Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development

Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

(2019) Antonio Cuadrado et al.   NATURE REVIEWS DRUG DISCOVERY

CXA-10, a Nitrated Fatty Acid, is Renoprotective in Deoxycorticosterone Acetate-Salt Nephropathy

(2019) Cynthia Arbeeny et al.   JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

NRF2 and the Hallmarks of Cancer

(2018) Montserrat Rojo de la Vega et al.   CANCER CELL

NRF2 addiction in cancer cells

(2018) Hiroshi Kitamura et al.   CANCER SCIENCE

Targeted Nrf2 activation therapy with RTA 408 enhances regenerative capacity of diabetic wounds

(2018) Piul S. Rabbani et al.   DIABETES RESEARCH AND CLINICAL PRACTICE

Discovery of a head-to-tail cyclic peptide as the Keap1-Nrf2 protein-protein interaction inhibitor with high cell potency

(2018) Meng-Chen Lu et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Glycogen synthase kinase-3 and its inhibitors: Potential target for various therapeutic conditions

(2018) A. Prasanth Saraswati et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Epigenetic versus Genetic Deregulation of the KEAP1/NRF2 Axis in Solid Tumors: Focus on Methylation and Noncoding RNAs

(2018) F. P. Fabrizio et al.   Oxidative Medicine and Cellular Longevity

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

(2018) Antonio Cuadrado et al.   PHARMACOLOGICAL REVIEWS

C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape

(2018) Sharadha Dayalan Naidu et al.   Scientific Reports

Dimethyl fumarate downregulates the immune response through the HCA 2 /GPR109A pathway: Implications for the treatment of multiple sclerosis

(2018) Felipe von Glehn et al.   Multiple Sclerosis and Related Disorders

Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis

(2018) Elizabeth A. Mills et al.   Frontiers in Neurology

Trehalose protects against oxidative stress by regulating the Keap1–Nrf2 and autophagy pathways

(2018) Yuhei Mizunoe et al.   Redox Biology

Replacement of a Naphthalene Scaffold in Kelch-like ECH-Associated Protein 1 (KEAP1)/Nuclear Factor (Erythroid-derived 2)-like 2 (NRF2) Inhibitors

(2018) Benjamin G. Richardson et al.   JOURNAL OF MEDICINAL CHEMISTRY

Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1

(2018) Evanna L. Mills et al.   NATURE

Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes

(2018) Daphne Pei Wen Wong et al.   PLoS One

MicroRNA-98-5p ameliorates oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal injury by inhibiting Bach1 and promoting Nrf2/ARE signaling

(2018) Xiuyan Sun et al.   BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia

(2018) David R. Lynch et al.   Annals of Clinical and Translational Neurology

The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice

(2017) Chika Higashi et al.   EUROPEAN JOURNAL OF PHARMACOLOGY

Recent progress in the development of small molecule Nrf2 modulators: a patent review (2012-2016)

(2017) Haopeng Sun et al.   EXPERT OPINION ON THERAPEUTIC PATENTS

Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation

(2017) Kouhei Tsuchida et al.   FREE RADICAL BIOLOGY AND MEDICINE

Stress-sensing mechanisms and the physiological roles of the Keap1–Nrf2 system during cellular stress

(2017) Takafumi Suzuki et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Identification of a novel series of anti-inflammatory and anti-oxidative phospholipid oxidation products containing the cyclopentenone moietyin vitroandin vivo: Implication in atherosclerosis

(2017) Jianhong Lu et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Characterization of the Potent, Selective Nrf2 Activator, 3-(Pyridin-3-Ylsulfonyl)-5-(Trifluoromethyl)-2 H -Chromen-2-One, in Cellular and In Vivo Models of Pulmonary Oxidative Stress

(2017) John G. Yonchuk et al.   JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

15-Deoxy-Δ12,14-prostaglandin J2 Exerts Antioxidant Effects While Exacerbating Inflammation in Mice Subjected to Ureteral Obstruction

(2017) Line Nilsson et al.   MEDIATORS OF INFLAMMATION

Brusatol overcomes chemoresistance through inhibition of protein translation

(2017) Bryan Harder et al.   MOLECULAR CARCINOGENESIS

A clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer

(2017) E-J Choi et al.   ONCOGENE

Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes

(2017) Annika S. Axelsson et al.   Science Translational Medicine

Controversy about pharmacological modulation of Nrf2 for cancer therapy

(2017) Lidija Milkovic et al.   Redox Biology

Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

(2017) Marta Pajares et al.   Redox Biology

Dimethyl fumarate alters B-cell memory and cytokine production in MS patients

(2017) Matthew D. Smith et al.   Annals of Clinical and Translational Neurology

Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors

(2016) Anju Singh et al.   ACS Chemical Biology

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

(2016) Marta Pajares et al.   Autophagy

Thermodynamic profiling of inhibitors of Nrf2:Keap1 interactions

(2016) Hamid R. Nasiri et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015)

