this month -...

Also in this issue:

Imaging intestinal lacteals 7

Dietary salt impairs immunity 8

Improving oncolytic virus replication 10

Direct targeting of HIV-infected cells 11

nucleoporin mutation drives ovarian

dysgenesisp. 6

A summary of the current issue ofthe Journal of Clinical investigation

november 2015

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This Month

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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

Steven P. Balk

Michael F. Beers

John A. Belperio

Nina Bhardwaj

Morris J. Birnbaum

Joyce Bischoff

Mina J. Bissell

Craig Blackstone

Bruce R. Blazar

Nancy Bonini

Brendan Boyce

Jonathan Bromberg

Frank C. Brosius

Hal E. Broxmeyer

Andrew Butler

Michael J. Caplan

Ruben D. Carrasco

Diego H. Castrillon

Harold Chapman

Ajay Chawla

Benjamin K. Chen

Benny J. Chen

Ju Chen

Marie-Françoise Chesselet

Vivian G. Cheung

Yongwon Choi

Thomas Clemens

Ronald G. Collman

Marco Colonna

George Cotsarelis

Shaun R. Coughlin

Christopher M. Counter

Peter D. Crompton

Tyler J. Curiel

David D’Alessio

Richard T. D’Aquila

Riccardo Dalla-Favera

Alan Daugherty

Ted Dawson

Sudhansu Dey

Harry C. Dietz III

Gianpietro Dotti

Michael Dustin

Connie J. Eaves

Dominique Eladari

Jack A. Elias

Joel K. Elmquist

Stephen G. Emerson

Jeffrey A. Engelman

Jonathan A. Epstein

Adrian Erlebacher

Joel D. Ernst

James M. Ervasti

Robert V. Farese Jr.

Eric R. Fearon

Edward A. Fisher

Susan Fisher

Richard A. Flavell

Tatiana Foroud

Velia M. Fowler

Martin Friedlander

Stephen J. Galli

J. Victor Garcia-Martinez

Alfred L. George Jr.

Stanton L. Gerson

Robert E. Gerszten

Todd Golde

Stanley Goldfarb

Larry B. Goldstein

Fred Sanford Gorelick

Kathleen J. Green

J. Timothy Greenamyre

Theresa A. Guise

David Hafler

Jonathan J. Hansen

Raymond C. Harris

Stanley L. Hazen

Peter Heeringa

Brian A. Hemmings

Meenhard Herlyn

Joachim Herz

Katherine A. High

Helen H. Hobbs

Ronald Hoffman

V. Michael Holers

Steven M. Holland

Michael J. Holtzman

Lawrence B. Holzman

Tamas L. Horvath

Gokhan S. Hotamisligil

Steven R. Houser

Scott J. Hultgren

Christopher A. Hunter

Ciro Indolfi

David E. James

William G. Kaelin Jr.

Klaus Kaestner

Mark L. Kahn

Raghu Kalluri

S. Ananth Karumanchi

Robert S. Kass

Masato Kasuga

Dontscho Kerjaschki

Sundeep Khosla

Richard N. Kitsis

Peter S. Klein

Steven Kliewer

Björn C. Knollmann

Walter J. Koch

Jay K. Kolls

Issei Komuro

Christopher D. Kontos

Murray Korc

Gary Koretzky

Calvin Kuo

Antonio La Cava

Fadi G. Lakkis

Terri Laufer

Mitchell A. Lazar

Brendan Lee

William M.F. Lee

Rudolph L. Leibel

Stanley M. Lemon

Jon D. Levine

Ross L. Levine

Klaus Ley

Richard M. Locksley

Gary Lopaschuk

Richard B. Mailman

Rama K. Mallampalli

Andrew R. Marks

Jack Martin

Steven O. Marx

Rodger P. McEver

Elizabeth McNally

Cornelius J. Melief

Shlomo Melmed

George Michalopoulos

Jeffrey H. Miner

Beverly Mitchell

Peter J. Mohler

Kelle Harbert Moley

Jeffery Molkentin

David D. Moore

Edward E. Morrisey

James H. Morrissey

Anthony J. Muslin

Martin G. Myers Jr.

Benjamin G. Neel

Eric N. Olson

Harry T. Orr

William C. Parks

Warren S. Pear

Richard M. Peek Jr.

Sallie R. Permar

David J. Pinsky

Edward Plow

Jeffrey Pollard

Kornelia Polyak

Catherine Postic

Josef Prchal

Alice S. Prince

Louis J. Ptáček

Luigi Puglielli

Pere Puigserver

Bali Pulendran

Ellen Puré

Susan E. Quaggin

Marlene Rabinovitch

Daniel J. Rader

Shahin Rafii

Gwendalyn J. Randolph

Barbara Rehermann

Steven L. Reiner

Sarah A. Robertson

Paul B. Rosenberg

Theodora S. Ross

Marc E. Rothenberg

Anil Rustgi

J. Evan Sadler

Junichi Sadoshima

Jose-Alain Sahel

Jean E. Schaffer

Philipp E. Scherer

Michael D. Schneider

Detlef Schuppan

Michael W. Schwartz

William K. Scott

Randy Seeley

Amita Sehgal

Clay Semenkovich

Gregg L. Semenza

John Seykora

Steven D. Shapiro

Mari Shinohara

Steven E. Shoelson

Gerald I. Shulman

Journal of Clinical Investigation Consulting Editors

Roy L. Silverstein

M. Celeste Simon

Mihaela Skobe

Lois Smith

Steven R. Smith

Susan S. Smyth

Weihong Song

Ashley L. St. John

Herman F. Staats

Jonathan S. Stamler

John R. Stanley

Colin L. Stewart

Doris Stoffers

Warren Strober

Maureen A. Su

Katalin Susztak

Catharina Svanborg

Ira Tabas

Alan R. Tall

Sakae Tanaka

Victor J. Thannickal

Andrei Thomas-Tikhonenko

Georgia D. Tomaras

Peter Tontonoz

Laurence A. Turka

Raphael H. Valdivia

Marcel R.M. van den Brink

Luc Van Kaer

Matthias von Herrath

Yisong Y. Wan

Hong Wang

David Weinstock

Jeffrey Weiser

Stephen J. Weiss

Bart O. Williams

Joseph C. Wu

Thomas A. Wynn

Rudolf Zechner

Kang Zhang

Len Zon

Ming-Hui Zou

Weiping Zou

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 n o v e m b e r 2 0 1 5 1

This MonthNovember 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: [email protected]

