jci.org/impact NOVEMBER 2014 ALSO IN THIS ISSUE: Mutations in cerebral small-vessel disease 7 Prime-boost vaccine strategies for HIV 8 Ibrutinib for chronic graft-versus-host disease 9 Calcium silencing in atrial fibrillation 11 A summary of this month’s Journal of Clinical Investigation Coronary artery stem formation p. 6 Image credit: Shutterstock Inc. Copyright: Elena Schweitzer Scan with your mobile device for the digital version of JCI Impact.
Transcript
jci.org/impactNovember 2014
Also in this issue:
Mutations in cerebral small-vessel disease 7
Prime-boost vaccine strategies for HIV 8
Ibrutinib for chronic graft-versus-host disease 9
Calcium silencing in atrial fibrillation 11
A summary of this month’s Journal of Clinical investigation
Coronary artery stem formationp. 6
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Scan with your mobile device for the digital version of JCI Impact.
Journal of Clinical Investigation Consulting Editors
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 / i m p a c t N o v 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
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 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.
ImpactNovember 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
Thomas Coffman, m.D., Associate editor, is the James R. Clapp Professor of Medicine, Chief of the Division of Nephrology, Senior Vice-Chair in the Department of Medicine, and Founding Director of the Duke Cardiovascular and Meta-bolic Disorder Program at Duke University Medical Center. He also serves as Director of the Cardiovascular and Metabolic Disorders Research Program and Executive Vice Dean at the Duke-NUS Graduate Medical School in Singapore. A national leader in the field of nephrology, Dr. Coffman is past president of the American Society of Nephrology, a mem-
ber of the American Society for Clinical Investigation and the Association of American Physicians, and has served on the Nephrology Subspecialty Board of the American Board of Internal Medicine. His research interests include the renin-angiotensin and prostanoid systems and their role in regulating blood pressure, kidney function, and renal inflammation.
Publication highlights
Crowley SD, Gurley SB, Oliverio MI, Pazmino AK, Griffiths R, Flannery PJ, Spurney RF, Kim H-S, Smithies O, Le TH, Coffman TM. Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J Clin Invest. 2005;115(4):1092–1099.
Gurley SB, Riquier ADM, Schnermann J, Sparks MA, Allen AM, Haase VH, Snouwaert JN, Le TH, McDonough AA, Koller BH, Coffman TM. AT1A angiotensin receptors in the renal proximal tubule regulate blood pressure. Cell Metab. 2011;13(4):469–475.
Crowley SD, Coffman TM. The inextricable role of the kidney in hypertension. J Clin Invest. 2014;124(6):2341–2347.
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AIDS/HIVHIV-specific humoral responses benefit from stronger prime in phase Ib clinical trialPierre-Alexandre Bart, Yunda Huang, Shelly T. Karuna, Samuel Chappuis, Julien Gaillard, Nidhi Kochar, Xiaoying Shen, Mary A. Allen, Song Ding, John Hural, Hua-Xin Liao, Barton F. Haynes, Barney S. Graham, Peter B. Gilbert, M. Juliana McElrath, David C. Montefiori, Georgia D. Tomaras, Giuseppe Pantaleo, and Nicole Frahm http://jci.me/75894
more, p. 8
Bone biologyRBP-J imposes a requirement for ITAM-mediated costimulation of osteoclastogenesisSusan Li, Christine H. Miller, Eugenia Giannopoulou, Xiaoyu Hu, Lionel B. Ivashkiv, and Baohong Zhao http://jci.me/71882
CardiologyTachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytesMaura Greiser, Benoît-Gilles Kerfant, George S.B. Williams, Niels Voigt, Erik Harks, Katharine M. Dibb, Anne Giese, Janos Meszaros, Sander Verheule, Ursula Ravens, Maurits A. Allessie, James S. Gammie, Jolanda van der Velden, W. Jonathan Lederer, Dobromir Dobrev, and Ulrich Schotten http://jci.me/70102
With related Commentary by Nieves Gomez-Hurtado and Björn C. Knollmann more, p. 11
PCP4 regulates Purkinje cell excitability and cardiac rhythmicityEugene E. Kim, Akshay Shekhar, Jia Lu, Xianming Lin, Fang-Yu Liu, Jie Zhang, Mario Delmar, and Glenn I. Fishman http://jci.me/77495
Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathyRongxue Wu, Hsiang-Chun Chang, Arineh Khechaduri, Kusum Chawla, Minh Tran, Xiaomeng Chai, Cory Wagg, Mohsen Ghanefar, Xinghang Jiang, Marina Bayeva, Frank Gonzalez, Gary Lopaschuk, and Hossein Ardehali http://jci.me/76737
EndocrinologyEnergy homeostasis targets chromosomal reconfiguration of the human GH1 locusHana Vakili, Yan Jin, and Peter A. Cattini http://jci.me/77126
more, p. 8