(2016) Valle Palomo et al.   EXPERT OPINION ON THERAPEUTIC PATENTS

An overview of chemical inhibitors of the Nrf2-ARE signaling pathway and their potential applications in cancer therapy

(2016) Jiayu Zhu et al.   FREE RADICAL BIOLOGY AND MEDICINE

Overdose Intake of Curcumin Initiates the Unbalanced State of Bodies

(2016) Peiyu Qiu et al.   JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY

Dimethyl Fumarate Treatment Mediates an Anti-Inflammatory Shift in B Cell Subsets of Patients with Multiple Sclerosis

(2016) Rui Li et al.   JOURNAL OF IMMUNOLOGY

Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites

(2016) Michael H. L. Wong et al.   JOURNAL OF MEDICINAL CHEMISTRY

Monoacidic Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1:NRF2) Protein–Protein Interaction with High Cell Potency Identified by Fragment-Based Discovery

(2016) Thomas G. Davies et al.   JOURNAL OF MEDICINAL CHEMISTRY

Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells

(2016) Tatsuro Iso et al.   MOLECULAR AND CELLULAR BIOLOGY

Sulforaphane and Other Nutrigenomic Nrf2 Activators: Can the Clinician’s Expectation Be Matched by the Reality?

(2016) Christine A. Houghton et al.   Oxidative Medicine and Cellular Longevity

Discovery of a novel Nrf2 inhibitor that induces apoptosis of human acute myeloid leukemia cells

(2016) JinFeng Zhang et al.   Oncotarget

A Small Molecule Inhibits Deregulated NRF2 Transcriptional Activity in Cancer

(2015) Michael J. Bollong et al.   ACS Chemical Biology

Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway

(2015) B.G. Richardson et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a ‘drug-prodrug’ mechanism of action

(2015) Javier Egea et al.   BRITISH JOURNAL OF PHARMACOLOGY

Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP

(2015) Antonio Cuadrado   FREE RADICAL BIOLOGY AND MEDICINE

Activation of NRF2 Signaling in HEK293 Cells by a First-in-Class Direct KEAP1-NRF2 Inhibitor

(2015) Xia Wen et al.   JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY

Structure–Activity and Structure–Property Relationship and Exploratory in Vivo Evaluation of the Nanomolar Keap1–Nrf2 Protein–Protein Interaction Inhibitor

(2015) Zheng-Yu Jiang et al.   JOURNAL OF MEDICINAL CHEMISTRY

Design, Synthesis, and Evaluation of Triazole Derivatives That Induce Nrf2 Dependent Gene Products and Inhibit the Keap1–Nrf2 Protein–Protein Interaction

(2015) Hélène C. Bertrand et al.   JOURNAL OF MEDICINAL CHEMISTRY

Cell-Permeable Peptide Targeting the Nrf2-Keap1 Interaction: A Potential Novel Therapy for Global Cerebral Ischemia

(2015) J. Tu et al.   JOURNAL OF NEUROSCIENCE

Application of Mass Spectrometry Profiling to Establish Brusatol as an Inhibitor of Global Protein Synthesis

(2015) Steffan Vartanian et al.   MOLECULAR & CELLULAR PROTEOMICS

Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response

(2015) Ryota Saito et al.   MOLECULAR AND CELLULAR BIOLOGY

The variable chemotherapeutic response of Malabaricone-A in leukemic and solid tumor cell lines depends on the degree of redox imbalance

(2015) Alak Manna et al.   PHYTOMEDICINE

Redox control of protein degradation

(2015) Marta Pajares et al.   Redox Biology

Alzheimer's disease, enzyme targets and drug discovery struggles: From natural products to drug prototypes

(2014) Tiago Silva et al.   AGEING RESEARCH REVIEWS

Oncogenic KRAS Confers Chemoresistance by Upregulating NRF2

(2014) S. Tao et al.   CANCER RESEARCH

Binding Mode and Structure-Activity Relationships around Direct Inhibitors of the Nrf2-Keap1 Complex

(2014) Eric Jnoff et al.   ChemMedChem

Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis

(2014) T. Wu et al.   GENES & DEVELOPMENT

Discovery of Potent Keap1–Nrf2 Protein–Protein Interaction Inhibitor Based on Molecular Binding Determinants Analysis

(2014) Zheng-Yu Jiang et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO

(2014) Anne Cleasby et al.   PLoS One

Induction of Heme Oxygenase I (HMOX1) by HPP-4382: A Novel Modulator of Bach1 Activity

(2014) Otis C. Attucks et al.   PLoS One

The Nrf2 regulatory network provides an interface between redox and intermediary metabolism