For the full JCI online, go to jci.me/125/11 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

Deborah M. Muoio, PhD, Associate Editor, is Associate Professor in Medicine, Division of Endocrinology, and Director of Basic Research at the Duke Molecular Physi-ology Institute. Her expertise lies in the areas of inter-mediary metabolism, lipid biochemistry, exercise physi-ology, and mitochondrial bioenergetics. The projects in her laboratory focus on metabolic networks that control skeletal muscle energy metabolism, with an emphasis on mechanisms linking obesity and physical inactiv-ity to mitochondrial stress and insulin resistance. Her

group works closely with the Metabolomics and Biomarkers Core Laboratory at the Stedman Center and in recent years has been applying metabolomics approaches to examine the interplay among mitochondrial energetics, redox balance, and insulin action in skeletal muscle. Ongoing studies aim to identify metabolic signatures that are predictive of disease risk and better understand the underlying causes of muscle dysfunction, which may help elucidate new strategies to treat and prevent cardio-metabolic disorders. Dr. Muoio previously served on the editorial boards of Trends in Endocrinology and Metabolism and the Journal of Lipid Research.

Publication highlights

Seiler SE, Koves TR, Gooding J, Wong KE, Stevens RS, Ilkayeva O, Hawkins A, DeBalsi K, Davies M, Lindeboom L, Schrauwen P, Schrauwen V, Muoio DM. Carnitine acetyltransferase mitigates metabolic inertia and muscle fatigue dur-ing exercise. Cell Metab. 2015;22(1):65–76.

Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insu-lin resistance. Cell Metab. 2008;7(1):45–56.

Koves TR, Li P, An J, Akimoto T, Slentz D, Ilkayeva O, Dohm GL, Yan Z, Newgard CB, Muoio DM. Peroxisome proliferator-activated receptor-gamma co-activator 1α-mediated metabolic remodeling of skeletal myocytes mimics exercise training and reverses lipid-induced mitochondrial inefficiency. J Biol Chem. 2005;280(39):33588–33598.

mailto:[email protected]

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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 n o v e m b e r 2 0 1 52

AIDS/HIVDual-Affinity Re-Targeting proteins direct T cell–mediated cytolysis of latently HIV-infected cellsJulia A.M. Sung, Joy Pickeral, Liqin Liu, Sherry A. Stanfield-Oakley, Chia-Ying Kao Lam, Carolina Garrido, Justin Pollara, Celia LaBranche, Mattia Bonsignori, M. Anthony Moody, Yinhua Yang, Robert Parks, Nancie Archin, Brigitte Allard, Jennifer Kirchherr, JoAnn D. Kuruc, Cynthia L. Gay, Myron S. Cohen, Chrisitina Ochsenbauer, Kelly Soderberg, Hua-Xin Liao, David Montefiori, Paul Moore, Syd Johnson, Scott Koenig, Barton F. Haynes, Jeffrey L. Nordstrom, David M. Margolis, and Guido Ferrari http://jci.me/82314

More, p. 11

CardiologyCardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasisZhan-Peng Huang, Masaharu Kataoka, Jinghai Chen, Gengze Wu, Jian Ding, Mao Nie, Zhiqiang Lin, Jianming Liu, Xiaoyun Hu, Lixin Ma, Bin Zhou, Hiroko Wakimoto, Chunyu Zeng, Jan Kyselovic, Zhong-Liang Deng, Christine E. Seidman, J.G. Seidman, William T. Pu, and Da-Zhi Wang http://jci.me/82423

EndocrinologyA mutation in the nucleoporin-107 gene causes XX gonadal dysgenesisAriella Weinberg-Shukron, Paul Renbaum, Rachel Kalifa, Sharon Zeligson, Ziva Ben-Neriah, Amatzia Dreifuss, Amal Abu-Rayyan, Noa Maatuk, Nilly Fardian, Dina Rekler, Moien Kanaan, Abraham O. Samson, Ephrat Levy-Lahad, Offer Gerlitz, and David Zangen http://jci.me/83553

With related Commentary by Haifan Lin and Martin M. Matzuk More, p. 6

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasisFan Fan, Chen Ji, Yumei Wu, Shawn M. Ferguson, Natalia Tamarina, Louis H. Philipson, and Xuelin Lou http://jci.me/80652

More, p. 7

GeneticsReengineering a transmembrane protein to treat muscular dystrophy using exon skippingQuan Q. Gao, Eugene Wyatt, Jeff A. Goldstein, Peter LoPresti, Lisa M. Castillo, Alec Gazda, Natalie Petrossian, Judy U. Earley, Michele Hadhazy, David Y. Barefield, Alexis R. Demonbreun, Carsten Bönnemann, Matthew Wolf, and Elizabeth M. McNally http://jci.me/82768

