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jci.org/this-month Microvascular leakage permits reverse neutrophil migration 3 Immunological correlates of severe COVID-19 disease 4 β3-Adrenergic receptor agonist improves insulin sensitivity 4 Bacterial CagA impairs gastric cell apoptosis during H. pylori infection 5 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. May 2020 This Month Qki-activated lipid metabolism preserves myelin integrity p. 2

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jci.org/this-month

Microvascular leakage permits reverse neutrophil migration 3

Immunological correlates of severe COVID-19 disease 4

β3-Adrenergic receptor agonist improves insulin sensitivity 4

Bacterial CagA impairs gastric cell apoptosis during H. pylori infection 5

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.

May 2020

This Month

Qki-activated lipid metabolism preserves myelin integrity p. 2

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Journal of Clinical Investigation Consulting Editors

Soman N. Abraham

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j c i . o r g / t h i s - m o n t h m a y 2 0 2 0 1

For the JCIEditorRexford S. Ahima

Deputy EditorsArturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli

Associate EditorsMark E. Anderson, Mary Y. Armanios, Nilofer S. Azad, 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

Staff EditorsExecutive EditorSarah C. Jackson

Senior Science EditorCorinne Williams

Science EditorElyse Dankoski

Assistant Science EditorLisa Conti

Editor at LargeUshma S. Neill

Editorial InternBouchra Taib

JCI This Month ISSN 2380-3029 (print)ISSN 2380-3037 (online)For the full JCI online: jci.me/130/5

This MonthMay 2020

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.

Leo Luznik, MD, Associate Editor, is professor in the Department of Oncology, Hematologic Malignancies, at Johns Hopkins University School of Medicine. His research focuses on understanding basic mechanisms of allogeneic immune response, with the overarching goal of improving the clinical application of allogeneic hematopoietic cell transplantation. Dr. Luznik is a member of the American Society for Clinical Investigation and served as the Series Editor

to create the JCI’s recent Review Series “Immunotherapy in Hematological Cancers” (visit http:/jci.me/review_series/10).

Publication highlightsZeidner JF, Knaus HA, Zeidan AM, Blackford AL, Montiel-Esparza R, Hackl H, Prince GT, Gondek LP, Ghiaur G, Showel MM, DeZern AE, Pratz KW, Smith DB, Levis MJ, Gore S, Coombs CC, Foster MC, Streicher H, Karp JE, Luznik L, Gojo I. Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS [published online January 3, 2020]. Leukemia. http://www.doi.org/10.1038/s41375-019-0693-4.

McCurdy SR, Luznik L. How we perform haploidentical stem cell transplantation with posttransplant cyclophosphamide. Blood. 2019;134(21):1802–1810.

Knaus HA, Berglund S, Hackl H, Blackford AL, Zeidner JF, Montiel-Esparza R, Mukhopadhyay R, Vanura K, Blazar BR, Karp JE, Luznik L, Gojo I. Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy. JCI Insight. 2018;3(21):e120974.

Wagner CL, Hanumanthu VS, Talbot CC Jr, Abraham RS, Hamm D, Gable DL, Kanakry CG, Applegate CD, Siliciano J, Jackson JB, Desiderio S, Alder JK, Luznik L, Armanios M. Short telomere syndromes cause a primary T cell immunodeficiency. J Clin Invest. 2018;128(12):5222–5234.

Kasamon YL, Ambinder RF, Fuchs EJ, Zahurak M, Rosner GL, Bolaños-Meade J, Levis MJ, Gladstone DE, Huff CA, Swinnen LJ, Matsui WH, Borrello I, Brodsky RA, Jones RJ, Luznik L. Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide. Blood Adv. 2017;1(4):288–292.

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

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research

Editor’s pickson the jci coverneuroscience

Oligodendrocyte protein Qki activates lipid metabolism to maintain adult myelin

HSP70-containing exosomes mitigate antibiotic-induced damage to auditory hair cellsAminoglycoside antibiotics (AAs) can damage and kill the hair cells of the inner ear, leading to irreversible hearing loss. In animal models, the heat shock protein HSP70 appears to reduce AA-mediated toxicity in hair cells and preserve hearing through a paracrine mechanism. Andrew Breglio, Lindsey May,

Melanie Barzik, and colleagues took a closer look at this protective response, revealing that glia-like supporting cells in the inner ear release exosomes that carry HSP70 to hair cells. Purified exosomes containing HSP70 attenuated AA-induced hair cell death by interacting with TLR4, a receptor for

HSP70, on hair cells. In the accompanying Commentary, Ulrich Müller describes how the elucidation of this paracrine signaling mechanism highlights targeting of both exosomes and the HSP70/TLR4 pathway as potential therapeutic approaches for preventing AA-induced hearing loss.

Exosomes mediate sensory hair cell protection in the inner earAndrew M. Breglio, Lindsey A. May, Melanie Barzik, Nora C. Welsh, Shimon P. Francis, Tucker Q. Costain, Lizhen Wang, D. Eric Anderson, Ronald S. Petralia, Ya-Xian Wang, Thomas B. Friedman, Matthew J.A. Wood, and Lisa L. Cunningham http://jci.me/128867

Related CommentaryExosome-mediated protection of auditory hair cells from ototoxic insultsUlrich Müller http://jci.me/135710

In multiple sclerosis, neurological symptoms are linked to loss of myelin, a lipid- and protein-based structure that forms an insulating sheath around nerves to support the propagation of electrical impulses. Myelin is produced by glial cells in the CNS called oligo-dendrocytes and appears to be under rigorous metabolic control, with recent evidence suggesting that its maintenance may critically depend on functional lipid metabolism. In this issue of the JCI, Xin Zhou et al. demonstrate the essential role of the oligodendrocyte protein Qki in myelin homeostasis and possibly the pathogenesis of demyelinating disease. In adult mice, oligodendrocyte- specific Qki depletion led to rapid demyelination and gradual neurological deficits that were linked to reduction of myelin lipid species. These effects were mitigated by high-fat diet. The study determined that Qki is a coactivator of the PPARβ-RXRα complex, which regulates lipid metabolic gene transcription, and further revealed that PPARβ/RXR agonists also alleviated the effects of Qki depletion. The findings highlight the importance of continuous lipid synthesis for preserving myelin integrity in the adult brain, an insight with probable implications for the treatment of multiple sclerosis and other demyelinating diseases. The cover image depicts myelin sheaths (in green) with active lipid supply from oligodendrocytes and an oligodendrocyte (in yellow) without proper lipid supply. Image credit: Ella Maru Studio.

Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα–mediated lipid metabolismXin Zhou, Chenxi He, Jiangong Ren, Congxin Dai, Sharon R. Stevens, Qianghu Wang, Daniel Zamler, Takashi Shingu, Liang Yuan, Chythra R. Chandregowda, Yunfei Wang, Visweswaran Ravikumar, Arvind U.K. Rao, Feng Zhou, Hongwu Zheng, Matthew N. Rasband, Yiwen Chen, Fei Lan, Amy B. Heimberger, Benjamin M. Segal, and Jian Hu http://jci.me/131800

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JCI | Research: Editor’s picks

neuroscience

inflammation

Elp1 loss impairs retrograde NGF signaling and sympathetic neuron survivalFamilial dysautonomia is a heritable form of sympathetic nervous system dysfunction affecting multiple organ systems. The disorder is linked to mutations in ELP1, encoding Elp1, a scaffolding protein in the highly conserved transcriptional Elongator complex. Warren Tourtellotte and colleagues explored the function of Elp1 in sympathetic neurons and identified its essential role in retrograde nerve growth factor (NGF) signaling. The study details an NGF- dependent mechanism by which Elp1 regulates Shp1 phosphatase activity to maintain TrkA receptor phosphorylation, thereby promoting sympathetic target tissue innervation and neuron survival. In an Elp1-deficient animal model, inhibiting Shp1 phospha-tase rescued sympathetic target tissue innervation (see the associated image) and neuron loss, demonstrating the mechanism by which loss of Elp1 leads to sympathetic nervous system dysfunction in familial dysautonomia. In the accompanying Commentary, David Kaplan and William Mobley outline the insights into how neuronal cells sustain innervation to remote targets.

Increased local vascular permeability promotes remote trafficking of inflammatory neutrophils

Retrograde nerve growth factor signaling abnormalities in familial dysautonomiaLin Li, Katherine Gruner, and Warren G. Tourtellotte http://jci.me/130401

Related Commentary(H)Elping nerve growth factor: Elp1 inhibits TrkA’s phosphatase to maintain retrograde signalingDavid R. Kaplan and William C. Mobley http://jci.me/136162

During an acute inflammatory response, activated neutrophils infiltrate local tissues by breaching endothelial cells that line postcapillary venules through transendothelial migration (TEM). Endothelial cells also mediate vascular permeability to macromolecules, but this process is regulated independently, and whether it influences neutrophil trafficking is unknown. Charlotte Owen-Woods, Régis Joulia, and colleagues now reveal that increased vascular permeability to proteins undermines neutrophil trafficking, promoting reversal of neutrophil TEM through the endothelial cell layer. The researchers demonstrated that increased permeability permits chemokines to diffuse from the site of inflammation into the bloodstream at a level sufficient to lure neutrophils back into the venular lumen. A newly designed labeling approach allowed visualization of activated neutrophils undergoing reverse TEM (see the associated images) and tracked them to distant organs.

Alex Marki and Klaus Ley’s accompanying Commentary posits that these findings may explain why tissue injury sometimes occurs in remote organs following localized tissue inflammation.

Local microvascular leakage promotes trafficking of activated neutrophils to remote organsCharlotte Owen-Woods, Régis Joulia, Anna Barkaway, Loïc Rolas, Bin Ma, Astrid Fee Nottebaum, Kenton P. Arkill, Monja Stein, Tamara Girbl, Matthew Golding, David O. Bates, Dietmar Vestweber, Mathieu-Benoit Voisin, and Sussan Nourshargh http://jci.me/133661

Related CommentaryLeaking chemokines confuse neutrophilsAlex Marki and Klaus Ley http://jci.me/136259

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JCI | Research: Editor’s picks

clinical medicine

β3-Adrenergic receptor agonist improves glucose homeostasis in two human trials

Comparing the immunological characteristics of moderate and severe COVID-19

Clinical and immunological features of severe and moderate coronavirus disease 2019Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, Xiaoping Zhang, Minxia Zhang, Shiji Wu, Jianxin Song, Tao Chen, Meifang Han, Shusheng Li, Xiaoping Luo, Jianping Zhao, and Qin Ning http://jci.me/137244

Related CommentarySARS-CoV-2: a storm is ragingSavannah F. Pedersen and Ya-Chi Ho http://jci.me/137647

The novel coronavirus SARS-CoV-2 emerged in Wuhan, China in December 2019 and has since spread across the globe. Initial studies of laboratory-confirmed cases of SARS-CoV-2–induced coronavirus disease (COVID-19) suggested that disease severity was linked to cytokine storm. Guang Chen, Di Wu, Wei Guo, Yong Cao, et al. performed a retrospective analysis on 21 patients with COVID-19 who were classified as having either severe (n = 11) or moderate (n = 10) disease. Nearly all patients exhibited decreases in CD4+ and CD8+ T cells, and decreases were more pronounced in patients with severe disease. The study also noted that severe COVID-19 is accompanied by a cytokine storm, with elevated levels of plasma IL-2R, IL-6, IL-10, and TNF-α, while IFN-γ production by CD4+ cells decreased. Savannah Pederson and Ya-Chi Ho’s accompanying Commentary points out that these immunological correlates for severe COVID-19 may provide important clinical insights into disease pathogenesis as well as highlight potential strategies to combat this emerging disease.

