this month - amazon web services · tejwani v, d’alessio fr. transcriptional signature in...
TRANSCRIPT
jci.org/this-month
SIRT1 supports leukemic stem cell maintenance 3
Impairing autophagy stunts lung development 3
Opioid-galanin receptors disassociate analgesia and euphoria 4
tRNA fragments predict seizure onset 4
JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
Scan for the digital version of JCI This Month.
July 2019
Controlling formation of deep vein thrombi p. 2
This Month
APPLICATIONS NOW BEING ACCEPTED
© 2018 Gilead Sciences, Inc. All rights reserved.Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc.
Supporting innovative scientific research that will advanceknowledge in the field of hematology/oncology,
with a focus on hematologic malignancies, that can be eitherbased around a clinical trial with strong correlative science or a
laboratory investigation, and provide support for research careerdevelopment for young researchers in Canada or the United States
Each award will be funded up to USD1 30,000, to be paidin annual installments of up to USD65,000
Awards are subject to separate terms and conditions
For more program information, and to submit an application,please visit the website:
http://researchscholars.gilead.comClick on the hematology/oncology program logo
Gilead SciencesResearch Scholars ProgramIn Hematology/Oncology
SCIENTIFIC REVIEW COMMITTEEApplications will be reviewed by a Committee ofinternationally recognized experts in basic and
clinical research in the field of hematology/oncology
Deadline for application submission isSeptember 6, 2019 11:59 PM, Pacific Daylight Time
Deadline for application submission isSeptember 6, 2019 11:59 PM, Pacific Daylight Time
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 9 1
For the JCIEditorRexford S. Ahima
Deputy EditorsArturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli
Associate EditorsMark E. Anderson, Mary Y. Armanios, Joel N. Blankson, William R. Bishai, Robert A. Brodsky, Peter A. Calabresi, Thomas L. Clemens, Franco R. D’Alessio, Ted M. Dawson, Angelo M. DeMarzo, Stephen Desiderio, Mark Donowitz, Andrew P. Feinberg, Paul M. Hassoun, Maureen R. Horton, Elizabeth M. Jaffee, Mariana J. Kaplan, Marikki Laiho, Leo Luznik, Marcela V. Maus, Timothy H. Moran, Laszlo Nagy, William Nelson, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, Thomas C. Quinn, Hamid Rabb, Jean-Pierre Raufman, Stuart C. Ray, Linda Smith Resar, Jeffrey D. Rothstein, Jonathan Schneck, Akrit S. Sodhi, Charlotte J. Sumner, Simeon I. Taylor, Robert G. Weiss, Sarah J. Wheelan, Marsha Wills-Karp
Editorial Advisory GroupPeter Agre, Carol W. Grieder, Diane E. Griffin, Paul B. Rothman, David Valle
BiostatisticianEliseo Guallar
Computational BiologistPatrick Cahan
JCI ScholarsAnthony Bowen, Olurotimi Mesubi
StaffExecutive EditorSarah C. Jackson
Senior Science EditorCorinne Williams
Science EditorElyse Dankoski
Editorial Board CoordinatorMonika Deshpande
Editor at LargeUshma S. Neill
JCI This Month ISSN 2324-7703 (print);ISSN 2325-4556 (online)
For the full JCI online: jci.me/129/7
This MonthJuly 2019
Contact the JCI and JCI Insight2015 Manchester Road, Ann Arbor, Michigan 48104, USAPhone: 734.222.6050Email: [email protected] (JCI); [email protected] (JCI Insight)
The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation and JCI Insight. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.
(ASCI) indicates corresponding authors who are ASCI members.
The JCI’s Editorial Board is composed of peer scientists at Johns Hopkins University School of Medicine, the University of Maryland School of Medicine, and the National Institutes of Health. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.
Featured Editor
Franco D’Alessio, MD, Associate Editor, is Assistant Professor of Medicine at Johns Hopkins University School of Medicine. His research focuses on immunological mechanisms underlying resolution of lung inflammation and injury. His work has uncovered a critical role for Tregs and pro-repair macrophages in controlling excessive innate immune responses in the lung to mediate resolu-tion of lung injury. Resolution of lung inflammation is an active process, distinct from early injury, in which Tregs’
cellular interactions with alveolar macrophages, alveolar epithelium, and other lymphocytes orchestrate a series of events that ultimately lead to lung repair. While cell-based therapy using Tregs represents a therapeutic strategy for acute respiratory distress syndrome (ARDS), strategies to augment their endogenous pro-repair function represent more feasible approaches to enhance resolution and improve ARDS outcomes. Dr. D’Alessio and fellow Associate Editor Dr. Hamid Rabb organized this issue’s Review series on Reparative Immunology (p. 6) and coauthored an article in the series.
Publication highlights
D’Alessio FR, Kurzhagen JT, Rabb H. Reparative T lymphocytes in organ injury. J Clin Invest. 2019;129(7):2608–2618.
Tejwani V, D’Alessio FR. Transcriptional signature in alveolar macrophages dictates ARDS outcomes [published online ahead of print May 19, 2019]. Am J Respir Crit Care Med. doi: 10.1164/rccm.201905-0952ED.
Mock JR, Garibaldi BT, Aggarwal NR, Jenkins J, Limjunyawong N, Singer BD, D'Alessio, F. Foxp3 regulatory T cells promote lung epithelial proliferation. Mucosal Immunol. 2014;7(6):1440–1451.
Singer BD, Mock JR, Aggarwal NR, Garibaldi BT, Sidhaye VK, Florez MA, D’Alessio, F. Regulatory T cell DNA methyltransferase inhibition accelerates resolution of lung inflam-mation. Am J Respir Cell Mol Biol. 2015;52(5):641–652.
D’Alessio F, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, Pipeling MR, Brower RG, Tuder RM, McDyer JF, King LS. CD4+CD25+Foxp3+ Tregs resolve experi-mental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119(10):2898–913.
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 92
research
Editor’s picks
on the jci cover vascular biology
ATP-hydrolyzing enzyme CD39 controls inflammasome IL-1β–mediated deep vein thrombosis
Immunoglobulin free light chains trigger progressive kidney injury
ENTPD-1 disrupts inflammasome IL-1β–driven venous thrombosisVinita Yadav, Liguo Chi, Raymond Zhao, Benjamin E. Tourdot, Srilakshmi Yalavarthi, Benjamin N. Jacobs, Alison Banka, Hui Liao, Sharon Koonse, Anuli C. Anyanwu, Scott H. Visovatti, Michael A. Holinstat, J. Michelle Kahlenberg, Jason S. Knight, David J. Pinsky, and Yogendra Kanthi http://jci.me/124804
Blood clots that form in the deep veins of the legs pose a risk for pulmonary embolism and other adverse cardiovascular events. These deep venous thrombi are the result of dysregulated coagulation that may be exacerbated by trauma, infection, or other inflammatory conditions. Despite the relatively high incidence of deep vein thrombosis (DVT) and its association with serious risks, little is known about the molecular pathways provoking it. In this issue of the JCI, Vinita Yadav, Liguo Chi, and colleagues investigated the role of the enzyme CD39 (also known as ENTPD-1) in venous thrombogenesis. From its position on the surface of circulating leukocytes and vascular endothelial cells, CD39 hydrolyzes ATP and ADP, thereby limiting inflammation associated with these locally circulating “danger signals.” In a model of flow-restricted venous thrombosis, the researchers observed that CD39 haploinsufficiency increased the incidence, size, and fibrin content of clots and increased neutrophil production of extracellular traps. Mechanistically, enhancement of NLRP3 inflammasome activation in CD39-deficient mice led to increases in circulating IL-1β, which mediated the increase in venous thrombogenesis. Blocking IL-1β markedly reduced venous thrombogenesis. These insights into the pivotal roles of CD39 and the inflammasome in regulating vascular thrombosis and inflammation point to potential interventions for DVT in high-risk individuals. The cover image depicts a fibrin- and NET-tethered neutrophil releasing IL-1β to prime a nearby cell, represent-ing its participation in a chain of self-propagating inflammation within the blood vessel. Image credit: Ella Maru and Alexander Tokarev.
nephrology
Chronic kidney disease induced by immunoglobulin free light chains (FLCs) is common in patients with multiple myeloma and severely worsens prognosis. Wei-Zhong Ying, Xingsheng Li, and colleagues discovered that renal FLC metabolism activates a redox-sensitive pathway that promotes kidney injury, inflammation, and fibrosis. In human kidney cells, they demon-strated that hydrogen peroxide generated by the VL domain of monoclonal κ ad λ FLCs activates JAK2/STAT1 signaling, leading to production of proinflammatory and profibrotic effectors in the kidney proximal tubule. The observations were confirmed in vivo, where the team showed that Stat1-deficient mice were protected from FLC-induced nephropathy. The accompanying Commentary by Erin Taylor and Michael Ryan discusses these
insights into the pathogenesis of kidney injury in multiple myeloma as well as other diseases associated with elevated circulating FLCs.