(2014) John D. Hayes et al.   TRENDS IN BIOCHEMICAL SCIENCES

Selective inhibition of bacterial topoisomerase I by alkynyl-bisbenzimidazoles

(2014) Nihar Ranjan et al.   MedChemComm

A Review of the Evidence that Ochratoxin A Is an Nrf2 Inhibitor: Implications for Nephrotoxicity and Renal Carcinogenicity

(2014) Alice Limonciel et al.   Toxins

Role of Nrf2 in Oxidative Stress and Toxicity

(2013) Qiang Ma   Annual Review of Pharmacology and Toxicology

Detection of fumarate–glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism

(2013) Stefan Dibbert et al.   ARCHIVES OF DERMATOLOGICAL RESEARCH

Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism

(2013) Douglas Marcotte et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Discovery of a small-molecule inhibitor and cellular probe of Keap1–Nrf2 protein–protein interaction

(2013) Longqin Hu et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Proteomic Analysis of Ubiquitin Ligase KEAP1 Reveals Associated Proteins That Inhibit NRF2 Ubiquitination

(2013) B. E. Hast et al.   CANCER RESEARCH

RXR  Inhibits the NRF2-ARE Signaling Pathway through a Direct Interaction with the Neh7 Domain of NRF2

(2013) H. Wang et al.   CANCER RESEARCH

Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs

(2013) Takumi Satoh et al.   FREE RADICAL BIOLOGY AND MEDICINE

Keap Calm, and Carry on Covalently

(2013) Anthony J. Wilson et al.   JOURNAL OF MEDICINAL CHEMISTRY

Reduction of atherogenic risk in patients with type 2 diabetes by curcuminoid extract: a randomized controlled trial

(2013) Somlak Chuengsamarn et al.   JOURNAL OF NUTRITIONAL BIOCHEMISTRY

Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction with improved binding and cellular activity

(2013) Rowena Hancock et al.   ORGANIC & BIOMOLECULAR CHEMISTRY

Sulforaphane as a Potential Protective Phytochemical against Neurodegenerative Diseases

(2013) Andrea Tarozzi et al.   Oxidative Medicine and Cellular Longevity

Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex

(2013) L. Baird et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Luteolin, a bioflavonoid inhibits Azoxymethane-induced colorectal cancer through activation of Nrf2 signaling

(2013) Ashok Kumar Pandurangan et al.   TOXICOLOGY MECHANISMS AND METHODS

Toward clinical application of the Keap1–Nrf2 pathway

(2013) Takafumi Suzuki et al.   TRENDS IN PHARMACOLOGICAL SCIENCES

Novel protein–protein interaction inhibitor of Nrf2–Keap1 discovered by structure-based virtual screening

(2013) Hao-Peng Sun et al.   MedChemComm

Amelioration of Alzheimer’s disease by neuroprotective effect of sulforaphane in animal model

(2012) Hyunjin Vincent Kim et al.   AMYLOID-JOURNAL OF PROTEIN FOLDING DISORDERS

Bardoxolone Brings Nrf2-Based Therapies to Light

(2012) Donna D. Zhang   ANTIOXIDANTS & REDOX SIGNALING

The high Nrf2 expression in human acute myeloid leukemia is driven by NF- B and underlies its chemo-resistance

(2012) S. A. Rushworth et al.   BLOOD

Broccoli sprouts powder could improve serum triglyceride and oxidized LDL/LDL-cholesterol ratio in type 2 diabetic patients: A randomized double-blind placebo-controlled clinical trial

(2012) Zahra Bahadoran et al.   DIABETES RESEARCH AND CLINICAL PRACTICE

Small Molecule Modulators of Keap1-Nrf2-ARE Pathway as Potential Preventive and Therapeutic Agents

(2012) Sadagopan Magesh et al.   MEDICINAL RESEARCH REVIEWS

Structural and Functional Characterization of Nrf2 Degradation by the Glycogen Synthase Kinase 3/ -TrCP Axis

(2012) P. Rada et al.   MOLECULAR AND CELLULAR BIOLOGY

Drug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and wogonin reverses it by down-regulating Nrf2-mediated cellular defense response

(2012) Yan Zhong et al.   MOLECULAR CARCINOGENESIS

Curcuminoids exert glucose-lowering effect in type 2 diabetes by decreasing serum free fatty acids: a double-blind, placebo-controlled trial

(2012) Li-Xin Na et al.   MOLECULAR NUTRITION & FOOD RESEARCH

Placebo-Controlled Phase 3 Study of Oral BG-12 or Glatiramer in Multiple Sclerosis

