Also in this issue:

Checkpoint dysfunction in Wiskott-Aldrich syndrome 7

The origins of hepatocellular carcinoma 10

Tribbles 1 alters hepatic lipogenesis 11

Bacterial mimicry in airway inflammation 11

targeting hyaluronan deposits in type 1 diabetes

p. 6

A summary of the current issue ofthe Journal of Clinical investigation

october 2015

jci.org/this-monthScan with your mobile device for the digital version of JCI This Month.

This Month

Alejandro Aballay

Abul K. Abbas

Domenico Accili

Rexford S. Ahima

Qais Al-Awqati

Kari Alitalo

James Allison

Dario C. Altieri

Masayuki Amagai

Mark E. Anderson

Brian H. Annex

Alan Attie

Jane E. Aubin

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John A. Belperio

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Mina J. Bissell

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Harold Chapman

Ajay Chawla

Benjamin K. Chen

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Ju Chen

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Yongwon Choi

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Marco Colonna

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David D’Alessio

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Harry C. Dietz III

Gianpietro Dotti

Michael Dustin

Connie J. Eaves

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Jack A. Elias

Joel K. Elmquist

Stephen G. Emerson

Jeffrey A. Engelman

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Adrian Erlebacher

Joel D. Ernst

James M. Ervasti

Robert V. Farese Jr.

Eric R. Fearon

Edward A. Fisher

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Martin Friedlander

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Journal of Clinical Investigation Consulting Editors

M. Celeste Simon

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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 / t h i s - m o n t h o c t o b e r 2 0 1 5 1

This MonthOctober 2015

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, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Yiping Yang

Clinical Medicine Associate editorsMichael A. Morse, Andrew J. Muir,Scott M. Palmer, Mark A. Stacy

Asia editorDavid M. Virshup

Chair, executive CouncilRobert J. Lefkowitz

BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen

BioethicistArthur L. Caplan

senior science editorSarah C. Jackson

science editorsJillian Hurst, Corinne 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.

Contact the JCiThe Journal of Clinical Investigation2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: staff@the-jci.org

For the full JCI online, go to jci.me/125/10 or scan the code at left with your mobile device.

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

David M. Virshup, M.D., Associate Editor, is the inaugural Director of the Program in Cancer and Stem Cell Biology at the Duke-NUS Graduate Medical School in Singapore. Until 2007, he was an investigator at the Huntsman Cancer Insti-tute and the first Willard Snow Hansen Presi-dential Professor of Cancer Research at the Uni-versity of Utah. Dr. Virshup received his medical degree in 1981 from the Johns Hopkins School of Medicine, where he also completed his clini-

cal training in pediatrics and pediatric hematology/oncology. His research training was in the departments of Pediatrics, Cell Biology and Anatomy, and Molecular Biology and Genetics at Johns Hopkins. Currently, his laboratory in Singapore studies the Wnt signaling pathways, with an emphasis on Wnt secretion. A related interest is in protein phosphorylation in the Wnt pathway, and in circadian rhythms.

Publication highlights

Madan B, Ke Z, Harmston N, Ho SY, Frois AO, Alam J, Jeyaraj DA, Pendharkar V, Ghosh K, Virshup IH, Manoharan V, Ong EH, Sangthongpitag K, Hill J, Petretto E, Keller TH, Lee MA, Matter A, Virshup DM. Wnt addiction of geneti-cally defined cancers reversed by PORCN inhibition [published online ahead of print August 10, 2015]. Oncogene. doi:10.1038/onc.2015.280.

Cheong JK, Zhang F, Chua PJ, Bay BH, Thorburn A, Virshup DM. Casein kinase 1α–dependent feedback loop controls autophagy in RAS-driven cancers. J Clin Invest. 2015;125(4):1401–1418.

Kabiri Z, Greicius G, Madan B, Biechele S, Zhong Z, Zaribafzadeh H, Edison, Aliyev J, Wu Y, Bunte R, Williams BO, Rossant J, Virshup DM. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development. 2014;141(11):2206–2215.