Immunoglobulin light chains generate proinflammatory and profibrotic kidney injuryWei-Zhong Ying, Xingsheng Li, Sunil Rangarajan, Wenguang Feng, Lisa M. Curtis, and Paul W. Sanders (ASCI) http://jci.me/125517
Related CommentaryFreedom isn’t always free: immunoglobulin free light chains promote renal fibrosisErin B. Taylor and Michael J. Ryan http://jci.me/129704
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 9 3
JCI | Research: Editor’s picks
pulmonology
hematology
Autophagy’s vital role in fetal lung development
SIRT1 enhances leukemic stem cell metabolism and persistenceBCR-ABL tyrosine kinase inhibitors can induce remission in chronic myeloid leukemia (CML), but prolonged treatment is required to prevent disease recurrence because leukemic stem cells (LSCs) resist elimination. Studies of both chronic and acute myeloid leukemia suggest that overexpression of the deacetylase SIRT1 may play a key role in enhancing LSC persistence. Ajay Abraham, Shaowei Qiu, and colleagues reveal that SIRT1’s deacetylation of PGC-1α boosts oxidative phosphorylation in CML LSCs. Notably, SIRT1’s enhancement of LSC metabolism occurred independently of BCR-ABL kinase. In the absence of SIRT1 expression, CML develop-ment was delayed and tyrosine kinase inhibitors more effectively inhibited CML hematopoiesis. This demonstration of SIRT1’s contribution to LSC maintenance provides a rationale for studying its impact on metabolism in other hematological malignancies.
SIRT1 regulates metabolism and leukemogenic potential in CML stem cellsAjay Abraham, Shaowei Qiu, Balu K. Chacko, Hui Li, Andrew Paterson, Jianbo He, Puneet Agarwal, Mansi Shah, Robert Welner, Victor M. Darley-Usmar, and Ravi Bhatia (ASCI) http://jci.me/127080
Aberrant α-spectrin splicing implicated in recessive form of hemolytic anemiaHemolysis in hereditary spherocytosis (HS), the most common inherited hemolytic anemia in Northern Europeans, is sometimes linked to deficiency in α-spectrin, a scaffolding protein that supports erythrocyte membrane integrity and flexibility. While mutations leading to HS in patients with dominant inheritance have been identified, the pathogenesis of α-spectrin deficiency in recessive HS remains unknown. Patrick Gallagher and colleagues characterized a rare intronic variant of SPTA1 (encoding α-spectrin) that was identified in a group of recessive HS probands. Their analyses suggest that the variant drives abnormal splicing of SPTA1 mRNA, creating an elongated transcript. They further demonstrate that the elongated variant triggers nonsense-mediated decay, leading to α-spectrin deficiency in affected erythrocytes. Narla Mohandas’ accompanying Commen-tary characterizes these alternate splicing mechanisms as a potential therapeutic target for some individuals with recessive HS.
Aberrant splicing contributes to severe α-spectrin–linked congenital hemolytic anemiaPatrick G. Gallagher (ASCI), Yelena Maksimova, Kimberly Lezon-Geyda, Peter E. Newburger, Desiree Medeiros, Robin D. Hanson, Jennifer Rothman, Sara Israels, Donna A. Wall, Robert F. Sidonio Jr., Colin Sieff, L. Kate Gowans, Nupur Mittal, Roland Rivera-Santiago, David W. Speicher, Susan J. Baserga, and Vincent P. Schulz http://jci.me/127195
Related CommentaryAnemia lurking in intronsNarla Mohandas http://jci.me/129443
Extremely preterm infants are at risk of developing bronchopulmonary dysplasia (BPD), a severe chronic lung disease that has been linked to interrupted lung development. Maturation of the lung’s branching epithelial and microvasculature structures requires precise coordination of cellular proliferation, differentiation, and metabolism. In this issue, Behzad Yeganeh and colleagues observed that autophagy-related proteins, including beclin-1 and LC3B-II, were upregulated during two stages of lung development (see the associated image). At both stages, upregulation of autophagy was linked to increased activation of the cellular energy sensor AMPK. Pharmacological and epithelium-specific genetic inhibition of autophagy lethally impaired lung development and recapitulated pathological features of infant BPD. In the accompanying Commentary, David Warburton and Saverio Bellusci outline the critical role of autophagy in normal lung development and implicate deficient autophagy as a possible driver of BPD in premature infants.
Autophagy is required for lung development and morphogenesisBehzad Yeganeh, Joyce Lee, Leonardo Ermini, Irene Lok, Cameron Ackerley, and Martin Post http://jci.me/127307
Related CommentaryNormal lung development needs self-eatingDavid Warburton and Saverio Bellusci http://jci.me/129442
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 94
JCI | Research: Editor’s picks
tRNA fragments increase prior to seizures in human epilepsy patientsUnpredictable seizures in treatment-refractory epilepsy pose a substantial safety risk to patients. Recent insights suggest that circulating levels of noncoding RNAs, particularly fragments derived from transfer RNA (tRNA), may represent useful biomarkers to predict seizure onset. Marion Hogg and colleagues collected blood samples from 16 patients with refractory focal epilepsy undergoing simultaneous EEG monitoring to assess the relative abundance of tRNA fragments before and after a recorded seizure. tRNA fragments were markedly increased in blood samples obtained prior to a seizure relative to control and post-seizure samples. In a validation cohort, tRNA fragments reliably distinguished pre- and post-seizure blood samples, indicating that these fragments may represent a valuable biomarker for predicting seizure onset.
Elevation of plasma tRNA fragments precedes seizures in human epilepsyMarion C. Hogg, Rana Raoof, Hany El Naggar, Naser Monsefi, Norman Delanty, Donncha F. O’Brien, Sebastian Bauer, Felix Rosenow, David C. Henshall, and Jochen H.M. Prehn http://jci.me/126346
neuroscience
Properties of morphine and methadone diverge at opioid–galanin receptor heteromersThe escalating abuse of µ-opioid receptor–targeting (MOR-targeting) painkillers such as morphine and oxycodone has motivated the search for medications that dissociate the analgesic and euphoric effects of opiates. Methadone, another MOR agonist, has long been used as a maintenance therapy in opioid use disorder because it lacks euphoric effects, but this property is not fully understood. A study from Sergi Ferré’s laboratory links methadone’s unique pharmacodynamics to the interaction of MOR with galanin-1 receptors (Gal1Rs). In rats, heteromerization between MOR and Gal1Rs mitigated the ability of methadone, but not morphine or other addictive MOR agonists, to stimulate dopamine release in the brain’s reward pathway. The associated image compares increases in rat forebrain metabolic activity induced by morphine (top) and methadone (bottom). In the accompanying Commentary, Randal Serafini and Venetia Zachariou support the investigation of MOR-Gal1R heteromers as targets for potentially safer analgesic strategies in individuals with chronic pain.
Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioidsNing-Sheng Cai, César Quiroz, Jordi Bonaventura, Alessandro Bonifazi, Thomas O. Cole, Julia Purks, Amy S. Billing, Ebonie Massey, Michael Wagner, Eric D. Wish, Xavier Guitart, William Rea, Sherry Lam, Estefanía Moreno, Verònica Casadó-Anguera, Aaron D. Greenblatt, Arthur E. Jacobson, Kenner C. Rice, Vicent Casadó, Amy H. Newman, John W. Winkelman, Michael Michaelides, Eric Weintraub, Nora D. Volkow, Annabelle M. Belcher, and Sergi Ferré http://jci.me/126912
Related CommentaryOpioid–galanin receptor heteromers differentiate the dopaminergic effects of morphine and methadoneRandal A. Serafini and Venetia Zachariou http://jci.me/128987
A D V E R T I S E M E N T
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 9 5
JCI | Research: Editor’s picks
cardiology
Mitochondrial dysfunction contributes to ciliopathy-linked heterotaxyCilia are known to play a role in establishing left-right asymmetry, and mutations in genes regulating cilia development and function are implicated in heterotaxy, a condition characterized by irregular orientation of organs. Martin Burkhalter and colleagues observed reduced mitochondrial DNA content in heterotaxy patients relative to healthy controls, and exome analysis identified rare variants in mitochondria-associated candidate genes in these patients. Knock down of the candidate genes increased the length of cilia in human fibroblasts (see the associated image). Similarly, ciliopathy phenotypes and elongated cilia were observed in candidate gene–deficient zebrafish embryos, features that could not be rescued by the identified patient variants. Overall, rare variant burden was higher in mitochondrial gene sets than in unrelated gene sets. In the accompanying Commentary, Bill Chaudhry and Deborah Henderson contextualize the implications of mitochondrial dysfunction as a cause for heterotaxy.
Imbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesisMartin D. Burkhalter, Arthi Sridhar, Pedro Sampaio, Raquel Jacinto, Martina S. Burczyk, Cornelia Donow, Max Angenendt, Competence Network for Congenital Heart Defects Investigators, Maja Hempel, Paul Walther, Petra Pennekamp, Heymut Omran, Susana S. Lopes, Stephanie M. Ware (ASCI), and Melanie Philipp http://jci.me/98890
Related CommentaryCilia, mitochondria, and cardiac developmentBill Chaudhry and Deborah J. Henderson http://jci.me/129827
oncology
Pretreatments limiting surgery-induced inflammation prevent tumor progression and metastasisInflammation induced by front-line cancer therapies, including surgical resection, chemotherapy, and radiation, can paradoxically promote cancer progression by impairing antitumor immunity. Dipak Panigrahy, Allison Gartung, Jun Yang, and colleagues explored the hypothesis that limiting inflammation or accelerating its resolution in combination with other anticancer approaches can prevent therapy-stimulated tumor progression and metastasis. Using metastasis-prone murine models of lung and breast cancer, the authors showed that preoperative treatment with the NSAID ketorolac substantially reduced surgically stimulated micrometastases by inhibiting COX-1/TXA2–mediated platelet aggregation. Ketorolac’s effects were enhanced by immune-checkpoint blockade and mitigated by adjuvant chemotherapy. Moreover, combined pretreatment with ketorolac and specialized proresolving lipid mediators synergized to prevent both surgery- and chemotherapy-stimulated metastasis and tumor recurrence. Esra Güç and Jeffrey Pollard call for further investigation of inflammation-
limiting and proresolving strategies to block the adverse effects of standard cancer approaches in the accompanying Commentary.
Preoperative stimulation of resolution and inflammation blockade eradicates micrometastasesåDipak Panigrahy, Allison Gartung, Jun Yang, Haixia Yang, Molly M. Gilligan, Megan L. Sulciner, Swati S. Bhasin, Diane R. Bielenberg, Jaimie Chang, Birgitta A. Schmidt, Julia Piwowarski, Anna Fishbein, Dulce Soler-Ferran, Matthew A. Sparks, Steven J. Staffa, Vidula Sukhatme, Bruce D. Hammock, Mark W. Kieran, Sui Huang, Manoj Bhasin, Charles N. Serhan, and Vikas P. Sukhatme http://jci.me/127282
Related CommentaryDampening the fire to prevent surgery- and chemotherapy–induced metastasisEsra Güç and Jeffrey W. Pollard http://jci.me/129705
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 96
JCI | Review Series
Immune cells to the rescue: innate and adaptive contributions to tissue repair
JCI Review Series
Reparative ImmunologySeries Editors: Hamid Rabb and Franco R. D’Alessio
The immune system mounts a rapid inflammatory response to injury to mobilize cells and molecular pathways that promote hemostasis and prevent infection, but this acute response is only the first phase of recovery. Wound repair and inflammation-resolving processes are essential to recovering homeostasis in the aftermath of an injury: inefficient healing or prolonged inflammation can drive chronic dysfunction in the affected tissue. In this issue, the Reparative Immunology series highlights the immune system’s contributions to these critical repair processes. Curated by JCI
Associate Editors Hamid Rabb and Franco D’Alessio, the Reviews cover the roles of T cells, macrophages, neutrophils, and innate lymphoid cells in physiological repair and pathological outcomes of injury. Together, the Reviews emphasize the complexity of the immune environment in injured tissue and indicate numerous potential opportunities to intervene in dysfunctional wound healing. In the featured image, Benjamin Singer and Navdeep Chandel show an alveolus affected by acute respiratory syndrome to illustrate metabolic features of the injured tissue microenvironment.
Immunometabolism of pro-repair cellsBenjamin D. Singer and Navdeep S. Chandel http://jci.me/124613
Reparative T lymphocytes in organ injuryFranco R. D’Alessio, Johanna T. Kurzhagen, and Hamid Rabb http://jci.me/124614
The role of macrophages in the resolution of inflammationSatoshi Watanabe, Michael Alexander, Alexander V. Misharin, and G.R. Scott Budinger (ASCI) http://jci.me/124615
More friend than foe: the emerging role of neutrophils in tissue repairMoritz Peiseler and Paul Kubes http://jci.me/124616
The balance of power: innate lymphoid cells in tissue inflammation and repairJim G. Castellanos and Randy S. Longman http://jci.me/124617
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 9 7
Current research articles
Human fibroblast with primary cilium
Human intestinal epithelium
DC-deficient bone marrow
cardiologyImbalanced mitochondrial function provokes heterotaxy via aberrant ciliogenesis p. 5Martin D. Burkhalter, Arthi Sridhar, Pedro Sampaio, Raquel Jacinto, Martina S. Burczyk, Cornelia Donow, Max Angenendt, Competence Network for Congenital Heart Defects Investigators, Maja Hempel, Paul Walther, Petra Pennekamp, Heymut Omran, Susana S. Lopes, Stephanie M. Ware (ASCI), and Melanie Philipp http://jci.me/98890
gastroenterologyNeurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel diseaseMichael Meir, Natalie Burkard, Hanna Ungewiß, Markus Diefenbacher, Sven Flemming, Felix Kannapin, Christoph-Thomas Germer, Matthias Schweinlin, Marco Metzger, Jens Waschke, and Nicolas Schlegel http://jci.me/120261
hematologyBone marrow dendritic cells regulate hematopoietic stem/ progenitor cell traffickingJingzhu Zhang, Teerawit Supakorndej, Joseph R. Krambs, Mahil Rao, Grazia Abou-Ezzi, Rachel Y. Ye, Sidan Li, Kathryn Trinkaus, and Daniel C. Link (ASCI) http://jci.me/124829
SIRT1 regulates metabolism and leukemogenic potential in CML stem cells p. 3Ajay Abraham, Shaowei Qiu, Balu K. Chacko, Hui Li, Andrew Paterson, Jianbo He, Puneet Agarwal, Mansi Shah, Robert Welner, Victor M. Darley-Usmar, and Ravi Bhatia (ASCI) http://jci.me/127080
Aberrant splicing contributes to severe α-spectrin–linked congenital hemolytic anemia p. 3Patrick G. Gallagher (ASCI), Yelena Maksimova, Kimberly Lezon-Geyda, Peter E. Newburger, Desiree Medeiros, Robin D. Hanson, Jennifer Rothman, Sara Israels, Donna A. Wall, Robert F. Sidonio Jr., Colin Sieff, L. Kate Gowans, Nupur Mittal, Roland Rivera-Santiago, David W. Speicher, Susan J. Baserga, and Vincent P. Schulz http://jci.me/127195
hepatologyPregnane X receptor activation potentiates ritonavir hepatotoxicityAmina I. Shehu, Jie Lu, Pengcheng Wang, Junjie Zhu, Yue Wang, Da Yang, Deborah McMahon, Wen Xie, Frank J. Gonzalez, and Xiaochao Ma http://jci.me/128274
immunologyT cell receptor grafting allows virological control of hepatitis B virus infectionKarin Wisskirchen, Janine Kah, Antje Malo, Theresa Asen, Tassilo Volz, Lena Allweiss, Jochen M. Wettengel, Marc Lütgehetmann, Stephan Urban, Tanja Bauer, Maura Dandri, and Ulrike Protzer http://jci.me/120228
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 98
Current research articles
Hippocampal Drp1 expression
Chaperone protein HSC70 regulates intercellular transfer of Y chromosome antigen DBYSascha Kretschmann, Stefanie Herda, Heiko Bruns, Josefine Russ, Edith D. van der Meijden, Ursula Schlötzer-Schrehardt, Marieke Griffioen, Il-Kang Na, Andreas Mackensen, and Anita N. Kremer http://jci.me/123105
Dendritic cell NLRC4 regulates influenza A virus–specific CD4+ T cell responses through FasL expressionEmma E. Hornick, Jargalsaikhan Dagvadorj, Zeb R. Zacharias, Ann M. Miller, Ryan A. Langlois, Peter Chen, Kevin L. Legge, Gail A. Bishop, Fayyaz S. Sutterwala (ASCI), and Suzanne L. Cassel http://jci.me/124937
Dok3–protein phosphatase 1 interaction attenuates Card9 signaling and neutrophil-dependent antifungal immunityJia Tong Loh, Shengli Xu, Jian Xin Huo, Susana Soo-Yeon Kim, Yue Wang, and Kong-Peng Lam http://jci.me/126341
USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenanceYu Zhang, Rong-bei Liu, Qian Cao, Ke-qi Fan, Ling-jie Huang, Jian-shuai Yu, Zheng-jun Gao, Tao Huang, Jiang-yan Zhong, Xin-tao Mao, Fei Wang, Peng Xiao, Yuan Zhao, Xin-hua Feng, Yi-yuan Li, and Jin Jin http://jci.me/123801
inflammationTranscription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritisNicole Hannemann, Shan Cao, Daniel Eriksson, Anne Schnelzer, Jutta Jordan, Martin Eberhardt, Ulrike Schleicher, Jürgen Rech, Andreas Ramming, Steffen Uebe, Arif Ekici, Juan D. Cañete, Xiaoxiang Chen, Tobias Bäuerle, Julio Vera, Christian Bogdan, Georg Schett, and Aline Bozec http://jci.me/96832
nephrologyImmunoglobulin light chains generate proinflammatory and profibrotic kidney injury p. 2Wei-Zhong Ying, Xingsheng Li, Sunil Rangarajan, Wenguang Feng, Lisa M. Curtis, Paul W. Sanders (ASCI) http://jci.me/125517
Drp1S600 phosphorylation regulates mitochondrial fission and progression of nephropathy in diabetic miceDaniel L. Galvan, Jianyin Long, Nathanael Green, Benny H. Chang, Jamie S. Lin, Paul Schumacker, Luan D. Truong, Paul Overbeek, and Farhad R. Danesh http://jci.me/127277
neuroscienceElevation of plasma tRNA fragments precedes seizures in human epilepsy p. 4Marion C. Hogg, Rana Raoof, Hany El Naggar, Naser Monsefi, Norman Delanty, Donncha F. O’Brien, Sebastian Bauer, Felix Rosenow, David C. Henshall, and Jochen H.M. Prehn http://jci.me/126346
Non-inflamed murine colon
HSC70 interacts with DBY antigen
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 9 9
Flip issue to read JCI Insight content.
