Catecholamine Research in the 21st Century

Catecholamine Research in the 21st Century

Abstracts and Graphical Abstracts, 10th International Catecholamine Symposium, 2012

1st Edition - December 5, 2013

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  • Editor: Lee Eiden
  • eBook ISBN: 9780128000731
  • Paperback ISBN: 9780128000441

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Through the use of extended graphical abstracts and some traditional text-only abstracts this collection provides, a record of and roadmap to, the research presented at The Tenth International Catecholamine Symposium (XICS) held in September of 2012. Organized around ten general themes, each is introduced by a short overview identifying interesting research programs, results and potential areas of growth. The collection is a roadmap to key research and future opportunities for new catecholamine research programs and will be of interest to neuroscientists and clinical neurologists interested in understanding the current and future state of catecholamine research.

Key Features

  • Details the leading research efforts and focus on catecholamines
  • Provides a guide to the diverse catecholamine research efforts across key themes including, Synthesis and Storage, Release and Re-uptake, Metabolism, Catecholamine Receptors and Catecholaminergic Signaling
  • Includes impact on clinical neurology, drug abuse and addiction and issues in psychiatry and psychology

Table of Contents

  • Preface

    Theme A: Catecholamine Biosynthesis and Storage

    Theme A Catecholamine Biosynthesis and Storage

    Genetic Manipulation of Catecholamine Signaling in the Mouse

    AADC Deficiency: Occurring in Humans; Modeled in Rodents; Treated in Patients

    Tyrosine Hydrolylase and Dopamine Beta-Hydroxylase: Role of Common Genetic Variation in Adrenergic Responses to Stress and in Hypertension

    Pharmacokinetic and Pharmacodynamic Properties of Etamicastat, a New DBH Inhibitor: Comparison to Nepicastat

    Estradiol-Mediated Regulation of Gene Expression of Catecholamine Biosynthetic Enzymes: The Role of Membrane-Initiated Signaling with Erα

    Structural Basis for Regulation of Tyrosine Hydroxlyase by the Catecholamines

    Unique Regulation of TH Gene Expression in Midbrain Dopamine Neurons

    Intracellular Stability of Tyrosine Hydroxylase: Phosphorylation and Proteasomal Digestion of the Enzyme

    The Peripheral Interaction of Tyrosine Hydroxylase and 14-3-3γ with Negatively Charged Phospholipidic Membranes


    Dynamic Regulation of Tyrosine Hydroxylase Gene Expression by Key Fate-Determining Transcription Factors during Dopaminergic Neuronal Development in Vivo and in Vitro

    Analysis of Tyrosine Hydroxylase Isoforms and Phosphorylation in Parkinson’s Disease

    Non-dopaminergic Neurons Partly Expressing Dopaminergic Phenotype: Functional Significance and Regulation

    Developing Brain as an Endocrine Organ: Catecholamines Secretion and Endocrine Action

    Brainstem DOPAergic System

    Imaging Norepinephrine Transporters in Humans; Translational Research with PET

    Imaging the Vesicular Monoamine Transporter (VMAT2) in Neurodegenerative Diseases

    GTP Cyclohydrolase Regulation: Implications for Brain Development and Function

    Neonatal Diagnosis of Menkes Disease by a Pattern of Plasma Catechols

    Catecholamine Metabolites Affected by the Copper-Dependent Enzyme Dopamine-Beta-Hydroxylase Provide Sensitive Blood and Csf Biomarkers for Viral Gene Therapy in Menkes Disease

    Are the Enzymes of the Catecholamine Biosynthetic Pathway Locally Synthesized in the Axon?

    Effects of Missense Mutations in Tyrosine Hydroxylase (TH) Found in Patients with Neurological Disorders Attributed to TH Deficiency

    Tetrahydrobiopterin Deficiency Impairs Postnatal Increase of TH Protein via Insufficient Dopamine Biosynthesis

    Selective Ablation of Dopamine Beta-Hydroxylase Neurons (Subpopulation of TH Neurons) in the Brain: New Insights into Brain Catecholaminergic Circuitry and Catecholamine-Related Diseases

    Neural Circuit Mechanism for Learning Dependent on Dopamine Transmission: Roles of Striatal Direct and Indirect Pathways in Sensory Discrimination

