Lipid droplets and liver disease: from basic biology to clinical implications

The Perilipins: Major Cytosolic Lipid Droplet–Associated Proteins and Their Roles in Cellular Lipid Storage, Mobilization, and Systemic Homeostasis

(2016) Alan R. Kimmel et al.   Annual Review of Nutrition

Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease

(2016) Joel T. Haas et al.   Annual Review of Physiology

The physics of lipid droplet nucleation, growth and budding

(2016) Abdou Rachid Thiam et al.   BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

Prevalence of metabolic syndrome in mainland china: a meta-analysis of published studies

(2016) Ri Li et al.   BMC PUBLIC HEALTH

Lipid droplet hijacking by intracellular pathogens

(2016) Philippe Roingeard et al.   CELLULAR MICROBIOLOGY

Pathophysiology of lipid droplet proteins in liver diseases

(2016) Rotonya M. Carr et al.   EXPERIMENTAL CELL RESEARCH

The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent

(2016) Rosellina Margherita Mancina et al.   GASTROENTEROLOGY

TANGO1 and Mia2/cTAGE5 (TALI) cooperate to export bulky pre-chylomicrons/VLDLs from the endoplasmic reticulum

(2016) António J.M. Santos et al.   JOURNAL OF CELL BIOLOGY

Epidemiology and natural history of non-alcoholic fatty liver disease

(2016) Yousef Fazel et al.   METABOLISM-CLINICAL AND EXPERIMENTAL

The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)

(2016) Elena Buzzetti et al.   METABOLISM-CLINICAL AND EXPERIMENTAL

Targeting Fat: Mechanisms of Protein Localization to Lipid Droplets

(2016) Nora Kory et al.   TRENDS IN CELL BIOLOGY

Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation

(2016) Caleb C. Lord et al.   Cell Reports

Nonalcoholic fatty liver disease

(2015) Timothy Hardy et al.   CURRENT OPINION IN GASTROENTEROLOGY

Protein Crowding Is a Determinant of Lipid Droplet Protein Composition

(2015) Nora Kory et al.   DEVELOPMENTAL CELL

Fatty Acid Trafficking in Starved Cells: Regulation by Lipid Droplet Lipolysis, Autophagy, and Mitochondrial Fusion Dynamics

(2015) Angelika S. Rambold et al.   DEVELOPMENTAL CELL

Nonalcoholic Steatohepatitis Is the Second Leading Etiology of Liver Disease Among Adults Awaiting Liver Transplantation in the United States

(2015) Robert J. Wong et al.   GASTROENTEROLOGY

Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease

(2015) Paul Angulo et al.   GASTROENTEROLOGY

Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis

(2015) Xu Xu et al.   HEPATOLOGY

CIDEC/FSP27 is regulated by peroxisome proliferator-activated receptor alpha and plays a critical role in fasting- and diet-induced hepatosteatosis

(2015) Cédric Langhi et al.   HEPATOLOGY

Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: Findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop

(2015) Arun J. Sanyal et al.   HEPATOLOGY

Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up

(2015) Mattias Ekstedt et al.   HEPATOLOGY

The seipin complex Fld1/Ldb16 stabilizes ER–lipid droplet contact sites

(2015) Alexandra Grippa et al.   JOURNAL OF CELL BIOLOGY

A conserved family of proteins facilitates nascent lipid droplet budding from the ER

(2015) Vineet Choudhary et al.   JOURNAL OF CELL BIOLOGY

Seipin performs dissectible functions in promoting lipid droplet biogenesis and regulating droplet morphology

(2015) Bethany R. Cartwright et al.   MOLECULAR BIOLOGY OF THE CELL

Degradation of lipid droplet-associated proteins by chaperone-mediated autophagy facilitates lipolysis

(2015) Susmita Kaushik et al.   NATURE CELL BIOLOGY

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis

(2015) Stephan Buch et al.   NATURE GENETICS

Transcriptional regulation of hepatic lipogenesis

(2015) Yuhui Wang et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Hepatitis C virus and lipid droplets: finding a niche