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CardiologyPerhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I productionYanhong Guo, Yanbo Fan, Jifeng Zhang, Gwen A. Lomberk, Zhou Zhou, Lijie Sun, Angela J. Mathison, Minerva T. Garcia-Barrio, Ji Zhang, Lixia Zeng, Lei Li, Subramaniam Pennathur, Cristen J. Willer, Daniel J. Rader, Raul Urrutia, and Y. Eugene Chen http://jci.me/79048

More, p. 9

EndocrinologyInsulin demand regulates β cell number via the unfolded protein responseRohit B. Sharma, Amy C. O’Donnell, Rachel E. Stamateris, Binh Ha, Karen M. McCloskey, Paul R. Reynolds, Peter Arvan, and Laura C. Alonso http://jci.me/79264

Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cellsMourad Ferdaoussi, Xiaoqing Dai, Mette V. Jensen, Runsheng Wang, Brett S. Peterson, Chao Huang, Olga Ilkayeva, Nancy Smith, Nathanael Miller, Catherine Hajmrle, Aliya F. Spigelman, Robert C. Wright, Gregory Plummer, Kunimasa Suzuki, James P. Mackay, Martijn van de Bunt, Anna L. Gloyn, Terence E. Ryan, Lisa D. Norquay, M. Julia Brosnan, Jeff K. Trimmer, Timothy P. Rolph, Richard G. Kibbey, Jocelyn E. Manning Fox, William F. Colmers, Orian S. Shirihai, P. Darrell Neufer, Edward T.H. Yeh, Christopher B. Newgard, and Patrick E. MacDonald http://jci.me/82498With related Commentary by Alan D. Attie More, p. 8

GeneticsProof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutationsDavid A. Zeevi, Gheona Altarescu, Ariella Weinberg-Shukron, Fouad Zahdeh, Tama Dinur, Gaya Chicco, Yair Herskovitz, Paul Renbaum, Deborah Elstein, Ephrat Levy-Lahad, Arndt Rolfs, and Ari Zimran http://jci.me/79322 More, p. 9

HematologyIDO1 suppresses inhibitor development in hemophilia A treated with factor VIIIDavide Matino, Marco Gargaro, Elena Santagostino, Matteo N.D. Di Minno, Giancarlo Castaman, Massimo Morfini, Angiola Rocino, Maria E. Mancuso, Giovanni Di Minno, Antonio Coppola, Vincenzo N. Talesa, Claudia Volpi, Carmine Vacca, Ciriana Orabona, Rossana Iannitti, Maria G. Mazzucconi, Cristina Santoro, Antonella Tosti, Sara Chiappalupi, Guglielmo Sorci, Giuseppe Tagariello, Donata Belvini, Paolo Radossi, Raffaele Landolfi, Dietmar Fuchs, Louis Boon,

Matteo Pirro, Emanuela Marchesini, Ursula Grohmann, Paolo Puccetti, Alfonso Iorio, and Francesca Fallarino http://jci.me/81859

More, p. 7

Research articles in the current issue of the JCI

FVIII-specific B cells

β cell proliferation

Atherosclerotic plaques

β cell insulin and SENP1

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Research articles in the current issue of the JCI

ImmunologyInhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitisNadine Nagy, Gernot Kaber, Pamela Y. Johnson, John A. Gebe, Anton Preisinger, Ben A. Falk, Vivekananda G. Sunkari, Michel D. Gooden, Robert B. Vernon, Marika Bogdani, Hedwich F. Kuipers, Anthony J. Day, Daniel J. Campbell, Thomas N. Wight, and Paul L. Bollyky http://jci.me/79271 More, p. 6

Stress-associated erythropoiesis initiation is regulated by type 1 conventional dendritic cellsTaeg S. Kim, Mark Hanak, Paul C. Trampont, and Thomas J. Braciale http://jci.me/81919

Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patientsFrancesca Pala, Henner Morbach, Maria Carmina Castiello, Jean-Nicolas Schickel, Samantha Scaramuzza, Nicolas Chamberlain, Barbara Cassani, Salome Glauzy, Neil Romberg, Fabio Candotti, Alessandro Aiuti, Marita Bosticardo, Anna Villa, and Eric Meffre http://jci.me/82249With related Commentary by Jean-Claude Weill and Claude-Agnès Reynaud More, p. 7

MetabolismTribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPαRobert C. Bauer, Makoto Sasaki, Daniel M. Cohen, Jian Cui, Mikhaila A. Smith, Batuhan O. Yenilmez, David J. Steger, and Daniel J. Rader http://jci.me/77095

More, p. 11

NeuroscienceM-current preservation contributes to anticonvulsant effects of valproic acidHee Yeon Kay, Derek L. Greene, Seungwoo Kang, Anastasia Kosenko, and Naoto Hoshi http://jci.me/79727