GeneticsAbolished InsP3R2 function inhibits sweat secretion in both humans and miceJoakim Klar, Chihiro Hisatsune, Shahid M. Baig, Muhammad Tariq, Anna C.V. Johansson, Mahmood Rasool, Naveed Altaf Malik, Adam Ameur, Kotomi Sugiura, Lars Feuk, Katsuhiko Mikoshiba, and Niklas Dahl http://jci.me/70720
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HematologyPleiotrophin mediates hematopoietic regeneration via activation of RASHeather A. Himburg, Xiao Yan, Phuong L. Doan, Mamle Quarmyne, Eva Micewicz, William McBride, Nelson J. Chao, Dennis J. Slamon, and John P. Chute http://jci.me/76838
HepatologyEngrafted human stem cell–derived hepatocytes establish an infectious HCV murine modelArnaud Carpentier, Abeba Tesfaye, Virginia Chu, Ila Nimgaonkar, Fang Zhang, Seung Bum Lee, Snorri S. Thorgeirsson, Stephen M. Feinstone, and T. Jake Liang http://jci.me/75456
ImmunologyMacrophages sense and kill bacteria through carbon monoxide–dependent inflammasome activationBarbara Wegiel, Rasmus Larsen, David Gallo, Beek Yoke Chin, Clair Harris, Praveen Mannam, Elzbieta Kaczmarek, Patty J. Lee, Brian S. Zuckerbraun, Richard Flavell, Miguel P. Soares, and Leo E. Otterbein http://jci.me/72853
TACI deficiency enhances antibody avidity and clearance of an intestinal pathogenShoichiro Tsuji, Lucas Stein, Nobuhiko Kamada, Gabriel Nuñez, Richard Bram, Bruce A. Valance, Ana E. Sousa, Jeffrey L. Platt, and Marilia Cascalho http://jci.me/74428
Ibrutinib treatment ameliorates murine chronic graft-versus-host diseaseJason A. Dubovsky, Ryan Flynn, Jing Du, Bonnie K. Harrington, Yiming Zhong, Benjamin Kaffenberger, Carrie Yang, William H. Towns, Amy Lehman, Amy J. Johnson, Natarajan Muthusamy, Steven M. Devine, Samantha Jaglowski, Jonathan S. Serody, William J. Murphy, David H. Munn, Leo Luznik, Geoffrey R. Hill, Henry K. Wong, Kelli K.P. MacDonald, Ivan Maillard, John Koreth, Laurence Elias, Corey Cutler, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz, Angela Panoskaltsis-Mortari, John C. Byrd, and Bruce R. Blazar http://jci.me/75328 More, p. 9Skin exposure promotes a Th2-dependent sensitization to peanut allergensLeticia Tordesillas, Ritobrata Goswami, Sara Benedé, Galina Grishina, David Dunkin, Kirsi M. Järvinen, Soheila J. Maleki, Hugh A. Sampson, and M. Cecilia Berin http://jci.me/75660 More, p. 9Neuropilin-1 mediates myeloid cell chemoattraction and influences retinal neuroimmune crosstalkAgnieszka Dejda, Gaelle Mawambo, Agustin Cerani, Khalil Miloudi, Zhuo Shao, Jean-Francois Daudelin, Salix Boulet, Malika Oubaha, Felix Beaudoin, Naoufal Akla, Sullivan Henriques, Catherine Menard, Andreas Stahl, Jean-Sébastien Delisle, Flavio A. Rezende, Nathalie Labrecque, and Przemyslaw Sapieha http://jci.me/76492
MetabolismLong–echo time MR spectroscopy for skeletal muscle acetylcarnitine detectionLucas Lindeboom, Christine I. Nabuurs, Joris Hoeks, Bram Brouwers, Esther Phielix, M. Eline Kooi, Matthijs K.C. Hesselink, Joachim E. Wildberger, Robert D. Stevens, Timothy Koves, Deborah M. Muoio, Patrick Schrauwen, and Vera B. Schrauwen-Hinderling http://jci.me/74830
Muscle biologyLeiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathyMichaela Yuen, Sarah A. Sandaradura, James J. Dowling, Alla S. Kostyukova, Natalia Moroz, Kate G. Quinlan, Vilma-Lotta Lehtokari, Gianina Ravenscroft, Emily J. Todd, Ozge Ceyhan-Birsoy, David S. Gokhin, Jérome Maluenda, Monkol Lek, Flora Nolent, Christopher T. Pappas, Stefanie M. Novak, Adele D’Amico, Edoardo Malfatti, Brett P. Thomas, Stacey B. Gabriel, Namrata Gupta, Mark J. Daly, Biljana Ilkovski, Peter J. Houweling, Ann E. Davidson, Lindsay C. Swanson, Catherine A. Brownstein, Vandana A. Gupta, Livija Medne, Patrick Shannon, Nicole Martin, David P. Bick, Anders Flisberg, Eva Holmberg, Peter Van den Bergh, Pablo Lapunzina, Leigh B. Waddell, Darcée D. Sloboda, Enrico Bertini, David Chitayat, William R. Telfer, Annie Laquerrière, Carol C. Gregorio, Coen A.C. Ottenheijm, Carsten G. Bönnemann, Katarina Pelin, Alan H. Beggs, Yukiko K. Hayashi, Norma B. Romero, Nigel G. Laing, Ichizo Nishino, Carina Wallgren-Pettersson, Judith Melki, Velia M. Fowler, Daniel G. MacArthur, Kathryn N. North, and Nigel F. Clarke http://jci.me/75199
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NephrologyTRPM2 mediates ischemic kidney injury and oxidant stress through RAC1Guofeng Gao, Weiwei Wang, Raghu K. Tadagavadi, Nicole E. Briley, Michael I. Love, Barbara A. Miller, and W. Brian Reeves http://jci.me/76042
Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3James A. McCormick, Chao-Ling Yang, Chong Zhang, Brittney Davidge, Katharina I. Blankenstein, Andrew S. Terker, Bethzaida Yarbrough, Nicholas P. Meermeier, Hae J. Park, Belinda McCully, Mark West, Aljona Borschewski, Nina Himmerkus, Markus Bleich, Sebastian Bachmann, Kerim Mutig, Eduardo R. Argaiz, Gerardo Gamba, Jeffrey D. Singer, and David H. Ellison http://jci.me/76126