Research articles in the current issue of the JCI

Cardiomyocyte hypertrophy

β Cell calcium signaling

Sarcolemmal leak in muscle

http://jci.me/82314?utm_medium=pdf







ImmunologyIL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitisYoujin Lee, Meike Mitsdoerffer, Sheng Xiao, Guangxiang Gu, Raymond A. Sobel, and Vijay K. Kuchroo http://jci.me/75933

Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiencyJolan E. Walter, Lindsey B. Rosen, Krisztian Csomos, Jacob M. Rosenberg, Divij Mathew, Marton Keszei, Boglarka Ujhazi, Karin Chen, Yu Nee Lee, Irit Tirosh, Kerry Dobbs, Waleed Al-Herz, Morton J. Cowan, Jennifer Puck, Jack J. Bleesing, Michael S. Grimley, Harry Malech, Suk See De Ravin, Andrew R. Gennery, Roshini S. Abraham, Avni Y. Joshi, Thomas G. Boyce, Manish J. Butte, Kari C. Nadeau, Imelda Balboni, Kathleen E. Sullivan, Javeed Akhter, Mehdi Adeli, Reem A. El-Feky, Dalia H. El-Ghoneimy, Ghassan Dbaibo, Rima Wakim, Chiara Azzari, Paolo Palma, Caterina Cancrini, Kelly Capuder, Antonio Condino-Neto, Beatriz T. Costa-Carvalho, Joao Bosco Oliveira, Chaim Roifman, David Buchbinder, Attila Kumanovics, Jose Luis Franco, Tim Niehues, Catharina Schuetz, Taco Kuijpers, Christina Yee, Janet Chou, Michel J. Masaad, Raif Geha, Gulbu Uzel, Rebecca Gelman, Steven M. Holland, Mike Recher, Paul J. Utz, Sarah K. Browne, and Luigi D. Notarangelo http://jci.me/80477

More, p. 9

High salt reduces the activation of IL-4– and IL-13–stimulated macrophagesKatrina J. Binger, Matthias Gebhardt, Matthias Heinig, Carola Rintisch, Agnes Schroeder, Wolfgang Neuhofer, Karl Hilgers, Arndt Manzel, Christian Schwartz, Markus Kleinewietfeld, Jakob Voelkl, Valentin Schatz, Ralf A. Linker, Florian Lang, David Voehringer, Mark D. Wright, Norbert Hubner, Ralf Dechend, Jonathan Jantsch, Jens Titze, and Dominik N. Müller http://jci.me/80919

With related Commentary by Booki Min and Robert L. Fairchild More, p. 8

Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitisArnaud Millet, Katherine R. Martin, Francis Bonnefoy, Philippe Saas, Julie Mocek, Manal Alkan, Benjamin Terrier, Anja Kerstein, Nicola Tamassia, Senthil Kumaran Satyanarayanan, Amiran Ariel, Jean-Antoine Ribeil, Loïc Guillevin, Marco A. Cassatella, Antje Mueller, Nathalie Thieblemont, Peter Lamprecht, Luc Mouthon, Sylvain Perruche, Véronique Witko-Sarsat http://jci.me/78182

More, p. 9

Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cellsAmanda L. Hernandez, Alexandra Kitz, Chuan Wu, Daniel E. Lowther, Donald M. Rodriguez, Nalini Vudattu, Songyan Deng, Kevan C. Herold, Vijay K. Kuchroo, Markus Kleinewietfeld, and David A. Hafler http://jci.me/81151

With related Commentary by Booki Min and Robert L. Fairchild More, p. 8

TIGIT predominantly regulates the immune response via regulatory T cellsSema Kurtulus, Kaori Sakuishi, Shin-Foong Ngiow, Nicole Joller, Dewar J. Tan, Michele W.L. Teng, Mark J. Smyth, Vijay K. Kuchroo, and Ana C. Anderson http://jci.me/81187

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN productionAnja Brehm, Yin Liu, Afzal Sheikh, Bernadette Marrero, Ebun Omoyinmi, Qing Zhou, Gina Montealegre, Angelique Biancotto, Adam Reinhardt, Adriana Almeida de Jesus, Martin Pelletier, Wanxia L. Tsai, Elaine F. Remmers, Lela Kardava, Suvimol Hill, Hanna Kim, Helen J. Lachmann, Andre Megarbane, Jae Jin Chae, Jilian Brady, Rhina D. Castillo, Diane Brown, Angel Vera Casano, Gao Ling, Dawn Chapelle, Yan Huang, Deborah Stone, Yongqing Chen, Franziska Sotzny, Chyi-Chia Richard Lee, Daniel L. Kastner, Antonio Torrelo, Abraham Zlotogorski, Susan Moir, Massimo Gadina, Phil McCoy, Robert Wesley, Kristina Rother, Peter W. Hildebrand, Paul Brogan, Elke Krüger, Ivona Aksentijevich, and Raphaela Goldbach-Mansky http://jci.me/81260

Meningeal inflammatory infiltrates

Granulomatous inflammation

Polyubiquitination in skin









ImmunologyMicroRNA-223 is a crucial mediator of PPARγ-regulated alternative macrophage activationWei Ying, Alexander Tseng, Richard Cheng-An Chang, Andrew Morin, Tyler Brehm, Karen Triff, Vijayalekshmi Nair, Guoqing Zhuang, Hui Song, Srikanth Kanameni, Haiqing Wang, Michael C. Golding, Fuller W. Bazer, Robert S. Chapkin, Stephen Safe, and Beiyan Zhou http://jci.me/81656

