polyphenolic constituents from botanicals and their relationship to human health. Many age-related diseases are associated with oxidative stress and tissue damage. One of the research goals of the Purdue-UAB Center is to investigate the bioavailability of bioactive natural compounds from a complex botanical mixture to the organ affected by the disease, determine the uptake and metabolism of these compounds and relate these data to a protective mechanism. Equally important is to screen commercially available botanicals for their safety and efficacy. The central aims of the Center include the investigation of botanicals and their relationship to bone antiresorptive capacity, cognitive function, vascular effects, and cancer prevention.
    Pharmaceutical Biology 08/2009; 47(8):768-773. · 1.21 Impact Factor
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    ABSTRACT: There is a need for novel strategies that target tumor vasculature, specifically those that synergize with cytotoxic therapy, in order to overcome resistance that can develop with current therapeutics. A chemistry-driven drug discovery screen was employed to identify novel compounds that inhibit endothelial cell tubule formation. Cell-based phenotypic screening revealed that noncytotoxic concentrations of (Z)-(+/-)-2-(1-benzenesulfonylindol-3-ylmethylene)-1-azabicyclo[2. 2.2]octan-3-ol (analog I) and (Z)-(+/-)-2-(1-benzylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol (analog II) inhibited endothelial cell migration and the ability to form capillary-like structures in Matrigel by > or =70%. The ability to undergo neoangiogenesis, as measured in a window-chamber model, was also inhibited by 70%. Screening of biochemical pathways revealed that analog II inhibited the enzyme ENOX1 (EC(50) = 10 microM). Retroviral-mediated shRNA suppression of endothelial ENOX1 expression inhibited cell migration and tubule formation, recapitulating the effects observed with the small-molecule analogs. Genetic or chemical suppression of ENOX1 significantly increased radiation-mediated Caspase3-activated apoptosis, coincident with suppression of p70S6K1 phosphorylation. Administration of analog II prior to fractionated X-irradiation significantly diminished the number and density of tumor microvessels, as well as delayed syngeneic and xenograft tumor growth compared to results obtained with radiation alone. Analysis of necropsies suggests that the analog was well tolerated. These results suggest that targeting ENOX1 activity represents a novel therapeutic strategy for enhancing the radiation response of tumors.
    The FASEB Journal 04/2009; 23(9):2986-95. · 5.70 Impact Factor
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    ABSTRACT: Phenoxodiol is an experimental anticancer drug under development as a chemosensitizer intended to reverse multidrug resistance mechanisms in ovarian and prostate cancer cells to most standard cytotoxics. The putative molecular target of phenoxodiol is a cell-surface, tumor-specific NADH oxidase, ENOX2 (tNOX), with phenoxodiol having no apparent effect on the constitutive form of this enzyme ENOX1 (CNOX). Using ENOX2 as the target, this study was conducted to explore the temporal relationship between phenoxodiol and paclitaxel or cisplatin in achieving chemosensitization in HeLa cells which are relatively resistant to both paclitaxel and cisplatin. Sequential addition of phenoxodiol and paclitaxel or phenoxodiol and cisplatin showed greater inhibition of HeLa cell ENOX1 activity and growth compared to adding the drugs simultaneously or individually. In parallel, a similar chemosensitizing response of phenoxodiol for cisplatin was observed. ENOX1 was not affected and trans-platinum had no effect. With spent media from phenoxodiol-treated cells sensitivity was enhanced to both paclitaxel and cisplatin if the cells were first pretreated with phenoxodiol. Similar results were obtained with ENOX2-enriched preparations stripped from the surfaces of phenoxodiol-treated cells. In keeping with a speculative prion model, it seems as though the ENOX2 "remembers" the phenoxodiol and "teaches" other ENOX2 molecules to respond to paclitaxel and cisplatin as if phenoxodiol were still present.
    Molecular Biotechnology 02/2009; 42(1):100-9. · 2.26 Impact Factor
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    ABSTRACT: ENOX proteins with an oscillatory pattern of production of superoxide (measured by ferricytochrome c reduction) and with a period length of 26 min increase linearity with age beginning at about 30 y to a maximum of about age 60. The proteins are shed and appear in serum, saliva and urine. Enhanced arNOX activity correlates with age and with oxidative changes contributing to skin aging. Topical cosmetic preparations containing substances that block arNOX activity are under evaluation to reduce visible symptoms of skin aging.
    BioFactors 02/2009; 34(3):237-44. · 3.09 Impact Factor

Publication Stats

8k Citations
1,754.20 Total Impact Points

Institutions

  • 1986–2012
    • Karolinska Institutet
      • Endocrinology Clinic
      Solna, Stockholm, Sweden
    • University of Hamburg
      Hamburg, Hamburg, Germany
    • Universidad Católica de Córdoba
      Córdoba, Córdoba, Argentina
  • 1964–2012
    • Purdue University
      • • Department of Biological Sciences
      • • Department of Medicinal Chemistry and Molecular Pharmacology (MCMP)
      • • Department of Animal Sciences
      • • Department of Botany and Plant Pathology
      West Lafayette, Indiana, United States
  • 2010
    • Universidad Pablo de Olavide
      Hispalis, Andalusia, Spain
  • 1988–2007
    • University of Geneva
      • Department of Botany and Plant Biology
      Genève, Geneva, Switzerland
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2006
    • University of Alabama at Birmingham
      • Department of Biology
      Birmingham, AL, United States
  • 2003
    • Purdue University Calumet
      • Department of Biological Sciences
      Hammond, IN, United States
  • 1991–1994
    • University of Bordeaux
      Burdeos, Aquitaine, France
    • Nara Women's University
      Nara, Nara, Japan
    • Universiteit Utrecht
      • Division of Cell Biology
      Utrecht, Provincie Utrecht, Netherlands
  • 1992–1993
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1987–1992
    • University of Cordoba (Spain)
      • • Facultad de Ciencias
      • • Departamento de Biología Celular, Fisiología e Inmunología
      Córdoba, Andalusia, Spain
    • Virginia Polytechnic Institute and State University
      Blacksburg, Virginia, United States
    • Paul Sabatier University - Toulouse III
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 1990
    • IVL Swedish Environmental Research Institute
      Tukholma, Stockholm, Sweden
  • 1980
    • Karolinska University Hospital
      • Endocrinology Unit
      Tukholma, Stockholm, Sweden
  • 1972
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1970
    • Pennsylvania State University
      University Park, Maryland, United States