More, p. 11

Identifying local and descending inputs for primary sensory neuronsYi Zhang, Shengli Zhao, Erica Rodriguez, Jun Takatoh, Bao-Xia Han, Xiang Zhou, and Fan Wang http://jci.me/81156

OncologyHepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartmentXueru Mu, Regina Español-Suñer, Ingmar Mederacke, Silvia Affò, Rita Manco, Christine Sempoux, Frédéric P. Lemaigre, Arlind Adili, Detian Yuan, Achim Weber, Kristian Unger, Mathias Heikenwälder, Isabelle A. Leclercq, and Robert F. Schwabe http://jci.me/77995

More, p. 10

Non-destructive insulitis

WAS mature naive B cells

Hepatic triglycerides

Murine hippocampus

Rostroventral medulla neurons

Hepatocyte-derived tumor

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Fluoromodule-based reporter/probes designed for in vivo fluorescence imagingMing Zhang, Subhasish K. Chakraborty, Padma Sampath, Juan J. Rojas, Weizhou Hou, Saumya Saurabh, Steve H. Thorne, Marcel P. Bruchez, and Alan S. Waggoner http://jci.me/81086

More, p. 10

Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytesCyrille J. Cohen, Jared J. Gartner, Miryam Horovitz-Fried, Katerina Shamalov, Kasia Trebska-McGowan, Valery V. Bliskovsky, Maria R. Parkhurst, Chen Ankri, Todd D. Prickett, Jessica S. Crystal, Yong F. Li, Mona El-Gamil, Steven A. Rosenberg, and Paul F. Robbins http://jci.me/82416

ZIC2-dependent OCT4 activation drives self-renewal of human liver cancer stem cellsPingping Zhu, Yanying Wang, Lei He, Guanling Huang, Ying Du, Geng Zhang, Xinlong Yan, Pengyan Xia, Buqing Ye, Shuo Wang, Lu Hao, Jiayi Wu, and Zusen Fan http://jci.me/81979

PulmonologyBacterial exploitation of phosphorylcholine mimicry suppresses inflammation to promote airway infectionChristopher B. Hergott, Aoife M. Roche, Nikhil A. Naidu, Clementina Mesaros, Ian A. Blair, and Jeffrey N. Weiser http://jci.me/81888

More, p. 11

TransplantationIL-34 is a Treg-specific cytokine and mediates transplant toleranceSéverine Bézie, Elodie Picarda, Jason Ossart, Laurent Tesson, Claire Usal, Karine Renaudin, Ignacio Anegon, and Carole Guillonneau http://jci.me/81227

With related Commentary by James I. Kim and Laurence A. Turka More, p. 12

Vascular biologyFOXC2 and fluid shear stress stabilize postnatal lymphatic vasculatureAmélie Sabine, Esther Bovay, Cansaran Saygili Demir, Wataru Kimura, Muriel Jaquet, Yan Agalarov, Nadine Zangger, Joshua P. Scallan, Werner Graber, Elgin Gulpinar, Brenda R. Kwak, Taija Mäkinen, Inés Martinez-Corral, Sagrario Ortega, Mauro Delorenzi, Friedemann Kiefer, Michael J. Davis, Valentin Djonov, Naoyuki Miura, and Tatiana V. Petrova http://jci.me/80454

More, p. 12

Research articles in the current issue of the JCI

Stress fiber formation

ZIC2 in liver cancer

Membrane-permeant fluorogen

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Research articles in the current issue of the JCI

The Journal of Clinical Investigation

All JCI review series: jci.org/review_series

Recent Review Series

AutoimmunityEdited by Antonio La Cava Published June 2015

Autoimmune disease encompasses a diverse group of over 80 chronic disorders. Each of these diseases has distinct clinical manifestations that are due to the differences in the cells and organ systems involved; however, these diseases are universally characterized by a loss of self-tolerance, resulting in autoreactive immune cells, autoantibodies, and elevated levels of inflammatory cytokines. Reviews in this series examine mechanisms underlying autoimmunity, including failure of B cell tolerance checkpoints, the generation of autoantibodies, cytokine dysregulation, aberrant T cell

signaling, and the loss of immune suppressive cells and functions. They also explore the influence of genetic background, environment, microRNAs, and sex-specific factors on the loss of immune homeostasis.jci.org/review_series/90