(2015) Ana Filipe et al.   TRENDS IN MOLECULAR MEDICINE

Genetic background in nonalcoholic fatty liver disease: A comprehensive review

(2015) Fabio Salvatore Macaluso   WORLD JOURNAL OF GASTROENTEROLOGY

Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion

(2015) Xin Rong et al.   eLife

Lipid droplet biogenesis

(2014) Florian Wilfling et al.   CURRENT OPINION IN CELL BIOLOGY

Perilipin 5, a lipid droplet protein adapted to mitochondrial energy utilization

(2014) Alan R. Kimmel et al.   CURRENT OPINION IN LIPIDOLOGY

Intestinal lipid absorption and lipoprotein formation

(2014) M. Mahmood Hussain   CURRENT OPINION IN LIPIDOLOGY

Pnpla3I148Mknockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis

(2014) Eriks Smagris et al.   HEPATOLOGY

PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells

(2014) Carlo Pirazzi et al.   HUMAN MOLECULAR GENETICS

The Hepatitis C Virus Core Protein Inhibits Adipose Triglyceride Lipase (ATGL)-mediated Lipid Mobilization and Enhances the ATGL Interaction with Comparative Gene Identification 58 (CGI-58) and Lipid Droplets

(2014) Gregory Camus et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Recent Advances in Understanding Proteins Involved in Lipid Droplet Formation, Growth and Fusion

(2014) Jolene S.Y. Tan et al.   Journal of Genetics and Genomics

Inborn errors of cytoplasmic triglyceride metabolism

(2014) Jiang Wei Wu et al.   JOURNAL OF INHERITED METABOLIC DISEASE

PNPLA3 mediates hepatocyte triacylglycerol remodeling

(2014) Hanna Ruhanen et al.   JOURNAL OF LIPID RESEARCH

Department of Error

(2014)   LANCET

Beneficial effects of phosphatidylcholine on high-fat diet-induced obesity, hyperlipidemia and fatty liver in mice

(2014) Ho Sung Lee et al.   LIFE SCIENCES

Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk

(2014) Oddgeir L Holmen et al.   NATURE GENETICS

Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease

(2014) Julia Kozlitina et al.   NATURE GENETICS

Absence of Perilipin 2 Prevents Hepatic Steatosis, Glucose Intolerance and Ceramide Accumulation in Alcohol-Fed Mice

(2014) Rotonya M. Carr et al.   PLoS One

TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content

(2014) H. Mahdessian et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Arf1/COPI machinery acts directly on lipid droplets and enables their connection to the ER for protein targeting

(2014) Florian Wilfling et al.   eLife

Recombinant PNPLA3 protein shows triglyceride hydrolase activity and its I148M mutation results in loss of function

(2013) Piero Pingitore et al.   BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

Triacylglycerol Synthesis Enzymes Mediate Lipid Droplet Growth by Relocalizing from the ER to Lipid Droplets

(2013) Florian Wilfling et al.   DEVELOPMENTAL CELL

Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial

(2013) H. Denison et al.   DIABETES OBESITY & METABOLISM

Diacylglycerol Acyltransferase-1 Localizes Hepatitis C Virus NS5A Protein to Lipid Droplets and Enhances NS5A Interaction with the Viral Capsid Core

(2013) Gregory Camus et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Acyl-CoA synthetase 3 promotes lipid droplet biogenesis in ER microdomains

(2013) Adam Kassan et al.   JOURNAL OF CELL BIOLOGY

Expression of oleosin and perilipins in yeast promotes formation of lipid droplets from the endoplasmic reticulum

(2013) N. Jacquier et al.   JOURNAL OF CELL SCIENCE

Metabolic Consequences of Adipose Triglyceride Lipase Deficiency in Humans: An In Vivo Study in Patients With Neutral Lipid Storage Disease With Myopathy

(2013) Andrea Natali et al.   JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM

Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease

(2013) Yuki Kawano et al.   JOURNAL OF GASTROENTEROLOGY

Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice

(2013) Feng Guo et al.   JOURNAL OF LIPID RESEARCH

The biophysics and cell biology of lipid droplets

(2013) Abdou Rachid Thiam et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

PNPLA3 I148M polymorphism and progressive liver disease

(2013) Paola Dongiovanni   WORLD JOURNAL OF GASTROENTEROLOGY

Perilipin1 promotes unilocular lipid droplet formation through the activation of Fsp27 in adipocytes

(2013) Zhiqi Sun et al.   Nature Communications

Hepatic Fatty Acid Trafficking: Multiple Forks in the Road

(2013) Douglas G. Mashek   Advances in Nutrition

Chronic Alcohol Exposure Stimulates Adipose Tissue Lipolysis in Mice

(2012) Wei Zhong et al.   AMERICAN JOURNAL OF PATHOLOGY

Lipid Droplets and Cellular Lipid Metabolism

(2012) Tobias C. Walther et al.   Annual Review of Biochemistry

CIDE Proteins and Lipid Metabolism

(2012) Li Xu et al.   ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY

Intracellular Trafficking and Secretion of VLDL

(2012) Samata Tiwari et al.   ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY

Adiponutrin Functions as a Nutritionally Regulated Lysophosphatidic Acid Acyltransferase

(2012) Manju Kumari et al.   Cell Metabolism

The Problem of Establishing Relationships between Hepatic Steatosis and Hepatic Insulin Resistance

(2012) Robert V. Farese et al.   Cell Metabolism

Diacylglycerol acyltransferase 2 acts upstream of diacylglycerol acyltransferase 1 and utilizes nascent diglycerides andde novosynthesized fatty acids in HepG2 cells

(2012) Haja R. Wurie et al.   FEBS Journal

Autophagy Releases Lipid That Promotes Fibrogenesis by Activated Hepatic Stellate Cells in Mice and in Human Tissues

(2012) Virginia Hernández–Gea et al.   GASTROENTEROLOGY

Studies on the Substrate and Stereo/Regioselectivity of Adipose Triglyceride Lipase, Hormone-sensitive Lipase, and Diacylglycerol-O-acyltransferases

(2012) Thomas O. Eichmann et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis

(2012) John Zhong Li et al.   JOURNAL OF CLINICAL INVESTIGATION

The use of stable isotope-labeled glycerol and oleic acid to differentiate the hepatic functions of DGAT1 and -2

(2012) Jenson Qi et al.   JOURNAL OF LIPID RESEARCH

Effects of perilipin 2 antisense oligonucleotide treatment on hepatic lipid metabolism and gene expression

(2012) Yumi Imai et al.   PHYSIOLOGICAL GENOMICS

Steatohepatitis and liver cirrhosis in Chanarin-Dorfman syndrome with a new ABDH5 mutation

(2012) E. Cakmak et al.   Clinics and Research in Hepatology and Gastroenterology

Inflammatory Mechanisms in Obesity

(2011) Margaret F. Gregor et al.   Annual Review of Immunology

Phosphatidylcholine protects against steatosis in mice but not non-alcoholic steatohepatitis

(2011) Lorissa J. Niebergall et al.   BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

Liver triacylglycerol lipases

(2011) Ariel D. Quiroga et al.   BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

Phosphatidylcholine Synthesis for Lipid Droplet Expansion Is Mediated by Localized Activation of CTP:Phosphocholine Cytidylyltransferase

(2011) Natalie Krahmer et al.   Cell Metabolism

Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C

(2011) M. E. Miquilena-Colina et al.   GUT

Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis

(2011) Aijun Qiao et al.   HEPATOLOGY

Hepatic ratio of phosphatidylcholine to phosphatidylethanolamine predicts survival after partial hepatectomy in mice