Arterial CD31 expression
Opioid–galanin receptor heteromers mediate the dopaminergic effects of opioids p. 4Ning-Sheng Cai, César Quiroz, Jordi Bonaventura, Alessandro Bonifazi, Thomas O. Cole, Julia Purks, Amy S. Billing, Ebonie Massey, Michael Wagner, Eric D. Wish, Xavier Guitart, William Rea, Sherry Lam, Estefanía Moreno, Verònica Casadó-Anguera, Aaron D. Greenblatt, Arthur E. Jacobson, Kenner C. Rice, Vicent Casadó, Amy H. Newman, John W. Winkelman, Michael Michaelides, Eric Weintraub, Nora D. Volkow, Annabelle M. Belcher, and Sergi Ferré http://jci.me/126912
oncologyPreoperative stimulation of resolution and inflammation blockade eradicates micrometastases p. 5Dipak Panigrahy, Allison Gartung, Jun Yang, Haixia Yang, Molly M. Gilligan, Megan L. Sulciner, Swati S. Bhasin, Diane R. Bielenberg, Jaimie Chang, Birgitta A. Schmidt, Julia Piwowarski, Anna Fishbein, Dulce Soler-Ferran, Matthew A. Sparks, Steven J. Staffa, Vidula Sukhatme, Bruce D. Hammock, Mark W. Kieran, Sui Huang, Manoj Bhasin, Charles N. Serhan, and Vikas P. Sukhatme http://jci.me/127282
SMAD signaling promotes melanoma metastasis independently of phenotype switchingEylul Tuncer, Raquel R. Calçada, Daniel Zingg, Sandra Varum, Phil Cheng, Sandra N. Freiberger, Chu-Xia Deng, Ingo Kleiter, Mitchell P. Levesque, Reinhard Dummer, and Lukas Sommer http://jci.me/94295
pulmonologyAutophagy is required for lung development and morphogenesis p. 3Behzad Yeganeh, Joyce Lee, Leonardo Ermini, Irene Lok, Cameron Ackerley, and Martin Post http://jci.me/127307
transplantationThioredoxin-1 confines T cell alloresponse and pathogenicity in graft-versus-host diseaseM. Hanief Sofi, Yongxia Wu, Steven D. Schutt, Min Dai, Anusara Daenthanasanmak, Jessica Heinrichs Voss, Hung Nguyen, David Bastian, Supinya Iamsawat, Shanmugam Panneer Selvam, Chen Liu, Nilanjana Maulik, Besim Ogretmen, Junfei Jin, Shikhar Mehrotra, and Xue-Zhong Yu http://jci.me/122899
Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cellsDarja Karpova, Michael P. Rettig, Julie Ritchey, Daniel Cancilla, Stephanie Christ, Leah Gehrs, Ezhilarasi Chendamarai, Moses O. Evbuomwan, Matthew Holt, Jingzhu Zhang, Grazia Abou-Ezzi, Hamza Celik, Eliza Wiercinska, Wei Yang, Feng Gao, Linda G. Eissenberg, Richard F. Heier, Stacy D. Arnett, Marvin J. Meyers, Michael J. Prinsen, David W. Griggs, Andreas Trumpp, Peter G. Ruminski, Dwight M. Morrow, Halvard B. Bonig, Daniel C. Link, and John F. DiPersio (ASCI) http://jci.me/124738
vascular biologyShear stress–induced endothelial adrenomedullin signaling regulates vascular tone and blood pressureAndras Iring, Young-June Jin, Julián Albarrán-Juárez, Mauro Siragusa, ShengPeng Wang, Péter T. Dancs, Akiko Nakayama, Sarah Tonack, Min Chen, Carsten Künne, Anna M. Sokol, Stefan Günther, Alfredo Martínez, Ingrid Fleming, Nina Wettschureck, Johannes Graumann, Lee S. Weinstein, and Stefan Offermanns http://jci.me/123825
ENTPD-1 disrupts inflammasome IL-1β–driven venous thrombosis p. 2Vinita Yadav, Liguo Chi, Raymond Zhao, Benjamin E. Tourdot, Srilakshmi Yalavarthi, Benjamin N. Jacobs, Alison Banka, Hui Liao, Sharon Koonse, Anuli C. Anyanwu, Scott H. Visovatti, Michael A. Holinstat, J. Michelle Kahlenberg, Jason S. Knight, David J. Pinsky, and Yogendra Kanthi http://jci.me/124804
jci.org/this-month
CCR4 on host T cells drives alloreactive responses 11
Modeling transthyretin amyloidosis patient treatment response 11
High-protein diet exacerbates lipogenesis 12
DOCK8 deficiency–associated lymphocyte defects ameliorated by HSCT 12
JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
July 2019
Down syndrome–associated enteric nervous system defects p. 10
This Month
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 917
Christopher M. Adams
Maria-Luisa Alegre
Ravi K. Amaravadi
John K. Amory
Jennifer H. Anolik
Cristian Apetrei
Rajendra S. Apte
Zoltan Arany
Hossein Ardehali
Kenneth I. Ataga
Joseph Bass
Alexander G. Bassuk
Antonio C. Bianco
Jonathan S. Bogan
Laura M. Bohn
Nunzio Bottini
Sebastien G. Bouret
Jason Brenchley
Renier J. Brentjens
G.R. Scott Budinger
George A. Calin
Stephen Chan
Timothy Chan
Yuan Chang
Zhou-Feng Chen
Keith A. Choate
Wendy Chung
Craig M. Coopersmith
George Cotsarelis
Peter Crawford
Lisa L. Cunningham
Ronald P. DeMatteo
Elia J. Duh
Sarah K. England
Mark W. Feinberg
John H. Fingert
Robert Flaumenhaft
Edward A. Fon
Lawrence Fong
Nikolaos G. Frangogiannis
Anthony R. French
Terrence L. Geiger
Noyan Gokce
Raphaela Goldbach-Mansky
Daniel R. Goldstein
Douglas K. Graham
Khalid A. Hanafy
Eric B. Haura
John Cijiang He
Robert O. Heuckeroth
Cory M. Hogaboam
Young-Kwon Hong
Benjamin D. Humphreys
Ken Inoki
Shingo Kajimura
Pawel Kalinski
John Y. Kao
Michael G. Kaplitt
Thomas W.H. Kay
Barbara I. Kazmierczak
Hans-Peter Kiem
William Y. Kim
David G. Kirsch
Claire E. Lewis
Mathias Lichterfeld
André Lieber
Michail S. Lionakis
Carey N. Lumeng
Ivan Maillard
Ziad Mallat
Peter Mannon
Franck Mauvais-Jarvis
Dermot P.B. McGovern
Borna Mehrad
Ingo K. Mellinghoff
David K. Meyerholz
Jason C. Mills
Joshua D. Milner
Satdarshan (Paul) Singh Monga
Hidayatullah G. Munshi
Matthias Nahrendorf
Mary Nakamura
Lisa F.P. Ng
Mark Nicolls
Laura J. Niedernhofer
S. Tiong Ong
Puneet Opal
Daniel Ory
Sophie Paczesny
Stephanie T. Page
Mary-Elizabeth Patti
Janos Peti-Peterdi
Fernando P. Polack
Matthew D. Ringel
Steven M. Rowe
Svati H. Shah
Vijay H. Shah
Alice T. Shaw
Rhonda F. Souza
Fayyaz S. Sutterwala
Shu Takeda
Natalie J. Torok
Stephen H. Tsang
Ellie Tzima
Fumihiko Urano
Deborah J. Veis
Charles P. Venditti
Joseph M. Vinetz
Sing Sing Way
Bernd Wollnik
Minna Woo
Prescott G. Woodruff
Lori M. Zeltser
Yutong Zhao
Binhua P. Zhou
JCI Insight Consulting Editors
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 9 10
For JCI InsightEditorHoward A. RockmanAssociate EditorsVann Bennett, Rodger A. Liddle, Yiping YangExecutive EditorSarah C. JacksonSenior Science EditorCorinne Williams
ASCI StaffExecutive DirectorJohn B. HawleyManaging DirectorKaren D. GuthAssociate DirectorMaya HoptmanAssociate Director, TechnologyShawn PyleProduction EditorsCatherine Ahmann, Ken Beauchamp, Molly Jean, Lara L. McCarronProduction AssistantKatherine A. BullenScientific IllustratorBruce WordenCopy EditorsClare Cross, Meredith Dimick, Barbara Fabyan, Rachel Nelson, Chet ProvodaAssociate Copy EditorMegan ReilleyAssociate Editor, Copy and ProductionRachel BullenEditorial AssistantCady VishniacPublications CoordinatorMegan JenkinsSystem Administrator and DeveloperBryan EnglishSoftware DevelopersAustin Brewer, Jose L. JardonScience Communications SpecialistNeha AggarwalAccounts ManagerPaula KremidasAdministrative AssistantTheresa KaiserFigures CoordinatorKeith Kalinowski
For JCI Insight online: jci.me/insight/4/11jci.me/insight/4/12
On the JCI Insight cover
This MonthJuly 2019
(ASCI) indicates corresponding authors who are ASCI members.
Enteric nervous system defects are present in Down syndrome mouse models
Children with Down syndrome (DS, also known as trisomy 21) are at increased risk for a variety of disease manifestations, such as heart defects, vision impairment, CNS dys-function, and gastrointestinal disease; however, the chromosome 21 genes that drive these disorders are poorly understood. DS dramatically increas-es the risk of Hirschsprung disease (HSCR), a severe gastrointestinal dis-order characterized by a lack of enteric
nervous system (ENS) in the distal bowel that causes serious bowel dysfunc-tion. Surgical intervention to remove aganglionic bowel can restore function. However, recovery from this surgery is challenging, especially for children with DS, and many continue to have problems with bowel function throughout their lives. In this issue, Ellen Schill, Christina Wright, and colleagues evalu-ated ENS development in two murine DS models (Ts65Dn and Tc1 mice) har-boring trisomy for many hypothesized HSCR-risk genes including Dscam and Dyrk1a. While both Ts65Dn and Tc1 mice exhibited normal migration of ENS precursors during development and near-normal myenteric plexus structure as adults, these mice had reduced neuron density in the submucosal plexus in many bowel regions. Normalization of Dscam or Dyrk1a copy number in Ts65Dn mice did not rescue this defect, indicating ENS dysfunction is not due to excess copies of these genes and instead may be the result of additional unidentified issues. The cover image shows neuron cell bodies (ANNA1, red) and nerve fibers (β3 tubulin, green) in mouse submucosal plexus.
Down syndrome mouse models have an abnormal enteric nervous systemEllen M. Schill, Christina M. Wright, Alisha Jamil, Jonathan M. LaCombe, Randall J. Roper, and Robert O. Heuckeroth (ASCI) http://jci.me/124510
Next JCI Insight Editor in Chief:
Kathleen L. Collins, MD, PhDDr. Collins will become the journal’s second Editor in Chief on September 1, 2019. http://jci.me/iehsj
JCI Insight’s first Impact Factor:
6.014Read more about JCI Insight’s Impact Factor, reported in the 2018 Journal Citation Reports (June 2019): http://jci.me/muhtx
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 911
Editor’s picks
transplantation
neuroscience
CCR4 on recipient T cells is a key driver of allograft rejectionOrgan rejection after transplant is driven by a lympho-cyte-mediated alloresponse that results from priming of recipient naive T cells in secondary lymphoid tissues by antigen-presenting cells (APCs). These allospecific T cells then traffic to the transplanted organ, where they release injury- inducing cytotoxic mediators. Vyacheslav Palchevskiy and colleagues have now demonstrated that CCR4 on naive T cells contributes to alloresponse development in a murine lung allograft model by promoting naive T cell trafficking to secondary lymphoid tissues, which express high levels of the CCR4 ligands CCL17 and CCL22. Lack of CCR4 on T cells in allograft recipients diminished allograft injury and in combina-tion with immunosuppression promoted long-term allograft survival (see the accompanying image). Overall, these results suggest that targeting CCR4 on recipient T cells should be further explored for long-term allograft survival.
Multiple factors predict treatment response in transthyretin amyloidosis patients
CCR4 expression on host T cells is a driver for alloreactive responses and lung rejectionVyacheslav Palchevskiy, Ying Ying Xue, Rita Kern, Stephen S. Weigt, Aric L. Gregson, Sophie X. Song, Michael C. Fishbein, Cory M. Hogaboam, David M. Sayah, Joseph P. Lynch III, Michael P. Keane, David G. Brooks, and John A. Belperio http://jci.me/121782
Hereditary transthyretin (TTR) amyloidoses are a set of neurodegenerative diseases that stem from autosomal dominant mutations in TTR. Severe forms of the disease rapidly progress, resulting in sensory, motor, and autonomic axonal neuropathy and ultimate incapacitation. Several disease-modifying drugs have been approved to treat the TTR amyloidoses; however, it is not clear which drugs are most efficacious and which patients benefit more from specific therapies. Cecília Monteiro and colleagues
performed a retrospective analysis of 210 TTR amyloidosis patients treated with 20 mg tafamidis. Of these patients, 34% exhibited a complete halt in disease progression, 36% exhibited a partial response, and 30% did not respond. Response was linked to disease severity, sex, and native TTR concentration at the outset of treatment. In male patients, plasma tafamidis levels at 12 months of treatment were also predictive of response. The authors built a model to predict tafamidis responsiveness, thereby
providing a tool to assess the likelihood of a patient benefiting from treatment.
Predictive model of response to tafamidis in hereditary ATTR polyneuropathyCecília Monteiro, Jaleh S. Mesgazardeh, João Anselmo, Joana Fernandes, Marta Novais, Carla Rodrigues, Gabriel J. Brighty, David L. Powers, Evan T. Powers, Teresa Coelho, and Jeffery W. Kelly http://jci.me/126526
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 9
JCI Insight | Editor’s picks
12
immunology
HSCT corrects DOCK8 deficiency–associated lymphocyte abnormalitiesPatients with mutations in the gene encoding DOCK8 present with a combined immunodeficiency that manifests as severe infection, eczema, allergies, malignancy, and impaired humoral immunity as the result of defects in the function of multiple populations of lymphocytes. Hematopoietic stem cell transplantation (HSCT) can cure DOCK8 deficiency; however, the long-term effects on the lymphocyte population have not been characterized. Bethany Pillay and colleagues investigated immune cell populations and functions in DOCK8-defcient patients before and after HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function, and the levels of αβ T, mucosal-associated invariant T, and γδ T cells were different in DOCK8-deficient patients compared with healthy individuals. HSCTs improved lymphocyte function, which was accompanied by a decrease in allergen- specific IgE. Together, these results provide in-depth information on DOCK8-specific lymphocyte defects and the dynamics of immune reconstitution, both of which have potential for the identification of biomarkers of both disease and treatment response.
Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patientsBethany A. Pillay, Danielle T. Avery, Joanne M. Smart, Theresa Cole, Sharon Choo, Damien Chan, Paul E. Gray, Katie Frith, Richard Mitchell, Tri Giang Phan, Melanie Wong, Dianne E. Campbell, Peter Hsu, John B. Ziegler, Jane Peake, Frank Alvaro, Capucine Picard, Jacinta Bustamante, Benedicte Neven, Andrew J. Cant, Gulbu Uzel, Peter D. Arkwright, Jean-Laurent Casanova, Helen C. Su, Alexandra F. Freeman, Nirali Shah, Dennis D. Hickstein, Stuart G. Tangye, and Cindy S. Ma http://jci.me/127527
Attrition of stem-like and resident immune populations underlie transition to myelomaMultiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS), a precursor state that does not always progress to malignant disease. It is not clear how the host response to premalignancy influences tumorigenic transformation and/or keeps disease progression at bay. Jithendra Bailur, Samuel McCachren, and colleagues analyzed immune cell populations in bone marrow from healthy volunteers and patients with MGUS or MM. Compared with those from healthy controls, memory T cells from MGUS and MM patients exhibited enhanced terminal differentiation. MGUS memory T cells, however, were also enriched with stem-like and tissue-resident-like properties that correlated to a distinct myeloid cell genomic profile and Dickkopf-1 levels in bone marrow plasma. Additionally, NK cell changes were also present in MGUS patients. This study indicates that attrition of stem-like and resident T cells linked to myeloid and tumor-derived signals during the premalignant stage may underlie impaired immune surveil-lance, thereby leading to MM development.