    Regulation of Tyrosine Hydroxylase by Ser19-Phosphorylation-Dependent Binding to 14-3-3γ

    Modeling the Dynamics of Dopamine Biosynthesis and its Regulation by Tyrosine Hydroxylase


    Reassessment of Intrinsic Dopaminergic Innervation in the Human Enteric Nervous System – Clinical Implications

    Midbrain Dopamine Neurons are Divided into Different Functional Groups

    Cell-, Region- and Species-Specific Expression of VMAT2: Implications for Medical Imaging With High-Affinity Transporter Ligands

    Theme B: Catecholamine Release and Re-uptake

    Theme B Catecholamine Release and Re-uptake

    Detecting Catecholamines – A Journey from Beaker to the Behaving Brain

    Functional Disturbances in DA Homeostasis and Signaling Revealed Through the Study of Rare Dopamine Transporter Coding Variants

    Norepinephrine Transporter A457P Knockin Mice Display Tachycardia and Anxiety-Like Behavior

    In Vivo Mutations in the Trafficking Domain of the Drosophila Vesicular Monoamine Transporter Disrupt Specific Amine-Dependent Behaviors

    Fate of the Chromaffin Granule Membrane and its Protein Constituents after Fusion


    Catestatin (Human Chromogranin A352-372) Induces Lipolysis and Fatty Acid Oxidation through Regulation of Adrenergic and Leptin Signaling

    Introduction: From Mystery Matrix Proteins to Precise Molecular Actions in Human Disease


    A New Take on Uptake: Dopamine Transporters & the Cellular Mechanisms of Amphetamine Action

    A Retrospective on PET and the Amphetamine Paradigm: Validation and Paradoxes


    The Corelease of Glutamate by Dopamine Neurons

    Psychostimulant-Induced Alterations of Monoaminergic Transporters: Implications for Neurotoxicity and Neuroprotection

    Trace Amine Associated Receptor 1 is a Catecholamine Receptor that Differentially Controls DAT and NET Internalization

    VGF-Derived Peptide TLQP-21: Structure, Function, and Biomedical Implications



    Chromogranins the Key Proteins for the Storage and Regulation of Exocytosis in Chromaffin Cells

    Chromogranin A in the Storage and Exocytosis of Catecholamines


    The Involvement of Vesicular ATP in the Storage and Exocytosis of Catecholamines of Bovine Chromaffin Cells


    The Role of Ca2+ Release from the Endoplasmic Reticulum in the Catecholamine Hypersecretion of Adrenal Chromaffin Cells from Spontaneously Hypertensive Rats

    PACAP as a Primary Effector of the Acute Sympatho-Adrenal Stress Response

    Amphetamine Induced Dopamine Release in Macaque Monkeys: Striking Differences Between Prefrontal Cortex and Caudate Nucleus

    Attenuated Amphetamine-Induced Dopamine Release in Subjects at Ultra-High Risk for Substance Dependence

    The Membrane-Raft Protein Flotillin-1 is Essential in Dopamine Neurons for Amphetamine-Induced Behavior in Drosophila

    Plant Flavonoids Affecting Adrenal Medullary Catecholamine Biosynthesis and Release

    A Protein Complex for Dopamine Synthesis and Vesicular Storage: Target for Cellular Oxidative Damage

    Overexpression of Parkin in The Nigrostriatal System Might Protect Dopaminergic Terminals From Methamphetamine Neurotoxicity Via Regulation of Dopamine Transporter

    Increased Catecholamine Toxicity in Mice with Low Expression of VMAT2

    Theme C: Metabolism

    Theme C Metabolism

    Renalase: A New Player in Catecholamine Metabolism

    Abnormal Monoamine Oxidase A VT in the Prefrontal and Anterior Cingulate Cortex During Major Depressive Episodes and High Risk States for Major Depressive Episodes

    CNS Catecholamine Metabolism – Emerging Concepts

    Catestatin (Human Chromogranin A352-372) Induces Lipolysis and Fatty Acid Oxidation through Regulation of Adrenergic and Leptin Signaling

    Triple Deuteration Modifies Pharmacokinetics and Pharmacodynamics of Dopamine in PD Models

    Understanding Catecholamine Metabolism as a Guide for Assessment of Sympathoadrenal Function and Dysfunction in Health and Disease