Enteric nervous systemEdited by Rodger A. Liddle Published March 2015

The enteric nervous system (ENS) encompasses extrinsic and intrinsic neurons, glia, and sensory epithelial cells that are embedded through-out the gastrointestinal tract. The circuits formed by these cells are responsible for interpreting sensory information in the gut lumen in order to regulate gut motility, secretion, food intake, and immune function. The ENS communicates with the CNS in a bidirectional manner, allowing stimuli in the gut to influence mood, food intake, and other behaviors. Reviews in this series examine the mechanisms by which the ENS develops from neural

crest cells, chemosensory mechanisms that allow for the detection of and response to fats and other nutrients within the gut lumen, the role of the enteric glia, regulation of ENS function by the immune system and inflam-mation, and the impact of surgery and the gut microbiota on ENS communication with the brain.jci.org/review_series/89

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Autoimmune type 1 diabetes (T1D) is characterized by the immune infiltration and destruction of pancre-atic β cells. Nadine Nagy and colleagues previously reported that extracellular matrix polysaccharide hyaluronan (HA) deposits accumulate within pan-creatic islets in patients with T1D with autoimmune insulitis; however, it was unclear whether these deposits are important in disease pathogenesis. In this month’s issue of the JCI, this research team used the DO11.10xRIPmOVA (DORmO) mouse model of T1D to demonstrate that HA deposits promote islet-destructive insulitis by impairing the differen-tiation of Tregs. Importantly, treatment of DORmO mice after the onset of insulitis with the HA synthase inhibitor 4-methylumbelliferone (4-MU) blocked HA deposition and prevented progression to autoim-mune diabetes. These effects were recapitulated in a second model of T1D, NOD mice, in which a single week of 4-MU markedly decreased the number of diabetic mice and provided durable improvements in blood glucose levels. In addition, Nagy and col-leagues showed that 4-MU treatment reestablishes a regulatory checkpoint that prevents β cell destruc-tion and promotes the differentiation of Tregs within pancreatic islets. In vitro induction of Tregs was like-wise diminished in the presence of HA or antibodies targeting the HA receptor CD44. These findings suggest that 4-MU, which is already used to treat bili-ary spasm, could potentially also be used therapeuti-cally to prevent T1D progression. The accompanying image shows insulin staining (brown), despite robust insulitis in pancreatic islets from a 15-week-old DORmO mouse treated with 4-MU for 7 weeks.

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitisNadine Nagy, Gernot Kaber, Pamela Y. Johnson, John A. Gebe, Anton Preisinger, Ben A. Falk, Vivekananda G. Sunkari, Michel D. Gooden, Robert B. Vernon, Marika Bogdani, Hedwich F. Kuipers, Anthony J. Day, Daniel J. Campbell, Thomas N. Wight, and Paul L. Bollyky http://jci.me/79271

Hyaluronan synthase inhibition prevents islet destruction in autoimmune diabetes

Editor’s picksResearch

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IDO1 mediates tolerance to clotting factor treatment in hemophilia

hemophilia A patients have a deficiency in the clotting protein factor VIII. Severe bleeding episodes in these patients require FVIII replacement therapy; however, patients frequently develop neutralizing antibodies or inhibitors to exogenous FVIII, reducing its effectiveness. Davide Matino and colleagues report that inhibitor-positive hemophilia A patients exhibit impaired induction of indoleamine 2,3-dioxygenase (IDO1), an enzyme that mediates peripheral tolerance through suppression of antigen-specific T cells and enhancement of Treg-mediated immune suppression. Using a murine hemophilia model, they found that IDO1-generated tryptophan metabolites prevented the generation of anti-FVIII antibodies. IDO1 is induced by activation of TLR9, and administration of a TLR9 agonist suppressed FVIII-specific B cells through IDO1-dependent induction of Tregs (see the accompanying image). These data identify mechanisms by which IDO1 induces tolerance to exogenous FVIII and suggest strategies to prevent the development of FVIII antibodies and inhibitors.

IDO1 suppresses inhibitor development in hemophilia A treated with factor VIIIDavide Matino, Marco Gargaro, Elena Santagostino, Matteo N.D. Di Minno, Giancarlo Castaman, Massimo Morfini, Angiola Rocino, Maria E. Mancuso, Giovanni Di Minno, Antonio Coppola, Vincenzo N. Talesa, Claudia Volpi, Carmine Vacca, Ciriana Orabona, Rossana Iannitti, Maria G. Mazzucconi, Cristina Santoro, Antonella Tosti, Sara Chiappalupi, Guglielmo Sorci, Giuseppe Tagariello, Donata Belvini, Paolo Radossi, Raffaele Landolfi, Dietmar Fuchs, Louis Boon, Matteo Pirro, Emanuela Marchesini, Ursula Grohmann, Paolo Puccetti, Alfonso Iorio, and Francesca Fallarino http://jci.me/81859

