jci.org/impactDecember 2014

Also in this issue:

Post-anesthesia memory impairment 7

Hepatic stellate cells in liver regeneration 8

Extracellular tumor vesicles promote metastasis 11

Polycystin trafficking in kidney disease 12

A summary of this month’s Journal of Clinical investigation

JC virus infection targets astrocytesp. 6

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t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t d e c e m b e r 2 0 1 4 1

editorHoward A. Rockman

Deputy editorsGarnett Kelsoe, Bryan L. Roth

Associate editorsSoman N. Abraham, Vann Bennett,Gerard C. Blobe, Kathleen M. Caron,Marc G. Caron, John P. Chute,Thomas M. Coffman, Anna Mae Diehl,Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Cam Patterson, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Yiping Yang

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Asia editorDavid M. Virshup

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senior science editorSarah C. Jackson

science editorJillian Hurst

Assistant science editorCorinne Williams

editor at largeUshma S. Neill

issn 2324-7703 (print)issn 2325-4556 (online)The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

ImpactDecember 2014

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The JCI’s Editorial Board is composed of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the board meets weekly to discuss the manuscripts undergoing review.

Featured Editor

cam Patterson, m.D., m.b.A., Associate editor, is the senior Vice President and Chief Operating Officer of New York-Presbyterian Hospital/Weill-Cornell Medical Center in New York. He was pre-viously Physician-in-Chief of the UNC Center for Heart and Vascular Care, the Chief of the Division of Cardiology, and the Director of the McAllister Heart Institute at the University of North Carolina at Chapel Hill. Dr. Patterson’s research interests are in the areas of angiogenesis and vascular development, cardiac hypertrophy, protein quality control, and translational genomics and metabo-

lomics. His major research accomplishments include the characterization of the role of ubiquitin ligases and protein quality control mechanisms in cardiac struc-ture and function; the discovery of transcriptional mechanisms that determine endothelial cell specification; and discovery and biochemical characterization of stress-dependent ubiquitin ligases such as CHIP. Dr. Patterson is the founder of two biotechnology companies, Dyzen Inc. and Enci Therapeutics. He is an Established Investigator of the American Heart Association, a recipient of the Judah Folkman Award in Vascular Biology, a Burroughs Wellcome Fund Clinical Scientist in Translational Research, a member of the American Society for Clini-cal Investigation, and President of the Association of Professors of Cardiology.

Publication highlights

Willis MS, Patterson C. Proteotoxicity and cardiac dysfunction — Alzheimer’s disease of the heart? N Engl J Med. 2013;368(5):455–464.

Xie L, Pi X, Mishra A, Fong G, Peng J, Patterson C. PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response. J Clin Invest. 2012;122(8):2827–2836.

Pi X, Schmitt CE, Xie L, Portbury AL, Wu Y, Lockyer P, Dyer LA, Moser M, Bu G, Flynn EJ 3rd, Jin SW, Patterson C. LRP1-dependent endocytic mechanism governs the signaling output of the bmp system in endothelial cells and in angiogenesis. Circ Res. 2012;111(5): 564–574.

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CardiologyCardiac myocyte–secreted cAMP exerts paracrine action via adenosine receptor activationYassine Sassi, Andrea Ahles, Dong-Jiunn Jeffery Truong, Younis Baqi, Sang-Yong Lee, Britta Husse, Jean-Sébastien Hulot, Ariana Foinquinos, Thomas Thum, Christa E. Müller, Andreas Dendorfer, Bernhard Laggerbauer, and Stefan Engelhardt http://jci.me/74349

DermatologyA GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasiaWilliam M. Gordon, Michael D. Zeller, Rachel H. Klein, William R. Swindell, Hsiang Ho, Francisco Espetia, Johann E. Gudjonsson, Pierre F. Baldi, and Bogi Andersen http://jci.me/77138

More, p. 9

GeneticsHair keratin mutations in tooth enamel increase dental decay riskOlivier Duverger, Takahiro Ohara, John R. Shaffer, Danielle Donahue, Patricia Zerfas, Andrew Dullnig, Christopher Crecelius, Elia Beniash, Mary L. Marazita, and Maria I. Morasso http://jci.me/78272

HepatologyKetogenesis prevents diet-induced fatty liver injury and hyperglycemiaDavid G. Cotter, Baris Ercal, Xiaojing Huang, Jamison M. Leid, D. André d’Avignon, Mark J. Graham, Dennis J. Dietzen, Elizabeth M. Brunt, Gary J. Patti, and Peter A. Crawford http://jci.me/76388

More, p. 8

Hepatic stellate cells contribute to progenitor cells and liver regenerationClaus Kordes, Iris Sawitza, Silke Götze, Diran Herebian, and Dieter Häussinger http://jci.me/74119

With related Commentary by Christopher J. Hindley, Gianmarco Mastrogiovanni, and Meritxell Huch More, p. 8

ImmunologyTGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translationAlessia Perino, Thijs Willem Hendrik Pols, Mitsunori Nomura, Sokrates Stein, Roberto Pellicciari, and Kristina Schoonjans http://jci.me/76289

Research articles in the current issue of the JCI

Molar fissures

Hepatic stellate cells

Extracellular cAMP

t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t d e c e m b e r 2 0 1 4 3

Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunityJuan Manuel Torres, Rubén Martinez-Barricarte, Sonia García-Gómez, Marina S. Mazariegos, Yuval Itan, Bertrand Boisson, Rita Álvarez, Anaïs Jiménez-Reinoso, Lucia del Pino, Rebecca Rodríguez-Pena, Antonio Ferreira, Enrique Hernández-Jiménez, Victor Toledano, Carolina Cubillos-Zapata, Mariana Díaz-Almirón, Eduardo López-Collazo, José L. Unzueta-Roch, Silvia Sánchez-Ramón, Jose R. Regueiro, Eduardo López-Granados, Jean-Laurent Casanova, and Rebecca Pérez de Diego http://jci.me/77493

Thymic stromal lymphopoietin–mediated epicutaneous inflammation promotes acute diarrhea and anaphylaxisHongwei Han, Tennille D. Thelen, Michael R. Comeau, and Steven F. Ziegler http://jci.me/77798

More, p. 9

Circulating T follicular regulatory and helper cells have memory-like propertiesPeter T. Sage, David Alvarez, Jernej Godec, Ulrich H. von Andrian, and Arlene H. Sharpe http://jci.me/76861

Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestationsNadia Jeremiah, Bénédicte Neven, Matteo Gentili, Isabelle Callebaut, Sophia Maschalidi, Marie-Claude Stolzenberg,

Nicolas Goudin, Marie-Louis Frémond, Patrick Nitschke, Thierry J. Molina, Stéphane Blanche, Capucine Picard, Gillian I. Rice, Yanick J. Crow, Nicolas Manel, Alain Fischer, Brigitte Bader-Meunier, and Frédéric Rieux-Laucat http://jci.me/79100

IL-12–producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansionAlexander Rölle, Julia Pollmann, Eva-Maria Ewen, Vu Thuy Khanh Le, Anne Halenius, Hartmut Hengel, and Adelheid Cerwenka http://jci.me/77440

NephrologyAltered trafficking and stability of polycystins underlie polycystic kidney diseaseYiqiang Cai, Sorin V. Fedeles, Ke Dong, Georgia Anyatonwu, Tamehito Onoe, Michihiro Mitobe, Jian-Dong Gao, Dayne Okuhara, Xin Tian, Anna-Rachel Gallagher, Zhangui Tang, Xiaoli Xie, Maria D. Lalioti, Ann-Hwee Lee, Barbara E. Ehrlich, and Stefan Somlo http://jci.me/67273

More, p. 12

NeuroscienceSustained increase in α5GAbAA receptor function impairs memory after anesthesiaAgnieszka A. Zurek, Jieying Yu, Dian-Shi Wang, Sean C. Haffey, Erica M. Bridgwater, Antonello Penna, Irene Lecker, Gang Lei, Tom Chang, Eric W.R. Salter, and Beverley A. Orser http://jci.me/76669

More, p. 7

Human glial chimeric mice reveal astrocytic dependence of JC virus infectionYoichi Kondo, Martha S. Windrem, Lisa Zou, Devin Chandler-Militello, Steven J. Schanz, Romane M. Auvergne, Sarah J. Betstadt, Amy R. Harrington, Mahlon Johnson, Alexander Kazarov, Leonid Gorelik, and Steven A. Goldman http://jci.me/76629

With related Commentary by Sheila A. Haley and Walter J. Atwood More, p. 6

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformationJaerak Chang, Seongju Lee, and Craig Blackstone http://jci.me/77598

More, p. 7

Research articles in the current issue of the JCI

T follicular cells in lymph node

JC virus–infected astroglia

4 t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t d e c e m b e r 2 0 1 4

OncologySphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAsEmilie Degagné, Ashok Pandurangan, Padmavathi Bandhuvula, Ashok Kumar, Abeer Eltanawy, Meng Zhang, Yuko Yoshinaga, Mikhail Nefedov, Pieter J. de Jong, Loren G. Fong, Stephen G. Young, Robert Brittman, Yasmin Ahmedi, and Julie D. Saba http://jci.me/74188

Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppressionRegina Lin, Ling Chen, Gang Chen, Chunyan Hu, Shan Jiang, Jose Sevilla, Ying Wan, John H. Sampson, Bo Zhu, and Qi-Jing Li http://jci.me/76561

Membrane protein CNNM4–dependent Mg2+ efflux suppresses tumor growthYosuke Funato, Daisuke Yamazaki, Shin Mizukami, Lisa Du, Kazuya Kikuchi, and Hiroaki Miki http://jci.me/76614

Targeting an IKBKE cytokine network impairs triple-negative breast cancer proliferationThanh U. Barbie, Gabriela Alexe, Amir R. Aref, Shunqiang Li, Zehua Zhu, Xiuli Zhang, Yu Imamura, Tran C. Thai, Ying Huang, Michaela Bowden, John Herndon, Travis J. Cohoon, Timothy Fleming, Pablo Tamayo, Jill P. Mesirov, Shuji Ogino, Kwok-Kin Wong, Matthew J. Ellis, William C. Hahn, David A. Barbie, and William E. Gillanders http://jci.me/75661

More, p. 11

NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cellsDi Zhao, Yan Mo, Meng-Tian Li, Shao-Wu Zou, Zhou-Li Cheng, Yi-Ping Sun, Yue Xiong, Kun-Liang Guan, and Qun-Ying Lei http://jci.me/76611

More, p. 10

Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancerEvgeniy B. Eruslanov, Pratik S. Bhojnagarwala, Jon G. Quatromoni, Tom Li Stephen, Anjana Ranganathan, Charuhas Deshpande, Tatiana Akimova, Anil Vachani, Leslie Litzky, Wayne W. Hancock, José R. Conejo-Garcia, Michael Feldman, Steven M. Albelda, and Sunil Singhal http://jci.me/77053