    Multiplex Immunoassay for Catecholamines

    Modifiers of Neurofibromatosis-Associated Tumors and the Potential Role for Catecholamines and Sex Differences

    Catecholamine Metabolism in Chromogranins Knock-Out Mice

    Translation Research in Autism and Cancer: Novel Roles of MAO

    COMT is a Major Contributor to Pain Perception: from Humans to Rats and Back to Humans

    Novel COMT Inhibitors in Parkinson Disease

    Effect of Opicapone, a New Catechol-O-Methyltransferase Inhibitor, in Levodopa Pharmakokinetics in the Cynomolgous Monkey


    Does Impaired Aldehyde Detoxification Play a Role in Parkinson’s Disease?

    The Role of Aldehyde Detoxification in Parkinson’s Disease

    Pharmacological Profile of Opicapone in Wistar rat


    Theme D: Catecholamine Receptors and Catecholaminergic Signaling

    Theme D Catecholamine Receptors and Catecholaminergic Signaling

    How Drugs Bind and Control their Targets: Characterizing GPCR Signaling through Long-Timescale Simulation

    Structural basis of Subtype Selectivity in Dopamine D3 and D2 Receptors


    Hormone-Mediated Activation of G Proteins by GPCRs: Insights from the Crystal Structure of a GPCR-G Protein Complex

    Towards Better Understanding of G(s) Coupling in Catecholamine Receptors

    Receptor Heteromerization: Understanding the Functional and Pathological Role of the Dopamine D4 Receptor

    Trace Amines and Their Receptors: New Opportunities for Modulation of Brain Dopaminergic Functions

    Cross-Talk between G Protein-Coupled Receptors: Challenges of Distinguishing Upstream from Downstream Mechanisms

    Growth Hormone Secretagogue Receptor (GHSR1a, aka Ghrelin Receptor) is an Allosteric Modulator of Dopamine Signaling in the Brain via Formation of GHSR1a:DRD2 and GHSR1a:DRD1 Heteromers

    Regulation of β2Adrenergic Receptor Trafficking and Signaling by Ubiquitination and Deubiquitination

    Sorting NEXIN-25 Interacts with D1 and D2Dopamine Receptors to Regulate Receptor Expression and Signaling

    Trafficking of the D2 Dopamine Receptor Promotes Drug-Induced Changes in Neuronal and Behavioral Plasticity

    D2 Receptors Control of Dopamine Levels

    Integrated Approaches to Understand the Actions of GPCRs: The b-Arrestin-Dependent D2R Mediated Signaling Through Akt/GSK3

    Hyperdopaminergic Modulation of Inhibitory Transmission is Dependent on GSK-3β Signaling-Mediated Trafficking of GABAA Receptors

    Simultaneous, Massively Parallel and Genome-Wide Interrogation of GPCR b-arrestin-ergic Signaling: Implications for GPCR Drug Discovery and Catecholamine Biology

    Backwards and Forwards with Molecular and Classical Pharmacology

    Targeting Beta-Arrestin Dependent Signaling in the Treatment of Parkinson’s Disease

    D2 Functionally Selective Ligands: novel Therapeutics?

    Investigation of the D1-D2 heteromer: pharmacology, subunit composition, and mechanisms of signaling

    β-Adrenergic Receptors, Caveolae and Caveolins: Receptor Localization and Function

    Protein Kinase C β and the Dopamine Transporter Influence Surface D2-Like Dopamine Receptor Localization

    Role of Adrenaline on the Maturation of β2-Adrenoceptors

    Deciphering the Functionally Selective Properties of D2R Ligands

    Chronic loss of Noradrenergic Tone Produces β-Arrestin2-Mediated Cocaine Hypersensitivity and a GαI to Gαs switch in D2 Receptor Coupling in the Nucleus Accumbens

    Probing the Functional Selectivity of β-adrenergic Receptors Reveals New Signaling Modes and Potential Therapeutic Applications


    Identification of Substituted Benzazepines as Functionally Selective Ligands of the D1 Dopamine Receptor

    Novel cAMP Sensor Links GPCR-Gs Signaling to ERK in Neuroscreen-1 Cells

    High-Throughput Screening for Modulators of the D2 Dopamine Receptor Yields Unique and Selective Pharmacological Chemotypes