Mucosal-associated invariant T cell–rich congenic mouse strain allows functional evaluationYue Cui, Katarzyna Franciszkiewicz, Yvonne K. Mburu, Stanislas Mondot, Lionel Le Bourhis, Virginie Premel, Emmanuel Martin, Alexandra Kachaner, Livine Duban, Molly A. Ingersoll, Sylvie Rabot, Jean Jaubert, Jean-Pierre De Villartay, Claire Soudais, and Olivier Lantz http://jci.me/82424

Sialylation of IgG Fc domain impairs complement-dependent cytotoxicityIsaak Quast, Christian W. Keller, Michael A. Maurer, John P. Giddens, Björn Tackenberg, Lai-Xi Wang, Christian Münz, Falk Nimmerjahn, Marinos C. Dalakas, and Jan D. Lünemann http://jci.me/82695

NephrologyInhibition of cyclooxygenase-2 in hematopoietic cells results in salt-sensitive hypertensionMing-Zhi Zhang, Bing Yao, Yinqiu Wang, Shilin Yang, Suwan Wang, Xiaofeng Fan, and Raymond C. Harris http://jci.me/81550

With related Commentary by Johannes Stegbauer and Thomas M. Coffman More, p. 12

MicroRNA-30 family members regulate calcium/calcineurin signaling in podocytesJunnan Wu, Chunxia Zheng, Xiao Wang, Shifeng Yun, Yue Zhao, Lin Liu, Yuqiu Lu, Yuting Ye, Xiaodong Zhu, Changming Zhang, Shaolin Shi, and Zhihong Liu http://jci.me/81061

More, p. 12

NeuroscienceDissociation of locomotor and cerebellar deficits in a murine Angelman syndrome modelCaroline F. Bruinsma, Martijn Schonewille, Zhenyu Gao, Eleonora M.A. Aronica, Matthew C. Judson, Benjamin D. Philpot, Freek E. Hoebeek, Geeske M. van Woerden, Chris I. De Zeeuw, and Ype Elgersma http://jci.me/83541

OncologyHistone deacetylase 6 inhibition enhances oncolytic viral replication in gliomaHiroshi Nakashima, Johanna K. Kaufmann, Pin-Yi Wang, Tran Nguyen, Maria-Carmela Speranza, Kazue Kasai, Kazuo Okemoto, Akihiro Otsuki, Ichiro Nakano, Soledad Fernandez, William F. Goins, Paola Grandi, Joseph C. Glorioso, Sean Lawler, Timothy P. Cripe, and E. Antonio Chiocca http://jci.me/80713

More, p. 10


Adipose-resident macrophages

Kidney arginase-1

Glomerular TRPC6

Oncolytic virus replication










LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitmentChristopher G. Peña, Yuji Nakada, Hatice D. Saatcioglu, Gina M. Aloisio, Ileana Cuevas, Song Zhang, David S. Miller, Jayanthi S. Lea, Kwok-Kin Wong, Ralph J. DeBerardinis, Antonio L. Amelio, Rolf A. Brekken, and Diego H. Castrillon http://jci.me/82152

STK4 regulates TLR pathways and protects against chronic inflammation–related hepatocellular carcinomaWeiyun Li, Jun Xiao, Xin Zhou, Ming Xu, Chaobo Hu, Xiaoyan Xu, Yao Lu, Chang Liu, Shengjie Xue, Lei Nie, Haibin Zhang, Zhiqi Li, Yanbo Zhang, Fu Ji, Lijian Hui, Wufan Tao, Bin Wei, and Hongyan Wang http://jci.me/81203

More, p. 10

Reproductive biologyExcess placental secreted frizzled-related protein 1 in maternal smokers impairs fetal growthAlice Wang, Zsuzsanna K. Zsengellér, Jonathan L. Hecht, Roberto Buccafusca, Suzanne D. Burke, Augustine Rajakumar, Emily Weingart, Paul B. Yu, Saira Salahuddin, and S. Ananth Karumanchi http://jci.me/80457

More, p. 11

TransplantationTherapeutic lymphangiogenesis ameliorates established acute lung allograft rejectionYe Cui, Kaifeng Liu, Maria E. Monzon-Medina, Robert F. Padera, Hao Wang, Gautam George, Demet Toprak, Elie Abdelnour, Emmanuel D’Agostino, Hilary J. Goldberg, Mark A. Perrella, Rosanna Malbran Forteza, Ivan O. Rosas, Gary Visner, and Souheil El-Chemaly http://jci.me/79693

With related Commentary by Jonathan S. Maltzman, Hasina Outtz Reed, and Mark L. Kahn More, p. 10

Vascular biologyIntravital imaging of intestinal lacteals unveils lipid drainage through contractilityKibaek Choe, Jeon Yeob Jang, Intae Park, Yeseul Kim, Soyeon Ahn, Dae-Young Park, Young-Kwon Hong, Kari Alitalo, Guo Young Koh, and Pilhan Kim http://jci.me/76509

More, p. 7

Uterine macrophages

Placental frizzled-related protein 1

Lung allograft lymphatics

Intestinal lacteals






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 n o v e m b e r 2 0 1 566 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 n o v e m b e r 2 0 1 5