More, p. 12
NeuroscienceCholestenoic acids regulate motor neuron survival via liver X receptorsSpyridon Theofilopoulos, William J. Griffiths, Peter J. Crick, Shanzheng Yang, Anna Meljon, Michael Ogundare, Satish Srinivas Kitambi, Andrew Lockhart, Karin Tuschl, Peter T. Clayton, Andrew A. Morris, Adelaida Martinez, M. Ashwin Reddy, Andrea Martinuzzi, Maria T. Bassi, Akira Honda, Tatsuki Mizuochi, Akihiko Kimura, Hiroshi Nittono, Giuseppe De Michele, Rosa Carbone, Chiara Criscuolo, Joyce L. Yau, Jonathan R. Seckl, Rebecca Schüle, Ludger Schöls, Andreas W. Sailer, Jens Kuhle, Matthew J. Fraidakis, Jan-Åke Gustafsson, Knut R. Steffensen, Ingemar Björkhem, Patrik Ernfors, Jan Sjövall, Ernest Arenas, and Yuqin Wang http://jci.me/68506
More, p. 12
Axonally derived matrilin-2 induces proinflammatory responses that exacerbate autoimmune neuroinflammationAnna Jonas, Stefan Thiem, Tanja Kuhlmann, Raimund Wagener, Attila Aszodi, Cameron Nowell, Karin Hagemeier, Louise Laverick, Victoria Perreau, Vilija Jokubaitis, Ben Emery, Trevor Kilpatrick, Helmut Butzkueven, and Melissa Gresle http://jci.me/71385
Cytokine therapy reverses NK cell anergy in MHC-deficient tumorsMichele Ardolino, Camillia S. Azimi, Alexandre Iannello, Troy N. Trevino, Lucas Horan, Lily Zhang, Weiwen Deng, Aaron M. Ring, Suzanne Fischer, K. Christopher Garcia, and David H. Raulet http://jci.me/74337With related Commentary by Laurence Zitvogel and Guido Kroemer More, p. 10
Efferocytosis produces a prometastatic landscape during postpartum mammary gland involutionJamie C. Stanford, Christian Young, Donna Hicks, Philip Owens, Andrew Williams, David B. Vaught, Meghan M. Morrison, Jiyeon Lim, Michelle Williams, Dana M. Brantley-Sieders, Justin M. Balko, Debra Tonetti, H. Shelton Earp III, and Rebecca S. Cook http://jci.me/76375
IER3 supports KRASG12D-dependent pancreatic cancer development by sustaining ERK1/2 phosphorylationMaria Noé Garcia, Daniel Grasso, Maria Belen Lopez-Millan, Tewfik Hamidi, Celine Loncle, Richard Tomasini, Gwen Lomberk, Françoise Porteu, Raul Urrutia, and Juan L. Iovanna http://jci.me/76037
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Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancerJun Qin, Hui-Ju Lee, San-Pin Wu, Shih-Chieh Lin, Rainer B. Lanz, Chad J. Creighton, Francesco J. DeMayo, Sophia Y. Tsai, and Ming-Jer Tsai http://jci.me/76412
BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemiaNiuscha Yaktapour, Frank Meiss, Justin Mastroianni, Thorsten Zenz, Hana Andrlova, Nimitha R. Mathew, Rainer Claus, Barbara Hutter, Stefan Fröhling, Benedikt Brors, Dietmar Pfeifer, Milena Pantic, Ingrid Bartsch, Timo S. Spehl, Philipp T. Meyer, Justus Duyster, Katja Zirlik, Tilman Brummer, and Robert Zeiser http://jci.me/76539
With related Attending Physician by Catherine J. Wu More, p. 10
Chronic allergic contact dermatitis promotes skin cancerShadmehr Demehri, Trevor J. Cunningham, Eva A. Hurst, Andras Schaffer, David M. Sheinbein, and Wayne M. Yokoyama http://jci.me/77843
Reproductive biologyEndometrial VEGF induces placental sFLT1 and leads to pregnancy complicationsXiujun Fan, Anshita Rai, Neeraja Kambham, Joyce F. Sung, Nirbhai Singh, Matthew Petitt, Sabita Dhal, Rani Agrawal, Richard E. Sutton, Maurice L. Druzin, Sanjiv S. Gambhir, Balamurali K. Ambati, James C. Cross, and Nihar R. Nayak http://jci.me/76864
With related Commentary by S. Lee Adamson More, p. 11
Vascular biologyPellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitinationHye-Young Park, Heounjeong Go, Ha Rim Song, Suhyeon Kim, Geun-Hyoung Ha, Yoon-Kyung Jeon, Ji-Eun Kim, Ho Lee, Hyeseong Cho, Ho Chul Kang, Hee-Young Chung, Chul-Woo Kim, Doo Hyun Chung, and Chang-Woo Lee http://jci.me/75667
Mutation of FOXC1 and PITX2 induces cerebral small-vessel diseaseCurtis R. French, Sudha Seshadri, Anita L. Destefano, Myriam Fornage, Corey R. Arnold, Philip J. Gage, Jonathan M. Skarie, William B. Dobyns, Kathleen J. Millen, Ting Liu, William Dietz, Tsutomu Kume, Marten Hofker, Derek J. Emery, Sarah J. Childs, Andrew J. Waskiewicz, and Ordan J. Lehmann http://jci.me/75109 More, p. 7
VEGF-C and aortic cardiomyocytes guide coronary artery stem developmentHeidi I. Chen, Aruna Poduri, Harri Numi, Riikka Kivela, Pipsa Saharinen, Andrew S. McKay, Brian Raftrey, Jared Churko, Xueying Tian, Bin Zhou, Joseph C. Wu, Kari Alitalo, and Kristy Red-Horse http://jci.me/77483 More, p. 6
Erythrocyte-derived sphingosine 1-phosphate is essential for vascular developmentYuquan Xiong, Peiying Yang, Richard L. Proia, and Timothy Hla http://jci.me/77685 More, p. 7