    Discovery and Characterization of TAAR1 Agonists, Modulators of Dopaminergic and Serotonergic Neurotransmission with Therapeutic Potential in Neuropsychiatric Disorders

    Theme E: Neurology

    Theme E Neurology

    Modeling Parkinson’s Disease in a Mouse Model Overexpressing Astrocytic Monoamine Oxidase B (MAO-B): Towards Exploring Novel Therapeutics

    3,4-Dihydroxyphenylacetaldehyde is an Autotoxic and Protein-Reactive Intermediate of Dopamine Catabolism

    Dopamine Oxidation and Quinone Modification of Proteins: Mechanisms of Toxicity and Implications for Parkinson’s Disease

    Insights into LRRK2-Mutation Related PD from PET Imaging Studies


    Norepinephrine Deficiency in Parkinson Disease

    Progressive Noradrenergic Degeneration in Mice with Reduced Expression of the Vesicular Monoamine Transporter (VMAT2)

    LRRK2 and Risk of PD

    Synuclein-Mitochondrial Interactions in Substantia Nigra Dopamine Neurons

    Mitochondria-Targeted Cholesterol Oximes Increase Dopamine-Related Gene Expression and Behavior in Mice Over-Expressing Alpha-Synuclein, a Model of Pre-Manifest Parkinson’s Disease

    Induction of Chaperone-Mediated Autophagy as a Means to Attenuate Alpha-Synuclein-Mediated Neurotoxicity

    The Link between Neuronal Phenotype and Vulnerability in Parkinson’s Disease

    Willie Sutton’s Getaway Car and the Pathogenesis of Parkinson Disease

    Contributions of Dopamine in the Dorsal Striatum to Behaviors Corresponding to Cognitive Dysfunction in Parkinson’s Disease

    Cardiac Sympathetic Denervation: A Biomarker of Lewy Body Diseases


    Cerebrospinal Fluid Biomarkers of Central Catecholamine Deficiency in Parkinson Disease and Other Synucleinopathies


    Comparison Between Myocardial Sympathetic and Striatal Dopaminergic Imaging in Lewy Body Diseases: “Union is strength!”

    A Role For Neuronal MHC-I Display in Parkinson’s Disease?

    Modeling of Preclinical and Clinical Stages of Parkinsonism in MPTP-treated Mice with Focus on Tyrosine Hydroxylase in Survived Nigrostriatal Dopaminergic Neurons

    Role of Multiple Factors in Susceptibility of Neurons in Parkinson’s Disease

    Modeling of Presymptomatic and Symptomatic Stages of Parkinsonism in MPTP-treated Mice: Extra-nigrostriatal Manifestations


    Basal and Graded 6-OHDA –induced Differences in Striatal Dopamine and its Metabolites in two Mouse Lines with A30P–Mutated Alpha-Synuclein

    Rasagiline Reduces Striatal Dopamine Release and Extracellular Oxidative Stress in a Rat Model of Early Parkinson’s Disease

    Approach Towards Development of Multifunctional Drugs As an Effective Strategy for Treatment of Parkinson’s Disease


    Triple Deuteration Modifies Pharmacokinetics and Pharmacodynamics of Dopamine in PD Models

    Theme F: Psychiatry and Psychology

    Theme F Psychiatry and Psychology

    Rewarding Dopamine

    Modulating Local Circuit Dynamics versus Long-Range Inputs

    Midbrain Dopamine Neurons are Divided into Different Functional Groups

    Dopamine System Dysregulation by the Hippocampus and the Pathophysiology of Schizophrenia

    The Enduring Centrality of Dopamine in the Pathophysiology of Schizophrenia: In Vivo Evidence from the Prodrome to the First Psychotic Episode

    Striatal Dopamine Release in Schizophrenia Comorbis with Substance Dependence

    Neuroimaging Studies of Central Catecholaminergic Function in Depression

    Central and Peripheral Norepinephrine Secretion in Major Depression is Activated, as Assessed by 24 hour CSF and Plasma Sampling

    Norepinephrine: A Broken Spoke on the Wheel of Depression

    PET Imaging of Serotonin Transmission in Monkeys: Effects of Maternal Separation and Long-Term Fluoxetine Treatment during Adolescence

    Opposing Regulation of Norepinephrine and Dopamine in Rat Limbic Brain Regions in Response to Aversive Stimuli