More, p. 10

Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progressionStéphanie Sungalee, Emilie Mamessier, Ester Morgado, Emilie Grégoire, Philip Z. Brohawn, Christopher A. Morehouse, Nathalie Jouve, Céline Monvoisin, Cédric Menard, Guilhaume Debroas, Mustapha Faroudi, Violaine Mechin, Jean-Marc Navarro, Charlotte Drevet, Franziska C. Eberle, Lionel Chasson, Fannie Baudimont, Stéphane J. Mancini, Julie Tellier, Jean-Michel Picquenot, Rachel Kelly, Paolo Vineis, Philippe Ruminy, Bruno Chetaille, Elaine S. Jaffe, Claudine Schiff, Jean Hardwigsen, David A. Tice, Brandon W. Higgs, Karin Tarte, Bertrand Nadel, and Sandrine Roulland http://jci.me/72415

With related Commentary by Srividya Swaminathan and Markus Müschen More, p. 10

miR-200–containing extracellular vesicles promote breast cancer cell metastasisMinh T.N. Le, Peter Hamar, Changying Guo, Emre Basar, Ricardo Perdigão-Henriques, Leonora Balaj, and Judy Lieberman http://jci.me/75695

With related Commentary by David M. Epstein More, p. 11

Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesisMichelle Marques Howarth, David Simpson, Siu P. Ngok, Bethsaida Nieves, Ron Chen, Zurab Siprashvili, Dedeepya Vaka, Marcus R. Breese, Brian D. Crompton, Gabriela Alexe, Doug S. Hawkins, Damon Jacobson, Alayne L. Brunner, Robert West, Jaume Mora, Kimberly Stegmaier, Paul Khavari, and E. Alejandro Sweet-Cordero http://jci.me/72124

Research articles in the current issue of the JCI

B cells in germinal center

IKBKE in breast cancer

Active STAT3 in colon

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GP130 activation induces myeloma and collaborates with MYCTobias Dechow, Sabine Steidle, Katharina S. Götze, Martina Rudelius, Kerstin Behnke, Konstanze Pechloff, Susanne Kratzat, Lars Bullinger, Falko Fend, Valeria Soberon, Nadya Mitova, Zhoulei Li, Markus Thaler, Jan Bauer, Elke Pietschmann, Corinna Albers, Rebekka Grundler, Marc Schmidt-Supprian, Jürgen Ruland, Christian Peschel, Justus Duyster, Stefan Rose-John, Florian Bassermann, and Ulrich Keller http://jci.me/69094

Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinomaJihun Kim, Cameron Fox, Shouyong Peng, Mark Pusung, Eirini Pectasides, Eric Matthee, Yong Sang Hong, In-Gu Do, Jiryeon Jang, Aaron R. Thorner, Paul Van Hummelen, Anil K. Rustgi, Kwok-Kin Wong, Zhongren Zhou, Ping Tang, Kyoung-Mee Kim, Jeeyun Lee, and Adam J. Bass http://jci.me/75200

LYN-activating mutations mediate antiestrogen resistance in estrogen receptor–positive breast cancerLuis J. Schwarz, Emily M. Fox, Justin M. Balko, Joan T. Garrett, María Gabriela Kuba, Mónica Valeria Estrada, Ana María González-Angulo, Gordon B. Mills, Monica Red-Brewer, Ingrid A. Mayer, Vandana Abramson, Monica Rizzo, Mark C. Kelley, Ingrid M. Meszoely, and Carlos L. Arteaga http://jci.me/72573

RASAL2 activates RAC1 to promote triple-negative breast cancer progressionMin Feng, Yi Bao, Zhimei Li, Juntao Li, Min Gong, Stella Lam, Jinhua Wang, Diego M. Marzese, Nicholas Donovan, Ern Yu Tan, Dave S.B. Hoon, and Qiang Yu http://jci.me/76711

PulmonologyTRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in miceShaik O. Rahaman, Lisa M. Grove, Sailaja Paruchuri, Brian D. Southern, Susamma Abraham, Kathryn A. Niese, Rachel G. Scheraga, Sudakshina Ghosh, Charles K. Thodeti, David X. Zhang, Magdalene M. Moran, William P. Schilling, Daniel J. Tschumperlin, and Mitchell A. Olman http://jci.me/75331

More, p. 9

Reproductive biologyHyaluronan in cervical epithelia protects against infection-mediated preterm birthYucel Akgul, R. Ann Word, Laura M. Ensign, Yu Yamaguchi, John Lydon, Justin Hanes, and Mala Mahendroo http://jci.me/78765

Vascular biologyOxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1Ziad A. Ali, Vinicio de Jesus Perez, Ke Yuan, Mark Orcholski, Stephen Pan, Wei Qi, Gaurav Chopra, Christopher Adams, Yoko Kojima, Nicholas J. Leeper, Xiumei Qu, Kathia Zaleta-Rivera, Kimihiko Kato, Yoshiji Yamada, Mitsutoshi Oguri, Allan Kuchinsky, Stanley L. Hazen, J. Wouter Jukema, Santhi K. Ganesh, Elizabeth G. Nabel, Keith Channon, Martin B. Leon, Alain Charest, Thomas Quertermous, and Euan A. Ashley http://jci.me/77484

With related Commentary by Judy B. de Haan More, p. 12

Targeting sortilin in immune cells reduces proinflammatory cytokines and atherosclerosisMartin B. Mortensen, Mads Kjolby, Stine Gunnersen, Jakob V. Larsen, Johan Palmfeldt, Erling Falk, Anders Nykjaer, and Jacob F. Bentzon http://jci.me/76002