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The heart functions to deliver blood through-out the body, yet cardiac tissue itself must have an adequate supply of oxygenated blood. Two coronary artery stems on the aorta are re-sponsible for supplying blood to the ventricu-lar myocardium. These coronary artery stems must be precisely located, and defects in pat-terning can lead to sudden death in infants. In this issue, Kristy Red-Horse and colleagues explore the factors in the outflow tract and aorta that determine the proper positioning of coronary artery stems. They found that the angiogenic factor VEGF-C is highly enriched around the outflow tract and mice deficient in VEGF-C did not complete the initial step in coronary stem formation, the development of peritruncal vessels. In the absence of peritrun-cal vessels, misplaced compensatory coronary artery stems often formed. Red-Horse and colleagues further showed that, while required for coronary artery stem formation, VEGF-C was not restricted to the regions of the aorta in which coronary artery stems develop, sug-gesting that its signaling did not determine the placement of the vessels. Instead, they demonstrated that cardiomyocytes were spe-cifically present in the aortic wall surround-ing the nascent stem and mice with a genetic mutation that decreases the number of aortic cardiomyocytes displayed defects in the placement of stems. Cumulatively, their work indicates that VEGF-C is required to establish vessels around the outflow tract and that positioning of the coronary artery stems is regulated by angiogenic cardiomyocytes. The accompanying image shows an embryonic day 14.5 murine heart immunostained for PROX1 (yellow), VE-cadherin (cyan), and cTnT (red).
VEGF-C and aortic cardiomyocytes guide coronary artery stem developmentHeidi I. Chen, Aruna Poduri, Harri Numi, Riikka Kivela, Pipsa Saharinen, Andrew S. McKay, Brian Raftrey, Jared Churko, Xueying Tian, Bin Zhou, Joseph C. Wu, Kari Alitalo, and Kristy Red-Horse http://jci.me/77483
A heart connection: determinants of coronary artery stem formation
Editor’s picksresearch
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Research | Editor’s picks
Cerebral small-vessel disease (CsVD) is a key risk factor that substantially increases stroke prevalence. In this issue, Curtis French and colleagues integrate human genetics and model organism analyses to implicate two pediatric glaucoma–causing genes in CSVD. Strikingly, patients with mutations in the forkhead transcription factor FOXC1 displayed MRI features of CSVD as early as 1 year of age and either overexpression or repression of foxc1-induced cerebral hemorrhage in a zebrafish model. Mechanistically, loss of foxc1 resulted in reduced PDGF signaling, impairing the migration of neural crest cells and recruitment of mural cells, which are essential for vascular stability. Additionally, perturbed function of PITX2, a FOXC1-interacting transcription factor, resulted in comparable phenotypes in patients and zebrafish mutants (see the accompanying image).
These studies define new pathways that contribute to cerebrovascular disease and offer insight into mechanisms contributing to declining visual function in pediatric glaucoma.
mutation of FOXC1 and PITX2 induces cerebral small-vessel diseaseCurtis R. French, Sudha Seshadri, Anita L. Destefano, Myriam Fornage, Corey R. Arnold, Philip J. Gage, Jonathan M. Skarie, William B. Dobyns, Kathleen J. Millen, Ting Liu, William Dietz, Tsutomu Kume, Marten Hofker, Derek J. Emery, Sarah J. Childs, Andrew J. Waskiewicz, and Ordan J. Lehmann http://jci.me/75109
Embryonic vascular development requires erythrocyte-derived sphingosine 1-phosphate sphingosine 1-phosphate (s1P) is a bioactive phospholipid that is required for development of the embryonic vasculature; however, the source of embryonic S1P is unknown. Because rbc are required for embryogenesis and their dysfunction underlies adult vascular abnormalities, Yuquan Xiong and colleagues hypothesized that rbc are a source of embryonic S1P. They found that mice with rbc-specific deletion of sphingosine kinases 1 and 2 (Sphk1 and Sphk2) died between E11.5 and 12.5 due to vascular defects (see the accompanying image). This defect was rescued by administration of an S1P1 receptor agonist to pregnant dams. Notably, Sphk1/2 deficiency did not impair erythrocyte differentiation, nor did it cause other rbc defects, indicating that the vascular defects were due to the loss of S1P. These findings identify a previously unrecognized role for erythrocytes in embryonic development.
erythrocyte-derived sphingosine 1-phosphate is essential for vascular developmentYuquan Xiong, Peiying Yang, Richard L. Proia, and Timothy Hla http://jci.me/77685
vascular biology
Identification of mutations underlying cerebral small-vessel disease
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Research | Editor’s picks
endocrinologypulmonology
Airway contractility is attenuated by the molecular scaffold IQGAP1
Asthma is characterized by airway smooth muscle hypercontractility, which leads to narrowing of the airways and breathing difficulties. Mallar Bhattacharya, Aparna Sundaram, and colleagues report a role for the intracellular scaffold protein IQGAP1 in airway contractility. Airway biopsies from patients with asthma had decreased IQGAP1 expression. Furthermore, IQGAP1-deficient mice exhibited greater airway responsiveness and increased agonist-induced contractile force within tracheal rings compared with WT controls. RhoA, which inactivates myosin light chain phosphatase to drive contraction, was active in airway smooth muscle cells from IQGAP1-deficient mice. Using human primary airway smooth muscle cells and murine trachea, Bhattacharya and colleagues showed that IQGAP1 mediates colocalization of
RhoA and its negative regulator p190A-RhoGAP. Thus, IQGAP1 serves as a brake on RhoA signaling to attenuate airway smooth muscle contraction. The accompanying image shows proximity ligation of RhoA and p190A-RhoGAP (green) in WT and Iqgap1–/– murine trachea.
Closing the loop on growth hormone production and energy homeostasisPlasma levels of pituitary growth hormone (Gh), a metabolic homeostatic factor that has strong lipolytic activity, decreases in response to excess caloric intake and hyperinsulinemia, prior to the onset of obesity. Hana Vakili and colleagues used transgenic mice expressing the human GH gene (GH1) to show that synthesis, like secretion, is affected by high caloric intake. GH1 expression is dependent on a long-range intrachromosomal interaction between remote enhancer and proximal promoter regions through looping out of intervening DNA. The authors found that high caloric intake disrupted this structure, leading to decreased recruitment of RNA polymerase and GH production. These effects were reversed by increased physical activity. These findings may offer insight into the limited effectiveness of GH secretagogues in some cases of obesity.
Energy homeostasis targets chromosomal reconfiguration of the human GH1 locusHana Vakili, Yan Jin, and Peter A. Cattini http://jci.me/77126
aids/hiv
Clinical trial measures HIV-specific immune responses to prime-boost immunization strategiesRecent hiV vaccination strategies have focused on the use of viral vector–based vaccines, which can induce both cellular and humoral responses. Many of these vaccines are given in a prime-boost regimen using a single vaccine vector. The efficacy of a prime-boost HIV vaccine regimen could potentially be improved by the use of two different viral vectors. Nicole Frahm and colleagues conducted a clinical trial in 80 subjects to assess the effects of priming dose and administration order of two previously
tested HIV vaccine vectors: vaccinia-based NYVAC-B and adenoviral-based rAd5. They found that an rAd5 prime dose followed by an NYVAC-B boost was superior to the reverse administration order for inducing cellular and humoral immune responses. These data indicate that future HIV vaccine trials should optimize heterologous prime-boost immunization strategies.
HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trialPierre-Alexandre Bart, Yunda Huang, Shelly T. Karuna, Samuel Chappuis, Julien Gaillard, Nidhi Kochar, Xiaoying Shen, Mary A. Allen, Song Ding, John Hural, Hua-Xin Liao, Barton F. Haynes, Barney S. Graham, Peter B. Gilbert, M. Juliana McElrath, David C. Montefiori, Georgia D. Tomaras, Giuseppe Pantaleo, and Nicole Frahm http://jci.me/75894
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Research | Editor’s picks
immunology
Skin exposure to peanut extract induces allergy in micePeanut allergy is the most common cause of food-induced anaphylaxis. Allergic reactions to peanuts can manifest in children without any previous oral exposure, suggesting that other routes of exposure may drive sensitization. In this issue, Cecilia Berin and colleagues report that epicutaneous exposure to a crude peanut extract can induce peanut allergy in mice. After 6 weeks of topical application of this extract, mice had robust IgE and IgG1 responses and intraperitoneal exposure caused severe anaphylaxis. Additionally, exposure to peanut allergens enhanced cytokine expression in isolated human keratinocytes and murine skin in vivo and modified dendritic cells to induce a Th2-biased T cell response. Although other allergens typically require some form of adjuvant to induce sensitization through the skin, sensitization to peanut allergens occurred independent of adjuvant. These results support the hypothesis that environmental exposure to peanut could promote sensitization.
Skin exposure promotes a Th2-dependent sensitization to peanut allergensLeticia Tordesillas, Ritobrata Goswami, Sara Benedé, Galina Grishina, David Dunkin, Kirsi M. Järvinen, Soheila J. Maleki, Hugh A. Sampson, and M. Cecilia Berin http://jci.me/75660
Anti-cancer drug ibrutinib ameliorates murine chronic graft-versus-host disease Chronic graft-versus-host disease (cGVhD) is a frequent, life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). cGVHD is mediated by CD4+ T cells and B cells, leading Jason Dubovsky, Ryan Flynn, and colleagues to hypothesize that pharmacological inhibition of these cell types could potentially reverse the disease. Dubovsky and colleagues tested the effects of ibrutinib, an FDA-approved inhibitor of Bruton’s tyrosine kinase (BTK) and IL-2 inducible T cell kinase (ITK), in two murine models of established cGVHD. In a model of T cell–driven sclerodermatous cGVHD, ibrutinib treatment ameliorated scleroderma and skin manifestations (see the accompanying image) and delayed progression of cGVHD while improving survival. In a model of alloantibody-driven multi-organ system cGVHD that includes lung pathology, ibrutinib treatment improved pulmonary function and reduced B and T cell–driven germinal center responses. Consistent with ibrutinib effects in this model, cGVHD was reduced when using donor bone marrow deficient in BTK or donor T cells deficient in ITK. These results suggest that B and T cell–targeted therapeutics such as ibrutinib could potentially be used for the treatment of cGVHD.
Ibrutinib treatment ameliorates murine chronic graft-versus-host diseaseJason A. Dubovsky, Ryan Flynn, Jing Du, Bonnie K. Harrington, Yiming Zhong, Benjamin Kaffenberger, Carrie Yang, William H. Towns, Amy Lehman, Amy J. Johnson, Natarajan Muthusamy, Steven M. Devine, Samantha Jaglowski, Jonathan S. Serody, William J. Murphy, David H. Munn, Leo Luznik, Geoffrey R. Hill, Henry K. Wong, Kelli K.P. MacDonald, Ivan Maillard, John Koreth, Laurence Elias, Corey Cutler, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz, Angela Panoskaltsis-Mortari, John C. Byrd, and Bruce R. Blazar http://jci.me/75328
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Research | Editor’s picks
oncology
Cytokines rescue NK-mediated elimination of MHC class I–deficient cancer cellsnatural killer (nK) cells identify and eliminate infected or malignant cells based on their expression of MHC markers. In healthy individuals, cells that lose expression of MHC class I markers, which inactivate NK cells, are rapidly targeted for elimination. Paradoxically, cancer cells, which are frequently MHC class I deficient, can evade NK cell–mediated elimination. Using a murine model of lymphoma, Michele Ardolino and colleagues found that MHC class I–deficient cancer cells induce NK cell anergy, which was characterized by attenuation of early activation signals, degranulation, and cytokine production. Importantly, NK cell anergy could be reversed by administration of cytokines, including a combination of IL-12 and IL-18 or a mutant form of IL-2, which have previously shown some efficacy in human clinical trials. These results demonstrate that MHC class I–deficient cancer cells functionally inactivate NK cells to escape immune elimination. In the accompanying Commentary, Laurence Zitvogel and Guido Kroemer discuss how cytokines could potentially be used to promote immunosurveillance in patients with MHC class I–deficient tumors.
Cytokine therapy reverses NK cell anergy in MHC-deficient tumorsMichele Ardolino, Camillia S. Azimi, Alexandre Iannello, Troy N. Trevino, Lucas Horan, Lily Zhang, Weiwen Deng, Aaron M. Ring, Suzanne Fischer, K. Christopher Garcia, and David H. Raulet http://jci.me/74337
Related CommentaryCytokines reinstate NK cell–mediated cancer immunosurveillanceLaurence Zitvogel and Guido Kroemer http://jci.me/78531
BRAF inhibition drives development of chronic lymphocytic leukemiathe RAs/BRAF/MeK/eRK pathway mediates survival and growth in a number of cancers. The BRAF kinase inhibitor vemurafenib is used to disrupt this pathway in cancers with BRAF-activating mutations. In cells with WT BRAF and activating mutations of RAS, however, vemurafenib treatment drives ERK activation, which is associated with the development of secondary cancers. In this issue, Niuscha Yaktapour, Frank Meiss, and colleagues report on a patient who developed the B cell malignancy chronic lymphocytic leukemia (CLL) shortly after undergoing vemurafenib therapy for metastatic BRAF mutant melanoma. Yaktapour and colleagues demonstrate that, unlike in previously reported secondary cancer, vemurafenib-driven ERK activation was not due to activating RAS mutations. Additionally, CLL ERK activation and proliferation were dependent on B cell antigen receptor (BCR) and BCR-proximal spleen tyrosine kinase (SYK). ERK activation and proliferation of CLL cells exposed to vemurafenib were reversed by SYK or MEK inhibition (see the accompanying image). In the accompanying Attending Physician article, Catherine Wu discusses the implications of these findings for therapeutic approaches using vemurafenib.
BRAF inhibitor–associated ERK activation drives development of chronic lymphocytic leukemiaNiuscha Yaktapour, Frank Meiss, Justin Mastroianni, Thorsten Zenz, Hana Andrlova, Nimitha R. Mathew, Rainer Claus, Barbara Hutter, Stefan Fröhling, Benedikt Brors, Dietmar Pfeifer, Milena Pantic, Ingrid Bartsch, Timo S. Spehl, Philipp T. Meyer, Justus Duyster, Katja Zirlik, Tilman Brummer, and Robert Zeiser http://jci.me/76539
Related Attending PhysicianShifting ecologies of malignant and nonmalignant cells following BRAF inhibitionCatherine J. Wu http://jci.me/78783
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Research | Editor’s picks
Atrial fibrillation (AF) is the most common form of abnormal heart rhythm and is characterized by sustained high atrial activation rates and unstable intracellular Ca2+ signaling, which is thought to contribute to the initiation and maintenance of AF. To understand the relationship between high atrial activation and calcium signaling, Maura Greiser and colleagues characterized intracellular Ca2+ signaling in a rabbit model of AF. They identified an array of alterations in atrial calcium signaling, including a response the authors term “calcium signaling silencing,” in which high atrial activation rates reduce central cellular calcium release to reduce whole-cell calcium transients and induce coordinated changes in calcium cycling proteins such as ryanodine receptor 2 (RyR2; see the accompanying image) and calmodulin kinase II (CaMKII). These alterations help to counteract the calcium signaling instability brought on by high atrial activation rates. Importantly, these alterations were recapitulated in atrial myocytes isolated from patients with
persistent AF. In the accompanying Commentary, Nieves Gomez-Hurtado and Björn Knollmann discuss the potentially protective role of calcium signaling silencing in chronic AF.
Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytesMaura Greiser, Benoît-Gilles Kerfant, George S.B. Williams, Niels Voigt, Erik Harks, Katharine M. Dibb, Anne Giese, Janos Meszaros, Sander Verheule, Ursula Ravens, Maurits A. Allessie, James S. Gammie, Jolanda van der Velden, W. Jonathan Lederer, Dobromir Dobrev, and Ulrich Schotten http://jci.me/70102
Related CommentaryCalcium in atrial fibrillation — pulling the trigger or not?Nieves Gomez-Hurtado and Björn C. Knollmann http://jci.me/77986
cardiology
reproductive biology
Preeclampsia is associated with placental vascular defects and overproduction of the endogenous VEGF antagonist soluble fms-like tyrosine kinase-1 (sFLT1). Preeclamptic women have higher serum levels of sFLT1; however, it is unclear why sFLT1 is upregulated in the setting of preeclampsia. Using samples from normal and preeclamptic pregnancies, Xiujun Fan and colleagues observed that women with preeclampsia exhibited locally elevated levels of VEGF in the maternal decidua and increased sFLT1 expression in adjacent placental trophoblasts (see the accompanying image). Similarly, endometrial-specific overexpression of VEGF in mice resulted in pregnancy complications similar to those seen in preeclampsia, including placental vascular defects, maternal hypertension and proteinuria, pregnancy loss, and enhanced
expression of placental sFLT1. Loss of placental sFLT1 caused placental vascular defects and exacerbated the detrimental effects of endometrial VEGF overexpression. These results indicate that placental sFLT1 expression increases to counteract excess endometrial VEGF. In the accompanying Commentary, Lee Adamson discusses how these findings implicate maternal decidua in the pathology of preeclampsia.
Endometrial VEGF induces placental sFLT1 and leads to pregnancy complicationsXiujun Fan, Anshita Rai, Neeraja Kambham, Joyce F. Sung, Nirbhai Singh, Matthew Petitt, Sabita Dhal, Rani Agrawal, Richard E. Sutton, Maurice L. Druzin, Sanjiv S. Gambhir, Balamurali K. Ambati, James C. Cross, and Nihar R. Nayak http://jci.me/76864
Related CommentarysFLT1 in preeclampsia: trophoblast defense against a decidual VEGFA barrage?S. Lee Adamson http://jci.me/78532
Interplay between decidual VEGF and placental sFLT1 underlies pregnancy complications
Coordinated alterations in calcium signaling underlie atrial fibrillation
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Familial hyperkalemic hypertension (Fhht) is a rare monogenic disease that results from mutations in the kinases WNK1 and WNK4 or mutations in the ubiquitin ligase cullin 3 (CUL3) or the CUL3 substrate adaptor kelch-like 3 (KLHL3). These mutations are associated with increased WNK kinase activity and excessive thiazide-sensitive Na-Cl transporter (NCC) activity, resulting in kidney pathology. James McCormick, Chao-Ling Yang, and colleagues demonstrated that FHHt-causing mutant CUL3 (CUL3 Δ403–459) exhibits enhanced ubiquitin ligase activity, leading to KLHL3 degradation and a subsequent increase in WNK kinase abundance. Additionally, nephron-specific loss of Cul3 in adult mice resulted in increased expression of WNK kinases and NCC activity, as well as renal dysfunction, inflammation, and fibrosis. These data delineate the pathological mechanisms underlying FHHt-causing CUL3 mutations and demonstrate an essential role for CUL3 in the kidney.
Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3James A. McCormick, Chao-Ling Yang, Chong Zhang, Brittney Davidge, Katharina I. Blankenstein, Andrew S. Terker, Bethzaida Yarbrough, Nicholas P. Meermeier, Hae J. Park, Belinda McCully, Mark West, Aljona Borschewski, Nina Himmerkus, Markus Bleich, Sebastian Bachmann, Kerim Mutig, Eduardo R. Argaiz, Gerardo Gamba, Jeffrey D. Singer, and David H. Ellison http://jci.me/76126
Research | Editor’s picks
Differential effects of chole-stenoic acids on motor neuron survivalsome motor neuron diseases, including hereditary spastic paresis type 5 (SPG5) and cerebrotendinous xanthomatosis (CTX), are caused by mutations in enzymes involved in the metabolism of cholestenoic acids (CAs). Spyridon Theofilopoulos, William Griffiths, and colleagues found that patients with SPG5 or CTX had reduced levels of 3β,7α-dihydroxycholest-5-en-26-oic acid (3β,7α-diHCA) in CSF and plasma compared with healthy controls. Using cultured neural cells, Theofilopoulos and colleagues showed that CAs bind and activate liver X receptors (LXRs). Treatment of zebrafish with 3β,7α-diHCA activated LXRs and increased expression of islet-1, a transcription factor that is required for motor neuron development. Different CA species had differential, LXR-dependent effects on the maturation and survival of rodent oculomotor neurons. Importantly, CSF and plasma from SPG5 patients had elevated levels of toxic CAs, while CTX and SPG5 patients had reduced levels of prosurvival species, which indicates that composition of CA species in the CSF mediates the balance of motor neuron survival and death.
Cholestenoic acids regulate motor neuron survival via liver X receptorsSpyridon Theofilopoulos, William J. Griffiths, Peter J. Crick, Shanzheng Yang, Anna Meljon, Michael Ogundare, Satish Srinivas Kitambi, Andrew Lockhart, Karin Tuschl, Peter T. Clayton, Andrew A. Morris, Adelaida Martinez, M. Ashwin Reddy, Andrea Martinuzzi, Maria T. Bassi, Akira Honda, Tatsuki Mizuochi, Akihiko Kimura, Hiroshi Nittono, Giuseppe De Michele, Rosa Carbone, Chiara Criscuolo, Joyce L. Yau, Jonathan R. Seckl, Rebecca Schüle, Ludger Schöls, Andreas W. Sailer, Jens Kuhle, Matthew J. Fraidakis, Jan-Åke Gustafsson, Knut R. Steffensen, Ingemar Björkhem, Patrik Ernfors, Jan Sjövall, Ernest Arenas, and Yuqin Wang http://jci.me/68506
nephrology
neuroscience
Activation of the ubiquitin ligase cullin 3 underlies hyperkalemic hypertension
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Features
review
conversations with giants in medicinehindsight
Peter AgrePeter Agre was awarded the 2003 nobel Prize for the discovery of aquaporins. He is currently the director of the Johns Hopkins Malaria Research Institute. Agre became interested in biomedical research while attending medical school at Johns Hopkins University, where he worked in Pedro Cuatrecasas’ lab to purify the E. coli toxin. After completing clinical training at Case Western Reserve University and the University of North Carolina, Agre joined the faculty at Johns Hopkins University, where his research was focused on determining the molecular identity of the Rh blood group antigen. Aquaporin was discovered during the process of purifying Rh. In a wide-ranging interview with JCI Editor-at-Large Ushma Neill, Agre discusses the serendipitous discovery of aquaporin, the hazards of research focused on diarrheal diseases, future directions in malaria research, and the need for greater representation of science in government. http://jci.me/77973
An evolutionary approach to fibrosisFibrosis is a predominant feature in various diseases that are increasingly causing mortality and morbidity. Unfortunately, our current understanding of fibrotic processes is limited, and there are few effective therapeutic approaches. In this issue, Victor Thannickal and colleagues take an evolutionary approach to understanding fibrosis, examining why fibrosis evolved in multicellular organisms in order to better understand how the process causes disease in humans. Thannickal and colleagues posit that fibrosis is an evolutionarily conserved, adaptive process that helps defend against pathogens and promotes wound healing in response to epithelial injury. Importantly, pathological fibrosis is mediated by the same molecular and cellular mechanisms that are required for the beneficial effects of fibrosis, which suggests that the etiology may relate to host defense responses to an unidentified pathogen/antigen or autoimmunity, or alterations in regeneration and wound healing (see the accompanying image) brought on by aging, epigenetic or genetic alterations, or environmental challenges.
Fibrosis: ultimate and proximate causesVictor J. Thannickal, Yong Zhou, Amit Gaggar, and Steven R. Duncan http://jci.me/74368
Mechanisms of allergen-specific immune toleranceAllergen-specific immunotherapy (Ait), which involves administration of gradually increasing doses of a specific allergen, promotes long-term tolerance in individuals with allergic disease. In this issue, Cezmi Akdis and Mübeccel Akdis reflect on two studies they and their colleagues published in the JCI in the late 1990s that provided important insight into the molecular and cellular mechanisms of T cell tolerance to allergens. The first study demonstrated that AIT, with the major allergenic component of bee venom phospholipase A2 (PLA2), induces an allergen-specific T cell tolerance in patients with bee sting allergy and revealed that T cell tolerance could be altered by the presence of certain cytokines, suggesting that effector T cell populations have plasticity and respond to their microenvironment. Their second study identified a population of IL-10–producing Tregs (Tr1 cells) that are induced following PLA2-specific AIT. Subsequent studies have shown that Tr1 cells are important for the maintenance of a healthy immune response in different diseases, including allergy, autoimmune conditions, transplantation tolerance, and graft-versus-host disease.
Mechanisms of immune tolerance to allergens: role of IL-10 and Treg cellsCezmi A. Akdis and Mübeccel Akdis http://jci.me/78891
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