Early alterations in stem-like/marrow-resident T cells and innate and myeloid cells in preneoplastic gammopathyJithendra Kini Bailur, Samuel S. McCachren, Deon B. Doxie, Mahesh Shrestha, Katherine Pendleton, Ajay K. Nooka, Natalia Neparidze, Terri L. Parker, Noffar Bar, Jonathan L. Kaufman, Craig C. Hofmeister, Lawrence H. Boise, Sagar Lonial, Melissa L. Kemp, Kavita M. Dhodapkar, and Madhav V. Dhodapkar (ASCI) http://jci.me/127807
metabolism
High-protein diet promotes lipogenesis in healthy individualsThe world-wide increase in obesity is associated with higher incidence of type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), and other metabolic syndromes. Increased lipid accumulation in the liver due to elevated de novo lipogenesis is a feature of both T2D and NAFLD, and dietary interventions have potential to ameliorate disease. Evelina Charidemou and colleagues developed a 3-way interventional study to evaluate the effect of a high-protein diet and specific amino acids on
lipogenesis in healthy males. Glutamate-rich, high-protein diets increased lipogenesis-associated triglycerides and liver-derived VLDL in plasma. Moreover, in hepatocytes, glutamate, glutamine, and leucine promoted triglyceride synthesis and decreased glucose uptake, which corresponded to activation of protein kinase B. These results indicate that caution is warranted for the use of high-protein diets rich in certain amino acids for managing T2D and NAFLD.
A randomized 3-way crossover study indicates that high-protein feeding induces de novo lipogenesis in healthy humansEvelina Charidemou, Tom Ashmore, Xuefei Li, Ben D. McNally, James A. West, Sonia Liggi, Matthew Harvey, Elise Orford, and Julian L. Griffin http://jci.me/124819
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 913
JCI Insight | Editor’s picks
pulmonology
oncology
Extracellular dimerization domain allows precise control of CAR T cell activation
B cells protect the lung from beryllium-induced injury
Workplace exposure to beryllium (Be) can have serious health effects, including development of chronic Be disease (CBD), a granulomatous lung disease characterized by the presence of Be-specific CD4+ T cells. CBD suscepti-bility is linked to βGlu69-containing HLA-DP molecules, in particular HLA-DP2. Be oxide–exposed (BeO-exposed) HLA-DP2–transgenic mice recapitulate the HLA-DP2–restricted CD4+ T cell response seen in CBD patients. Now, Shaikh Atif, Douglas Mack, and colleagues have shown that B cells infiltrate the lungs of HLA-DP2 mice after BeO exposure and sequester BeO particles within ectopic lymphoid aggregates and granulomas (see the accompanying image). Moreover, B cell depletion prevented lymphoid aggregates and granuloma formation,
Chimeric antigen receptor (CAR) T cells have shown remarkable efficacy for several cancers; however, the risk of severe side effects and impaired long-term persistence hampers their use in complex tumors and requires improved antigen receptor designs. Wai-Hang Leung and colleagues have developed a controllable and adaptable antigen recognition system termed dimerizing agent–regulated immunoreceptor complex (DARIC). The authors have shown that DARIC T cell activation is antigen dependent but only occurs in the presence of low levels of the dimerizing drug
rapamycin, allowing precise control over T cell functionality. DARIC T cells exhibit highly potent antitumor activity in murine xenograft models at subimmunosuppressive concentrations of rapamycin and could be reactivated after an extended period of rapamycin cessation. In addition, extracellular positioning of the dimeriza-tion domains enables administration of recombi-nant retargeting modules with potential to extend antigen targeting. Cumulatively, the results support further investigation of DARIC T cells as a potent and durable T cell therapy.
Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerizationWai-Hang Leung, Joel Gay, Unja Martin, Tracy E. Garrett, Holly M. Horton, Michael T. Certo, Bruce R. Blazar, Richard A. Morgan, Philip D. Gregory, Jordan Jarjour, and Alexander Astrakhan http://jci.me/124430
resulting in increased lung injury in BeO-exposed transgenic animals. Important-ly, B cell accumulation was also observed in the lungs of CBD patients. Together, these results support a modulatory role for B cells in protection against sterile particulate exposure.
Protective role of B cells in sterile particulate–induced lung injuryShaikh M. Atif, Douglas G. Mack, Amy S. McKee, Javier Rangel-Moreno, Allison K. Martin, Andrew Getahun, Lisa A. Maier, John C. Cambier, Rubin Tuder, and Andrew P. Fontenot (ASCI) http://jci.me/125494
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 9 14
Current articlesWIPI1 is a conserved mediator of right ventricular failureChristos Tzimas, Christoph D. Rau, Petra E. Buergisser, Gaston Jean-Louis Jr., Katherine Lee, Jeffrey Chukwuneke, Wen Dun, Yibin Wang, and Emily J. Tsai http://jci.me/122929Stabilization of the cardiac sarcolemma by sarcospan rescues DMD-associated cardiomyopathyMichelle S. Parvatiyar, Alexandra J. Brownstein, Rosemeire M. Kanashiro-Takeuchi, Judd R. Collado, Karissa M. Dieseldorff Jones, Jay Gopal, Katherine G. Hammond, Jamie L. Marshall, Abel Ferrel, Aaron M. Beedle, Jeffrey S. Chamberlain, Jose Renato Pinto, and Rachelle H. Crosbie http://jci.me/123855Tertiary lymphoid structures in the choroid plexus in neuropsychiatric lupusAriel D. Stock, Evan Der, Sivan Gelb, Michelle Huang, Karen Weidenheim, Ayal Ben-Zvi, and Chaim Putterman (ASCI) http://jci.me/124203Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization p. 13Wai-Hang Leung, Joel Gay, Unja Martin, Tracy E. Garrett, Holly M. Horton, Michael T. Certo, Bruce R. Blazar, Richard A. Morgan, Philip D. Gregory, Jordan Jarjour, and Alexander Astrakhan http://jci.me/124430Down syndrome mouse models have an abnormal enteric nervous system p. 10Ellen M. Schill, Christina M. Wright, Alisha Jamil, Jonathan M. LaCombe, Randall J. Roper, and Robert O. Heuckeroth (ASCI) http://jci.me/124510Ryanodine receptor–bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardiaYoshihide Nakamura, Takeshi Yamamoto, Shigeki Kobayashi, Masaki Tamitani, Yoriomi Hamada, Go Fukui, Xiaojuan Xu, Shigehiko Nishimura, Takayoshi Kato, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, and Masafumi Yano http://jci.me/126112Safety and early efficacy outcomes for lentiviral fibroblast gene therapy in recessive dystrophic epidermolysis bullosaSu M. Lwin, Farhatullah Syed, Wei-Li Di, Tendai Kadiyirire, Lu Liu, Alyson Guy, Anastasia Petrova, Alya Abdul-Wahab, Fiona Reid, Rachel Phillips, Maria Elstad, Christos Georgiadis, Sophia Aristodemou, Patricia A. Lovell, James R. McMillan, John Mee, Snaigune Miskinyte, Matthias Titeux, Linda Ozoemena, Rashida Pramanik, Sonia Serrano, Racheal Rowles, Clarisse Maurin, Elizabeth Orrin, Magdalena Martinez-Queipo, Ellie Rashidghamat, Christos Tziotzios, Alexandros Onoufriadis, Mei Chen, Lucas Chan, Farzin Farzaneh, Marcela Del Rio, Jakub Tolar, Johann W. Bauer, Fernando Larcher, Michael N. Antoniou, Alain Hovnanian, Adrian J. Thrasher, Jemima E. Mellerio, Waseem Qasim, and John A. McGrath http://jci.me/126243The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearanceMelinde Wijers, Paolo Zanoni, Nalan Liv, Dyonne Y. Vos, Michelle Y. Jäckstein, Marieke Smit, Sanne Wilbrink, Justina C. Wolters, Ydwine T. van der Veen, Nicolette Huijkman, Daphne Dekker, Niels Kloosterhuis, Theo H. van Dijk, Daniel D. Billadeau, Folkert Kuipers, Judith Klumperman, Arnold von Eckardstein, Jan Albert Kuivenhoven, and Bart van de Sluis http://jci.me/126462Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injuryJenny B. Koenig, David Cantu, Cho Low, Mary Sommer, Farzad Noubary, Danielle Croker, Michael Whalen, Dong Kong, and Chris G. Dulla http://jci.me/126506Potassium acts through mTOR to regulate its own secretionMads Vaarby Sørensen, Bidisha Saha, Iben Skov Jensen, Peng Wu, Niklas Ayasse, Catherine E. Gleason, Samuel Levi Svendsen, Wen-Hui Wang, and David Pearce http://jci.me/126910Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunityLaurent Bartolo, Stéphanie Li Chung Tong, Pascal Chappert, Dominique Urbain, Fanny Collaud, Pasqualina Colella, Isabelle Richard, Giuseppe Ronzitti, Jocelyne Demengeot, David A. Gross, Federico Mingozzi, and Jean Davoust http://jci.me/127008Intracellular cholesterol biosynthesis in enchondroma and chondrosarcomaHongyuan