    The Locus Coeruleus, Stress, Opioids and Behavioral Flexibility

    Measurements of Dopaminergic Function in the Rat Brain Using [18F]FDOPA PET and Microdialysis

    Evaluation of [11C]ORM-13070 as a PET tracer for α2C-adrenoceptors in the human brain

    Theme G: Drug Abuse and Addiction

    Theme G Drug Abuse and Addiction

    Addiction: Story of an Unbalanced Brain

    Essential Catecholamine Influences on Dorsolateral Prefrontal Cortical Cognitive Function: Molecular Signaling Pathways

    Neural Mechanisms Underlying the Cognition-Enhancing Actions of Pyschostimulants: Relevance to ADHD

    Frontostriatal Systems and Differential Roles of Dopamine D1- and D2-Like Receptors in Impulsivity and Response Inhibition


    Catecholamine Strategies for Remediating Fronto-Executive Deficits in Stimulant Addiction and Related Disorders


    Ultrastructural and Optogenetic Evidence for Dual Neuronal Signaling by Dopamine Neurons of the Ventral Tegmental Area (VTA)

    Seeking reward: Upstream modulation of VTA dopamine neurons by orexin/hypocretin inputs

    Striatal Dopamine, Self-control and Decision-Making: Identifying Therapeutic Targets for Addiction through Brain Imaging

    Imaging Neurochemical Transmission in Substance Abuse: Commonalities and Differences Across Addictions

    Dopamine Transmission in Cocaine Addiction: Linking the Animal and Human Studies

    Growth Associated Protein-43, Amphetamine and Dopamine Transporter Activity

    The Role of Ion Binding in Transporter Conformational Transition


    Evidence for the Contribution of D4 Receptors to Cocaine Self-Administration in Monkeys

    Drug Design for Addiction – Molecular Determinants of Selectivity and Efficacy at the Dopamine D3 Receptor

    Cue-Induced Dopamine Release in Striatal and Extra-striatal Regions in Cocaine Dependent Users: A High Resolution PET [18F]Fallypride Study

    β-arrestin Regulation of Ghrelin Signaling in modulating Addictive Behavior

    Dopamine D3 and D4 Receptors as Therapeutic Targets for Nicotine Addiction


    Long-Term Cocaine Exposure Affects Dopamine D3 Receptor Function

    Theme H: Catecholamines in the Periphery

    Theme H Catecholamines in the Periphery

    Recurrent Hypoglycemic Stress Differentially Regulates Catecholamine Release and Transmitter Gene Expression

    Sympathetic Mechanism of Hypertension


    Harnessing the Autonomic System for Therapeutic Intervention

    Norepinephrine Transporter Function and Human Cardiovascular Regulation

    Role of Common Genetic Variation in Control of Human Adrenergic Function and Blood Pressure: Focus on the Chromogranins

    What is the Optimal Biochemical Diagnostic Strategy for Pheochromocytoma?

    SDHx-Related Pheochromocytoms: New Advances in Genetics and Functional Imaging

    Novel Methods Peripheral Autonomic Assessment

    Identification and Functional Characterization of Genetic Variants of the Catecholamine Release-Inhibitory Peptide Catestatin in an Indian Population

    The Osmopressor Response in Human Physiology


    Adrenergic Derived Myocardium: Anatomic Substrate for Stress Induced Cardiomyopathies

    The Relationship of Norepinephrine to Stress Induced Hypertension

    Regulation of Adrenal Phenylethanolamine N-methyltransferase Gene Expression and Adrenaline Synthesis in a Fetal Programming Model of Hypertension

    Chronic Unpredictable Stress Induces Catecholaminergic System Changes in Mouse Adrenal Gland


    Effect of Daidzein on Mean Arterial Pressure and Vascular Dysfunction in CLP-Induced Septic Mice

    Adrenal-Specific G Protein-Coupled Receptor Kinase (GRK)-2 Deficiency Reduces Circulating Catecholamine Levels and Improves Cardiac Function after Myocardial Infarction

    Serotonin and Catecholamines In Regulation of Myocardium Functions in Children with Congenital Heart Diseases

    “Genetic and Acquired Determinants of Postural Tachycardia Syndrome”