Obesity remains a rising health problem worldwide, and pharmacological approaches that enhance energy expenditure may be a powerful tool in combating obesity-related metabolic diseases. In this issue, two clinical studies explore the potential for mirabegron, a β3-adrenergic receptor (β3-AR) agonist currently approved for overactive bladder, in treating metabolic disease. The β3-AR is expressed on urinary bladder, gallbladder, and adipose tissue, and studies in rodents support its positive effects on thermo-genesis and glucose tolerance. Alana O’Mara, James Johnson, and colleagues observed that chronic

mirabegron treatment increased metabolically active brown adipose tissue (see the accompanying image), thereby enhancing resting energy expenditure and improving insulin sensitivity in 14 healthy women. Brian Finlin, Hasiyet Memetimin, and colleagues reported that mirabegron treatment improved glucose homeostasis and produced favorable changes in both white adipose tissue and muscle in 13 subjects with obesity. Jeffrey Flier’s accompanying Commentary speculates that the results of these studies may renew interest in developing β3-AR–targeting therapeutics for the treatment of metabolic disease.

Related ResearchChronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivityAlana E. O’Mara, James W. Johnson, Joyce D. Linderman, Robert J. Brychta, Suzanne McGehee, Laura A. Fletcher, Yael A. Fink, Devika Kapuria, Thomas M. Cassimatis, Nathan Kelsey, Cheryl Cero, Zahraa Abdul Sater, Francesca Piccinini, Alison S. Baskin, Brooks P. Leitner, Hongyi Cai, Corina M. Millo, William Dieckmann, Mary Walter, Norman B. Javitt, Yaron Rotman, Peter J. Walter, Marilyn Ader, Richard N. Bergman, Peter Herscovitch, Kong Y. Chen, and Aaron M. Cypess (ASCI) http://jci.me/131126

The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humansBrian S. Finlin, Hasiyet Memetimin, Beibei Zhu, Amy L. Confides, Hemendra J. Vekaria, Riham H. El Khouli, Zachary R. Johnson, Philip M. Westgate, Jianzhong Chen, Andrew J. Morris, Patrick G. Sullivan, Esther E. Dupont-Versteegden, and Philip A. Kern (ASCI) http://jci.me/134892

Related CommentaryMight β3-adrenergic receptor agonists be useful in disorders of glucose homeostasis?Jeffrey S. Flier (ASCI) http://jci.me/136476

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JCI | Research: Editor’s picks

clinical medicine gastroenterology

Modified immune cell infusion is well tolerated in kidney transplantation

H. pylori protein impairs apoptotic responses in gastric epithelial cellsOver half of the world’s population is infected with Helicobacter pylori, a stomach pathogen that increases risk of gastric cancer. Manikandan Palrasu and colleagues investigated the host and bacterial factors influencing tumorigenesis resulting from H. pylori infection, focusing on the host protein Siva1. H. pylori infection led to downregulation of Siva1 in human and mouse cells. This downregulation occurred in a strain-dependent manner, and more robust downregulation was observed after infection with tumorigenic strain 7.13 compared with its parental nontumorigenic strain B128. These differences were attributed to strain 7.13’s enhanced delivery of the bacterial protein CagA. CagA drove increased degradation of Siva1, leading to attenuated gastric epithelial cell apoptosis in response to infection. In the accompanying Commentary, José Sáenz and Jason Mills discuss how the discovery that Siva1 loss permits survival of gastric epithelial cells illuminates a checkpoint in the progression to gastric cancer.

Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cellsManikandan Palrasu, Elena Zaika, Wael El-Rifai, Monica Garcia-Buitrago, Maria Blanca Piazuelo, Keith T. Wilson, Richard M. Peek Jr., and Alexander I. Zaika http://jci.me/130015

Related CommentaryHelicobacter pylori: preying on SIVA for survival in the stomachJosé B. Sáenz and Jason C. Mills (ASCI) http://jci.me/135508

Piezo1 activates TRPV4-mediated calcium signaling to trigger pressure-induced pancreatitisSurgery, trauma, and gallstones can all produce acute increases in pancreatic pressure that lead to pancreatitis. Activation of the mechanosensitive calcium-permeable channel Piezo1 is an initial trigger of pressure-induced pancreatitis, but the link between Piezo1-mediated increases in intracellular calcium and pathological outcomes remains unclear. Sandip Swain and colleagues reveal that activation of Piezo1 in pancreatic acinar cells triggered the opening of TRPV4 channels, producing sustained elevation of intracellular calcium that provoked mitochondrial depolarization and cell death. Mechanistically, Piezo activation stimulated TRPV4 opening via increases in the phospholipase PLA2, and this 1 interaction occurred independently of the pancreatitis-linked peptides cerulein and CCK. In the accompanying Commentary, Fred Gorelick and Michael Nathanson highlight these insights into how Piezo1- and TRPV4-dependent calcium signals contribute to the pathogenesis of pancreatitis.

TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activationSandip M. Swain, Joelle M.-J. Romac, Rafiq A. Shahid, Stephen J. Pandol, Wolfgang Liedtke, Steven R. Vigna, and Rodger A. Liddle (ASCI) http://jci.me/134111

Related CommentaryTRPV4 helps Piezo1 put the squeeze on pancreatic acinar cellsFred Gorelick (ASCI) and Michael H. Nathanson http://jci.me/136525

Over half of graft losses following kidney transplantation are the result of chronic rejection, which conventional immunosuppressive therapies are unable to prevent. Cellular approaches may better control allograft rejection, with fewer side effects, and preclinical models suggest that modified immune cells (MICs) from the graft donor can induce donor-specific immunosuppression in the recipient. In a phase I trial, Christian Morath, Anita Schmitt, and colleagues examined the safety of intravenous administration of donor-derived MICs to ten kidney recipients prior to transplantation. The study determined that these MIC infusions were well tolerated and were not associated with any adverse events. Moreover, the patients achieved hyporesponsiveness specific to the donor and displayed a substantial increase in regulatory B lymphocytes. Sam Kant and Daniel Brennan highlight the study’s supportive data for further development of MICs as an antirejection therapy in the accompanying Commentary.