Research articles in the current issue of the JCI

STAT3 in multiple myeloma

LYN in breast cancer

Cervical epithelia

Murine myofibroblasts

66

Progressive multifocal leukoencephalopathy is a rare demyelinating disorder that is caused by JC virus (JCV) infection of glial cells. JCV is com-monly found in the general population, but only triggers disease in people with a compromised immune system, such as HIV-positive individu-als or those on immunosuppressive regimens. JCV is specific to human glial cells, and the lack of an appropriate animal model has ham-pered studies of the in vivo phenotypes of viral infection. In a study in this month’s JCI, Steven Goldman and colleagues showed that human-ized glial chimeric mice can be infected with JCV, and they took advantage of this system to explore the targets for JCV in the brain. Although the demyelination observed in patients had long suggested that oligodendrocytes might be the primary target of JCV, the research team surpris-ingly found that astrocytes were the preferential target of viral infection in cultured cells. Further-more, they demonstrated in vivo that astrocytes promoted viral replication much more efficiently than oligodendrocytes. Using mice chimeric for human astrocytes and glial progenitor cells but not oligodendrocytes, the researchers subse-quently showed that astroglia are sufficient to support infection and viral spread in vivo. Their studies support a model in which astrocytes serve as the primary reservoir for infection, with oligodendrocyte cell death and demyelination occurring as secondary effects. In an accompa-nying commentary, Haley and Atwood discuss how the development of an animal model pro-vides an important tool for studying JC virus pathogenesis and treatment. The image here shows a JCV-infected oligodendrocyte stained for oligodendrocyte marker O4 (red), phospho-p53(Ser15) (green), and viral T antigen (blue).

A human glial chimeric model for JC virus infection

Editor’s picksresearch

t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t d e c e m b e r 2 0 1 4

Human glial chimeric mice reveal astrocytic dependence of JC virus infectionYoichi Kondo, Martha S. Windrem, Lisa Zou, Devin Chandler-Militello, Steven J. Schanz, Romane M. Auvergne, Sarah J. Betstadt, Amy R. Harrington, Mahlon Johnson, Alexander Kazarov, Leonid Gorelik, and Steven A. Goldman http://jci.me/76629

Related CommentaryAn animal model for progressive multifocal leukoencephalopathySheila A. Haley and Walter J. Atwood http://jci.me/79186

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Research | Editor’s picks

General anesthesia is frequently associated with cognitive dysfunction and memory deficits that can last for many days after an operation. Moreover, the duration of anesthesia is positively correlated with the incidence of such deficits. In this issue, Agnieszka Zurek and colleagues identify mechanisms underlying postoperative cognitive dysfunction. They found that mice treated with a single, sedative dose of the common GABAergic anesthetic etomidate experienced memory impairment for up to 72 hours after exposure. Experiments using hippocampal slices from mice treated with a single dose of etomidate revealed a reduction in synaptic plasticity and a sustained increase in tonic current and cell-surface expression of α5GABAA receptors (α5GABAARs). Changes in α5GABAAR expression persisted for up to one week after anesthesia, indicating that changes in receptor expression may underlie persistent memory deficits after anesthesia. Furthermore, the memory-impairing effects of etomidate were reversed by α5GABAAR inhibition.

Sustained increase in α5GABAA receptor function impairs memory after anesthesiaAgnieszka A. Zurek, Jieying Yu, Dian-Shi Wang, Sean C. Haffey, Erica M. Bridgwater, Antonello Penna, Irene Lecker, Gang Lei, Tom Chang, Eric W.R. Salter, and Beverley A. Orser http://jci.me/76669

Hereditary spastic paraplegia genes maintain lysosomal biogenesis

Postanesthesia memory impairment is caused by increased GABAA receptor activity

neuroscience

hereditary spastic paraplegias (hsPs) are a group of disorders characterized by distal axon degeneration of long corticospinal neurons. The two most common autosomal recessive HSPs are caused by loss-of-function mutations in spatacsin (SPG11) and spastizin (SPG15). In this issue, Craig Blackstone and colleagues demonstrated that spatacsin and spastizin play a critical role in maintaining a sufficient supply of lysosomes during autophagic clearance of intracellular components. During autophagy, intracellular components are enclosed in a double-membrane vesicle known as an autophagosome. The autophagosome then fuses with a lysosome to form an autolysosome, and the contents are degraded by lysosomal proteases. New lysosomes can be generated by autophagic lysosome reformation (ALR). Using cell lines and patient fibroblasts, Blackstone and colleagues found that loss of spastizin or spatacsin resulted in the accumulation of autolysosomes. Mechanistically, spastizin and spatacsin form a complex on autolysosomes that is required for lysosome tubulation, the first step of ALR. Loss of ALR results in accumulation of autophagic materials, thereby contributing to neurodegen-eration (see the accompanying image).

Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformationJaerak Chang, Seongju Lee, and Craig Blackstone http://jci.me/77598

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the liver is distinguished from other organs by its ability to regenerate; however, it is not entirely clear which cells contribute to this process. Hepatic stellate cells (HSCs), which reside in the space of Disse within the liver, contain high levels of retinoids and show characteristics of mesenchymal stem cells (MSCs) from the BM, suggesting that they serve as a form of liver-resident MSC. Claus Kordes and colleagues investigated the contribution of

HSCs to liver regeneration by isolating HSCs from GFP-expressing rats and transplanting them into WT rats that underwent partial hepatectomy in the presence of toxic substances, which suppress hepatocyte proliferation. The transplanted HSCs engrafted in the BM and homed to the injured liver. Additionally, they differentiated into mesenchymal and epithelial cells such as cholangiocytes and hepatocytes (see the accompanying image) by transient formation of hepatic progenitor cells. In the related Commentary, Meritxell Huch and colleagues discuss how these findings alter the current understanding of HSCs.

Hepatic stellate cells contribute to progenitor cells and liver regenerationClaus Kordes, Iris Sawitza, Silke Götze, Diran Herebian, and Dieter Häussinger http://jci.me/74119

Related CommentaryThe plastic liver: differentiated cells, stem cells, every cell?Christopher J. Hindley, Gianmarco Mastrogiovanni, and Meritxell Huch http://jci.me/78372

Research | Editor’s picks

nonalcoholic fatty liver disease (nAFlD) is the most common liver disease in Western countries and is associated with insulin resistance, metabolic syndrome, and obesity. Because much of the liver’s fat can be disposed of through ketogenesis, researchers hypothesized that defects in ketogenesis drive NAFLD spectrum disorders. David Cotter, Baris Ercal, Xiaojing Huang, and colleagues demonstrate that ketogenesis prevents diet-induced steatohepatitis in mice. Genetically induced ketogenic insufficiency in adult mice stimulated excess glucose and lipid production by the liver. High fat/high carbohydrate feeding of ketogenesis-insufficient mice caused a cascade of

metabolic abnormalities in the liver, widespread hepatocyte injury, and hepatic inflammation. These results demonstrate that hepatic ketogenesis preserves metabolic dynamics in the setting of overnutrition and suggest that therapeutic strategies targeting ketogenesis could potentially be used to treat NAFLD.

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemiaDavid G. Cotter, Baris Ercal, Xiaojing Huang, Jamison M. Leid, D. André d’Avignon, Mark J. Graham, Dennis J. Dietzen, Elizabeth M. Brunt, Gary J. Patti, and Peter A. Crawford http://jci.me/76388

Hepatic stellate cells participate in liver regeneration

Burning fat in nonalcoholic fatty liver disease

hepatology

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Research | Editor’s picks

immunology

Lung fibrogenesis is regulated by cation channel TRPV4

Linking atopic dermatitis and gastrointestinal allergy

pulmonology

The transcription factor GRHL3 attenuates immune-mediated skin damage

dermatology

Food allergy prevalence has increased in recent decades, with patients exhibiting a range of responses that progress from atopic dermatitis to asthma. Skin barrier defects are associated with food allergy, indicating that allergen permeation of the skin may bypass oral tolerance and induce allergy. Hongwei Han and colleagues show that thymic stromal lymphopoietin (TSLP), an IL-7–related cytokine, initiates an immunological cascade that links epicutaneous sensitization and gastrointestinal inflamma-tion, resulting in food allergy. Mice sensitized epicutaneously to ovalbumin or peanut in the presence of TSLP developed allergic diarrhea and anaphylaxis following oral antigen challenge. Loss of TSLPR in dendritic cells, IL-25 receptor deficiency, or CD4+ T cell depletion blocked the development of allergic diarrhea in response to antigen challenge. Interestingly, oral exposure to the antigen prior to skin sensitization induced tolerance. These data support a role for TSLP in the development of food allergies through epicutaneous sensitization.

Thymic stromal lymphopoietin–mediated epicutaneous inflammation promotes acute diarrhea and anaphylaxisHongwei Han, Tennille D. Thelen, Michael R. Comeau, and Steven F. Ziegler http://jci.me/77798

idiopathic pulmonary fibrosis (iPF) is a fatal lung disorder in which the tissue becomes scarred and fibrotic, impeding lung function. Myofibroblasts, which mediate fibrosis, are generated by both TGF-β signaling and mechanical signals such as matrix stiffness; however, the mechanisms whereby myofibroblasts sense and transmit mechanical signals are unclear. In this issue, Shaik Rahaman and colleagues demonstrated that the transient receptor potential vanilloid 4 (TRPV4) channel mediates mechanical signals that trigger myofibroblast differentiation. They showed that IPF lung fibroblasts have enhanced TRPV4 activity. Moreover, genetic ablation or pharmacological inhibition of TRPV4 blocks myofibroblast differentiation and fibrosis in a murine IPF model (see the accompanying image). These data identify a TRPV4 as a critical mediator of myofibroblast differentiation and suggest that TRPV4 modulation is a potential therapeutic strategy in IPF.

TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice

Shaik O. Rahaman, Lisa M. Grove, Sailaja Paruchuri, Brian D. Southern, Susamma Abraham, Kathryn A. Niese, Rachel G. Scheraga, Sudakshina Ghosh, Charles K. Thodeti, David X. Zhang, Magdalene M. Moran, William P. Schilling, Daniel J. Tschumperlin, and Mitchell A. Olman http://jci.me/75331

immune-mediated skin diseases such as psoriasis are characterized by the infiltration of T cells into the epidermis. While T cells secrete cytokines that contribute to disease, the epidermis also produces an array of molecules, but it is unclear how they affect pathogenesis. In this issue, William Gordon and colleagues demonstrate that the transcription factor grainyhead-like 3 (GRHL3) is required for the repair of barrier-disrupting epidermal lesions in adult skin. In a murine model of immune-mediated skin damage, loss of GRHL3 resulted in increased skin damage compared with WT animals. Grhl3-deficient animals exhibited impaired epidermal barrier repair, increased immune cell infiltration (see the accompanying image), and delayed lesion healing. Chromatin immunoprecipitation studies and gene expression profiling indicated that GRHL3 suppresses the expression of inflammatory genes after immune injury.