Research | Editor’s picks

Wiskott-Aldrich syndrome patients provide insight into B cell tolerance checkpointsWiskott-Aldrich syndrome (WAs) is an X-linked immunodeficiency caused by mutations in the WAS protein (WASp). To determine the effects of WASp deficiency on B cell tolerance, Francesca Pala and colleagues tested the reactivity of antibodies isolated from individual B cells in four WAS patients before and after gene therapy. Prior to gene therapy, WAS patients had fewer autoreactive B cells exiting the BM and greater numbers of autoreactive, mature peripheral B cells compared with unaffected individuals. These findings indicate that there is increased negative selection at the central tolerance checkpoint and a defect in the peripheral tolerance checkpoint associated with impaired Treg-mediated suppression. WASp gene therapy corrected alterations in both central and peripheral tolerance. In the accompanying Commentary, Jean-Claude Weill and Claude-Agnès Reyanud discuss how these findings suggest that WASp plays a critical role in the establishment and maintenance of B cell tolerance.

Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patientsFrancesca Pala, Henner Morbach, Maria Carmina Castiello, Jean-Nicolas Schickel, Samantha Scaramuzza, Nicolas Chamberlain, Barbara Cassani, Salome Glauzy, Neil Romberg, Fabio Candotti, Alessandro Aiuti, Marita Bosticardo, Anna Villa, and Eric Meffre http://jci.me/82249

Related CommentaryThe ups and downs of negative (and positive) selection of B cellsJean-Claude Weill and Claude-Agnès Reynaud http://jci.me/84009

immunologyhematology

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Research | Editor’s picks

A pathway to amplify insulin secretionendocrinology

insulin secretion from pancreatic β cells is triggered by glucose-stimulated electrical activity and opening of voltage-dependent Ca2+ channels to elicit exocytosis; however, this pathway does not account for the entire magnitude of the secretory response. Using isolated human islets and transgenic murine models, Mourad Ferdaoussi, Xiaoqing Dai, and colleagues demonstrate in this issue that cytosolic isocitrate dehydrogenase (ICDc) transfers reducing equivalents to generate NADPH and reduced glutathione (GSH). NAPDH and GSH serve as coupling factors that act through sentrin/SUMO-specific protease-1 (SENP1) to amplify Ca2+-induced insulin exocytosis (see the accompanying image, in which insulin is labeled green and SENP1 is labeled red). Notably, the glucose-dependent amplification of insulin exocytosis is impaired in human type 2 diabetes (T2D) and an in vitro model of human islet dysfunction. Exocytosis in these models was rescued by supplementation of signaling intermediates in the ICDc/SENP1 pathway. In the accompany-ing Commentary, Alan Attie discusses how this study elucidates a mechanism linking glucose metabo-lism to the amplification of insulin secretion that is disrupted in T2D.

Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cellsMourad Ferdaoussi, Xiaoqing Dai, Mette V. Jensen, Runsheng Wang, Brett S. Peterson, Chao Huang, Olga Ilkayeva, Nancy Smith, Nathanael Miller, Catherine Hajmrle, Aliya F. Spigelman, Robert C. Wright, Gregory Plummer, Kunimasa Suzuki, James P. Mackay, Martijn van de Bunt, Anna L. Gloyn, Terence E. Ryan, Lisa D. Norquay, M. Julia Brosnan, Jeff K. Trimmer, Timothy P. Rolph, Richard G. Kibbey, Jocelyn E. Manning Fox, William F. Colmers, Orian S. Shirihai, P. Darrell Neufer, Edward T.H. Yeh, Christopher B. Newgard, and Patrick E. MacDonald http://jci.me/82498

Related CommentaryHow do reducing equivalents increase insulin secretion?Alan D. Attie http://jci.me/84011

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Research | Editor’s picks

Perhexiline reduces atherosclerosis via Krüppel-like factor 14Genetic variants in Krüppel-like factor 14 (KlF14) are strongly associated with elevated plasma HDL levels, metabolic syndrome, and coronary artery disease. Yanhong Guo and colleagues found that KLF14 is reduced in murine models of hepatic dyslipidemia. Mice with liver-specific KLF14 deficiency had decreased plasma HDL, while overexpression of KLF14 in the liver increased plasma HDL and cholesterol efflux capacity. Mechanistically, KLF14 regulates plasma HDL and cholesterol efflux capacity by modulating hepatic production of apolipoprotein A-I (ApoA-I). To identify pharmacological interventions that enhance KLF14 activity, Guo and colleagues screened a chemical library for compounds that increase KLF14 expression. They found that perhexiline, which is approved for treatment of angina and heart failure, increases KLF14 expression, plasma HDL levels, and ApoA-I levels in mice. Additionally, perhexiline attenuated the development of atherosclerosis in a murine model of the disease (see the accompanying image).

Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I productionYanhong Guo, Yanbo Fan, Jifeng Zhang, Gwen A. Lomberk, Zhou Zhou, Lijie Sun, Angela J. Mathison, Minerva T. Garcia-Barrio, Ji Zhang, Lixia Zeng, Lei Li, Subramaniam Pennathur, Cristen J. Willer, Daniel J. Rader, Raul Urrutia, and Y. Eugene Chen http://jci.me/79048

Noninvasive prenatal diagnosis of recessive monogenic diseasenoninvasive prenatal genetic testing (niPGt) is a method of examining cell-free fetal DnA in the maternal bloodstream that is currently used for the diagnosis of chromosomal abnormalities. As discussed in this issue, David Zeevi and colleagues developed an NIPGT method to diagnose monogenic disorders caused by autosomal recessive mutations. Zeevi and colleagues collected blood samples from eight couples of Ashkenazi Jewish heritage that were at risk of passing on type I Gaucher disease–causing

alleles of acid β-glucosidase (GBA) as well as from mutation carrier family members and unrelated individuals who were homozygous for disease-causing mutations. The samples were subjected to high-throughput sequencing of GBA-flanking SNPs and fine mapped to establish a consensus disease-associated haplotype. Zeevi and colleagues then used this haplotype to diagnose six unrelated fetuses. This study establishes a method for the rapid, prenatal diagnosis of recessive disease-causing mutations.

Proof-of-principle rapid noninvasive prenatal diagnosis of autosomal recessive founder mutationsDavid A. Zeevi, Gheona Altarescu, Ariella Weinberg-Shukron, Fouad Zahdeh, Tama Dinur, Gaya Chicco, Yair Herskovitz, Paul Renbaum, Deborah Elstein, Ephrat Levy-Lahad, Arndt Rolfs, and Ari Zimran http://jci.me/79322

cardiology

genetics

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Research | Editor’s picks

Tracing the origins of hepatocellular carcinoma

An activatable fluorescent reporter for whole animal imagingnoninvasive imaging of whole living animals is a powerful method for monitoring tumor growth, immune responses, vascularization, and treatment effects in longitudinal studies. Such studies rely upon the ability to tag specific tissues and cells of interest with labels that generate signals that are detectable through tissue. Ming Zhang and colleagues report the development of a fluoromodule-based reporter/probe system consisting of a fluorogenic dye, SC1, which is dark in solution but becomes highly fluorescent when bound to its cognate reporter, Mars1. Notably, these fluorogens maximally absorb and emit light at a wavelength that is minimally absorbed by tissue. The accompanying image shows fluorescence imaging of a nude mouse implanted with Mars1-expressing cells labeled with SC1.

Fluoromodule-based reporter/probes designed for in vivo fluorescence imagingMing Zhang, Subhasish K. Chakraborty, Padma Sampath, Juan J. Rojas, Weizhou Hou, Saumya Saurabh, Steve H. Thorne, Marcel P. Bruchez, and Alan S. Waggoner http://jci.me/81086

oncology

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartmentXueru Mu, Regina Español-Suñer, Ingmar Mederacke, Silvia Affò, Rita Manco, Christine Sempoux, Frédéric P. Lemaigre, Arlind Adili, Detian Yuan, Achim Weber, Kristian Unger, Mathias Heikenwälder, Isabelle A. Leclercq, and Robert F. Schwabe http://jci.me/77995

Many cancers originate from the stem or progenitor compartment of a given organ; however, the liver does not have a defined stem cell population, and the cellular origin of hepatocellular carcinoma (HCC) is not clear.

Importantly, HCCs with a progenitor signature carry a worse prognosis. Xueru Mu, Regina Español-Suñer, and colleagues used complementary fate-tracing strategies to label the progenitor/biliary compartment and

hepatocytes in genotoxic and genetic models of murine hepatocarcinogen-esis. They found that HCCs arose exclusively from hepatocytes in both models. Additionally, cells with a progenitor signature within HCCs were

derived from hepatocytes, suggesting that these cells result from dedifferen-tiation of hepatocytes. The accompany-ing image shows HCC in a murine HCC model in which hepatocytes were labeled with GFP.