XX gonadal dysgenesis is a rare disorder that clini-cally presents with primary amenorrhea and a failure to spontaneously undergo puberty. In affected young women, ovaries fail to produce estrogen, despite high levels of gonadotropin-releasing hormone, follicle-stimulating hormone, and luteinizing hormone, which results in hypergonadotropic hypogonadism. While several recessively inherited mutations in genes encod-ing components of the signaling pathways that respond to these hormones have been identified, the down-stream mediators are not well characterized. In this issue of the JCI, David Zangen, Offer Gerlitz, Ephrat Levy-Lahad, and colleagues report a missense muta-tion in nucleoporin-107 (NUP107) that was identified by homozygosity mapping and whole-exome sequenc-ing in a family with multiple females affected by XX go-nadal dysgenesis. NUP107 encodes an essential compo-nent of the nuclear pore complex that is evolutionarily conserved in Drosophila. A nup107 deletion allele is em-bryonically lethal in the fly but can be rescued by exoge-nously expressed WT Nup107. The research team found that transgenic expression of the functionally equivalent Drosophila Nup107 missense mutation in flies rescued viability but not ovarian development defects, resulting in impaired oocyte production and reduced fertility. As shown in the accompanying image, ovarioles from a fly expressing transgenic mutant Nup107 (in red) frequently exhibited collapsed nuclear envelopes, with

condensed nuclei (green), and increased apoptosis (cleaved caspase-3, blue). In an associated Commentary, Haifan Lin and Martin Matzuk discuss how these findings shed light on tissue-specific functions of NUP107 and suggest that other compo-nents of the nuclear pore complex may have oogenesis-specific functions. Image credit: Rachel Kalifa.

A mutation in the nucleoporin-107 gene causes XX gonadal dysgenesisAriella Weinberg-Shukron, Paul Renbaum, Rachel Kalifa, Sharon Zeligson, Ziva Ben-Neriah, Amatzia Dreifuss, Amal Abu-Rayyan, Noa Maatuk, Nilly Fardian, Dina Rekler, Moien Kanaan, Abraham O. Samson, Ephrat Levy-Lahad, Offer Gerlitz, and David Zangen http://jci.me/83553

Related CommentaryPoreless eggshellsHaifan Lin and Martin M. Matzuk http://jci.me/84692

A nucleoporin-107 mutation drives ovarian dysgenesis

Editor’s picksResearch




Dynamin 2 regulates insulin secretory capacityPancreatic β cell dysfunction in diabetes mellitus is characterized by alterations in insulin granule trafficking. In this issue, Fan Fan and colleagues identified an endocytic regulatory mechanism of insulin secretory capacity using a mouse model with tamoxifen-inducible deletion of dynamin 2 (Dnm2), which mediates release of free endocytic vessels from the plasma membrane. Loss of DNM2 in β cells resulted in glucose intolerance and a reduction in the second phase of glucose-stimulated insulin secretion. DNM2-deficient cells maintained normal glucose metabolism and Ca2+ signaling and retained similar numbers of insulin granules compared with WT cells; however, DNM2 deficiency impaired exocytosis-endocytosis coupling efficiency and clathrin-mediated endocytosis, resulting in the accumulation of clathrin-coated endocytic intermediates at the plasma membrane (see the accompanying image) as well as a marked restructuring of actin filaments and impairment of insulin granule recruitment during the second phase of insulin release. These results identify a role for DNM2 in insulin secretion and link defects in β cell endocytosis to diabetes mellitus.

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasisFan Fan, Chen Ji, Yumei Wu, Shawn M. Ferguson, Natalia Tamarina, Louis H. Philipson, and Xuelin Lou http://jci.me/80652

Research | Editor’s picks

endocrinology

vascular biology

Intestinal lacteals put the squeeze on dietary lipids

intestinal lacteals are lymphatic vessels located within the center of each intestinal villus. Lacteals serve as the primary conduit for the transport of intestinally absorbed lipids and lipophilic molecules to the

systemic circulation, but the mechanism by which lacteals mediate transport is unknown. Kibaek Choe and colleagues used real-time intravital microscopy to visualize the transport of fatty acids through the intestinal lacteals of mice with fluorescently labeled lymphatic vessels. They found that fatty acids were absorbed by enterocytes, distributed over the lamina, and transported into the lacteals, which contract in order to drain dietary lipids (see the accompanying image). Further analysis revealed that the autonomic nervous system mediates contraction of the smooth muscle surrounding each lacteal, helping to remove the absorbed molecules from the intestinal villus.

Intravital imaging of intestinal lacteals unveils lipid drainage through contractilityKibaek Choe, Jeon Yeob Jang, Intae Park, Yeseul Kim, Soyeon Ahn, Dae-Young Park, Young-Kwon Hong, Kari Alitalo, Gou Young Koh, and Pilhan Kim http://jci.me/76509




Shaking out the effect of dietary salt in autoimmunity


immunology

high dietary salt intake is associated with the development of hypertension, chronic inflammation, and autoimmune diseases. In this issue, research groups led by Dominik N. Müller and David A. Hafler report that salt contributes to immune imbalances. Müller and colleagues found that high dietary salt reduced activation of noninflammatory (M2) macrophages and impaired their ability to suppress effector T cell proliferation in vitro. Additionally, mice fed a high-salt diet exhibited reduced M2 macrophage activation and delayed wound healing. Hafler and colleagues demonstrated that high salt impairs the function of Tregs, which are required for the maintenance of self-tolerance and are frequently defective in autoimmunity. Tregs exposed to high salt exhibited increased IFN-γ secretion and decreased suppressive activity in vitro, as well as in murine models of xenogeneic graft versus host disease and experimental colitis. IFN-γ–targeted neutralizing antibodies or knockdown of Ifng restored Treg suppressive activity. In the accompany-ing Commentary, Booki Min and Robert Fairchild discuss how these studies demonstrate a putative role for diet in altered immune homeostasis and autoimmunity.