Zhang, Qingxia Wei, Hidetoshi Tsushima, Vijitha Puviindran, Yuning J. Tang, Sinthu Pathmanapan, Raymond Poon, Eyal Ramu, Mushriq Al-Jazrawe, Jay Wunder, and Benjamin A. Alman http://jci.me/127232Targeting self- and neoepitopes with a modular self-adjuvanting cancer vaccineElodie Belnoue, Jean-François Mayol, Susanna Carboni, Wilma Di Berardino Besson, Eloise Dupuychaffray, Annika Nelde, Stefan Stevanovic, Marie-Laure Santiago-Raber, Paul R. Walker, and Madiha Derouazi http://jci.me/127305Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients p. 12Bethany A. Pillay, Danielle T. Avery, Joanne M. Smart, Theresa Cole, Sharon Choo, Damien Chan, Paul E. Gray, Katie Frith, Richard Mitchell, Tri Giang Phan, Melanie Wong, Dianne E. Campbell, Peter Hsu, John B. Ziegler, Jane Peake, Frank Alvaro, Capucine Picard, Jacinta Bustamante, Benedicte Neven, Andrew J. Cant, Gulbu Uzel, Peter D. Arkwright, Jean-Laurent Casanova, Helen C. Su, Alexandra F. Freeman, Nirali Shah, Dennis D. Hickstein, Stuart G. Tangye, and Cindy S. Ma http://jci.me/127527Pretransplant transcriptomic signature in peripheral blood predicts early acute rejectionWeijia Zhang, Zhengzi Yi, Chengguo Wei, Karen L. Keung, Zeguo Sun, Caixia Xi, Christopher Woytovich, Samira Farouk, Lorenzo Gallon, Madhav C. Menon, Ciara Magee, Nader Najafian, Milagros D. Samaniego, Arjang Djamali, Stephen I. Alexander, Ivy A. Rosales, Rex Neal Smith, Philip J. O’Connell, Robert Colvin, Paolo Cravedi, and Barbara Murphy http://jci.me/127543Systems pharmacology–based integration of human and mouse data for drug repurposing to treat thoracic aneurysmsJens Hansen, Josephine Galatioto, Cristina I. Caescu, Pauline Arnaud, Rhodora C. Calizo, Bart Spronck, Sae-Il Murtada, Roshan Borkar, Alan Weinberg, Evren U. Azeloglu, Maria Bintanel-Morcillo, James M. Gallo, Jay D. Humphrey, Guillaume Jondeau, Catherine Boileau, Francesco Ramirez, and Ravi Iyengar http://jci.me/127652TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremiaGregory Q. Del Prete, W. Gregory Alvord, Yuan Li, Claire Deleage, Mukta Nag, Kelli Oswald, James A. Thomas, Cathi Pyle, William J. Bosche, Vicky Coalter, Adam Wiles, Rodney Wiles, Brian Berkemeier, Michael Hull, Elizabeth Chipriano, Lorna Silipino, Randy Fast, Jacob Kiser, Rebecca Kiser, Tyler Malys, Joshua Kramer, Matthew W. Breed, Charles M. Trubey, Jacob D. Estes, Tiffany L. Barnes, Joseph Hesselgesser, Romas Geleziunas, and Jeffrey D. Lifson http://jci.me/127717
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 915
Current articlesImpaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liverJustin A. Fletcher, Stanisław Deja, Santhosh Satapati, Xiaorong Fu, Shawn C. Burgess, and Jeffrey D. Browning http://jci.me/127737Early alterations in stem-like/marrow-resident T cells and innate and myeloid cells in preneoplastic gammopathy p. 12Jithendra Kini Bailur, Samuel S. McCachren, Deon B. Doxie, Mahesh Shrestha, Katherine Pendleton, Ajay K. Nooka, Natalia Neparidze, Terri L. Parker, Noffar Bar, Jonathan L. Kaufman, Craig C. Hofmeister, Lawrence H. Boise, Sagar Lonial, Melissa L. Kemp, Kavita M. Dhodapkar, and Madhav V. Dhodapkar (ASCI) http://jci.me/127807Activation of the calcium-sensing receptor attenuates TRPV6-dependent intestinal calcium absorptionJustin J. Lee, Xiong Liu, Debbie O’Neill, Megan R. Beggs, Petra Weissgerber, Veit Flockerzi, Xing-Zhen Chen, Henrik Dimke, and R. Todd Alexander http://jci.me/128013
Eosinophils downregulate lung alloimmunity by decreasing TCR signal transductionOscar Okwudiri Onyema, Yizhan Guo, Bayan Mahgoub, Qing Wang, Amir Manafi, Zhongcheng Mei, Anirban Banerjee, Dongge Li, Mark H. Stoler, Melissa T. Zaidi, Adam G. Schrum, Daniel Kreisel, Andrew E. Gelman, Elizabeth A. Jacobsen, and Alexander Sasha Krupnick (ASCI) http://jci.me/128241Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosisChristelle Guillermier, Sean P. Doherty, Adam G. Whitney, Vladimir R. Babaev, MacRae F. Linton, Matthew L. Steinhauser, and Jonathan D. Brown http://jci.me/128528Heterogeneity of the action potential duration is required for sustained atrial fibrillationUma Mahesh R. Avula, Jeffrey Abrams, Alexander Katchman, Sergey Zakharov, Sergey Mironov, Joseph Bayne, Daniel Roybal, Anirudh Gorti, Lin Yang, Vivek Iyer, Marc Waase, Deepak Saluja, Edward J. Ciaccio, Hasan Garan, Andrew R. Marks, Steven O. Marx, and Elaine Y. Wan http://jci.me/128765Robust surgical approach for cutaneous neurofibroma in neurofibromatosis type 1Bahir H. Chamseddin, La’Nette Hernandez, Dezehree Solorzano, Juan Vega, and Lu Q. Le (ASCI) http://jci.me/128881
Functional methylome analysis of human diabetic kidney diseaseJihwan Park, Yuting Guan, Xin Sheng, Caroline Gluck, Matthew J. Seasock, A. Ari Hakimi, Chengxiang Qiu, James Pullman, Amit Verma, Hongzhe Li, Matthew Palmer, and Katalin Susztak (ASCI) http://jci.me/128886Critical role of IL-21 and T follicular helper cells in hypertension and vascular dysfunctionBethany L. Dale, Arvind K. Pandey, Yuhan Chen, Charles D. Smart, Fanny Laroumanie, Mingfang Ao, Liang Xiao, Anna E. Dikalova, Sergey I. Dikalov, Fernando Elijovich, Jason D. Foss, Natalia R. Barbaro, Justin P. Van Beusecum, Serpil M. Deger, Aseel Alsouqi, Hana A. Itani, Allison E. Norlander, Matthew R. Alexander, Shilin Zhao, T. Alp Ikizler, Holly M. Scott Algood, and Meena S. Madhur http://jci.me/129278PARP-1 controls NK cell recruitment to the site of viral infectionQiyang Shou, Huiying Fu, Xiaopei Huang, and Yiping Yang (ASCI) http://jci.me/121291CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection p. 11Vyacheslav Palchevskiy, Ying Ying Xue, Rita Kern, Stephen S. Weigt, Aric L. Gregson, Sophie X. Song, Michael C. Fishbein, Cory M. Hogaboam, David M. Sayah, Joseph P. Lynch III, Michael P. Keane, David G. Brooks, and John A. Belperio http://jci.me/121782A randomized 3-way crossover study indicates that high-protein feeding induces de novo lipogenesis in healthy humans p. 12Evelina Charidemou, Tom Ashmore, Xuefei Li, Ben D. McNally, James A. West, Sonia Liggi, Matthew Harvey, Elise Orford, and Julian L. Griffin http://jci.me/124819Therapeutic discovery for marrow failure with MDS predisposition using pluripotent stem cellsMelisa Ruiz-Gutierrez, Özge Vargel Bölükbaşı, Gabriela Alexe, Adriana G. Kotini, Kaitlyn Ballotti, Cailin E. Joyce, David W. Russell, Kimberly Stegmaier, Kasiani Myers, Carl D. Novina, Eirini P. Papapetrou, and Akiko Shimamura http://jci.me/125157Keratinocyte growth factor impairs human thymic recovery from lymphopeniaAlasdair J. Coles, Laura Azzopardi, Onajite Kousin-Ezewu, Harpreet Kaur Mullay, Sara A.J. Thompson, Lorna Jarvis, Jessica Davies, Sarah Howlett, Daniel Rainbow, Judith Babar, Timothy J. Sadler, J. William L. Brown, Edward Needham, Karen May, Zoya G. Georgieva, Adam E. Handel, Stefano Maio, Mary Deadman, Ioanna Rota, Georg Hollander, Sarah Dawson, David Jayne, Ruth Seggewiss-Bernhardt, Daniel C. Douek, John D. Isaacs, and Joanne L. Jones http://jci.me/125377Protective role of B cells in sterile particulate–induced lung injury p. 13Shaikh M. Atif, Douglas G. Mack, Amy S. McKee, Javier Rangel-Moreno, Allison K. Martin, Andrew Getahun, Lisa A. Maier, John C. Cambier, Rubin Tuder, and Andrew P. Fontenot (ASCI) http://jci.me/125494Antisense oligonucleotide treatment ameliorates IFN-γ–induced proteinuria in APOL1-transgenic miceMariam Aghajan, Sheri L. Booten, Magnus Althage, Christopher E. Hart, Anette Ericsson, Ingela Maxvall, Joseph Ochaba, Angela Menschik-Lundin, Judith Hartleib, Steven Kuntz, Danielle Gattis, Christine Ahlström, Andrew T. Watt, Jeffery A. Engelhardt, Brett P. Monia, Maria Chiara Magnone, and Shuling Guo http://jci.me/126124Development of a two-dimensional atlas of the human kidney with imaging mass cytometryNikhil Singh, Zachary M. Avigan, Judith A. Kliegel, Brian M. Shuch, Ruth R. Montgomery, Gilbert W. Moeckel, and Lloyd G. Cantley http://jci.me/129477Biomarkers of cavernous angioma with symptomatic hemorrhageSeán B. Lyne, Romuald Girard, Janne Koskimäki, Hussein A. Zeineddine, Dongdong Zhang, Ying Cao, Yan Li, Agnieszka Stadnik, Thomas Moore, Rhonda Lightle, Changbin Shi, Robert Shenkar, Julián Carrión-Penagos, Sean P. Polster, Sharbel Romanos, Amy Akers, Miguel Lopez-Ramirez, Kevin J. Whitehead, Mark L. Kahn, Mark H. Ginsberg, Douglas A. Marchuk, and Issam A. Awad http://jci.me/128577
j c i . o r g / t h i s - m o n t h j u l y 2 0 1 9 16
Flip issue to read JCI content.