(2012) Robert J. Fox et al.   NEW ENGLAND JOURNAL OF MEDICINE

Placebo-Controlled Phase 3 Study of Oral BG-12 for Relapsing Multiple Sclerosis

(2012) Ralf Gold et al.   NEW ENGLAND JOURNAL OF MEDICINE

Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity

(2012) A Arlt et al.   ONCOGENE

Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity

(2012) S Chowdhry et al.   ONCOGENE

Anti-inflammatory Effect of a Cell-Penetrating Peptide Targeting the Nrf2/Keap1 Interaction

(2012) Richard Steel et al.   ACS Medicinal Chemistry Letters

Pharmacological Targeting of the Transcription Factor Nrf2 at the Basal Ganglia Provides Disease Modifying Therapy for Experimental Parkinsonism

(2011) Agnieszka Jazwa et al.   ANTIOXIDANTS & REDOX SIGNALING

Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway

(2011) Ralf A. Linker et al.   BRAIN

MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism

(2011) Muhua Yang et al.   BREAST CANCER RESEARCH AND TREATMENT

Kinetic Analyses of Keap1-Nrf2 Interaction and Determination of the Minimal Nrf2 Peptide Sequence Required for Keap1 Binding Using Surface Plasmon Resonance

(2011) Yu Chen et al.   Chemical Biology & Drug Design

Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs

(2011) Xiuwen Tang et al.   FREE RADICAL BIOLOGY AND MEDICINE

Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction

(2011) Rowena Hancock et al.   FREE RADICAL BIOLOGY AND MEDICINE

Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: Role of glycogen synthase kinase-3

(2011) Ana I. Rojo et al.   FREE RADICAL BIOLOGY AND MEDICINE

Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution

(2011) Keiko Taguchi et al.   GENES TO CELLS

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

(2011) Emilia Kansanen et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

(2011) Gina M. DeNicola et al.   NATURE

Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes

(2011) Pablo E. Pergola et al.   NEW ENGLAND JOURNAL OF MEDICINE

Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism

(2011) D. Ren et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Enhanced Hepatic Nrf2 Activation After Ursodeoxycholic Acid Treatment in Patients with Primary Biliary Cirrhosis

(2010) Kazuhito Kawata et al.   ANTIOXIDANTS & REDOX SIGNALING

microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease

(2010) C. Sangokoya et al.   BLOOD

Sulforaphane protects brains against hypoxic–ischemic injury through induction of Nrf2-dependent phase 2 enzyme

(2010) Zhang Ping et al.   BRAIN RESEARCH

Activation of the NRF2 Signaling Pathway by Copper-Mediated Redox Cycling of Para- and Ortho-Hydroquinones

(2010) Xiu Jun Wang et al.   CHEMISTRY & BIOLOGY

Nrf2 and Keap1 Abnormalities in Non-Small Cell Lung Carcinoma and Association with Clinicopathologic Features

(2010) L. M. Solis et al.   CLINICAL CANCER RESEARCH

Small molecule modulators of antioxidant response pathway

(2010) Wooyoung Hur et al.   CURRENT OPINION IN CHEMICAL BIOLOGY

Activation of NRF2 by Nitrosative Agents and H2O2Involves KEAP1 Disulfide Formation

(2010) Simon Fourquet et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

p62/SQSTM1Is a Target Gene for Transcription Factor NRF2 and Creates a Positive Feedback Loop by Inducing Antioxidant Response Element-driven Gene Transcription

(2010) Ashish Jain et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

A Noncanonical Mechanism of Nrf2 Activation by Autophagy Deficiency: Direct Interaction between Keap1 and p62

(2010) A. Lau et al.   MOLECULAR AND CELLULAR BIOLOGY

The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1

(2010) Masaaki Komatsu et al.   NATURE CELL BIOLOGY

GSK3 signalling in neural development

(2010) Eun-Mi Hur et al.   NATURE REVIEWS NEUROSCIENCE

Protection against amyloid beta cytotoxicity by sulforaphane: Role of the proteasome

(2009) Hyun-Min Park et al.   ARCHIVES OF PHARMACAL RESEARCH

Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice

(2008) Kosuke Okada et al.   AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY

Glycogen synthase kinase 3β (GSK3β) in tumorigenesis and cancer chemotherapy

(2008) Jia Luo   CANCER LETTERS

Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth

(2008) T. Ohta et al.   CANCER RESEARCH

Curcumin: From ancient medicine to current clinical trials

(2008) H. Hatcher et al.   CELLULAR AND MOLECULAR LIFE SCIENCES

Prospective Type 1 and Type 2 Disulfides of Keap1 Protein

(2008) Ryan Holland et al.   CHEMICAL RESEARCH IN TOXICOLOGY

Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity

(2008) T. Yamamoto et al.   MOLECULAR AND CELLULAR BIOLOGY

Small molecule enhancers of autophagy for neurodegenerative diseases

(2008) Sovan Sarkar et al.   Molecular BioSystems

Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy

(2008) T. Shibata et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA