This Month

A vitamin D3 metabolite enables bone fracture repair 3 Neuroprotectin D1 and GPR37 resolve inflammatory pain 4 Bowman’s capsule insulates podocytes from immune injury 4 Microbiota-induced IgA averts opportunistic infection 5

August 2018 JCI This Month is a summary of the most recent articles in Film stars: The Journal of fibrin barriers obstruct Clinical Investigation and JCI Insight bacterial invasion p. 2 jci.org/this-month

Scan for the digital version of JCI This Month. Journal of Clinical Investigation Consulting Editors

Soman N. Abraham Richard T. D'Aquila Helen H. Hobbs Mitchell A. Lazar David J. Pinsky M. Celeste Simon John S. Adams Alan Daugherty Ronald Hoffman Brendan Lee Edward Plow Mihaela Skobe Qais Al-Awqati Sudhansu Dey V. Michael Holers William M.F. Lee Catherine Postic Donald Small Kari Alitalo Anna Mae Diehl Steven Holland Rudolph L. Leibel Alice S. Prince Lois Smith Dario C. Altieri Harry C. Dietz III David Holtzman Wayne I. Lencer Louis J. Ptacek Akrit Sodhi Masayuki Amagai Gianpietro Dotti Michael J. Holtzman Jon D. Levine Luigi Puglielli Weihong Song Brian H. Annex Michael Dustin Lawrence B. Holzman Ross L. Levine Pere Puigserver Ashley L. St. John M. Amin Arnaout Connie J. Eaves Maureen Horton Klaus Ley Bali Pulendran Jonathan Stamler Alan Attie Dominique Eladari Tamas L. Horvath Rodger A. Liddle Ellen Puré Colin L. Stewart Jane E. Aubin Joel K. Elmquist Gokhan S. Hotamisligil Richard Locksley Susan E. Quaggin Doris Stoffers Michael F. Beers Stephen G. Emerson Steven R. Houser Fanxin Long Marlene Rabinovitch Warren Strober Vann Bennett Jonathan A. Epstein Ralph H. Hruban Gary Lopaschuk Daniel J. Rader Maureen A. Su Gregory K. Bergey Adrian Erlebacher Christopher A. Hunter Nigel Mackman Shahin Rafii D. James Surmeier Nina Bhardwaj Joel D. Ernst David James Richard B. Mailman Gwendalyn J. Randolph Katalin Susztak Morris J. Birnbaum James M. Ervasti Richard J. Jones Rama K. Mallampalli Jeffrey C. Rathmell Catharina Svanborg Joyce Bischoff Robert V. Farese Jr. William G. Kaelin Jr. Kieren A. Marr W. Kimryn Rathmell Ira Tabas Craig Blackstone Eric R. Fearon Klaus Kaestner Jack Martin Barbara Rehermann Alan R. Tall Bruce R. Blazar Anthony W. Ferrante Jr. Mark L. Kahn Steven O. Marx Muredach P. Reilly Sakae Tanaka Gerard C. Blobe Edward A. Fisher Raghu Kalluri Rodger P. McEver Linda Resar Victor J. Thannickal William A. Boisvert Richard A. Flavell S. Ananth Karumanchi Elizabeth McNally Ryan Riddle Andrei Thomas-Tikhonenko Nancy Bonini Alessia Fornoni David A. Kass Cornelis J. Melief Sarah A. Robertson Georgia D. Tomaras Brendan Boyce Tatiana Foroud Robert S. Kass Shlomo Melmed Howard A. Rockman Peter Tontonoz Jonathan Bromberg Martin Friedlander Masato Kasuga George Michalopoulos Paul B. Rosenberg Laurence A. Turka Frank C. Brosius Stephen J. Galli Daniel P. Kelly Jeffrey H. Miner Theodora S. Ross Marcel R.M. van den Brink Hal E. Broxmeyer J. Victor Garcia-Martinez Dontscho Kerjaschki Peter J. Mohler Marc E. Rothenberg Luc Van Kaer Michael J. Caplan Alfred L. George Jr. Sundeep Khosla Jeffrey D. Molkentin Anil Rustgi David M. Virshup Diego H. Castrillon Stanton L. Gerson Richard N. Kitsis David D. Moore Scheherazade Sadegh-Nasseri Matthias von Herrath Harold Chapman Robert E. Gerszten Peter S. Klein Edward E. Morrisey J. Evan Sadler Kathryn R. Wagner Ajay Chawla Todd Golde Steven Kliewer James H. Morrissey Junichi Sadoshima Yisong Y. Wan Benjamin K. Chen Sherita Golden Björn C. Knollmann Deborah M. Muoio Jose-Alain Sahel Bart O. Williams Benny J. Chen Stanley Goldfarb Walter J. Koch Anthony J. Muslin Jean E. Schaffer Allan W. Wolkoff Ju Chen Larry B. Goldstein Jay K. Kolls Martin G. Myers Jr. Philipp E. Scherer Joseph C. Wu Jun Chen Fred Sanford Gorelick Issei Komuro Benjamin G. Neel Michael D. Schneider Thomas A. Wynn Marie-Françoise Chesselet Kathleen J. Green Christopher D. Kontos Paul W. Noble Detlef Schuppan Ramnik J. Xavier Vivian G. Cheung Steven K. Grinspoon Murray Korc Guillermo Oliver Amita Sehgal Yiping Yang Raymond Chung David Hafler Gary Koretzky Eric N. Olson Clay Semenkovich Srinivasan Yegnasubramanian Jeanne M. Clark Jonathan J. Hansen Stavroula Kousteni Harry T. Orr Jonathan S. Serody Mone Zaidi Sheila Collins Raymond Clement Harris John W. Krakauer Leo E. Otterbein John Seykora Kang Zhang Ronald G. Collman Stanley L. Hazen Rohit N. Kulkarni Roberto Pacifici Theresa A. Shapiro Len Zon Marco Colonna Peter Heeringa Chulan Kwon Akhilesh Pandey Mari Shinohara Weiping Zou Shaun R. Coughlin Meenhard Herlyn Antonio La Cava William C. Parks Steven E. Shoelson R. Suzanne Zukin Tyler J. Curiel Joachim Herz Fadi G. Lakkis Warren S. Pear Gerald I. Shulman David D'Alessio Katherine A. High Terri Laufer Sallie R. Permar Roy L. Silverstein Featured Editor The JCI’s Editorial Board is composed of peer scientists at Johns Hopkins University School of Medicine, the This Month University of Maryland School of Medicine, and the National Institutes of Health. Editorial Board members August 2018 review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.

For the JCI Gregg Semenza, MD, PhD, Deputy Editor Editor, is an American Society Rexford S. Ahima Research Professor and the C. Michael Deputy Editors Armstrong Professor at the Johns Arturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli Hopkins University School of Medicine, Associate Editors with appointments in Genetic Medicine, Richard F. Ambinder, Mark E. Anderson, Pediatrics, Medicine, Oncology, Mary Y. Armanios, William R. Bishai, Robert A. Brodsky, Radiation Oncology, and Biological Peter A. Calabresi, Thomas L. Clemens, Chemistry. He is also founding director Franco R. D’Alessio, Ted M. Dawson, Angelo M. DeMarzo, Stephen Desiderio, Mark Donowitz, Andrew P. Feinberg, of the Vascular Program of the Johns Sharon Gerecht, Paul M. Hassoun, Elizabeth M. Jaffe, Hopkins Institute for Cell Engineering. Mariana J. Kaplan, Leo Luznik, Marcela V. Maus, Dr. Semenza’s laboratory discovered Timothy H. Moran, Laszlo Nagy, William Nelson, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, hypoxia-inducible factor 1 (HIF-1), a Thomas C. Quinn, Hamid Rabb, Jean-Pierre Raufman, master regulator that directs responses Stuart C. Ray, Jeffrey D. Rothstein, Jonathan Schneck, to decreased oxygen availability; and Robert F. Siliciano, Akrit S. Sodhi, Charlotte Sumner, his laboratory has shown that HIF-1 plays important roles in cardiovascular Simeon I. Taylor, David L. Thomas, Robert G. Weiss, Sarah J. Wheelan, Marsha Wills-Karp disorders, cancer, chronic obstructive pulmonary disease, diabetes, sleep Biostatistician apnea, transplant rejection, and hematologic disorders. He is a member of the Eliseo Guallar Society for Pediatric Research, American Society for Clinical Investigation, Computational Biologist Association of American Physicians, National Academy of Medicine, and Patrick Cahan National Academy of Sciences. An associate editor on JCI’s editorial board JCI Scholars since July 2017, Dr. Semenza took on the role of deputy editor in July 2018. Justin Lowenthal, Austin K. Mattox Staff Editors Publication highlights Executive Editor Sarah C. Jackson Lu H, Tran L, Park Y, Chen I, Lan J, Xie Y, Semenza GL. Reciprocal regulation of DUSP9 and DUSP16 expression by HIF-1 controls ERK and p38 MAP Science Editors Elyse Dankoski, Monika Deshpande, kinase activity and mediates chemotherapy-induced stem cell Corinne Williams enrichment. Cancer Res. 2018:canres.0270.2018. Editor at Large Ushma S. Neill Samanta D, Park Y, Ni X, Li H, Zahnow CA, Gabrielson E, Pan F, Semenza + + + JCI This Month ISSN 2324-7703 (print); GL. Chemotherapy induces enrichment of CD47 /CD73 /PDL1 immune ISSN 2325-4556 (online) evasive triple-negative breast cancer cells. Proc Natl Acad Sci U S A. For the full JCI online: jci.me/128/8 2018;115(6):E1239–E1248. Lu H, Chen I, Shimoda LA, Park Y, Zhang C, Tran L, Zhang H, Semenza Contact the JCI and JCI Insight GL. Chemotherapy-induced Ca2+ release stimulates breast cancer stem cell 2015 Manchester Road Ann Arbor, Michigan 48104, USA enrichment. Cell Rep. 2017;18(8):1946–1957. Phone: 734.222.6050 Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, He X, Semenza GL. Email: [email protected] (JCI); [email protected] (JCI Insight) Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation and Proc Natl Acad Sci U S A. 2016;113(14):E2047–E2056. JCI Insight. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

jci.org/this-month august 2018 1 research Editor’s picks

on the jci cover hematology Fibrin forms protective films at the blood-air interface Hemostatic responses to vascular injury not only prevent life-threatening loss of blood, but also form a barrier against pathogen entry at the blood-air interface. During coagulation, fibrin polymerizes into chain-like fibers that control its structure and rigidity in the newly formed clot. However, fibrin’s structure at the critical blood-air interface has not been described. In this issue of the JCI, Macrae et al. investigate the observation that films rapidly form on the air-exposed surface of blood clots. They report that these films are composed of layers of densely packed fibrin monomers that aggregate perpendicularly to the surface of the blood-air interface. In vivo models of dermal injury demonstrated that intact fibrin films impair the migration of bacteria into clots, indicating their important role in controlling infection during the acute phase of wound healing. An accompanying Commentary by Sean Gu and Steven Lentz describes this study’s insights into the intersection of innate immunity and hemostatic mechanisms. On the cover of this issue, SEM imaging reveals a fibrin film at the air-exposed surface of a blood clot. A perforation in the film exposes the RBC and polymerized fiber strands contained within. A fibrin biofilm covers blood clots and protects from microbial invasion Fraser L. Macrae, Cédric Duval, Praveen Papareddy, Stephen R. Baker, Nadira Yuldasheva, Katherine J. Kearney, Helen R. McPherson, Nathan Asquith, Joke Konings, Alessandro Casini, Jay L. Degen, Simon D. Connell, Helen Philippou, Alisa S. Wolberg, Heiko Herwald, and Robert A.S. Ariëns http://jci.me/98734 Related Commentary Fibrin films: overlooked hemostatic barriers against microbial infiltration Sean X. Gu and Steven R. Lentz http://jci.me/121858

metabolism Restoring leptin signaling improves metabolic abnormalities independently of food intake Individuals with lipodystrophy have a deficiency of adipose tissue and Metreleptin-mediated improvements in insulin therefore produce inadequate amounts of leptin, a hormonal signal that sensitivity are independent of food intake helps control caloric intake. Hyperphagia driven by leptin deficiency in humans with lipodystrophy contributes to ectopic fat storage and severe metabolic abnormalities. The Rebecca J. Brown, Areli Valencia, Megan Startzell, Elaine Cochran, leptin analog metreleptin ameliorates hyperphagia as well as its metabolic Peter J. Walter, H. Martin Garraffo, Hongyi Cai, Ahmed M. Gharib, consequences. The National Institute of Diabetes and Digestive and Kidney Ronald Ouwerkerk, Amber B. Courville, Shanna Bernstein, Robert J. Brychta, Diseases investigated the metabolic benefits of metreleptin in a clinical Kong Y. Chen, Mary Walter, Sungyoung Auh, and Phillip Gorden study of lipodystrophic patients maintained on a controlled diet. In 14 http://jci.me/95476 patients, initiation of metreleptin treatment improved insulin sensitivity as Related Commentary well as triglyceride levels over a 2-week period. The results support leptin’s Physiological responses to leptin levels in diet-independent effects on metabolism. An accompanying Commentary by lipodystrophy: a model for other hypoleptinemias? Michael Rosenbaum and Rudolph Leibel highlights this study’s contribution Michael Rosenbaum and Rudolph L. Leibel http://jci.me/122042 to our understanding of the complex role of leptin in metabolism.

2 jci.org/this-month august 2018 JCI | Research: Editor’s picks

immunology CXCR4-haploinsufficient cells have an advantage against WHIM immunodeficiency syndrome Gain-of-function mutations in the chemokine into Cxcr4+/w recipients. The donor Cxcr4- Cxcr4-haploinsufficient bone receptor CXCR4 produce WHIM syndrome, a haploinsufficient leukocytes had both marrow transplantation corrects rare immunodeficiency disorder characterized engraftment and proliferative advantages leukopenia in an unconditioned in part by BM retention of neutrophils and over Cxcr4+/w leukocytes and did not require WHIM syndrome model leukopenia. A recent report of a WHIM irradiation conditioning. Unconditioned Ji-Liang Gao, Erin Yim, Marie Siwicki, syndrome patient’s recovery following Cxcr4+/w mice transplanted with Cxcr4-haplo­ Alexander Yang, Qian Liu, Ari Azani, spontaneous deletion of the CXCR4-containing insufficient cells survived and displayed Albert Owusu-Ansah, David H. McDermott, and chromosome in a single hematopoietic stem improvements in leukopenia. In an Philip M. Murphy http://jci.me/120375 cell indicates that gene-deleting strategies accom­panying Commentary, Hal Broxmeyer Related Commentary may be a potential cure. In a mouse model of summarizes the evidence supporting the Enhancement of stem cell WHIM syndrome (Cxcr4+/w), Ji-Liang Gao and curative effect of WHIM allele deletion and engraftment on a WHIM colleagues demonstrated the successful indicates that CXCR4 haploinsufficiency may also Hal E. Broxmeyer http://jci.me/121857 engraftment of Cxcr4-haploinsufficient BM enhance other BM transplantation strategies.

endocrinology

Vitamin D3 metabolite promotes effective bone healing after fracture

Most fractures induce a secondary bone-healing response that is initiated by acute inflammation and recruitment of immune cells and osteogenic progenitors. A soft callus forms at the fracture site and is later mineralized and ossified. Corine Martineau and labmates examined the role of vitamin D in bone healing after noting that ossification is impaired in Cyp24a1-deficient mice, which are unable to synthesize the

vitamin D metabolite 24R,25-dihydroxyvitamin D3. Gene expression comparisons identified an upregulation of Fam57b2 in the fracture callus of Cyp24a1-deficient mice. Further investigation revealed that an interaction between FAM57B2

and 24R,25-dihydroxyvitamin D3 in chondrocytes produces lactosylceramide, which supports callus mineralization. Lactosylceramide supplementation improved mineralization in both Cyp24a1- and Fam57b2-deficient calluses (see the accompanying image). These findings indicate a targetable

24R,25-dihydroxyvitamin D3–dependent pathway with the potential to optimize bone repair after fracture.

Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2 Corine Martineau, Roy Pascal Naja, Abdallah Husseini, Bachar Hamade, Martin Kaufmann, Omar Akhouayri, Alice Arabian, Glenville Jones, and René St-Arnaud http://jci.me/98093

jci.org/this-month august 2018 3 JCI | Research: Editor’s picks

nephrology inflammation Bowman’s capsule insulates podocytes Neuroprotectin D1/GPR37 signaling against cytotoxic enables macrophage-mediated T cells resolution of inflammatory pain Cellular injury induces inflammation that promotes tissue repair but also produces pain as a warning signal to limit further damage. Active resolution of inflammation is mediated by a family of lipid-based molecules known as specialized proresolving mediators (SPMs) that signal through GPCRs. A study led by Ru-Rong Ji revealed that macrophages express GPR37, a GPCR with known roles in the CNS and neurological disorders. The researchers demonstrated that the SPM neuroprotectin D1 (NPD1) is a ligand for GPR37 and that NPD1/GPR37 signaling is necessary for phagocytosis (see the associated image). During zymosan-induced inflammation, GPR37-expressing macrophages were also found to play a crucial role in the resolution of inflammatory pain. In an accompanying Commentary, Lintao Qu and Michael Caterina propose that the identification of an NPD1 receptor exposes an essential pathway in the Crescentic glomerulonephritis (GN) is a precursor to resolution of inflammatory pain as well as potential targets for pain relief. kidney failure that arises from injury to glomerular endothe- lial cells and podocytes. Although a mechanism for CD8+ T cell–mediated podocyte targeting was described in vitro, whether these T cells contribute to in vivo podocyte injury has been unclear. Anqun Chen and colleagues administered EGFP-targeting CD8+ T cells to mice with EGFP-expressing podocytes. The treatment did not affect kidney function in normal mice. However, in the setting of experimentally induced inflammation, damage to the periglomerular Bowman’s capsule facilitated EGFP-targeting T cell migration into the glomerulus (see the associated image), leading to podocyte loss, enhanced proteinuria, and elevated blood urea. These findings outline a pathological mechanism in which damage to Bowman’s capsule exposes podocytes to cytotoxic CD8+ T cells. Richard Kitching and Maliha Alikhan speculate that these immune cells are a possible therapeutic target against rapidly progressing GN in an accompanying Commentary. GPR37 regulates macrophage phagocytosis Bowman’s capsule provides a protective and resolution of inflammatory pain niche for podocytes from cytotoxic Sangsu Bang, Ya-Kai Xie, Zhi-Jun Zhang, Zilong Wang, CD8+ T cells Zhen-Zhong Xu, and Ru-Rong Ji Anqun Chen, Kyung Lee, Vivette D. D’Agati, Chengguo Wei, http://jci.me/99888 Jia Fu, Tian-Jun Guan, John Cijiang He, Detlef Schlondorff, Related Commentary and Judith Agudo http://jci.me/97879 Accelerating the reversal of inflammatory pain Related Commentary with NPD1 and its receptor GPR37 CD8+ cells and glomerular crescent Lintao Qu and Michael J. Caterina formation: outside-in as well as inside-out http://jci.me/122203 A. Richard Kitching and Maliha A. Alikhan http://jci.me/122045

4 jci.org/this-month august 2018 JCI | Research: Editor’s picks

infectious disease Microbiota-stimulated immunity protects against opportunistic P. aeruginosa infection Broad-spectrum antibiotic treatment increases a patient’s risk of acquiring infections with Pseudomonas aeruginosa and other antibiotic-resistant pathogens, but mechanisms underlying this enhanced susceptibility are unclear. Oliver Robak and coworkers discovered that resident microbiota play a key role in defending against this opportunistic pathogen. Clinical samples indicate that antibiotic therapies decrease pulmonary IgA production in human ICU patients. In a mouse model, antibiotic-induced microbiome depletion lowered IgA levels, reduced the frequency of IgA+ immune cells in the lung, and impaired antibacterial defense. Delivery of exogenous IgA to the lung attenuated P. aeruginosa susceptibility in mice. In an accompanying Commentary, Juergen Lohmeyer, Rory Morty, and Susanne Herold suggest that restoring pulmonary IgA levels in vulnerable patients may be a tenable strategy for preventing life-threatening infections. Antibiotic treatment–induced secondary IgA deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia Oliver H. Robak, Markus M. Heimesaat, Andrey A. Kruglov, Sandra Prepens, Justus Ninnemann, Birgitt Gutbier, Katrin Reppe, Hubertus Hochrein, Mark Suter, Carsten J. Kirschning, Veena Marathe, Jan Buer, Mathias W. Hornef, Markus Schnare, Pascal Schneider, Martin Witzenrath, Stefan Bereswill, Ulrich Steinhoff, Norbert Suttorp, Leif E. Sander, Catherine Chaput, and Bastian Opitz http://jci.me/97065 Related Commentary Antibiotic therapy–induced collateral damage: IgA takes center stage in pulmonary host defense Juergen Lohmeyer, Rory E. Morty, and Susanne Herold http://jci.me/122032 Vaginal epithelial dendritic cells permit HIV-1 entry and persistence HIV-1 establishes systemic infection by targeting CD4+ T cells, which can sustain high levels of viral replication. CD4+ T cells are not present in the outermost epithelial layers of the genitalia, suggesting that the virus must transfer from cell to cell to access its preferred target. Victor Pena-Cruz and coworkers investigated the role of vaginal epithelial dendritic cells (VEDCs) in heterosexual HIV-1 transmission. They report that VEDCs are a distinct subtype of DCs, expressing the C-type lectin receptor langerin but not the C-type lectin DC-SIGN, and lacking the Birbeck granules that typify skin DCs, termed Langerhans cells. VEDCs are particularly susceptible to HIV-1 variants that enter via CCR5, and CCR5-dependent variants demonstrated a postentry replication advantage. In virologically suppressed women, VEDCs harbored a latent reservoir of HIV-1, consistent with predictions that DCs can support long-term viral maintenance. Stephan Caucheteux and Vincent Piguet discuss how these findings advance understanding of heterosexual HIV-1 transmission and obstacles to viral eradication in an accompanying Commentary. HIV-1 replicates and persists in vaginal epithelial dendritic cells Victor Pena-Cruz, Luis M. Agosto, Hisashi Akiyama, Alex Olson, Yvetane Moreau, Jean-Robert Larrieux, Andrew Henderson, Suryaram Gummuluru, and Manish Sagar http://jci.me/98943 Related Commentary Vaginal epidermal dendritic cells: defense against HIV-1 or a safe haven? Stephan Caucheteux and Vincent Piguet http://jci.me/121744

jci.org/this-month august 2018 5 JCI | Features

reviews Checkpoint-modulating strategies join forces to improve antitumor immune responses

Strategies that appropriate the immune system’s ability to monitor and eliminate cellular threats are Emerging strategies for combination emerging as successful cancer therapies. The exploitation of immune checkpoints, a system of inhibitory and checkpoint modulators in stimulatory receptors that balance tolerance and immune attack, has produced positive clinical results against cancer immunotherapy a number of tumor types. However, checkpoint-targeting therapies are hindered by a number of challenges, Aleksandra Popovic, Elizabeth M. Jaffee, including difficulties in producing a durable response, overcoming resistance mechanisms, and mitigating and Neeha Zaidi plasticity within the tumor microenvironment. In this issue, Aleksandra Popovic, Elizabeth Jaffee, and Neeha http://jci.me/120775 Zaidi review the immune checkpoint modulators currently in preclinical and clinical development as well as combinatorial strategies designed to optimize their efficacy against immunosuppressive obstacles.

Steps in the path to curing conversations with giants in medicine spinal muscular atrophy Cornelia Spinal muscular atrophy (SMA) is a disease of motor that leads to muscle wasting and progressive loss of voluntary movement. Motor Bargmann neurons deteriorate as a result of loss-of-function mutations in the Cornelia Bargmann’s lifelong survival motor 1 gene (SMN1) that lead to deficiency in the SMN interest in behavior led her to protein. Humans possess a second SMN-encoding gene, SMN2, that study the genetic basis of the differs from SMN1 by a single bp, altering pre-mRNA splicing and neural circuitry underlying producing a shortened, rapidly degraded SMN. The FDA recently approved olfaction in C. elegans. Her work two breakthrough genetic approaches for correcting SMN deficiency in has been recognized with the SMA patients: nusinersen, an antisense oligonucleotide that corrects and the Breakthrough altered SMN2 splicing, and Avexis-101, an SMN1 cDNA that replaces the Prize in Life Sciences. In addition nonfunctional gene. In this issue, a review by Charlotte Sumner and to leading an internationally Thomas Crawford details the clinical trials supporting each successful recognized research group at , Bargmann cochaired the therapy and the important biological and clinical questions that remain ambitious BRAIN Initiative and was recently named president of the unanswered. While both gene-targeting therapies represent an enormous multi-billion-dollar Chan Zuckerberg Initiative to support scientific and advance for treating SMA, overcoming lingering obstacles will require technological advancement. Dr. Bargmann joined JCI’s Editor-at-Large Ushma continued research efforts. Neill to discuss what motivated her to pursue the genetic basis of behavior and her vision for the future of science. A video of the full interview can be Two breakthrough gene-targeted treatments for accessed on the JCI’s website. http://jci.me/122804 spinal muscular atrophy: challenges remain Charlotte J. Sumner and Thomas O. Crawford http://jci.me/121658

6 jci.org/this-month august 2018 Current research articles development Eupatilin rescues ciliary transition zone defects to ameliorate ciliopathy-related phenotypes Yong Joon Kim, Sungsoo Kim, Yooju Jung, Eunji Jung, Ho Jeong Kwon, and Joon Kim http://jci.me/99232 endocrinology Neuronatin regulates pancreatic β cell insulin content and secretion Steven J. Millership, Gabriela Da Silva Xavier, Agharul I. Choudhury, Sergio Bertazzo, Pauline Chabosseau, Silvia M.A. Pedroni, Elaine E. Irvine, Alex Montoya, Peter Faull, William R. Taylor, Julie Kerr-Conte, Francois Pattou, Jorge Ferrer, Mark Christian, Rosalind M. John, Mathieu Latreille, Ming Liu, Guy A. Rutter, James Scott, and Dominic J. Withers http://jci.me/120115 Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice Marlies Ballegeer, Kelly Van Looveren, Steven Timmermans, Melanie Eggermont, Sofie Vandevyver, Fabien Thery, Karen Dendoncker, Jolien Souffriau, Jolien Vandewalle, Lisa Van Wyngene, Riet De Rycke, Nozomi Takahashi, Peter Vandenabeele, Jan Tuckermann, Holger M. Reichardt, Francis Impens, Rudi Beyaert, Karolien De Bosscher, Roosmarijn E. Vandenbroucke, and Claude Libert http://jci.me/96636

Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2 p. 3 Corine Martineau, Roy Pascal Naja, Abdallah Husseini, Bachar Hamade, Martin Kaufmann, Omar Akhouayri, Alice Arabian, Glenville Jones, and René St-Arnaud http://jci.me/98093 hematology Hijacking a key chromatin modulator creates epigenetic vulnerability for MYC-driven cancer Zhenhua Yang, Kushani Shah, Theodore Busby, Keith Giles, Alireza Khodadadi-Jamayran, Wei Li, and Hao Jiang http://jci.me/97072 A fibrin biofilm covers blood clots and protects from microbial invasion p. 2 Fraser L. Macrae, Cédric Duval, Praveen Papareddy, Stephen R. Baker, Nadira Yuldasheva, Katherine J. Kearney, Helen R. McPherson, Nathan Asquith, Joke Konings, Alessandro Casini, Jay L. Degen, Simon D. Connell, Helen Philippou, Alisa S. Wolberg, Heiko Herwald, and Robert A.S. Ariëns http://jci.me/98734 PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature David J. Corrigan, Larry L. Luchsinger, Mariana Justino de Almeida, Linda J. Williams, Alexandros Strikoudis, and Hans-Willem Snoeck http://jci.me/99862 immunology Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model p. 3 Ji-Liang Gao, Erin Yim, Marie Siwicki, Alexander Yang, Qian Liu, Ari Azani, Albert Owusu-Ansah, David H. McDermott, and Philip M. Murphy http://jci.me/120375 Autoreactive T effector memory differentiation mirrorsβ cell function in type 1 diabetes Lorraine Yeo, Alyssa Woodwyk, Sanjana Sood, Anna Lorenc, Martin Eichmann, Irma Pujol-Autonell, Rosella Melchiotti, Ania Skowera, Efthymios Fidanis, Garry M. Dolton, Katie Tungatt, Andrew K. Sewell, Susanne Heck, Alka Saxena, Craig A. Beam, and Mark Peakman http://jci.me/120555 TNF overproduction impairs epithelial staphylococcal response in hyper IgE syndrome Ian A. Myles, Erik D. Anderson, Noah J. Earland, Kol A. Zarember, Inka Sastalla, Kelli W. Williams, Portia Gough, Ian N. Moore, Sundar Ganesan, Cedar J. Fowler, Arian Laurence, Mary Garofalo, Douglas B. Kuhns, Mark D. Kieh, Arhum Saleem, Pamela A. Welch, Dirk A. Darnell, John I. Gallin, Alexandra F. Freeman, Steven M. Holland, and Sandip K. Datta http://jci.me/121486

jci.org/this-month august 2018 7 Current research articles infectious disease Antibiotic treatment–induced secondary IgA deficiency enhances susceptibility to Pseudomonas aeruginosa pneumonia p. 5 Oliver H. Robak, Markus M. Heimesaat, Andrey A. Kruglov, Sandra Prepens, Justus Ninnemann, Birgitt Gutbier, Katrin Reppe, Hubertus Hochrein, Mark Suter, Carsten J. Kirschning, Veena Marathe, Jan Buer, Mathias W. Hornef, Markus Schnare, Pascal Schneider, Martin Witzenrath, Stefan Bereswill, Ulrich Steinhoff, Norbert Suttorp, Leif E. Sander, Catherine Chaput, and Bastian Opitz http://jci.me/97065 HIV-1 replicates and persists in vaginal epithelial dendritic cells p. 5 Victor Pena-Cruz, Luis M. Agosto, Hisashi Akiyama, Alex Olson, Yvetane Moreau, Jsean-Robert Larrieux, Andrew Henderson, Suryaram Gummuluru, and Manish Sagar http://jci.me/98943 Enterotoxigenic Escherichia coli–blood group A interactions intensify diarrheal severity Pardeep Kumar, F. Matthew Kuhlmann, Subhra Chakraborty, A. Louis Bourgeois, Jennifer Foulke-Abel, Brunda Tumala, Tim J. Vickers, David A. Sack, Barbara DeNearing, Clayton D. Harro, W. Shea Wright, Jeffrey C. Gildersleeve, Matthew A. Ciorba, Srikanth Santhanam, Chad K. Porter, Ramiro L. Gutierrez, Michael G. Prouty, Mark S. Riddle, Alexander Polino, Alaullah Sheikh, Mark Donowitz, and James M. Fleckenstein http://jci.me/97659 inflammation The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction Joaquim Miguel Vieira, Sophie Norman, Cristina Villa del Campo, Thomas J. Cahill, Damien N. Barnette, Mala Gunadasa-Rohling, Louise A. Johnson, David R. Greaves, Carolyn A. Carr, David G. Jackson, and Paul R. Riley http://jci.me/97192 GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain p. 4 Sangsu Bang, Ya-Kai Xie, Zhi-Jun Zhang, Zilong Wang, Zhen-Zhong Xu, and Ru-Rong Ji http://jci.me/99888 metabolism Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy p. 2 Rebecca J. Brown, Areli Valencia, Megan Startzell, Elaine Cochran, Peter J. Walter, H. Martin Garraffo, Hongyi Cai, Ahmed M. Gharib, Ronald Ouwerkerk, Amber B. Courville, Shanna Berstein, Robert J. Brychta, Kong Y. Chen, Mary Walter, Sungyoung Auh, and Phillip Gorden http://jci.me/95476 muscle Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction Samir R. Nath, Zhigang Yu, Theresa A. Gipson, Gregory B. Marsh, Eriko Yoshidome, Diane M. Robins, Sokol V. Todi, David E. Housman, and Andrew P. Lieberman http://jci.me/99042 nephrology Bowman’s capsule provides a protective niche for podocytes from cytotoxic CD8+ T cells p. 4 Anqun Chen, Kyung Lee, Vivette D. D’Agati, Chengguo Wei, Jia Fu, Tian-Jun Guan, John Cijiang He, Detlef Schlondorff, and Judith Agudo http://jci.me/97879 CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease Kayaho Maeda, Kotaro Otomo, Nobuya Yoshida, Mones S. Abu-Asab, Kunihiro Ichinose, Tomoya Nishino, Michihito Kono, Andrew Ferretti, Rhea Bhargava, Shoichi Maruyama, Sean Bickerton, Tarek M. Fahmy, Maria G. Tsokos, and George C. Tsokos http://jci.me/99507 The COPII cargo adapter SEC24C is essential for neuronal homeostasis Bo Wang, Joung Hyuck Joo, Rebecca Mount, Brett J. W. Teubner, Alison Krenzer, Amber L. Ward, Viraj P. Ichhaporia, Elizabeth J. Adams, Rami Khoriaty, Samuel T. Peters, Shondra M. Pruett-Miller, Stanislav S. Zakharenko, David Ginsburg, and Mondira Kundu http://jci.me/98194

8 jci.org/this-month august 2018 Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome Didier Dulon, Samantha Papal, Pranav Patni, Matteo Cortese, Philippe F.Y. Vincent, Margot Tertrais, Alice Emptoz, Abdelaziz Tlili, Yohan Bouleau, Vincent Michel, Sedigheh Delmaghani, Alain Aghaie, Elise Pepermans, Olinda Alegria-Prevot, Omar Akil, Lawrence Lustig, Paul Avan, Saaid Safieddine, , and Aziz El-Amraoui http://jci.me/94351 Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models Alex McCampbell, Tracy Cole, Amy J. Wegener, Giulio S. Tomassy, Amy Setnicka, Brandon J. Farley, Kathleen M. Schoch, Mariah L. Hoye, Mark Shabsovich, Linhong Sun, Yi Luo, Mingdi Zhang, Sai Thankamony, David W. Salzman, Merit Cudkowicz, Danielle L. Graham, C. Frank Bennett, Holly B. Kordasiewicz, Eric E. Swayze, and Timothy M. Miller http://jci.me/99081 oncology Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression Khaled Aziz, Cynthia J. Sieben, Karthik B. Jeganathan, Masakazu Hamada, Brian A. Davies, Raul O. Fierro Velasco, Nazneen Rahman, David J. Katzmann, and Jan M. van Deursen http://jci.me/120316 The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis Motoyuki Tsuda, Akihisa Fukuda, Nilotpal Roy, Yukiko Hiramatsu, Laura Leonhardt, Nobuyuki Kakiuchi, Kaja Hoyer, Satoshi Ogawa, Norihiro Goto, Kozo Ikuta, Yoshito Kimura, Yoshihide Matsumoto, Yutaka Takada, Takuto Yoshioka, Takahisa Maruno, Yuichi Yamaga, Grace E. Kim, Haruhiko Akiyama, Seishi Ogawa, Christopher V. Wright, Dieter Saur, Kyoichi Takaori, Shinji Uemoto, Matthias Hebrok, Tsutomu Chiba, and Hiroshi Seno http://jci.me/94287

CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis Roberta Lugano, Kalyani Vemuri, Di Yu, Micahel Bergqvist, Anja Smits, Magnus Essand, Staffan Johansson, Elisabetta Dejana, and Anna Dimberg http://jci.me/97459 Trefoil factor 1 inhibits epithelial-mesenchymal transition of pancreatic intraepithelial neoplasm Junpei Yamaguchi, Yukihiro Yokoyama, Toshio Kokuryo, Tomoki Ebata, Atsushi Enomoto, and Masato Nagino http://jci.me/97755 Spleen mediates a distinct hematopoietic progenitor response supporting tumor-promoting myelopoiesis Chong Wu, Huiheng Ning, Mingyu Liu, Jie Lin, Shufeng Luo, Wenjie Zhu, Jing Xu, Wen-Chao Wu, Jing Liang, Chun-Kui Shao, Jiaqi Ren, Bin Wei, Jun Cui, Min-Shan Chen, and Limin Zheng http://jci.me/97973 HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Bo Hu, Tae Hyun Hwang, William Douglas Figg, Cody J. Peer, Caly Chien, Vadim S. Koshkin, Prateek Mendiratta, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, and Nima Sharifi http://jci.me/98319 Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma Behrouz Hassannia, Bartosz Wiernicki, Irina Ingold, Feng Qu, Simon Van Herck, Yulia Y. Tyurina, Hülya Bayir, Behnaz A. Abhari, Jose Pedro Friedmann Angeli, Sze Men Choi, Eline Meul, Karen Heyninck, Ken Declerck, Chandra Sekhar Chirumamilla, Maija Lahtela-Kakkonen, Guy Van Camp, Dmitri V. Krysko, Paul G. Ekert, Simone Fulda, Bruno G. De Geest, Marcus Conrad, Valerian E. Kagan, Wim Vanden Berghe, Peter Vandenabeele, and Tom Vanden Berghe http://jci.me/99032 transplantation Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration Carola Ledderose, Kaifeng Liu, Yutaka Kondo, Christian J. Slubowski, Thomas Dertnig, Sara Denicoló, Mona Arbab, Johannes Hubner, Kirstin Konrad, Mahtab Fakhari, James A. Lederer, Simon C. Robson, Gary A. Visner, and Wolfgang G. Junger http://jci.me/120972 P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes Francesca D’Addio, Andrea Vergani, Luciano Potena, Anna Maestroni, Vera Usuelli, Moufida Ben Nasr, Roberto Bassi, Sara Tezza, Sergio Dellepiane, Basset El Essawy, Maria Iascone, Attilio Iacovoni, Laura Borgese, Kaifeng Liu, Gary Visner, Sirano Dhe Paganon, Domenico Corradi, Reza Abdi, Randall C. Starling, Franco Folli, Gian Vincenzo Zuccotti, Mohamed H. Sayegh, Peter S. Heeger, Anil Chandraker, Francesco Grigioni, and Paolo Fiorina http://jci.me/94524 Flip issue to read JCI Insight content.

jci.org/this-month august 2018 9 This Month

Visualizing glymphatic transport in the brain p. 10

August 2018 JCI This Month is a summary of the Psoriasis-associated TCR gene usage 12 most recent articles in Tristetraprolin posttranscriptionally regulates hepatic FGF21 12 The Journal of Clinical Investigation and JCI Insight SLC26A3 inhibition reduces colonic fluid absorption 13 Predicting rare CFTR variant drug response 13 jci.org/this-month A nonhuman primate model of familial Parkinson’s disease 13 JCI Insight Consulting Editors

Christopher M. Adams Peter Crawford Thomas W.H. Kay Daniel Ory Maria-Luisa Alegre Lisa L. Cunningham Barbara I. Kazmierczak Sophie Paczesny Ravi K. Amaravadi Ronald P. DeMatteo Hans-Peter Kiem Stephanie T. Page John K. Amory Elia J. Duh William Y. Kim Mary-Elizabeth Patti Jennifer H. Anolik Sarah K. England David G. Kirsch Janos Peti-Peterdi Cristian Apetrei Mark W. Feinberg Claire E. Lewis Fernando P. Polack Rajendra S. Apte John H. Fingert Mathias Lichterfeld Matthew D. Ringel Zoltan Arany Robert Flaumenhaft André Lieber Steven M. Rowe Hossein Ardehali Edward A. Fon Michail S. Lionakis Svati H. Shah Kenneth I. Ataga Lawrence Fong Carey N. Lumeng Vijay H. Shah Joseph Bass Nikolaos G. Frangogiannis Ivan Maillard Alice T. Shaw Alexander G. Bassuk Anthony R. French Ziad Mallat Rhonda F. Souza Antonio C. Bianco Terrence L. Geiger Peter Mannon Fayyaz S. Sutterwala Jonathan S. Bogan Noyan Gokce Franck Mauvais-Jarvis Shu Takeda Laura M. Bohn Raphaela Goldbach-Mansky Dermot P.B. McGovern Natalie J. Torok Nunzio Bottini Daniel R. Goldstein Borna Mehrad Stephen H. Tsang Sebastien G. Bouret Douglas K. Graham Ingo K. Mellinghoff Ellie Tzima Jason Brenchley Khalid A. Hanafy David K. Meyerholz Fumihiko Urano Renier J. Brentjens Eric B. Haura Jason C. Mills Deborah J. Veis G.R. Scott Budinger John Cijiang He Joshua D. Milner Charles P. Venditti George A. Calin Robert O. Heuckeroth Satdarshan (Paul) Singh Monga Joseph M. Vinetz Stephen Chan Cory M. Hogaboam Hidayatullah G. Munshi Sing Sing Way Timothy Chan Young-Kwon Hong Matthias Nahrendorf Bernd Wollnik Yuan Chang Benjamin D. Humphreys Mary Nakamura Minna Woo Zhou-Feng Chen Ken Inoki Lisa F.P. Ng Prescott G. Woodruff Keith A. Choate Shingo Kajimura Mark Nicolls Lori M. Zeltser Wendy Chung Pawel Kalinski Laura J. Niedernhofer Yutong Zhao Craig M. Coopersmith John Y. Kao S. Tiong Ong Binhua P. Zhou George Cotsarelis Michael G. Kaplitt Puneet Opal On the JCI Insight cover This Month Glymphatic transport of an MRI tracer August 2018 in the human brain

For JCI Insight Drug delivery is a major Editor challenge for treating diseases Howard A. Rockman of the CNS, as the blood-brain Associate Editors barrier (BBB) limits access of Rodger A. Liddle, Yiping Yang molecules delivered by the Executive Editor circulation. Direct delivery to Sarah C. Jackson the subarachnoid cerebrospinal Science Editor Corinne Williams fluid (CSF) space has potential to improve drug distribution in ASCI Staff the CNS; however, it is not fully Executive Director understood how substances are John B. Hawley Managing Director transported and cleared from Karen D. Guth the interstitial spaces of the human brain. In this issue, Geir Ringstad and Associate Director colleagues evaluated distribution of the CSF tracer gadobutrol, which is Maya Hoptman confined to the extravascular brain compartment by the BBB, over time via Associate Director, Technology MRI in a small cohort of healthy individuals and patients with dementia Shawn Pyle and suspected compromise of CSF circulation. Volunteers were scanned Production Editors Catherine Ahmann, Ken Beauchamp, prior to and then at multiple defined points, up to 4 weeks, after intrathecal Molly Jean, Lara L. McCarron gadobutrol injection. Within 24 hours of injection, the tracer was present Scientific Illustrator in all subregions of the brain, indicating active transport from the site Bruce Worden of injection. After peak enhancement at 24 hours, the level of the tracer Copy Editors declined, and it was fully cleared by 4 weeks. Compared with the healthy Clare Cross, Meredith Dimick, Barbara Fabyan, Rachel Nelson, reference cohort, glymphatic clearance of gadobutrol was delayed in Chet Provoda the dementia cohort. Together, these results provide strong evidence of Associate Copy Editor glymphatic transport in the human brain and support further exploration Megan O'Reilly of subarachnoid drug delivery to the brain. The cover shows gadobutrol Associate Editor, Copy and Production distribution in different brain regions of a healthy volunteer at various times Rachel Bullen over a 24-hour period after intrathecal injection. Publications Coordinator Megan Jenkins Brain-wide glymphatic enhancement and clearance in humans assessed with MRI System Administrator and Developer Geir Ringstad, Lars M. Valnes, Anders M. Dale, Are H. Pripp, Svein-Are S. Vatnehol, Kyrre E. Emblem, Bryan English Kent-Andre Mardal, and Per K. Eide Web Developer http://jci.me/121537 Austin Brewer Science Communications Specialist Neha Aggarwal Accounts Manager Paula Kremidas Administrative Assistant Make your 18-hour days count. Theresa Kaiser Figures Coordinator Keith Kalinowski Submit your work to JCI Insight today. For JCI Insight online: jci.me/insight/3/13 jci.me/insight/3/14

jci.org/this-month august 2018 10 Editor’s picks

aids/hiv In vivo imaging of SIV-associated CD4+ T cell dynamics

Total body CD4+ T cell dynamics in treated and untreated SIV infection revealed by in vivo imaging Michele Di Mascio, Sharat Srinivasula, Insook Kim, Gorka Duralde, Alexis St. Claire, Paula DeGrange, Marisa St. Claire, Keith A. Reimann, Erin E. Gabriel, Jorge Carrasquillo, Richard C. Reba, Chang Paik, and Henry C. Lane http://jci.me/97880

A hallmark of HIV infection is the large-scale depletion of CD4+ T cells in the reconstitution in response to cART appeared to be stochastic among lymph node blood. There is debate over whether the decrease in these cells is due to clusters within a single animal (see the accompanying image). After treatment alterations in lymphocyte trafficking to other sites or to an overall decrease in interruption, changes to the circulating CD4+ T cell population were due to T cell pools. Moreover, the source of the CD4+ T cell pool following combination alterations of the whole-body CD4+ T cell pool and not changes in lymphocyte traf- antiretroviral therapy (cART) is not fully understood. Using a nonhuman primate ficking. Moreover, lymph node CD4+ T cell pools in cART-treated animals compared SIV model, Michele Di Mascio and colleagues used noninvasive imaging to analyze with healthy controls; however, pools in the spleen were similar. This study lays the CD4+ T cell pool dynamics before, during, and after cART. CD4+ T cell pool groundwork for further investigation into drivers of T cell dynamics.

immunology TCR repertoire predicts response to anti–CTLA-4 in pancreatic cancer Cancer immunotherapies, such as checkpoint inhibitors, provide remarkable clinical benefit for some patients; T cell receptor repertoire however, this advance has not notably extended to pancreatic cancer. Moreover, identifying patients who may features associated with benefit from combination immunotherapies remains challenging. Alexander Hopkins and colleagues evaluated survival in immunotherapy- T cell receptor (TCR) repertoires at baseline and after treatment in patients with metastatic pancreatic cancer. treated pancreatic ductal One cohort was treated with the CTLA-4–targeting mAb ipilimumab with or without the pancreatic cancer vaccine adenocarcinoma GVAX. A second cohort was treated with GVAX and mesothelin-expressing Listeria monocytogenes, with some Alexander C. Hopkins, Mark Yarchoan, patients receiving the anti–PD-1 mAB nivolumab. TCR repertoire diversity in the majority of individuals increased Jennifer N. Durham, Erik C. Yusko, following treatment, especially for those who received ipilimumab and GVAX. While low clonality at baseline and Julie A. Rytlewski, Harlan S. Robins, a high number of expanded clones following treatment was predictive of longer survival in ipilimumab-treated Daniel A. Laheru, Dung T. Le, patients, changes in TCR repertoire did not associate with nivolumab response. These results demonstrate that Eric R. Lutz, and Elizabeth M. Jaffee repertoire clonality can be used to predict long-term survival following anti–CTLA-4 treatment, and they support http://jci.me/122092 TCR analysis for identifying biomarkers of checkpoint inhibitor response.

11 jci.org/this-month august 2018 JCI Insight | Editor’s picks

dermatology therapeutics Characterization of TCR gene usage in psoriasis patients Soluble ST2-targeting Psoriasis is an autoimmune skin disease that is driven by aberrant T cell activation. compound improves Variations in T cell receptor (TCR) gene usage have been linked to psoriatic phenotypes; however, there is debate about whether γδ T cells or αβ T cells are more important for murine GVHD disease progression. Alexander Merleev, Alina I. Marusina, and colleagues evaluated TCR Cytokines are important mediators of the gene segment usage in multiple RNA sequencing (RNA-Seq) data sets from patients with immune response and act through binding psoriasis and identified an association between psoriasis, TRAJ23 expression, and psoriasis- cognate receptors on target cells. Once the associated cytokine IL-17A. TRAJ39 was prevalent in healthy skin, and CDR3 usage was not response is no longer needed, several linked to disease. TRGV5 also associated with psoriasis and IL-36 expression, but not IL-17A. strategies are employed to halt cytokine- Together, these results identify psoriasis-associated TCRs and demonstrate that mining mediated signaling. Among these is the RNA-Seq data can provide important information about T cell repertoire. release of soluble receptors, which bind Meta-analysis of RNA sequencing datasets reveals and sequester their cognate cytokine but an association between TRAJ23, psoriasis, and IL-17A do not initiate downstream responses. The Alexander A. Merleev, Alina I. Marusina, Chelsea Ma, James T. Elder, Lam C. Tsoi, soluble form of the IL-33–binding receptor Siba Raychauduri, Stephan Weidinger, Elizabeth A. Wang, Iannis E. Adamopoulos, ST2 (sST2) is a biomarker of several Guillaume Luxardi, Johann E. Gudjonsson, Michiko Shimoda, disease states, including cardiovascular and Emanual Maverakis http://jci.me/120682 disease and graft-versus-host disease (GVHD). An ST2-targeting antibody improves survival in murine GVHD models; however, development of sST2-targeting metabolism small-molecule inhibitors has remained a challenge. Using a combination of high-throughput screening, computational Tristetraprolin-mediated regulation analysis, and toxicity screening, Abdulraouf of hepatic FGF21 influences Ramadan and colleagues identified three sST2-targeting compounds with low whole-body metabolism toxicity. The most effective of these, iST2-1, reduced plasma sST2 levels, alleviated Metabolic homeostasis is a complex process that involves precise coordination of a variety of disease symptoms, and improved survival pathways and organ systems. The liver is a key player in systemic energy balance and in murine GVHD models. Moreover, iST2-1 produces several regulatory molecules, including the hormone FGF21; however, little is known maintained graft-versus-leukemia activity, about posttranscriptional regulation of hepatic metabolic factors. Konrad Sawicki, Hsiang-Chun supporting further evaluation of this Chang, Jason Shapiro, and colleagues determined that expression of the RNA-binding compound for treating diseases associated protein tristetraprolin (TTP) is increased in murine livers in response to insulin, and they with elevated sST2. found that hepatic TTP levels are reduced in the liver of both mice and humans with diabetes. Compared with WT animals, mice with liver-specific Ttp deletion had improved From proteomics to discovery glucose tolerance and peripheral insulin sensitivity in response to a high-fat diet (HFD). TTP of first-in-class ST2 inhibitors posttranscriptionally suppressed FGF21 expression, and viral-mediated Fgf21 repression in active in vivo the liver of HFD-fed TTP-deficient mice eliminated the beneficial effects of hepatic Ttp Abdulraouf M. Ramadan, Etienne Daguindau, deletion alone. Together, these results identify TTP as a regulator of hepatic metabolic Jason C. Rech, Krishnapriya Chinnaswamy, function via targeting of FGF21. Jilu Zhang, Greg L. Hura, Brad Griesenauer, Zachary Bolten, Aaron Robida, Martha Larsen, Hepatic tristetraprolin promotes insulin resistance Jeanne A. Stuckey, Chao-Yie Yang, through RNA destabilization of FGF21 and Sophie Paczesny Konrad T. Sawicki, Hsiang-Chun Chang, Jason S. Shapiro, Marina Bayeva, http://jci.me/99208 Adam De Jesus, Brian N. Finck, Jason A. Wertheim, Perry J. Blackshear, and Hossein Ardehali http://jci.me/95948

jci.org/this-month august 2018 12 JCI Insight | Editor’s picks

neuroscience Nonhuman primate model of familial Parkinson’s disease Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by impaired movement and linked to the gradual loss of dopamine delivery to the striatum, predominantly via the loss of dopaminergic neurons in the substantia nigra pars compacta. The etiology of PD is not fully understood, and current animal models do not fully recapitulate all aspects of the disease, especially congenital forms. Nadine Mestre-Francés, Nicolas Serratrice, and colleagues explored the use of canine adenovirus type 2 (CAV-2) as a potential vector for delivering PD-associated cDNAs to the CNS of the nonhuman primate Exogenous LRRK2G2019S induces parkinsonian-like Microcebus murinus, which naturally develops neurodegenerative lesions. CAV-2 pathology in a nonhuman primate vectors showed long-term neuron-specific tropism and did not induce adaptive Nadine Mestre-Francés, Nicolas Serratrice, Aurélie Gennetier, Gina Devau, immune response. Next, CAV-2 was used to deliver a PD-associated variant of Stéphanie Cobo, Stéphanie G. Trouche, Pascaline Fontès, Charleine Zussy, leucine-rich repeat kinase 2 (LRRK2G2019S). LRRK2G2019S expression induced PD-like Philippe De Deurwaerdere, Sara Salinas, Franck J.D. Mennechet, motor dysfunction and histological changes (see the accompanying image) less Julien Dusonchet, Bernard L. Schneider, Isabella Saggio, Vasiliki Kalatzis, than 4 months after injection, suggesting that this model has utility for further M. Rosario Luquin-Piudo, Jean-Michel Verdier, and Eric J. Kremer investigation of LRRK2G2019S-associated PD and potential therapies. http://jci.me/98202

genetics gastroenterology Residual activity predicts Targeting anion exchanger drug response of SLC26A3 reduces colonic cystic fibrosis mutants fluid absorption Cystic fibrosis (CF) results from mutations in the CF transmembrane conductance The anion exchanger SLC26A3 is expressed on the luminal regulator (CFTR). The development of drugs that target specific CFTR alterations has membrane of enterocytes in the colon and small intestine, and markedly improved treatment of CF patients; however, many patients express rare loss-of-function SLC26A3 mutations underlie congenital chloride- CFTR mutations, and responses of these variants to current drugs are largely unknown losing diarrhea due to impaired NaCl absorption. Peter Haggie and and untested. Garry Cutting and colleagues generated human CF bronchial epithelial colleagues screened small molecules in SLC26A3-expressing reporter lines that stably express 43 rare CFTR missense variants and evaluated their response cells and identified inhibitors of this anion exchanger. Dimethyl­ to ivacaftor, lumacaftor, and combination therapy. Drug response correlated to residual coumarin DRAinh-A250 was found to potently and reversibly inhibit CFTR function of each variant, a result that was recapitulated in Fischer rat thyroid SLC26A3 without targeting homologous anion exchangers or other

(FRT) cells expressing an additional 16 rare CFTR mutations. Moreover, the response to related proteins. In mice, DRAinh-A250 blocked fluid absorption in combination treatment for the majority of these CFTRs was greater than the response closed colonic loops but not jejunal loops. Moreover, DRAinh-A250 to single-agent treatment. The results of this study indicate that many CF patients reduced constipation in loperamide-treated WT and cystic fibrosis with missense CFTR variants will favorably respond to current drugs and that mice. These results support further investigation of DRAinh-A250 evaluation of functional activity of CFTR variants can predict drug response. for treating constipation. Residual function of cystic fibrosis mutants predicts response SLC26A3 inhibitor identified in small molecule to small molecule CFTR modulators screen blocks colonic fluid absorption Sangwoo T. Han, Andras Rab, Matthew J. Pellicore, Emily F. Davis, and reduces constipation Allison F. McCague, Taylor A. Evans, Anya T. Joynt, Zhongzhou Lu, Zhiwei Cai, Peter M. Haggie, Onur Cil, Sujin Lee, Joseph-Anthony Tan, Karen S. Raraigh, Jeong S. Hong, David N. Sheppard, Eric J. Sorscher, Amber A. Rivera, Puay-Wah Phuan, and Alan S. Verkman and Garry R. Cutting http://jci.me/121159 http://jci.me/121370

13 jci.org/this-month august 2018 Current articles

Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis Tinhinane Fali, Véronique Fabre-Mersseman, Takuya Yamamoto, Charles Bayard, Laura Papagno, Solène Fastenackels, Rima Zoorab, Richard A. Koup, Jacques Boddaert, Delphine Sauce, and Victor Appay http://jci.me/95319

Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21 p. 12 Konrad T. Sawicki, Hsiang-Chun Chang, Jason S. Shapiro, Marina Bayeva, Adam De Jesus, Brian N. Finck, Jason A. Wertheim, Perry J. Blackshear, and Hossein Ardehali http://jci.me/95948 Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation Juhyun Lee, Vijay Vedula, Kyung In Baek, Junjie Chen, Jeffrey J. Hsu, Yichen Ding, Chih-Chiang Chang, Hanul Kang, Adam Small, Peng Fei, Cheng-min Chuong, Rongsong Li, Linda Demer, René R. Sevag Packard, Alison L. Marsden, and Tzung K. Hsiai http://jci.me/96672 CTLA4 methylation predicts response to anti–PD-1 and anti–CTLA-4 immunotherapy in melanoma patients Diane Goltz, Heidrun Gevensleben, Timo J. Vogt, Joern Dietrich, Carsten Golletz, Friedrich Bootz, Glen Kristiansen, Jennifer Landsberg, and Dimo Dietrich http://jci.me/96793 Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival Geoffrey J. Markowitz, Lauren S. Havel, Michael J.P. Crowley, Yi Ban, Sharrell B. Lee, Jennifer S. Thalappillil, Navneet Narula, Bhavneet Bhinder, Olivier Elemento, Stephen T.C. Wong, Dingcheng Gao, Nasser K. Altorki, and Vivek Mittal http://jci.me/96836

Total body CD4+ T cell dynamics in treated and untreated SIV infection revealed by in vivo imaging p. 11 Michele Di Mascio, Sharat Srinivasula, Insook Kim, Gorka Duralde, Alexis St. Claire, Paula DeGrange, Marisa St. Claire, Keith A. Reimann, Erin E. Gabriel, Jorge Carrasquillo, Richard C. Reba, Chang Paik, and Henry C. Lane http://jci.me/97880 TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung Swati Bhattacharyya, Wenxia Wang, Wenyi Qin, Kui Cheng, Sara Coulup, Sherry Chavez, Shuangshang Jiang, Kirtee Raparia, Lucia Maria V. De Almeida, Christian Stehlik, Zenshiro Tamaki, Hang Yin, and John Varga http://jci.me/98850 HIV infection results in clonal expansions containing integrations within pathogenesis-related biological pathways Kevin G. Haworth, Lauren E. Schefter, Zachary K. Norgaard, Christina Ironside, Jennifer E. Adair, and Hans-Peter Kiem http://jci.me/99127 Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies John J. Brewington, Erin T. Filbrandt, F.J. LaRosa III, Jessica D. Moncivaiz, Alicia J. Ostmann, Lauren M. Strecker, and John P. Clancy http://jci.me/99385 TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy Jane Rasaiyaah, Christos Georgiadis, Roland Preece, Ulrike Mock, and Waseem Qasim http://jci.me/99442 Vaginal microbiome modulates topical antiretroviral drug pharmacokinetics Ekaterina Taneva, Shada Sinclair, Pedro M.M. Mesquita, Brian Weinrick, Scott A. Cameron, Natalia Cheshenko, Kerry Reagle, Bruce Frank, Sujatha Srinivasan, David Fredricks, Marla J. Keller, and Betsy C. Herold http://jci.me/99545 Circulating RIPK3 levels are associated with mortality and organ failure during critical illness Kevin C. Ma, Edward J. Schenck, Ilias I. Siempos, Suzanne M. Cloonan, Eli J. Finkelzstein, Maria A. Pabon, Clara Oromendia, Karla V. Ballman, Rebecca M. Baron, Laura E. Fredenburgh, Angelica Higuera, Jin Young Lee, Chi Ryang Chung, Kyeongman Jeon, Jeong Hoon Yang, Judie A. Howrylak, Jin-Won Huh, Gee Young Suh, and Augustine M.K. Choi http://jci.me/99692 Defective BTLA functionality is rescued by restoring lipid metabolism in lupus CD4+ T cells Matthieu Sawaf, Jean-Daniel Fauny, Renaud Felten, Flora Sagez, Jacques-Eric Gottenberg, Hélène Dumortier, and Fanny Monneaux http://jci.me/99711 Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing Omar H. Maarouf, Mayuko Uehara, Vivek Kasinath, Zhabiz Solhjou, Naima Banouni, Baharak Bahmani, Liwei Jiang, Osman A. Yilmam, Indira Guleria, Scott B. Lovitch, Jane L. Grogan, Paolo Fiorina, Peter T. Sage, Jonathan S. Bromberg, Martina M. McGrath, and Reza Abdi http://jci.me/120546

jci.org/this-month august 2018 14 Current articles

Meta-analysis of RNA sequencing datasets reveals an association between TRAJ23, psoriasis, and IL-17A p. 12 Alexander A. Merleev, Alina I. Marusina, Chelsea Ma, James T. Elder, Lam C. Tsoi, Siba Raychauduri, Stephan Weidinger, Elizabeth A. Wang, Iannis E. Adamopoulos, Guillaume Luxardi, Johann E. Gudjonsson, Michiko Shimoda, and Emanual Maverakis http://jci.me/120682 Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia Sungsam Gong, Ulla Sovio, Irving L.M.H. Aye, Francesca Gaccioli, Justyna Dopierala, Michelle D. Johnson, Angela M. Wood, Emma Cook, Benjamin J. Jenkins, Albert Koulman, Robert A. Casero Jr., Miguel Constância, D. Stephen Charnock-Jones, and Gordon C.S. Smith http://jci.me/120723 Safety and immunogenicity of an oral tablet norovirus vaccine, a phase I randomized, placebo-controlled trial Leesun Kim, David Liebowitz, Karen Lin, Kassandra Kasparek, Marcela F. Pasetti, Shaily J. Garg, Keith Gottlieb, George Trager, and Sean N. Tucker http://jci.me/121077 Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment Mary K. McCarthy, Bennett J. Davenport, Glennys V. Reynoso, Erin D. Lucas, Nicholas A. May, Susan A. Elmore, Beth A. Tamburini, Heather D. Hickman, and Thomas E. Morrison http://jci.me/121100 Concurrent cell type–specific isolation and profiling of mouse brains in inflammation and Alzheimer’s disease Dan B. Swartzlander, Nicholas E. Propson, Ethan R. Roy, Takashi Saito, Takaomi Saido, Baiping Wang, and Hui Zheng http://jci.me/121109 Antibody-modified conduits for highly selective cytokine elimination from blood J. Brian McAlvin, Ryan G. Wylie, Krithika Ramchander, Minh T. Nguyen, Charles K. Lok, Morgan Moroi, Andre Shomorony, Nikolay V. Vasilyev, Patrick Armstrong, Jason Yang, Alexander M. Lieber, Obiajulu S. Okonkwo, Rohit Karnik, and Daniel S. Kohane http://jci.me/121133 Plasma copeptin and chronic kidney disease risk in 3 European cohorts from the general population Ray El Boustany, Irina Tasevska, Esther Meijer, Lyanne M. Kieneker, Sofia Enhörning, Guillaume Lefèvre, Kamel Mohammed, Michel Marre, Frédéric Fumeron, Beverly Balkau, Nadine Bouby, Lise Bankir, Stephan J.L. Bakker, Ronan Roussel, Olle Melander, Ron T. Gansevoort, and Gilberto Velho http://jci.me/121479

Brain-wide glymphatic enhancement and clearance in humans assessed with MRI p. 10 Geir Ringstad, Lars M. Valnes, Anders M. Dale, Are H. Pripp, Svein-Are S. Vatnehol, Kyrre E. Emblem, Kent-Andre Mardal, and Per K. Eide http://jci.me/121537 Overview of inactivating mutations in the protein-coding genome of the mouse reference strain C57BL/6J Steven Timmermans and Claude Libert http://jci.me/121758 T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma p. 11 Alexander C. Hopkins, Mark Yarchoan, Jennifer N. Durham, Erik C. Yusko, Julie A. Rytlewski, Harlan S. Robins, Daniel A. Laheru, Dung T. Le, Eric R. Lutz, and Elizabeth M. Jaffee http://jci.me/122092 Hnf4a deletion in the mouse kidney phenocopies Fanconi renotubular syndrome Sierra S. Marable, Eunah Chung, Mike Adam, S. Steven Potter, and Joo-Seop Park http://jci.me/97497

Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate p. 13 Nadine Mestre-Francés, Nicolas Serratrice, Aurélie Gennetier, Gina Devau, Stéphanie Cobo, Stéphanie G. Trouche, Pascaline Fontès, Charleine Zussy, Philippe De Deurwaerdere, Sara Salinas, Franck J.D. Mennechet, Julien Dusonchet, Bernard L. Schneider, Isabella Saggio, Vasiliki Kalatzis, M. Rosario Luquin-Piudo, Jean-Michel Verdier, and Eric J. Kremer http://jci.me/98202 Aldosterone deficiency in mice burdens respiration and accentuates diet-induced hyperinsulinemia and obesity Wan-Hui Liao, Claudia Suendermann, Andrea Eva Steuer, Gustavo Pacheco Lopez, Alex Odermatt, Nourdine Faresse, Maciej Henneberg, and Wolfgang Langhans http://jci.me/99015

From proteomics to discovery of first-in-class ST2 inhibitors active in vivo p. 12 Abdulraouf M. Ramadan, Etienne Daguindau, Jason C. Rech, Krishnapriya Chinnaswamy, Jilu Zhang, Greg L. Hura, Brad Griesenauer, Zachary Bolten, Aaron Robida, Martha Larsen, Jeanne A. Stuckey, Chao-Yie Yang, and Sophie Paczesny http://jci.me/99208

11 jci.org/this-month august 2018 The mutational landscape of recurrent versus nonrecurrent human papillomavirus–related oropharyngeal cancer R. Alex Harbison, Mark Kubik, Eric Q. Konnick, Qing Zhang, Seok-Geun Lee, Heuijoon Park, Jianan Zhang, Christopher S. Carlson, Chu Chen, Stephen M. Schwartz, Cristina P. Rodriguez, Umamaheswar Duvvuri, and Eduardo Méndez http://jci.me/99327 Extreme erythrocyte macrocytic and microcytic percentages are highly predictive of morbidity and mortality Benjamin D. Horne, Joseph B. Muhlestein, Sterling T. Bennett, Joseph Boone Muhlestein, Kurt R. Jensen, Diane Marshall, Tami L. Bair, Heidi T. May, John F. Carlquist, Matthew Hegewald, Stacey Knight, Viet T. Le, T. Jared Bunch, Donald L. Lappé, Jeffrey L. Anderson, and Kirk U. Knowlton http://jci.me/120183 Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes Divya Ramnath, Katharine M. Irvine, Samuel W. Lukowski, Leigh U. Horsfall, Zhixuan Loh, Andrew D. Clouston, Preya Patel, Kevin J. Fagan, Abishek Iyer, Guy Lampe, Jennifer L. Stow, Kate Schroder, David P. Fairlie, Joseph E. Powell, Elizabeth E. Powell, and Matthew J. Sweet http://jci.me/120274 The RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma Orsi Giricz, Yongkai Mo, Kimberly B. Dahlman, Xiomaris M. Cotto-Rios, Chiara Vardabasso, Hoa Nguyen, Bernice Matusow, Matthias Bartenstein, Veronika Polishchuk, Douglas B. Johnson, Tushar D. Bhagat, Rafe Shellooe, Elizabeth Burton, James Tsai, Chao Zhang, Gaston Habets, John M. Greally, Yiting Yu, Paraic A. Kenny, Gregg B. Fields, Kith Pradhan, E. Richard Stanley, Emily Bernstein, Gideon Bollag, Evripidis Gavathiotis, Brian L. West, Jeffrey A. Sosman, and Amit K. Verm http://jci.me/120422 FGFR1 underlies obesity-associated progression of estrogen receptor–positive breast cancer after estrogen deprivation Elizabeth A. Wellberg, Peter Kabos, Austin E. Gillen, Britta M. Jacobsen, Heather M. Brechbuhl, Stevi J. Johnson, Michael C. Rudolph, Susan M. Edgerton, Ann D. Thor, Steven M. Anderson, Anthony Elias, Xi Kathy Zhou, Neil M. Iyengar, Monica Morrow, Domenick J. Falcone, Omar El-Hely, Andrew J. Dannenberg, Carol A. Sartorius, and Paul S. MacLean http://jci.me/120594 Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes Jasmine C. Wong, Victoria Bryant, Tamara Lamprecht, Jing Ma, Michael Walsh, Jason Schwartz, Maria del pilar Alzamora, Charles G. Mullighan, Mignon L. Loh, Raul Ribeiro, James R. Downing, William L. Carroll, Jeffrey Davis, Stuart Gold, Paul C. Rogers, Sara Israels, Rochelle Yanofsky, Kevin Shannon, and Jeffery M. Klco http://jci.me/121086 CD226 opposes TIGIT to disrupt Tregs in melanoma Julien Fourcade, Zhaojun Sun, Joe-Marc Chauvin, Mignane Ka, Diwakar Davar, Ornella Pagliano, Hong Wang, Sofiane Saada, Carmine Menna, Rada Amin, Cindy Sander, John M. Kirkwood, Alan J. Korman, and Hassane M. Zarour http://jci.me/121157

Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators p. 13 Sangwoo T. Han, Andras Rab, Matthew J. Pellicore, Emily F. Davis, Allison F. McCague, Taylor A. Evans, Anya T. Joynt, Zhongzhou Lu, Zhiwei Cai, Karen S. Raraigh, Jeong S. Hong, David N. Sheppard, Eric J. Sorscher, and Garry R. Cutting http://jci.me/121159 Cachexia’s adipose loss induced by tumor-secreted leukemia inhibitory factor is counterbalanced by decreased leptin Gurpreet Arora, Arun Gupta, Sriram Narayanan, Tong Guo, Puneeth Iyengar, and Rodney Infante http://jci.me/121221 SLC26A3 inhibitor identified in small molecule screen blocks colonic fluid absorption and reduces constipation p. 13 Peter M. Haggie, Onur Cil, Sujin Lee, Joseph-Anthony Tan, Amber A. Rivera, Puay-Wah Phuan, and Alan S. Verkman http://jci.me/121370 Site-1 protease deficiency causes human skeletal dysplasia due to defective inter-organelle protein trafficking Yuji Kondo, Jianxin Fu, Hua Wang, Christopher Hoover, J. Michael McDaniel, Richard Steet, Debabrata Patra, Jianhua Song, Laura Pollard, Sara Cathey, Tadayuki Yago, Graham Wiley, Susan Macwana, Joel Guthridge, Samuel McGee, Shibo Li, Courtney Griffin, Koichi Furukawa, Judith A. James, Changgeng Ruan, Rodger P. McEver, Klaas J. Wierenga, Patrick M. Gaffney, and Lijun Xia http://jci.me/121596 Inhibiting neutral amino acid transport for the treatment of phenylketonuria Adam M. Belanger, Malgorzata Przybylska, Estelle Gefteas, Matthew Furgerson, Sarah Geller, Alla Kloss, Seng H. Cheng, Yunxiang Zhu, and Nelson S. Yew http://jci.me/121762 Flip issue to read JCI content.

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