Related ResearchHigh salt reduces the activation of IL-4– and IL-13–stimulated macrophagesKatrina J. Binger, Matthias Gebhardt, Matthias Heinig, Carola Rintisch, Agnes Schroeder, Wolfgang Neuhofer, Karl Hilgers, Arndt Manzel, Christian Schwartz, Markus Kleinewietfeld, Jakob Voelkl, Valentin Schatz, Ralf A. Linker, Florian Lang, David Voehringer, Mark D. Wright, Norbert Hubner, Ralf Dechend, Jonathan Jantsch, Jens Titze, and Dominik N. Müller http://jci.me/80919

Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cellsAmanda L. Hernandez, Alexandra Kitz, Chuan Wu, Daniel E. Lowther, Donald M. Rodriguez, Nalini Vudattu, Songyan Deng, Kevan C. Herold, Vijay K. Kuchroo, Markus Kleinewietfeld, and David A. Hafler http://jci.me/81151

Related CommentaryOver-salting ruins the balance of the immune menuBooki Min and Robert L. Fairchild http://jci.me/84690




http://www.jci.org/?utm_source=this-month&utm_medium=pdf&utm_campaign=this-month_2015_november



Viral infection influences autoantibody production in primary immunodeficiencyMutations resulting in impaired activity of the recombination-activating genes RAG1 and RAG2 cause immune disorders ranging from severe combined immunodeficiency (SCID) to autoimmunity. Jolan Walter, Lindsey Rosen, and colleagues analyzed the antibodies from patients with RAG1/2 deficiencies and found that patients with delayed-onset combined immunodeficiency and granulomatous/autoimmune manifestations (CID-G/AI) produce a broad range of autoantibodies, including neutral-izing antibodies against the inflammatory cytokines IFN-α and IFN-ω, which were associated with a history of severe viral infections. To test the hypothesis that recurrent or chronic viral infections can contribute to immune dysregulation, Walter, Rosen, and colleagues mimicked viral infection by challenging RAG-deficient mice with TLR agonists and found that such stimulation elicits autoantibody production. These data support the idea that environmental factors such as viral exposure influence the presentation of immune dysregulation in RAG-deficient patients.

Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiencyJolan E. Walter, Lindsey B. Rosen, Krisztian Csomos, Jacob M. Rosenberg, Divij Mathew, Marton Keszei, Boglarka Ujhazi, Karin Chen, Yu Nee Lee, Irit Tirosh, Kerry Dobbs, Waleed Al-Herz, Morton J. Cowan, Jennifer Puck, Jack J. Bleesing, Michael S. Grimley, Harry Malech, Suk See De Ravin, Andrew R. Gennery, Roshini S. Abraham, Avni Y. Joshi, Thomas G. Boyce, Manish J. Butte, Kari C. Nadeau, Imelda Balboni, Kathleen E. Sullivan, Javeed Akhter, Mehdi Adeli, Reem A. El-Feky, Dalia H. El-Ghoneimy, Ghassan Dbaibo, Rima Wakim, Chiara Azzari, Paolo Palma, Caterina Cancrini, Kelly Capuder, Antonio Condino-Neto, Beatriz T. Costa-Carvalho, Joao Bosco Oliveira, Chaim Roifman, David Buchbinder, Attila Kumanovics, Jose Luis Franco, Tim Niehues, Catharina Schuetz, Taco Kuijpers, Christina Yee, Janet Chou, Michel J. Masaad, Raif Geha, Gulbu Uzel, Rebecca Gelman, Steven M. Holland, Mike Recher, Paul J. Utz, Sarah K. Browne, and Luigi D. Notarangelo http://jci.me/80477

Proteinase 3 on apoptotic neutrophils drives autoimmune inflammation

Granulomatosis with polyangiitis (GPA) is a form of autoimmune necrotizing vasculitis that is associated with anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). Arnaud Millet, Katherine Martin, and colleagues found that PR3 expression was increased on the surface of apoptotic neutrophils from GPA patients. Engulfment of PR3-express-ing apoptotic cells triggered release of inflamma-tory cytokines through a serine protease–depen-dent pathway in macrophages. Injection of mice with PR3-expressing apoptotic cells skewed plasmacytoid dendritic cells (pDCs) to promote generation of Th9/Th2 cells, while simultaneous injection of anti-PR3 ANCAs induced an inflammatory Th17 response. A similar distribu-tion of the immune cell population was observed in GPA patients. Further, macrophages, pDCs, and PR3-expressing apoptotic neutrophils were

located within granulomatous lesions in GPA patients (see the accompanying image). Taken together, these data demonstrate that PR3 disrupts immune silencing and drives inflammation through multiple mechanisms in GPA.

Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitisArnaud Millet, Katherine R. Martin, Francis Bonnefoy, Philippe Saas, Julie Mocek, Manal Alkan, BenjaminTerrier, Anja Kerstein, Nicola Tamassia, Senthil Kumaran Satyanarayanan, Amiram Ariel, Jean-Antoine Ribeil, Loïc Guillevin, Marco A. Cassatella, Antje Mueller, Nathalie Thieblemont, Peter Lamprecht, Luc Mouthon, Sylvain Perruche, and Véronique Witko-Sarsat http://jci.me/78182





Histone deacetylase 6 inhibition enhances oncolytic virus replication

STK4 attenuates macrophage inflammatory responses in hepatocellular carcinomaseveral forms of cancer are linked to chronic inflammation, which can predispose cells to oncogenic transformation and contribute to tumor develop-ment. Weiyun Li, Jun Xiao, and colleagues examined the mechanisms by which pathogen-induced chronic inflammation contributes to hepatocellular carcinoma (HCC). Using murine HCC models, they found that the tumor suppressor serine/threonine-protein kinase 4 (STK4) differentially regulates macrophage inflamma-tory responses to protect against HCC. Mechanistically, STK4 abrogated TLR4/9-induced proinflammatory cytokine production and enhanced TLR3/4-induced IFN-β by triggering the degradation of IL-1R–associated kinase 1 (IRAK1). Treatment of STK4 KO mice with an IRAK1 inhibitor reduced liver tumors. Importantly, STK4 levels were substantially reduced in macrophages or serum from human HCC patients and were inversely associated with the levels of IRAK1, IL-6, and phospho-p65 or phospho-STAT3. This study suggests that STK4 may be a therapeutic target in inflammation-induced HCC.

STK4 regulates TLR pathways and protects against chronic inflammation–related hepatocellular carcinomaWeiyun Li, Jun Xiao, Xin Zhou, Ming Xu, Chaobo Hu, Xiaoyan Xu, Yao Lu, Chang Liu, Shengjie Xue, Lei Nie, Haibin Zhang, Zhiqi Li, Yanbo Zhang, Fu Ji, Lijian Hui, Wufan Tao, Bin Wei, and Hongyan Wang http://jci.me/81203

oncology

oncolytic viruses (oVs) preferentially infect and kill cancer cells; however, host antiviral defenses may impair infection of the tumor. In this issue, Hiroshi Nakashima, Johanna Kaufmann, and colleagues report that inhibition of histone deacetylase 6 (HDAC6) alters the intracellular trafficking of OVs, redirecting them from the nucleus to lysosomes. In human glioma cell lines and patient-derived primary glioma cells, pharmacologic or genetic inhibition of HDAC6 markedly improved replication of oncolytic herpes simplex virus–1 and improved survival in a murine orthotopic tumor model. These data identify HDAC6 as a mediator of intrinsic cellular defense and suggest that HDAC6 inhibitors may improve OV-based therapy.

Histone deacetylase 6 inhibition enhances oncolytic viral replication in gliomaHiroshi Nakashima, Johanna K. Kaufmann, Pin-Yi Wang, Tran Nguyen, Maria-Carmela Speranza, Kazue Kasai, Kazuo Okemoto, Akihiro Otsuki, Ichiro Nakano, Soledad Fernandez, William F. Goins, Paola Grandi, Joseph C. Glorioso, Sean Lawler, Timothy P. Cripe, and E. Antonio Chiocca http://jci.me/80713

Lymphangiogenesis improves lung transplantation in micelung transplantation requires surgical reestablishment of airway, arterial, and venous connections; however, due to technical challenges, lymphatic vessels are not surgically reconnected, and the role of the lymphatic vasculature in transplant survival is unclear. Using a murine model of lung transplantation, Ye Cui and colleagues observed that rejected lung allografts are characterized by a decrease in lymphatic vessel density and the accumulation of hyaluronan (HA). Stimulation of lymphangiogenesis with VEGF-C abrogated the rejection response and improved the clearance of HA in mice. HA clearance was also associated with the resolution of acute graft rejection in human lung transplant recipients (see the accompanying image). In the related Commentary, Mark Kahn and colleagues discuss how lymphatic-mediated removal of HA improves graft survival after lung transplantation.

Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejectionYe Cui, Kaifeng Liu, Maria E. Monzon-Medina, Robert F. Padera, Hao Wang, Gautam George, Demet Toprak, Elie Abdelnour, Emmanuel D’Agostino, Hilary J. Goldberg, Mark A. Perrella, Rosanna Malbran Forteza, Ivan O. Rosas, Gary Visner, and Souheil El-Chemaly http://jci.me/79693

Related CommentaryHA-ving lymphatics improves lung transplantationJonathan S. Maltzman, Hasina Outtz Reed, and Mark L. Kahn http://jci.me/84549

transplantation






Disrupted WNT signaling underlies smoking-related fetal growth restriction


reproductive biology

A DART hits latently HIV-infected cells

even though antiretroviral therapy can suppress hiV to undetectable levels, the virus persists in latently infected resting CD4+ T cells, which are not recognized and eliminated by the immune system; thus, HIV eradication will likely require enhancement of HIV-specific immunity. Researchers led by Guido

aids/hiv

Ferrari, Barton Haynes, Scott Koenig, and David Margolis designed antibody-based Dual-Affinity Re-Targeting proteins (DARTs) that bind both the HIV-1 Env protein and the CD3 subunit of the T cell receptor of cytolytic lymphocytes (HIVxCD3 DARTs), specifically redirecting T cells to engage and kill HIV-infected cells (see the accompanying image). HIVxCD3 DARTs mediated clearance by CD8+ T cells of both CD4+ T cells from seronegative donors that were infected with autologous reservoir viruses isolated from resting CD4+ T cells and latently infected CD4+ T cells that had been treated to induce latent virus expression. These data demonstrate that DART proteins could be used to enable T cells to clear the latent viral reservoir.

Dual-Affinity Re-Targeting proteins direct T cell–mediated cytolysis of latently HIV-infected cellsJulia A.M. Sung, Joy Pickeral, Liqin Liu, Sherry A. Stanfield-Oakley, Chia-Ying Kao Lam, Carolina Garrido, Justin Pollara, Celia LaBranche, Mattia Bonsignori, M. Anthony Moody, Yinhua Yang, Robert Parks, Nancie Archin, Brigitte Allard, Jennifer Kirchherr, JoAnn D. Kuruc, Cynthia L. Gay, Myron S. Cohen, Christina Ochsenbauer, Kelly Soderberg, Hua-Xin Liao, David Montefiori, Paul Moore, Syd Johnson, Scott Koenig, Barton F. Haynes, Jeffrey L. Nordstrom, David M. Margolis, and Guido Ferrari http://jci.me/82314

Maternal cigarette smoking during pregnancy is a common cause of fetal growth restriction (FGR). Alice Wang and col-leagues performed transcriptional profiling of placentas from smoking mothers to identify the molecular mechanisms linking cigarette smoke and FGR. They found that levels of the WNT signaling antagonist secreted frizzled-related protein 1 (sFRP1) were markedly upregulated in placentas of smoking mothers compared with those of nonsmoker mothers (see the accompanying image). Administra-tion of exogenous sFRP1 in mice induced FGR and nuclear fragmentation in the uterine junctional zone and decreased trophoblast proliferation. Treatment of a human

trophoblast cell line with the carbon monoxide analog CO-RM2 increased sFRP1 expression and suppressed WNT signaling, leading to decreased proliferation. Taken together, these data demonstrate that disrupted WNT signaling underlies smoking-related FGR.