Phase I trial of donor-derived modified immune cell infusion in kidney transplantationChristian Morath, Anita Schmitt, Christian Kleist, Volker Daniel, Gerhard Opelz, Caner Süsal, Eman Ibrahim, Florian Kälble, Claudius Speer, Christian Nusshag, Luiza Pego da Silva, Claudia Sommerer, Lei Wang, Ming Ni, Angela Hückelhoven-Krauss, David Czock, Uta Merle, Arianeb Mehrabi, Anja Sander, Matthes Hackbusch, Christoph Eckert, Rüdiger Waldherr, Paul Schnitzler, Carsten Müller-Tidow, Jörg D. Hoheisel, Shakhawan A. Mustafa, Mohamed S.S. Alhamdani, Andrea S. Bauer, Jochen Reiser, Martin Zeier, Michael Schmitt, Matthias Schaier, and Peter Terness http://jci.me/133595

Related CommentaryMoving from transplant as a treatment to transplant as a cureSam Kant and Daniel C. Brennan http://jci.me/136475

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JCI | Features

review

A D V E R T I S E M E N T viewpoint

Examining the posttreatment complications of chronic Lyme diseaseLyme disease is a tick-borne illness that begins with an acute infection but can persist for months or years, causing long-term neurologic and cardiac abnormalities and arthritis. Acute Lyme disease is usually cleared by oral antibiotics, but later manifestations of disease are more difficult to treat successfully. If oral antibiotic therapy fails to resolve chronic Lyme disease symptoms, patients are started on intravenous antibiotics; however, some patients develop disabling neurologic or arthritic postantibiotic syndromes, complicating the clinical decision-making process. In a Viewpoint, Allen Steere makes a case for and against treating patients with chronic Lyme disease using long-term antibiotics. His discussion weighs the outcomes of clinical trials and preclinical studies and presents theories for the immune origin of postantibiotic syndromes.

Posttreatment Lyme disease syndromes: distinct pathogenesis caused by maladaptive host responsesAllen C. Steere (ASCI) http://jci.me/138062

Leveraging neuroimmune mechanisms to control chronic painMillions of adults worldwide live with chronic pain that is often poorly managed by existing therapeutic approaches. In this issue, Thomas Buchheit, Yul Huh, William Maixner, Jianguo Cheng, and Ru-Rong Ji describe a relatively new concept in treating chronic pain. Regenerative pain medicine seeks to promote analgesia by targeting the neuroimmune mechanisms underlying pain perception and pain sensitization. Cellular and exosome-based therapies targeting immune mediators of chronic pain are currently being explored in clinical trials. These include systemic or local injection of platelet-rich plasma, monocyte-derived cytokines, and delivery of pro-resolving or antiinflammatory molecules (see the accompanying image). In their Review, Thomas Buchheit et al. describe the major clinical and preclinical advances in regenerative pain medicine as well as future questions and directions for the field.

Neuroimmune modulation of pain and regenerative pain medicineThomas Buchheit, Yul Huh, William Maixner, Jianguo Cheng, and Ru-Rong Ji http://jci.me/134439

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Current research articles

aids/hivBCL-2 antagonism sensitizes cytotoxic T cell–resistant HIV reservoirs to elimination ex vivoYanqin Ren, Szu Han Huang, Shabnum Patel, Winiffer D. Conce Alberto, Dean Magat, Dughan Ahimovic, Amanda B. Macedo, Ryan Durga, Dora Chan, Elizabeth Zale, Talia M. Mota, Ronald Truong, Thomas Rohwetter, Chase D. McCann, Colin M. Kovacs, Erika Benko, Avery Wimpelberg, Christopher Cannon, W. David Hardy, Alberto Bosque, Catherine M. Bollard, and R. Brad Jones http://jci.me/132374

autoimmunityCytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosisTakashi Maehara, Naoki Kaneko, Cory A. Perugino, Hamid Mattoo, Jesper Kers, Hugues Allard-Chamard, Vinay S. Mahajan, Hang Liu, Samuel J.H. Murphy, Musie Ghebremichael, David Fox, Aimee S. Payne, Robert Lafyatis, John H. Stone, Dinesh Khanna, and Shiv Pillai http://jci.me/131700

cardiologyErythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasmJohanne Poisson, Marion Tanguy, Hortense Davy, Fatoumata Camara, Marie-Belle El Mdawar, Marouane Kheloufi, Tracy Dagher, Cécile Devue, Juliette Lasselin, Aurélie Plessier, Salma Merchant, Olivier Blanc-Brude, Michèle Souyri, Nathalie Mougenot, Florent Dingli, Damarys Loew, Stephane N. Hatem, Chloé James, Jean-Luc Villeval, Chantal M. Boulanger, and Pierre-Emmanuel Rautou http://jci.me/124566

clinical medicineTargetable ERBB2 mutations identified in neurofibroma/schwannoma hybrid nerve sheath tumorsMichael W. Ronellenfitsch, Patrick N. Harter, Martina Kirchner, Christoph Heining, Barbara Hutter, Laura Gieldon, Jens Schittenhelm, Martin U. Schuhmann, Marcos Tatagiba, Gerhard Marquardt, Marlies Wagner, Volker Endris, Christian H. Brandts, Victor-Felix Mautner, Evelin Schröck, Wilko Weichert, Benedikt Brors, Andreas von Deimling, Michel Mittelbronn, Joachim P. Steinbach, David E. Reuss, Hanno Glimm, Albrecht Stenzinger, and Stefan Fröhling http://jci.me/130787

Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity p. 4Alana E. O’Mara, James W. Johnson, Joyce D. Linderman, Robert J. Brychta, Suzanne McGehee, Laura A. Fletcher, Yael A. Fink, Devika Kapuria, Thomas M. Cassimatis, Nathan Kelsey, Cheryl Cero, Zahraa Abdul Sater, Francesca Piccinini, Alison S. Baskin, Brooks P. Leitner, Hongyi Cai, Corina M. Millo, William Dieckmann, Mary Walter, Norman B. Javitt, Yaron Rotman, Peter J. Walter, Marilyn Ader, Richard N. Bergman, Peter Herscovitch, Kong Y. Chen, and Aaron M. Cypess (ASCI) http://jci.me/131126

The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans p. 4Brian S. Finlin, Hasiyet Memetimin, Beibei Zhu, Amy L. Confides, Hemendra J. Vekaria, Riham H. El Khouli, Zachary R. Johnson, Philip M. Westgate, Jianzhong Chen, Andrew J. Morris, Patrick G. Sullivan, Esther E. Dupont-Versteegden, and Philip A. Kern (ASCI) http://jci.me/134892

Donor glucose-6-phosphate dehydrogenase deficiency decreases blood quality for transfusionRichard O. Francis, Angelo D’Alessandro, Andrew Eisenberger, Mark Soffing, Randy Yeh, Esther Coronel, Arif Sheikh, Francesca Rapido, Francesca La Carpia, Julie A. Reisz, Sarah Gehrke, Travis Nemkov, Tiffany Thomas, Joseph Schwartz, Chaitanya Divgi, Debra Kessler, Beth H. Shaz, Yelena Ginzburg, James C. Zimring, Steven L. Spitalnik (ASCI), and Eldad A. Hod http://jci.me/133530

Clinical and immunological features of severe and moderate coronavirus disease 2019 p. 4Guang Chen, Di Wu, Wei Guo, Yong Cao, Da Huang, Hongwu Wang, Tao Wang, Xiaoyun Zhang, Huilong Chen, Haijing Yu, Xiaoping Zhang, Minxia Zhang, Shiji Wu, Jianxin Song, Tao Chen, Meifang Han, Shusheng Li, Xiaoping Luo, Jianping Zhao, and Qin Ning http://jci.me/137244

Phase I trial of donor-derived modified immune cell infusion in kidney transplantation p. 5Christian Morath, Anita Schmitt, Christian Kleist, Volker Daniel, Gerhard Opelz, Caner Süsal, Eman Ibrahim, Florian Kälble, Claudius Speer, Christian Nusshag, Luiza Pego da Silva, Claudia Sommerer, Lei Wang, Ming Ni, Angela Hückelhoven-Krauss, David Czock, Uta Merle, Arianeb Mehrabi, Anja Sander, Matthes Hackbusch, Christoph Eckert, Rüdiger Waldherr, Paul Schnitzler, Carsten Müller-Tidow, Jörg D. Hoheisel, Shakhawan A. Mustafa, Mohamed S.S. Alhamdani, Andrea S. Bauer, Jochen Reiser, Martin Zeier, Michael Schmitt, Matthias Schaier, and Peter Terness http://jci.me/133595

gastroenterologyBacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells p. 5Manikandan Palrasu, Elena Zaika, Wael El-Rifai, Monica Garcia-Buitrago, Maria Blanca Piazuelo, Keith T. Wilson, Richard M. Peek Jr., and Alexander I. Zaika http://jci.me/130015

Distinct immune characteristics distinguish hereditary and idiopathic chronic pancreatitisBomi Lee, Julia Z. Adamska, Hong Namkoong, Melena D. Bellin, Josh Wilhelm, Gregory L. Szot, David M. Louis, Mark M. Davis, Stephen J. Pandol, and Aida Habtezion (ASCI) http://jci.me/134066

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Current research articles

TRPV4 channel opening mediates pressure-induced pancreatitis initiated by Piezo1 activation p. 5Sandip M. Swain, Joelle M.-J. Romac, Rafiq A. Shahid, Stephen J. Pandol, Wolfgang Liedtke, Steven R. Vigna, and Rodger A. Liddle (ASCI) http://jci.me/134111

hepatologyMolecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancerPeter Dietrich, Laura Wormser, Valerie Fritz, Tatjana Seitz, Monica De Maria, Alexandra Schambony, Andreas E. Kremer, Claudia Günther, Timo Itzel, Wolfgang E. Thasler, Andreas Teufel, Jonel Trebicka, Arndt Hartmann, Markus F. Neurath, Stephan von Hörsten, Anja K. Bosserhoff, and Claus Hellerbrand http://jci.me/131919

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injuryKojiro Nakamura, Shoichi Kageyama, Fady M. Kaldas, Hirofumi Hirao, Takahiro Ito, Kentaro Kadono, Kenneth J. Dery, Hidenobu Kojima, David W. Gjertson, Rebecca A. Sosa, Maciej Kujawski, Ronald W. Busuttil, Elaine F. Reed, and Jerzy W. Kupiec-Weglinski http://jci.me/133142

immunologyTGF-β–induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosisClara Dees, Sebastian Pötter, Yun Zhang, Christina Bergmann, Xiang Zhou, Markus Luber, Thomas Wohlfahrt, Emmanuel Karouzakis, Andreas Ramming, Kolja Gelse, Akihiko Yoshimura, Rudolf Jaenisch, Oliver Distler, Georg Schett, and Jörg H.W. Distler http://jci.me/122462

IL-17–producing γδ T cells protect against Clostridium difficile infectionYee-Shiuan Chen, Iuan-Bor Chen, Giang Pham, Tzu-Yu Shao, Hansraj Bangar, Sing Sing Way, and David B. Haslam http://jci.me/127242

Specificity of bispecific T cell receptors and antibodies targeting peptide-HLAChristopher J. Holland, Rory M. Crean, Johanne M. Pentier, Ben de Wet, Angharad Lloyd, Velupillai Srikannathasan, Nikolai Lissin, Katy A. Lloyd, Thomas H. Blicher, Paul J. Conroy, Miriam Hock, Robert J. Pengelly, Thomas E. Spinner, Brian Cameron, Elizabeth A. Potter, Anitha Jeyanthan, Peter E. Molloy, Malkit Sami, Milos Aleksic, Nathaniel Liddy, Ross A. Robinson, Stephen Harper, Marco Lepore, Chris R. Pudney, Marc W. van der Kamp, Pierre J. Rizkallah, Bent K. Jakobsen, Annelise Vuidepot, and David K. Cole http://jci.me/130562

The neonatal microenvironment programs innate γδ T cells through the transcription factor STAT5Darshana Kadekar, Rasmus Agerholm, John Rizk, Heidi A. Neubauer, Tobias Suske, Barbara Maurer, Monica Torrellas Viñals, Elena M. Comelli, Amel Taibi, Richard Moriggl, and Vasileios Bekiaris http://jci.me/131241

Live attenuated pertussis vaccine BPZE1 induces a broad antibody response in humansAng Lin, Danijela Apostolovic, Maja Jahnmatz, Frank Liang, Sebastian Ols, Teghesti Tecleab, Chenyan Wu, Marianne van Hage, Ken Solovay, Keith Rubin, Camille Locht, Rigmor Thorstensson, Marcel Thalen, and Karin Loré http://jci.me/135020

The lymph node stromal laminin α5 shapes alloimmunityLushen Li, Marina W. Shirkey, Tianshu Zhang, Yanbao Xiong, Wenji Piao, Vikas Saxena, Christina Paluskievicz, Young Lee, Nicholas Toney, Benjamin M. Cerel, Qinshan Li, Thomas Simon, Kyle D. Smith, Keli L. Hippen, Bruce R. Blazar, Reza Abdi, and Jonathan S. Bromberg http://jci.me/135099

inflammationLocal microvascular leakage promotes trafficking of activated neutrophils to remote organs p. 3Charlotte Owen-Woods, Régis Joulia, Anna Barkaway, Loïc Rolas, Bin Ma, Astrid Fee Nottebaum, Kenton P. Arkill, Monja Stein, Tamara Girbl, Matthew Golding, David O. Bates, Dietmar Vestweber, Mathieu-Benoit Voisin, and Sussan Nourshargh http://jci.me/133661

metabolismParental metabolic syndrome epigenetically reprograms offspring hepatic lipid metabolism in miceDario F. De Jesus, Kazuki Orime, Dorota Kaminska, Tomohiko Kimura, Giorgio Basile, Chih-Hao Wang, Larissa Haertle, Renzo Riemens, Natalie K. Brown, Jiang Hu, Ville Männistö, Amélia M. Silva, Ercument Dirice, Yu-Hua Tseng, Thomas Haaf, Jussi Pihlajamäki, and Rohit N. Kulkarni (ASCI) http://jci.me/127502

Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditureWei Zou, Nidhi Rohatgi, Jonathan R. Brestoff, John R. Moley, Yongjia Li, Jesse W. Williams, Yael Alippe, Hua Pan, Terri A. Pietka, Gabriel Mbalaviele, Elizabeth P. Newberry, Nicholas O. Davidson, Anwesha Dey, Kooresh I. Shoghi, Richard D. Head, Samuel A. Wickline, Gwendalyn J. Randolph, Nada A. Abumrad, and Steven L. Teitelbaum (ASCI) http://jci.me/128687

Fetal alcohol spectrum disorder predisposes to metabolic abnormalities in adulthoodOlivia Weeks, Gabriel D. Bossé, Isaac M. Oderberg, Sebastian Akle, Yariv Houvras, Paul J. Wrighton, Kyle LaBella, Isabelle Iversen, Sahar Tavakoli, Isaac Adatto, Arkadi Schwartz, Daan Kloosterman, Allison Tsomides, Michael E. Charness, Randall T. Peterson, Matthew L. Steinhauser, Pouneh K. Fazeli, and Wolfram Goessling (ASCI) http://jci.me/132139

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muscle biologyDysfunctional polycomb transcriptional repression contributes to lamin A/C–dependent muscular dystrophyAndrea Bianchi, Chiara Mozzetta, Gloria Pegoli, Federica Lucini, Sara Valsoni, Valentina Rosti, Cristiano Petrini, Alice Cortesi, Francesco Gregoretti, Laura Antonelli, Gennaro Oliva, Marco De Bardi, Roberto Rizzi, Beatrice Bodega, Diego Pasini, Francesco Ferrari, Claudia Bearzi, and Chiara Lanzuolo http://jci.me/128161

Transcriptional and cytopathological hallmarks of FSHD in chronic DUX4-expressing miceDarko Bosnakovski, Ahmed S. Shams, Ce Yuan, Meiricris T. da Silva, Elizabeth T. Ener, Cory W. Baumann, Angus J. Lindsay, Mayank Verma, Atsushi Asakura, Dawn A. Lowe, and Michael Kyba http://jci.me/133303

neuroscienceExosomes mediate sensory hair cell protection in the inner ear p. 2Andrew M. Breglio, Lindsey A. May, Melanie Barzik, Nora C. Welsh, Shimon P. Francis, Tucker Q. Costain, Lizhen Wang, D. Eric Anderson, Ronald S. Petralia, Ya-Xian Wang, Thomas B. Friedman, Matthew J.A. Wood, and Lisa L. Cunningham http://jci.me/128867

Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα–mediated lipid metabolism p. 2Xin Zhou, Chenxi He, Jiangong Ren, Congxin Dai, Sharon R. Stevens, Qianghu Wang, Daniel Zamler, Takashi Shingu, Liang Yuan, Chythra R. Chandregowda, Yunfei Wang, Visweswaran Ravikumar, Arvind U.K. Rao, Feng Zhou, Hongwu Zheng, Matthew N. Rasband, Yiwen Chen, Fei Lan, Amy B. Heimberger, Benjamin M. Segal, and Jian Hu http://jci.me/131800

Retrograde nerve growth factor signaling abnormalities in familial dysautonomia p. 3Lin Li, Katherine Gruner, and Warren G. Tourtellotte http://jci.me/130401

GPR160 de-orphanization reveals critical roles in neuropathic pain in rodentsGina L.C. Yosten, Caron M. Harada, Chris Haddock, Luigino Antonio Giancotti, Grant R. Kolar, Ryan Patel, Chun Guo, Zhoumou Chen, Jinsong Zhang, Timothy M. Doyle, Anthony H. Dickenson, Willis K. Samson, and Daniela Salvemini http://jci.me/133270