A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasiaWilliam M. Gordon, Michael D. Zeller, Rachel H. Klein, William R. Swindell, Hsiang Ho, Francisco Espetia, Johann E. Gudjonsson, Pierre F. Baldi, and Bogi Andersen http://jci.me/77138

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Research | Editor’s picks

oncology

Repeated germinal center visits promote B cell mutation and lymphomagenesisGerminal centers (GCs) are the sites wherein mature B cells proliferate, differentiate, switch, and mutate their antibody-encoding genes in response to an infection. Lymphomas are thought to arise from the accumulation of genetic lesions that are acquired with repeated GC engagement. To gain a better understanding of the initial events in lymphomagen-esis, Stéphanie Sungalee and colleagues tracked human follicular lymphoma (FL) single precursor cells and engineered a murine model of FL in which B cells sporadically acquire an oncogenic BCL2:IGH-like translocation that causes constitutive expression of BCL2. This allowed the B cells to survive multiple GC reentries after immunization. They found that B cells that repeatedly entered GCs accumulated mutations that eventually led to FL in situ, a precursor form of FL. In the accompanying Commentary, Srividya Swaminathan and Markus Müschen discuss how these studies link chronic infection and follicular lymphomagenesis.

Germinal center reentries of BCL2-overexpressing B cells drive follicular lymphoma progressionStéphanie Sungalee, Emilie Mamessier, Ester Morgado, Emilie Grégoire, Philip Z. Brohawn, Christopher A. Morehouse, Nathalie Jouve, Céline Monvoisin, Cédric Menard, Guilhaume Debroas, Mustapha Faroudi, Violaine Mechin, Jean-Marc Navarro, Charlotte Drevet, Franziska C. Eberle, Lionel Chasson, Fannie Baudimont, Stéphane J. Mancini, Julie Tellier, Jean-Michel Picquenot, Rachel Kelly, Paolo Vineis, Philippe Ruminy, Bruno Chetaille, Elaine S. Jaffe, Claudine Schiff, Jean Hardwigsen, David A. Tice, Brandon W. Higgs, Karin Tarte, Bertrand Nadel, and Sandrine Roulland http://jci.me/72415

Related CommentaryFollicular lymphoma: too many reminders for a memory B cellSrividya Swaminathan and Markus Müschen http://jci.me/79189

Breast cancer stem cell self-renewal is inhibited by ALDH1A1 acetylation

Tumor-associated neutrophils promote inflammation and T cell activation

Cancer stem cells (CsCs) are characterized by elevated expression of aldehyde dehydrogenase 1 (ALDH1A1), and high ALDH1A1 activity in breast cancer is correlated with advanced disease stage and poor prognosis. Activation of the NOTCH signaling pathway is also known to promote CSC self-renewal and tumorigenesis. Di Zhao and colleagues report a mechanistic link between NOTCH signaling and ALDH1A1 activity in breast cancer. Using breast cancer cell lines and human primary breast cancer samples, they show that ALDH1A1 activity is inhibited by acetylation of lysine 353 (K353). Mechanistically, ALDH1A1 acetylation was mediated by the acetyltransferase PCAF, while

deacetylation was mediated by sirtuin 2. NOTCH signaling induced expression of SIRT2, thereby promoting deacetylation and enhancing the activity of ALDH1A1. Expression of the acetylation mimetic K353Q mutant (ALDH1A1K353Q) repressed ALDH1A1 activity, inhibited CSC self-renewal, and decreased tumor growth in murine breast cancer xenografts.

NOTCH-induced aldehyde dehydrogenase 1A1 deacetylation promotes breast cancer stem cellsDi Zhao, Yan Mo, Meng-Tian Li, Shao-Wu Zou, Zhou-Li Cheng, Yi-Ping Sun, Yue Xiong, Kun-Liang Guan, and Qun-Ying Lei http://jci.me/76611

tumor-associated neutrophils (tAns) are part of the inflammatory cell population found in the lung tumor microenvironment, but their role in tumor progression is unclear. Evgeniy Eruslanov and colleagues found that TANs represented 5%–25% of cells in tumors isolated from lung cancer patients undergoing surgical tumor resections (see the accompanying image; TANs are brown). Further characterization of TANs revealed that these cells have an activated phenotype with a novel repertoire of chemokine receptors and produce substantial amounts of proinflammatory factors. Importantly, Eruslanov and colleagues demonstrated that in the earliest stages of lung cancer, TANs are not hypofunctional and immunosuppressive, but rather stimulate T cell responses.

Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancerEvgeniy B. Eruslanov, Pratik S. Bhojnagarwala,

Jon G. Quatromoni, Tom Li Stephen, Anjana Ranganathan, Charuhas Deshpande, Tatiana Akimova, Anil Vachani, Leslie Litzky, Wayne W. Hancock, José R. Conejo-Garcia, Michael Feldman, Steven M. Albelda, and Sunil Singhal http://jci.me/77053

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Research | Editor’s picks

Many current breast cancer therapeutics target hormone receptors; however, triple-negative breast cancers (TNBCs) are defined by a lack of hormone receptor expression, limiting treatment options. Recent studies have indicated that a subset of TNBCs has an inflammatory phenotype characterized by immune cell infiltration, stem cell features, and epithelial-mesenchymal transition. In this issue, Thanh Barbie and colleagues reported that inducible IκB kinase–related kinase ε (IKBKE) expression and JAK/STAT pathway activation mediate a cytokine signaling network that drives progression in inflammatory TNBCs. CYT387, an IKBKE and JAK signaling inhibitor, disrupted expression of protumori-genic cytokines and impaired growth of IKBKE-driven TNBC cell lines. Moreover,