(2011) Ji Ling et al.   HEPATOLOGY

Hepatitis C Virus Core Protein Decreases Lipid Droplet Turnover

(2011) Charles Harris et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Expression and Characterization of a PNPLA3 Protein Isoform (I148M) Associated with Nonalcoholic Fatty Liver Disease

(2011) Yongcheng Huang et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Fsp27 promotes lipid droplet growth by lipid exchange and transfer at lipid droplet contact sites

(2011) Jingyi Gong et al.   JOURNAL OF CELL BIOLOGY

Lipid droplets are functionally connected to the endoplasmic reticulum in Saccharomyces cerevisiae

(2011) N. Jacquier et al.   JOURNAL OF CELL SCIENCE

A role for autophagy during hepatic stellate cell activation

(2011) Lien F.R. Thoen et al.   JOURNAL OF HEPATOLOGY

Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria

(2011) Hong Wang et al.   JOURNAL OF LIPID RESEARCH

Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites

(2011) Jeffrey L. Pitman et al.   JOURNAL OF LIPID RESEARCH

Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease

(2011) N. Kumashiro et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2

(2011) F. R. Jornayvaz et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Human Fatty Liver Disease: Old Questions and New Insights

(2011) J. C. Cohen et al.   SCIENCE

Unique ties between hepatitis C virus replication and intracellular lipids

(2011) Eva Herker et al.   TRENDS IN ENDOCRINOLOGY AND METABOLISM

Defective Hepatic Autophagy in Obesity Promotes ER Stress and Causes Insulin Resistance

(2010) Ling Yang et al.   Cell Metabolism

Sphingolipids and insulin resistance: the five Ws

(2010) Scott A Summers   CURRENT OPINION IN LIPIDOLOGY

Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery

(2010) J Mark Brown et al.   CURRENT OPINION IN LIPIDOLOGY

Coenzyme A: Diacylglycerol acyltransferase 1 inhibitor ameliorates obesity, liver steatosis, and lipid metabolism abnormality in KKAy mice fed high-fat or high-carbohydrate diets

(2010) Toshihiro Yamamoto et al.   EUROPEAN JOURNAL OF PHARMACOLOGY

Adipose triglyceride lipase is a major hepatic lipase that regulates triacylglycerol turnover and fatty acid signaling and partitioning

(2010) Kuok Teong Ong et al.   HEPATOLOGY

Patatin-like phospholipase domain-containing 3/adiponutrin deficiency in mice is not associated with fatty liver disease

(2010) Weiqin Chen et al.   HEPATOLOGY

Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease

(2010) Luca Valenti et al.   HEPATOLOGY

Dorfman-Chanarin syndrome: A rare neutral lipid storage disease

(2010) Souvik Mitra et al.   Indian Journal of Pathology and Microbiology

Interactions of Perilipin-5 (Plin5) with Adipose Triglyceride Lipase

(2010) James G. Granneman et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Topological Orientation of Acyl-CoA:Diacylglycerol Acyltransferase-1 (DGAT1) and Identification of a Putative Active Site Histidine and the Role of the N Terminus in Dimer/Tetramer Formation

(2010) Pamela J. McFie et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome

(2010) Mahesh K. Basantani et al.   JOURNAL OF LIPID RESEARCH

CGI-58 knockdown in mice causes hepatic steatosis but prevents diet-induced obesity and glucose intolerance

(2010) J. Mark Brown et al.   JOURNAL OF LIPID RESEARCH

Lipid-induced insulin resistance: unravelling the mechanism

(2010) Varman T Samuel et al.   LANCET

Induction of Liver Steatosis and Lipid Droplet Formation in ATF6α-Knockout Mice Burdened with Pharmacological Endoplasmic Reticulum Stress

(2010) Keisuke Yamamoto et al.   MOLECULAR BIOLOGY OF THE CELL

Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1

(2010) Eva Herker et al.   NATURE MEDICINE

Quantitative Analysis of Lipid Droplet Fusion: Inefficient Steady State Fusion but Rapid Stimulation by Chemical Fusogens