Excess placental secreted frizzled-related protein 1 in maternal smokers impairs fetal growthAlice Wang, Zsuzsanna K. Zsengellér, Jonathan L. Hecht, Roberto Buccafusca, Suzanne D. Burke, Augustine Rajakumar, Emily Weingart, Paul B. Yu, Saira Salahuddin, and S. Ananth Karumanchi http://jci.me/80457




Loss of miR-30 enhances calcineurin signaling and promotes podocyte injuryPodocyte injury is a central feature of glomerular disease, but the underlying mechanisms are poorly understood. Junnan Wu, Chunxia Zheng, and colleagues found that the miR-30 microRNA family is downregulated in a rat model of purine aminonucleo-side nephropathy (PAN) and in patients with focal segmental glomerulosclerosis. Loss of miR-30 increased expression of multiple components of the calcium/calcineurin signaling pathway, including the transient receptor potential cation channel 6 (TRPC6); the calcineurin subunits PPP3CA, PPP3CB, and PPP3R1; and the transcription factor NFATC3. Increased expression of these proteins increased intracellular calcium levels and calcineurin activity, leading to podocyte cytoskeletal damage and dysfunction. The calcineurin inhibitor FK506 attenuated podocyte damage (see the accompanying image), indicating that the calcineurin pathway may be a suitable therapeutic target for the prevention of podocyte injury.

MicroRNA-30 family members regulate calcium/calcineurin signaling in podocytesJunnan Wu, Chunxia Zheng, Xiao Wang, Shifeng Yun, Yue Zhao, Lin Liu, Yuqiu Lu, Yuting Ye, Xiaodong Zhu, Changming Zhang, Shaolin Shi, and Zhihong Liu http://jci.me/81061


Hematopoietic prostaglandins maintain homeostasis in response to dietary salt

experimental and epidemiological evidence has linked alterations in the COX/prostaglandin system to salt-sensitive hypertension. Ming-Zhi Zhang and colleagues observed that high-salt treatment of WT mice increased the expression of COX-2 and prostaglandin E synthase–1 (PGES-1) in kidney-resident macro-phages. Transplantation of bone marrow from Cox2–/– or Pges1–/– mice into WT mice or macrophage-specific deletion of the prostaglandin E2 type 4 receptor (EP4) resulted in salt-sensitive hypertension, increased phosphorylation of the renal sodium chloride cotransporter (NCC), and enhanced immune cell infiltration and inflammatory cytokines in kidney compared with those of mice with WT macrophages. Salt deposition in the skin is associated with salt-sensitive hyperten-sion, and Zhang and colleagues found that mice with genetic or pharmacologic COX-2 inhibition exhibited increased skin sodium content, abnormal lymphangio-genesis (see the accompanying image), and decreased lymphatic flow. In the accompanying Commentary, Johannes Stegbauer and Thomas Coffman discuss how these studies identify a role for the hematopoietic COX-2/prostaglandin system in salt-sensitive hypertension.

Inhibition of cyclooxygenase-2 in hematopoietic cells results in salt-sensitive hypertensionMing-Zhi Zhang, Bing Yao, Yinqiu Wang, Shilin Yang, Suwan Wang, Xiaofeng Fan, and Raymond C. Harris http://jci.me/81550

Related CommentarySkin tight: macrophage-specific COX-2 induction links salt handling in kidney and skinJohannes Stegbauer and Thomas M. Coffman http://jci.me/84753

nephrology





Features

Oliver Smithies

Naughty by nature: creating incentives for research integrityin this month’s issue of the JCI, behavioral economists Nina Mazar and Dan Ariely take a fascinating look at dishonesty as part of the human condition and provide their perspective on how this influences integrity in preclinical and clinical research. Their Op-Ed describes their own studies on motivated reasoning and conflict of interest and suggests how their findings can be extrap-olated to the choices faced by biomedical research investigators. They discuss a multipronged strategy to promote a culture of research integrity, including straightforward changes to the education of students and postdocs, implemen-tation of regular moral reminders, and more substantive changes to the rewards given by institutions and grant agencies that can inadvertently drive dishonest research practices.

Dishonesty in scientific researchNina Mazar and Dan Ariely http://jci.me/84722

conversations with giants in medicine

op-ed

oliver smithies of the university of north Carolina at Chapel hill was awarded the 2007 Nobel Prize in Physiology or Medicine for pioneering homologous recombination of transgenic DNA, which allowed for the creation of knockout and transgenic mice. Smithies’s lab created the first murine models of cystic fibrosis. He has also identified genetic factors involved in heart disease, atherosclerosis, and other disorders. In an interview with JCI Editor-at-Large

Ushma Neill, Dr. Smithies discusses his early interest in science, including his propensity for tinkering, the invention of starch gel electrophoresis, and his first molecular genetic studies of haptoglobin. Smithies also describes the three-year development of his protocol for genetic transformation of human cells, his feelings on winning the Nobel Prize, and his admiration for Johann Sebastian Bach.

http://jci.me/84087



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