MicroRnAs from the miR-200 family are critical regulators of mesenchymal-to-epithelial transition, and previous studies have demonstrated that ectopic expression of miR-200 can confer metastatic capability in breast cancer cells. Tumor cell–derived extracellular vesicles (EVs) deliver a variety of bioactive molecules, including miRNAs, to distant sites, leading Minh Le and colleagues to investigate whether metastatic capability could be transferred between metastatic and nonmetastatic breast cancer cells via tumor-derived EVs. Using human and murine metastatic breast cancer cell lines, Le and colleagues showed that highly metastatic cancer cells secreted EVs containing miR-200 and that these vesicles were enriched in the circulation of mice bearing highly metastatic tumors. Coculture studies of metastatic and nonmetastatic cell lines showed that miR-200 was transferred between cells via tumor-derived EVs (see the accompanying image). Moreover, poorly metastatic tumors could acquire metastatic capability from a distal meta-static tumor in vivo. In the accompanying Commentary, David Epstein discusses how these studies demonstrate that tumor cells communicate with each other via EVs to promote metastasis.

Special delivery: tumor-derived extracellular vesicles confer metastatic capability

Inflammatory triple-negative breast cancers stopped by IKBKE inhibition

miR-200–containing extracellular vesicles promote breast cancer cell metastasisMinh T.N. Le, Peter Hamar, Changying Guo, Emre Basar, Ricardo Perdigão-Henriques, Leonora Balaj, and Judy Lieberman http://jci.me/75695

Related CommentarySpecial delivery: microRNA-200–containing extracellular vesicles provide metastatic message to distal tumor cellsDavid M. Epstein http://jci.me/79191

combined CYT387 and MEK inhibitor therapy effectively blocked tumor growth and angiogenesis of an aggressive patient-derived TNBC xenograft. The accompanying image shows tumors treated with vehicle (top) and a combination of CTY387 and the MEK inhibitor GSK1120212 (bottom). These results demon-strate that IKBKE-mediated cytokine expression promotes TNBC tumorigenicity and suggest a potential combinatory treatment strategy.

Targeting an IKBKE cytokine network impairs triple-negative breast cancer growthThanh U. Barbie, Gabriela Alexe, Amir R. Aref, Shunqiang Li, Zehua Zhu, Xiuli Zhang, Yu Imamura, Tran C. Thai, Ying Huang, Michaela Bowden,

John Herndon, Travis J. Cohoon, Timothy Fleming, Pablo Tamayo, Jill P. Mesirov, Shuji Ogino, Kwok-Kin Wong, Matthew J. Ellis, William C. Hahn, David A. Barbie, and William E. Gillanders http://jci.me/75661

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Research | Editor’s picks

Vascular remodeling is mediated by the receptor tyrosine kinase ROS1

Polycystic kidney disease–associated mutations block trafficking of polycystin-1Autosomal dominant polycystic kidney disease (ADPKD) is most commonly caused by mutations in the gene encoding polycystin-1 (PC1), a complex polytopic membrane protein that is expressed in the primary cilium. Mutations in poylcystin-2 (PC2), a member of the transient receptor potential family of cation channels, cause a less severe form of ADPKD. Yiqiang Cai and colleagues used a cell-based system to elucidate the mechanisms underlying ADPKD-associated mutations and found that a subset of pathogenic missense mutations block trafficking of

PC1 to the cilia. A missense mutation in PC2 exhibited similar trafficking defects. Additionally, autoproteolytic cleavage at a GPCR proteolytic site (GPS) in PC1 was required for trafficking of PC1 to the cilia. Cai and colleagues established a murine BAC transgenic model to show that only cleaved PC1 exits the endoplasmic reticulum; the steady-state expression of cleaved PC1 was dependent on intact interaction with PC2. These findings indicate that defective polycystin trafficking underlies a subset of missense mutations in both forms of ADPKD.

Altered trafficking and stability of polycystins underlie polycystic kidney diseaseYiqiang Cai, Sorin V. Fedeles, Ke Dong, Georgia Anyatonwu, Tamehito Onoe, Michihiro Mitobe, Jian-Dong Gao, Dayne Okuhara, Xin Tian, Anna-Rachel Gallagher, Zhangui Tang, Xiaoli Xie, Maria D. Lalioti, Ann-Hwee Lee, Barbara E. Ehrlich, and Stefan Somlo http://jci.me/67273

vascular biology

nephrology

Angioplasty and stenting, the primary treatment for flow-limiting atherosclerosis, are limited by pathological vascular remodeling. Glutathione peroxidase-1 (GPX1), a selenoprotein antioxidant enzyme, has previously been shown to be associated with cardiovascular events in humans with atherosclerotic disease. In this issue, Ziad Ali and colleagues demonstrate mechanistically how GPX1 mediates pathological vascular remodeling via the orphan receptor tyrosine kinase ROS1. Using transcriptional profiling of human coronary artery atherectomy specimens, they identify an interaction between gene variants of GPX1 and ROS1. Mechanistically, loss of GPX1 function was associated with oxidoreductive stress driving ROS1 activity via S-glutathiolation of critical residues of the ROS1 tyrosine phosphatase SHP-2 (see the accompanying image). Inhibition of ROS1 attenuated the effects of Gpx1 deletion. In the accompanying Commentary, Judy de Haan discusses how the redox axis is a potential therapeutic target in pathological vascular remodeling.

Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1Ziad A. Ali, Vinicio de Jesus Perez, Ke Yuan, Mark Orcholski, Stephen Pan, Wei Qi, Gaurav Chopra, Christopher Adams, Yoko Kojima, Nicholas J. Leeper, Xiumei Qu, Kathia Zaleta-Rivera, Kimihiko Kato, Yoshiji Yamada, Mitsutoshi Oguri, Allan Kuchinsky, Stanley L. Hazen, J. Wouter Jukema, Santhi K. Ganesh, Elizabeth G. Nabel, Keith Channon, Martin B. Leon, Alain Charest, Thomas Quertermous, and Euan A. Ashley http://jci.me/77484

Related CommentaryLimiting reductive stress for treating in-stent stenosis: the heart of the matter?Judy B. de Haan http://jci.me/79423

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Features

op-ed

conversations with giants in medicine

first author perspectives

David Nathan

For what it’s worth: investing in biomedical research

Dr. David nathan, a pioneer in pediatric hematology, is the Stranahan Distinguished Professor of Pediatrics and professor of medicine at Harvard Medical School, president emeritus of the Dana-Farber Cancer Institute, and physician-in-chief emeritus of Children’s Hospital Boston. He is also the author of Nathan and Oski’s Hematology of Infancy and Childhood, the world’s leading textbook on pediatric hematology and oncology, as well as two popular science books, Genes, Blood, and Courage and The Cancer Treatment Revolution. Dr. Nathan has specialized in congenital anemias and participated in the development of the first prenatal test for thalassemia and sickle cell disease. In this issue, JCI Editor-at-Large Ushma Neill interviews Nathan about his long career at Harvard Medical School, his forced entry into the field of hematology, the use of new technologies to answer medical questions, and his decision to be a physician rather than an English professor.

http://jci.me/78143

in this month’s JCI, Norman Augustine provides his perspective on the challenges of assessing the long-term value of biomedical research. Augustine, retired chairman and CEO of the Lockheed Martin Corporation and a member of the National Academy of Sciences, has frequently testified in Congressional hearings in support of increased investment in fundamental research in biomedical sciences. In his Op-Ed article, he discusses the difficulties in providing a cost-benefit analysis for research investments, gains from research that are beyond monetary value, and how the case can be made for research outside the scientific community.

Is biomedical research a good investment?Norman R. Augustine http://jci.me/79617

An interview with Jaerak Chang and Seongju Leethe JCI’s online feature “First Author Perspectives,” introduced this past summer, provides insight into the research process underlying a recently published manuscript. In an interview accompanying a research article highlighted in this issue of JCI Impact (see page 7), husband and wife scientists Dr. Jaerak Chang and Dr. Seongju Lee discuss their research into the mechanisms underlying two commonly mutated genes in hereditary spastic paraplegia. Dr. Chang and Dr. Lee reveal how this project came together, their thoughts on extending their findings, and what it is like to be a married scientific team.

http://jci.me/vafdt

For a listing of all First Author Perspectives, visit http://jci.me/njiwn

The JCI welcomes submissions in the following categories:

Regular: Substantial new mechanistic insights into biology and disease.

Technical advance: New and important research tools and techniques with the potential for broad impact.

Brief report: Discrete, highly significant findings in a short format.

Sample article: brown adipose tissue regulates glucose homeostasis and insulin sensitivityKristin I. Stanford, Roeland J.W. Middelbeek, Kristy L. Townsend, Ding An, Eva B. Nygaard, Kristen M. Hitchcox, Kathleen R. Markan, Kazuhiro Nakano, Michael F. Hirshman, Yu-Hua Tseng, and Laurie J. Goodyear

Published January 2013 http://jci.me/62308 Times cited: 64

Sample article: Parthenogenetic stem cells for tissue-engineered heart repairMichael Didié, Peter Christalla, Michael Rubart, Vijayakumar Muppala, Stephan Döker, Bernhard Unsöld, Ali El-Armouche, Thomas Rau, Thomas Eschenhagen, Alexander P. Schwoerer, Heimo Ehmke, Udo Schumacher, Sigrid Fuchs, Claudia Lange, Alexander Becker, Wen Tao, John A. Scherschel, Mark H. Soonpaa, Tao Yang, Qiong Lin, Martin Zenke, Dong-Wook Han, Hans R. Schöler, Cornelia Rudolph, Doris Steinemann, Brigitte Schlegelberger, Steve Kattman, Alec Witty, Gordon Keller, Loren J. Field, and Wolfram-Hubertus Zimmermann

Published March 2013 http://jci.me/66854 Times cited: 27

Sample article: recruited brown adipose tissue as an antiobesity agent in humansTakeshi Yoneshiro, Sayuri Aita, Mami Matsushita, Takashi Kayahara, Toshimitsu Kameya, Yuko Kawai, Toshihiko Iwanaga, and Masayuki Saito

Published August 2013 http://jci.me/67803 Times cited: 35

Clinical medicine:research that reports early-stage, effective new therapies that impact disease outcomes in patients.

Sample article: exenatide and the treatment of patients with Parkinson’s diseaseIciar Aviles-Olmos, John Dickson, Zinovia Kefalopoulou, Atbin Djamshidian, Peter Ell, Therese Soderlund, Peter Whitton, Richard Wyse, Tom Isaacs, Andrew Lees, Patricia Limousin, and Thomas Foltynie

Published June 2013 http://jci.me/68295 Times cited: 30

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