(2010) Samantha Murphy et al.   PLoS One

Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ABHD5

(2009) Martina Schweiger et al.   AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM

Conditions of endoplasmic reticulum stress stimulate lipid droplet formation inSaccharomyces cerevisiae

(2009) Weihua Fei et al.   BIOCHEMICAL JOURNAL

Cideb, an ER- and Lipid Droplet-Associated Protein, Mediates VLDL Lipidation and Maturation by Interacting with Apolipoprotein B

(2009) Jing Ye et al.   Cell Metabolism

Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications

(2009) Elisa Fabbrini et al.   HEPATOLOGY

Specific role for acyl CoA:Diacylglycerol acyltransferase 1 (Dgat1) in hepatic steatosis due to exogenous fatty acids

(2009) Claudio J. Villanueva et al.   HEPATOLOGY

A Sequence Variation (I148M) in PNPLA3 Associated with Nonalcoholic Fatty Liver Disease Disrupts Triglyceride Hydrolysis

(2009) Shaoqing He et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Autophagy regulates lipid metabolism

(2009) Rajat Singh et al.   NATURE

Population-Based Genome-wide Association Studies Reveal Six Loci Influencing Plasma Levels of Liver Enzymes

(2008) Xin Yuan et al.   AMERICAN JOURNAL OF HUMAN GENETICS

Gene expression in human NAFLD

(2008) Dario Greco et al.   AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY

Hepatic stellate cell lipid droplets: A specialized lipid droplet for retinoid storage

(2008) William S. Blaner et al.   BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

Hepatic Steatosis in Leptin-Deficient Mice Is Promoted by the PPARγ Target Gene Fsp27

(2008) Kimihiko Matsusue et al.   Cell Metabolism

Selective versus Total Insulin Resistance: A Pathogenic Paradox

(2008) Michael S. Brown et al.   Cell Metabolism

Differential pattern of lipid droplet-associated proteins andde novoperilipin expression in hepatocyte steatogenesis

(2008) Beate Katharina Straub et al.   HEPATOLOGY

The Endoplasmic Reticulum Enzyme DGAT2 Is Found in Mitochondria-associated Membranes and Has a Mitochondrial Targeting Signal That Promotes Its Association with Mitochondria

(2008) Scot J. Stone et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Hepatic Overexpression of Hormone-sensitive Lipase and Adipose Triglyceride Lipase Promotes Fatty Acid Oxidation, Stimulates Direct Release of Free Fatty Acids, and Ameliorates Steatosis

(2008) Brendan N. Reid et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast

(2008) Weihua Fei et al.   JOURNAL OF CELL BIOLOGY

Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice

(2008) Kaori Minehira et al.   JOURNAL OF LIPID RESEARCH

Thematic Review Series: Glycerolipids.DGAT enzymes and triacylglycerol biosynthesis

(2008) Chi-Liang Eric Yen et al.   JOURNAL OF LIPID RESEARCH

The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism

(2008) Henry N. Ginsberg et al.   JOURNAL OF LIPID RESEARCH

Functional genomic screen reveals genes involved in lipid-droplet formation and utilization

(2008) Yi Guo et al.   NATURE

Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease

(2008) Stefano Romeo et al.   NATURE GENETICS

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

(2008) Scott L. Friedman   PHYSIOLOGICAL REVIEWS

Regulation of Hepatic Lipogenesis by the Transcription Factor XBP1

(2008) A.-H. Lee et al.   SCIENCE

Imaging of Lipid Biosynthesis: How a Neutral Lipid Enters Lipid Droplets

(2008) Lars Kuerschner et al.   TRAFFIC

Nonalcoholic fatty liver disease and mitochondrial dysfunction

(2008) Yongzhong Wei et al.   WORLD JOURNAL OF GASTROENTEROLOGY

COPI Complex Is a Regulator of Lipid Homeostasis

(2008) Mathias Beller et al.   PLOS BIOLOGY