The combination of loss of glyoxalase1 and obesity results in hyperglycemiaElisabeth Lodd, Lucas M. Wiggenhauser, Jakob Morgenstern, Thomas H. Fleming, Gernot Poschet, Michael Büttner, Christoph T. Tabler, David P. Wohlfart, Peter P. Nawroth, and Jens Kroll http://jci.me/126154Predictive model of response to tafamidis in hereditary ATTR polyneuropathy p. 11Cecília Monteiro, Jaleh S. Mesgazardeh, João Anselmo, Joana Fernandes, Marta Novais, Carla Rodrigues, Gabriel J. Brighty, David L. Powers, Evan T. Powers, Teresa Coelho, and Jeffery W. Kelly http://jci.me/126526Effect of HIV infection and antiretroviral therapy on immune cellular functionsMarek Korencak, Morgan Byrne, Enrico Richter, Bruce T. Schultz, Patrick Juszczak, Julie A. Ake, Anuradha Ganesan, Jason F. Okulicz, Merlin L. Robb, Buena de los Reyes, Sandra Winning, Joachim Fandrey, Timothy H. Burgess, Stefan Esser, Nelson L. Michael, Brian K. Agan, and Hendrik Streeck http://jci.me/126675CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosisGiovanni Ligresti, Nunzia Caporarello, Jeffrey A. Meridew, Dakota L. Jones, Qi Tan, Kyoung Moo Choi, Andrew J. Haak, Aja Aravamudhan, Anja C. Roden, Y.S. Prakash, Gwen Lomberk, Raul A. Urrutia, and Daniel J. Tschumperlin http://jci.me/127111Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesisSören Brandenburg, Jan Pawlowitz, Benjamin Eikenbusch, Jonas Peper, Tobias Kohl, Gyuzel Y. Mitronova, Samuel Sossalla, Gerd Hasenfuss, Xander H.T. Wehrens, Peter Kohl, Eva A. Rog-Zielinska, and Stephan E. Lehnart http://jci.me/127116Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patientsKazushiro Takata, Panos Stathopoulos, Michelangelo Cao, Marina Mané-Damas, Miriam L. Fichtner, Erik S. Benotti, Leslie Jacobson, Patrick Waters, Sarosh R. Irani, Pilar Martinez-Martinez, David Beeson, Mario Losen, Angela Vincent, Richard J. Nowak, and Kevin C. O’Connor http://jci.me/127167Pyruvate kinase M2 is requisite for Th1 and Th17 differentiationMichihito Kono, Kayaho Maeda, Irina Stocton-Gavanescu, Wenliang Pan, Masataka Umeda, Eri Katsuyama, Catalina Burbano, Seo Yeon K. Orite, Milena Vukelic, Maria G. Tsokos, Nobuya Yoshida, and George C. Tsokos http://jci.me/127395Noncovalent inhibitors reveal BTK gatekeeper and auto-inhibitory residues that control its transforming activityShenqiu Wang, Sayan Mondal, Chunying Zhao, Marjan Berishaj, Phani Ghanakota, Connie Lee Batlevi, Ahmet Dogan, Venkatraman E. Seshan, Robert Abel, Michael R. Green, Anas Younes, and Hans-Guido Wendel (ASCI) http://jci.me/127566Engulfment and cell motility protein 1 potentiates diabetic cardiomyopathy via Rac-dependent and Rac-independent ROS productionMasao Kakoki, Edward M. Bahnson, John R. Hagaman, Robin M. Siletzky, Ruriko Grant, Yukako Kayashima, Feng Li, Esther Y. Lee, Michelle T. Sun, Joan M. Taylor, Jessica C. Rice, Michael F. Almeida, Ben A. Bahr, J. Charles Jennette, Oliver Smithies, and Nobuyo Maeda-Smithies http://jci.me/127660A glucose-dependent spatial patterning of exocytosis in human β cells is disrupted in type 2 diabetesJianyang Fu, John Maringa Githaka, Xiaoqing Dai, Gregory Plummer, Kunimasa Suzuki, Aliya F. Spigelman, Austin Bautista, Ryekjang Kim, Dafna Greitzer-Antes, Jocelyn E. Manning Fox, Herbert Y. Gaisano, and Patrick E. MacDonald http://jci.me/127896Identification of dicarbonyl and L-xylulose reductase as a therapeutic target in human chronic kidney diseasePaul Perco, Wenjun Ju, Julia Kerschbaum, Johannes Leierer, Rajasree Menon, Catherine Zhu, Matthias Kretzler, Gert Mayer, Michael Rudnicki, and Nephrotic Syndrome Study Network (NEPTUNE) http://jci.me/128120Dietary carbohydrate restriction improves metabolic syndrome independent of weight lossParker N. Hyde, Teryn N. Sapper, Christopher D. Crabtree, Richard A. LaFountain, Madison L. Bowling, Alex Buga, Brandon Fell, Fionn T. McSwiney, Ryan M. Dickerson, Vincent J. Miller, Debbie Scandling, Orlando P. Simonetti, Stephen D. Phinney, William J. Kraemer, Sarah A. King, Ronald M. Krauss, and Jeff S. Volek http://jci.me/128308Clones of infected cells arise early in HIV-infected individualsJohn M. Coffin, David Wells, Jennifer M. Zerbato, Joann D. Kuruc, Shuang Guo, Brian T. Luke, Joseph J. Eron, Michael Bale, Jonathan Spindler, Francesco R. Simonetti, Shawn Hill, Mary F. Kearney, Frank Maldarelli, Xiaolin Wu, John W. Mellors, and Stephen H. Hughes http://jci.me/128432TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearingTatsuya Katsuno, Inna A. Belyantseva, Alexander X. Cartagena-Rivera, Keisuke Ohta, Shawn M. Crump, Ronald S. Petralia, Kazuya Ono, Risa Tona, Ayesha Imtiaz, Atteeq Rehman, Hiroshi Kiyonari, Mari Kaneko, Ya-Xian Wang, Takaya Abe, Makoto Ikeya, Cristina Fenollar-Ferrer, Gavin P. Riordan, Elisabeth A. Wilson, Tracy S. Fitzgerald, Kohei Segawa, Koichi Omori, Juichi Ito, Gregory I. Frolenkov, Thomas B. Friedman, and Shin-ichiro Kitajiri http://jci.me/128561Genomic analysis of benign prostatic hyperplasia implicates cellular relandscaping in disease pathogenesisLance W. Middleton, Zhewei Shen, Sushama Varma, Anna S. Pollack, Xue Gong, Shirley Zhu, Chunfang Zhu, Joseph W. Foley, Sujay Vennam, Robert T. Sweeney, Karen Tu, Jewison Biscocho, Okyaz Eminaga, Rosalie Nolley, Robert Tibshirani, James D. Brooks, Robert B. West, and Jonathan R. Pollack (ASCI) http://jci.me/129749
reviewThe ex vivo human lung: research value for translational scienceJames T. Ross, Nicolas Nesseler, Jae-Woo Lee, Lorraine B. Ware, and Michael A. Matthay http://jci.me/128833