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Research | Editor’s picks

metabolism

Understanding the anticonvulsant effects of valproic acid

A bacterial impostor helps streptococci evade neutrophilsneutrophils are critical for the acute inflammatory response to control pathogens; thus, microbes must evade neutrophils in order to successfully infect a host. Christopher Hergott and colleagues report that the leading respiratory pathogen Streptococcus pneumoniae utilizes molecular mimicry to disable neutrophils. The exterior of S. pneumoniae is decorated with phosphorylcholine (ChoP) moieties, a structure also found on the host-derived inflammatory phospholipid platelet-activating factor (PAF). This mimicry allows S. pneumoniae to utilize a ChoP-remodeling enzyme, Pce, to deplete PAF from the airway, thereby reducing the viability, activation, and bactericidal capacity of neutrophils. Neutrophils rapidly cleared Pce-deficient S. pneumoniae, but abrogation of PAF signaling allowed Pce-deficient bacteria to persist. These data identify a mechanism by which bacteria evade the acute inflammatory response to establish stable infection.

Bacterial exploitation of phosphorylcholine mimicry suppresses inflammation to promote airway infectionChristopher B. Hergott, Aoife M. Roche, Nikhil A. Naidu, Clementina Mesaros, Ian A. Blair, and Jeffrey N. Weiser http://jci.me/81888

neuroscience

The trouble with tribbles-1 in hepatic lipid metabolism

Genetic variants near tribbles-1 (tRiB1) are associated with alterations in plasma lipid profiles and liver enzymes, and in coronary artery disease in humans. Robert Bauer and colleagues investigated the role of TRIB1 in hepatic lipid metabolism by generating mice with a liver-specific Trib1 KO (Trib1_LSKO). These mice exhibited increased total plasma cholesterol and

triglycerides, as well as greater hepatic lipogenesis, steatosis (see the accompanying image), and markedly dysregulated hepatic gene expression. Gene expression analysis of Trib1_LSKO livers revealed increased expression of genes downstream of C/EBPα. TRIB1 deficiency was associated with elevated levels of C/EBPα protein but decreased levels of transcript. C/EBPα overexpression in WT mice phenocopied the Trib1_LSKO liver phenotype, while C/EBPα deficiency in Trib1_LSKO mice decreased hepatic lipogenesis to WT levels. Importantly, Trib1_LSKO mice had increased DNA-bound C/EBPα near lipogenic genes and the Trib1 gene, indicating that C/EBPα and TRIB1 are part of a feedback loop regulating hepatic lipogenesis.

Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPαRobert C. Bauer, Makoto Sasaki, Daniel M. Cohen, Jian Cui, Mikhaila A. Smith, Batuhan O. Yenilmez, David J. Steger, and Daniel J. Rader http://jci.me/77095

pulmonology

Valproic acid (VPA) is commonly used to treat epilepsy; however, its mechanism of action is not well understood. Hee Yeon Kay, Derek Greene, and colleagues report that the anticonvulsant effects of VPA are mediated through preservation of the M-current during seizures. The M-current is a low-threshold, noninactivating current mediated by delayed rectifier potassium channels (KCNQ); suppression of the M-current induces neuronal hyperexcitability through the activation of various Gq-coupled GPCRs, including the M1 muscarinic acetylcholine receptor (M1R). Using primary neurons, cell lines, and a murine seizure model, Kay, Greene,

and colleagues found that VPA reduced palmitoylation of the signaling scaffold A-kinase anchoring protein 150 (AKAP150), thereby disrupting M1R-mediated M-current suppression. These studies demonstrate that M-current suppression contributes to seizures, and they elucidate the mechanism by which VPA acts as an anticonvul-sant.

M-current preservation contributes to anticonvulsant effects of valproic acidHee Yeon Kay, Derek L. Greene, Seungwoo Kang, Anastasia Kosenko, and Naoto Hoshi http://jci.me/79727

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Research | Editor’s picks

FOXC2 promotes lymphatic vessel homeostasis

Treg-secreted IL-34 teaches tolerance

As vessels mature, a complex signaling network provides cues to arrest endothelial cell proliferation, stabilize cell-cell junctions, and induce mural cell coverage. In this issue, Amélie Sabine and colleagues examine the factors that maintain lymphatic vessel homeostasis, which has been poorly understood. They show that the transcription factor FOXC2 acts under conditions of disturbed fluid flow to induce quiescence in lymphatic endothelial cells and increase the integrity of cell-cell junctions. Using conditional Foxc2 knockout mice, they demonstrate that these effects are mediated by the Hippo pathway and that inducible loss of Foxc2 causes lymphatic vascular dysfunction. The accompanying image shows that a FOXC2+ cell has continuous cell-cell junctions (arrows), while neighboring knockdown cells having zigzag junctions (arrowheads).

FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculatureAmélie Sabine, Esther Bovay, Cansaran Saygili Demir, Wataru Kimura, Muriel Jaquet, Yan Agalarov, Nadine Zangger, Joshua P. Scallan, Werner Graber, Elgin Gulpinar, Brenda R. Kwak, Taija Mäkinen, Inés Martinez-Corral, Sagrario Ortega, Mauro Delorenzi, Friedemann Kiefer, Michael J. Davis, Valentin Djonov, Naoyuki Miura, and Tatiana V. Petrova http://jci.me/80454

transplantation

vascular biology

the induction and maintenance of immune tolerance of transplanted tissues involves multiple mechanisms, including Treg-mediated suppression of graft-specific T cells. In this issue, Séverine Bézie and colleagues demon-strate that Treg secretion of the cytokine IL-34 promotes graft tolerance. Using a rodent heart transplant model, they observed that IL-34 levels were markedly increased in the spleens and grafts of tolerized heart transplant recipients, but that IL-34 was decreased in rats with graft rejection. Overexpression of IL-34 prolonged graft survival on its own and had

synergistic effects in combination with the immunosuppressant rapamycin. Moreover, adoptive transfer of Tregs from tolerant animals induced tolerance in sublethally irradiated naive animals. Using blood from healthy human volunteers, Bézie and colleagues demonstrated that IL-34 induces differentiation of macro-phages into a phenotype that potentiates the suppressive capacity of Tregs. In the accompa-nying Commentary, James Kim and Laurence Turka discuss additional experiments that will be required to understand the interactions between Tregs and macrophages.

IL-34 is a Treg-specific cytokine and mediates transplant toleranceSéverine Bézie, Elodie Picarda, Jason Ossart, Laurent Tesson, Claire Usal, Karine Renaudin, Ignacio Anegon, and Carole Guillonneau http://jci.me/81227

Related CommentaryTransplant tolerance: a new role for IL-34James I. Kim and Laurence A. Turka http://jci.me/84010

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Features

Helen Hobbs

A blueprint for building the physician-scientist workforcein this month’s JCI, Dianna Milewicz and colleagues on the Executive Committee of the National Association of MD-PhD Programs provide their perspective on specific action items that can be taken to improve retention of trainees in the physician-scientist workforce pipeline. Their proposal calls for better integration of research into clinical training programs, early career grants designated specifically for physician-scientists, promotion of diversity in physician-scientist training programs, and the establishment of centralized offices at individual institutions to support and facilitate mentorship of new physician-scientists. They also call for an improved national dialogue on postgraduate physician-scientist training to share effective training strategies across institutions. Such strategies are geared toward shortening the time for investigators to achieve independence by 5 years and reducing attrition during the long training period, particularly during the extended postgraduate training period.

Rescuing the physician-scientist workforce: the time for action is nowDianna M. Milewicz, Robin G. Lorenz, Terence S. Dermody, Lawrence F. Brass, and the National Association of MD-PhD Programs Executive Committee http://jci.me/84170

conversations with giants in medicine

A D V E R T I S E M E N Tpersonal perspective

helen hobbs is an investigator of the Howard Hughes Medical Institute and a professor of Internal Medicine and Molecular Genetics at the University of Texas Southwest-ern Medical Center. Additionally, she is the director of the Dallas Heart Study, a longitudinal, multiethnic population-based study of more than 6,000 adults that aims to identify genetic, protein, and imaging biomarkers for early detection of cardiovascu-lar disease as well as social, behavioral, and environmental factors that contribute to cardiovascular disease risk. By studying

outliers in this population, Dr. Hobbs identified a genetic defect in PCSK9 that is responsible for low plasma LDL levels. In an interview with JCI Editor-at-Large Ushma Neill, Dr. Hobbs discusses her early scientific training at Parkland Memorial Hospital in Dallas under the direction of Donald Seldin, who guided her to scientific bench training. She also discusses the initiation of the Dallas Heart Study and the development of a therapeutic inhibitor of PCSK9 for lowering LDL.

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