    Neurotransmitter dopamine regulates tumor growth

    Extra Virgin Olive Oil Increases Uncoupling Protein 1 Content in Brown Adipose Tissue and Enhances Noradrenaline and Adrenaline Secretions in Rats

    Neurovisceral Integration and Regulation of Peripheral Indices of ANS Function

    Theme I: Catecholamines in Integrative Function

    Theme I Catecholamines in Integrative Function

    Neuropeptide Y Infusion to Rats Attenuates Development of PTSD-Like Symptoms to Traumatic Stress

    PTSD and the Locus Coeeurleus

    Systems Biology and the Stress Response: From Pythagoras and the Epicureans to Modern Medicine

    Reactive Oxygen Species and Neuropeptide Y Signaling in Altered Catecholamine Synthesis during Intermittent Hypoxia

    Stress, HIF1a, and Adrenergic Function

    Characterization of Cerebrospinal Fluid (CSF) and Plasma NPY Levels in Normal Volunteers over a 24-h Timeframe

    NPY: Low Cerebrospinal Fluid (CSF) Levels in Posttraumatic Stress Disorder in Comparison to Combat and Civilian, non-combat Control Subjects

    Developmental Neuroendocrinology of Posttraumatic Stress Disorder in Children and Adolescents after Motor Vehicle Accidents


    Repeated and Novel Stress-triggered Changes in Adipocyte Catecholamine System

    Jekyll and Hyde: Noradrenergic Modulation in Acute and Chronic Stress

    Early Life Stress Increases Nucleus Accumbens Dopamine Signaling

    Modulation of Inflammatory Cytokine Release by Hypoxia Mediated Tyrosine Hydroxylase Induction in Mixed Synovial Cells of Patients with Rheumatoid Arthritis and Osteoarthritis

    Theme J: Catecholamine Interactions with Other Transmitters

    Theme J Catecholamine Interactions with Other Transmitters

    Catecholamine Release Modulation by Adenosine through A2AReceptors in Mouse Chromaffin Cell Culture

    Morphological and Functional Significance of Coexistence of PACAP with Catecholamine in Nerve Terminals Innervating Hypothalamic Neuroendocrine Cells

    Interactions of Neuropeptide Y, Catecholamines and Angiotensin at the Vascular Neuroeffector Junction

    Overview: Neuropeptide-Catecholamine Interactions in Stress

    Neuropeptide Regulation of the Locus Coeruleus (LC) in the Mediation of Stress Responses

    Breaking Down Monoamine “Silos”: We’re all in this Together

    Orexin/hypocretin in the Ventral Tegmental Area is Necessary for Morphine-Induced Synaptic Plasticity of Dopamine Neurons

    The Adrenomedullary Angiotensin II Type 2 Receptor: Stress-Triggered Regulation and Role in Catecholamine Biosynthesis

    Angiotensin AT1 Receptor Blockade Prevents Excessive Brain and Peripheral Sympathetic Stimulation During Stress

    Catecholamine Release Modulation by Adenosine Through A2a Receptors in Mouse Chromaffin Cells in Culture


    Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), A Master Regulator in Central and Peripheral Stress Responses

    Novel Catecholamine Mechanisms in Memory Consolidation and Retrieval During Stress

    Catecholaminergic Regulation of Peptide Synthesis and Release Programs in Paraventricular CRH Neurons

    Control of Dopamine Neurotransmission in the Prefrontal Cortex: Focus on Serotonin and Norepinephrine Systems

    Unfaithful Neurotransmitter Transporters: Focus on Biogenic Amine Reuptake and Implications for Antidepressant Efficacy

    L-DOPA and the Brain Pattern of Dopamine Extracellular Levels: a New Deal Imposed by Serotonergic and Noradrenergic Fibres

    Individual Differences in Nicotinic Acetylcholine Receptor Modulation of Dopamine Signals in the Nucleus Accumbens Shell

    Insulin Induces Long-term Depression in VTA DA Neurons via an Endocannabinoid-mediated Mechanism

Product details

  • No. of pages: 328
  • Language: English
  • Copyright: © Academic Press 2013
  • Published: December 5, 2013
  • Imprint: Academic Press
  • eBook ISBN: 9780128000731
  • Paperback ISBN: 9780128000441

About the Editor

Lee Eiden

Affiliations and Expertise

Laboratory of Cellular and Molecular Regulation, National Institutes of Health, MD, USA

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