Striatal Kir2 K+ channel inhibition mediates the antidyskinetic effects of amantadineWeixing Shen, Wenjie Ren, Shenyu Zhai, Ben Yang, Carlos G. Vanoye, Ananya Mitra, Alfred L. George Jr., and D. James Surmeier http://jci.me/133398

oncologyCDCP1 overexpression drives prostate cancer progression and can be targeted in vivoAbdullah Alajati, Mariantonietta D’Ambrosio, Martina Troiani, Simone Mosole, Laura Pellegrini, Jingjing Chen, Ajinkya Revandkar, Marco Bolis, Jean-Philippe Theurillat, Ilaria Guccini, Marco Losa, Arianna Calcinotto, Gaston De Bernardis, Emiliano Pasquini, Rocco D’Antuono, Adam Sharp, Ines Figueiredo, Daniel Nava Rodrigues, Jonathan Welti, Veronica Gil, Wei Yuan, Tatjana Vlajnic, Lukas Bubendorf, Giovanna Chiorino, Letizia Gnetti, Verónica Torrano, Arkaitz Carracedo, Laura Camplese, Susumu Hirabayashi, Elena Canato, Gianfranco Pasut, Monica Montopoli, Jan Hendrik Rüschoff, Peter Wild, Holger Moch, Johann De Bono, and Andrea Alimonti http://jci.me/131133

Pembrolizumab plus allogeneic NK cells in advanced non–small cell lung cancer patientsMao Lin, Haihua Luo, Shuzhen Liang, Jibing Chen, Aihua Liu, Lizhi Niu, and Yong Jiang http://jci.me/132712

A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti–PD-1 immunotherapyBalamayoora Theivanthiran, Kathy S. Evans, Nicholas C. DeVito, Michael Plebanek, Michael Sturdivant, Luke P. Wachsmuth, April K.S. Salama, Yubin Kang, David Hsu, Justin M. Balko, Douglas B. Johnson, Mark Starr, Andrew Nixon, Alisha Holtzhausen, and Brent A. Hanks http://jci.me/133055

Pathogenesis of peritumoral hyperexcitability in an immunocompetent CRISPR-based glioblastoma modelAsante Hatcher, Kwanha Yu, Jochen Meyer, Isamu Aiba, Benjamin Deneen, and Jeffrey L. Noebels http://jci.me/133316

Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapyJing Li, Weichao Wang, Yajia Zhang, Marcin Cieślik, Jipeng Guo, Mengyao Tan, Michael D. Green, Weimin Wang, Heng Lin, Wei Li, Shuang Wei, Jiajia Zhou, Gaopeng Li, Xiaojun Jing, Linda Vatan, Lili Zhao, Benjamin Bitler, Rugang Zhang, Kathleen R. Cho, Yali Dou, Ilona Kryczek, Timothy A. Chan, David Huntsman, Arul M. Chinnaiyan, and Weiping Zou http://jci.me/134402

therapeuticsMarked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory controlXiaotong Cheng, Maria Prange-Barczynska, James W. Fielding, Minghao Zhang, Alana L. Burrell, Joanna D.C.C. Lima, Luise Eckardt, Isobel L.A. Argles, Christopher W. Pugh, Keith J. Buckler, Peter A. Robbins, Emma J. Hodson, Richard K. Bruick, Lucy M. Collinson, Fraydoon Rastinejad, Tammie Bishop, and Peter J. Ratcliffe http://jci.me/133194

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jci.org/this-month

Acinetobacter baumannii pneumonia linked to sex 12

Innate immune cells limit Klebsiella pneumoniae infectivity 12

TCF7L2 allele alters pulsatile insulin secretion 13

JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight

May 2020

NETs in atherosclerosis p. 11

This Month

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17

Pilar Alcaide

John F. Alcorn

Maria-Luisa Alegre

Ravi K. Amaravadi

Cristian Apetrei

Rajendra S. Apte

Zoltan Arany

Hossein Ardehali

Julio Ayala

Sami J. Barmada

Alexander G. Bassuk

Vann Bennett

Sudha B. Biddinger

Jonathan S. Bogan

Laura M. Bohn

Nunzio Bottini

Sebastien G. Bouret

Jason Brenchley

Renier J. Brentjens

G.R. Scott Budinger

George A. Calin

Stephen Y. Chan

Timothy A. Chan

Yuan Chang

Benjamin K. Chen

Kang Chen

Zhou-Feng Chen

Wendy Chung

Matthew Ciorba

Janice E. Clements

Craig M. Coopersmith

George Cotsarelis

Peter A. Crawford

Lisa L. Cunningham

Jennifer Davis

Ronald P. DeMatteo

Madhav V. Dhodapkar

Elia J. Duh

Sarah K. England

Carmella Evans-Molina

Robert L. Fairchild

Eric R. Fearon

Brian Finck

John H. Fingert

Robert Flaumenhaft

Edward A. Fon

Lawrence Fong

Nikolaos G. Frangogiannis

Anthony R. French

Katherine A. Gallagher

Terrence L. Geiger

Raphaela Goldbach-Mansky

Daniel R. Goldstein

Douglas K. Graham

Johann E. Gudjonsson

Kirk Habegger

Khalid A. Hanafy

Eric B. Haura

John Cijiang He

Adam Steven Helms

Robert O. Heuckeroth

Cory M. Hogaboam

Young-Kwon Hong

Eric J. Huang

Benjamin D. Humphreys

Ken Inoki

Rajan Jain

Daniel P. Judge

J. Michelle Kahlenberg

Shingo Kajimura

Pawel Kalinski

Nobuhiko Kamada

Thomas W.H. Kay

Barbara I. Kazmierczak

Catherine E. Keegan

Hans-Peter Kiem

William Y. Kim

Frank Kirchhoff

David G. Kirsch

Jason S. Knight

Donald E. Kohan

Maria Kontaridis

Laura A. Kresty

Jongsoon Lee

Michael Lehrke

Claire E. Lewis

Mathias Lichterfeld

Rodger A. Liddle

André Lieber

Michail S. Lionakis

Ivan Maillard

Ziad Mallat

Peter Mannon

Eric Martens

Franck Mauvais-Jarvis

Linda McAllister-Lucas

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

David K. Meyerholz

Jason C. Mills

Joshua D. Milner

Satdarshan Paul Monga

Hidayatullah G. Munshi

William J. Murphy

Matthias Nahrendorf

Mary C. Nakamura

Patrick Nana-Sinkam

Lisa F.P. Ng

Mark Nicolls

Laura J. Niedernhofer

Una O’Doherty

S. Tiong Ong

Akira Ono

Puneet Opal

Olabisi Opeyemi

Daniel Ory

Sophie Paczesny

Rulan Parekh

Victoria N. Parikh

Mary-Elizabeth Patti

Janos Peti-Peterdi

Fernando P. Polack

Benjamin Prosser

Ling Qi

Dominic Raj

Jalees Rehman

Florian Rieder

Matthew D. Ringel

Howard A. Rockman

Steven M. Rowe

Linda C. Samuelson

Victoria L. Seewaldt

Svati H. Shah

Vijay H. Shah

Yatrik M. Shah

Vikram Shakkottai

Guo-Ping Shi

Kanakadurga Singer

Natasha Snider

Scott Soleimanpour

Rhonda F. Souza

Fayyaz S. Sutterwala

Shu Takeda

James E. Talmadge

Muneesh Tewari

John P. Thyfault

Natalie J. Torok

Stephen H. Tsang

Hubert M. Tse

Fumihiko Urano

Jolanda van der Velden

Deborah J. Veis

Charles P. Venditti

Claudio J. Villanueva

Joseph Vinetz

Stephanie M. Ware

Sing Sing Way

Kevin W. Williams

Minna Woo

Prescott G. Woodruff

Jing Yang

Tianxin Yang

Yiping Yang

Vincent B. Young

Lori M. Zeltser

Zhen Zhang

Yutong Zhao

Binhua P. Zhou

JCI Insight Consulting Editors

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For JCI InsightEditor Kathleen CollinsDeputy Editors Andrew Lieberman, Donna Martin, Pavan ReddyAssociate Editors Sharlene M. Day, Gregory R. Dressler, David A. Fox, Santhi Ganesh, John Y. Kao, Nobuhiko Kamada, Celina G. Kleer, Carey Lumeng, Lona Mody, Bethany B. Moore, Marina Pasca di Magliano, Subramaniam Pennathur, Darleen Sandoval, Andrew Tai, Weiping ZouExecutive Editor Sarah C. JacksonSenior Science Editor Corinne WilliamsComputational Biologist Alexey Nesvizhskii

ASCI StaffExecutive Director John B. HawleyManaging Director Karen D. GuthAssociate Director Maya HoptmanProduction Editors Catherine Ahmann, Ken Beauchamp, Molly Jean, Lara L. McCarronProduction Assistant Samantha SmithScientific Illustrator Bruce WordenCopy Editors Clare Cross, Meredith Dimick, Barbara Fabyan, Rachel Nelson, Chet ProvodaAssociate Copy Editors Darla Nagel, Megan ReilleyAssociate Editor, Copy and Production Rachel BullenEditorial Assistant Cady VishniacAccounts Manager Paula KremidasAuthor Services Manager Megan JenkinsAuthor Services Representatives Katherine A. Bullen, Keith KalinowskiExecutive Administrator Theresa KaiserScience Communications Specialist Neha AggarwalProgram Manager Ashley HastonSenior Engineer and Technical Lead Austin BrewerSenior Engineer, Systems and Analytics Bryan EnglishSoftware Developer Jose L. Jardon

This MonthMay 2020

For JCI Insight online:jci.me/insight/5/7jci.me/insight/5/8

Nicholas Lukacs, PhD, Associate Editor, is the Godfrey D. Stobbe Professor of Pathology and Scientific Director of the Mary H. Weiser Food Allergy Center at the University of Michigan Medical School. Dr. Lukacs’s research has examined leukocyte migration and chemokine biology during acute and chronic inflammatory disease. His laboratory is currently focused on the innate and acquired immune responses in allergen- and respiratory virus–induced diseases, as well as the role of the gut microbiome in early-life immune system development.

Publication highlightsElesela S, Morris SB, Narayanan S, Kumar S, Lombard DB, Lukacs NW. Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells. PLoS Pathog. 2020;16(2):e1008319.

Malinczak CA, Rasky AJ, Fonseca W, Schaller MA, Allen RM, Ptaschinski C, Morris S, Lukacs NW. Upregulation of H3K27 demethylase KDM6 during respiratory syncytial virus infection enhances proinflammatory responses and immunopathology. J Immunol. 2020;204(1):159–168.

Fonseca W, Rasky AJ, Ptaschinski C, Morris SH, Best SKK, Phillips M, Malinczak CA, Lukacs NW. Group 2 innate lymphoid cells (ILC2) are regulated by stem cell factor during chronic asthmatic disease. Mucosal Immunol. 2019;12(2):445–456.

Ptaschinski C, Hrycaj SM, Schaller MA, Wellik DM, Lukacs NW. Hox5 paralogous genes modulate Th2 cell function during chronic allergic inflammation via regulation of Gata3. J Immunol. 2017;199(2):501– 509.

JCI Insight’s Editorial Board is composed of peer scientists at the University of Michigan and the University of Pennsylvania. Members of the Editorial Board review and oversee the peer review process of manuscripts directly submitted to JCI Insight, evaluate all transferred manuscripts, and meet weekly to discuss manuscripts under review.

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Editor’s picks

on the jci insight covercardiology

The NET effect on macrophages in atherosclerosisNeutrophil extracellular traps (NETs) are proinflammatory and have been linked to a variety of disease states, including atherosclerosis and diabetes. Resolution of atherosclerosis is impaired in patients with diabetes, potentially due to increased NET-associated plaque inflammation. Tatjana Josefs, Tessa Barrett, and colleagues performed transcriptional profiling of plaque macrophages from NET+ and NET– areas of atherosclerotic Ldlr–/– mice and determined that NETs associated with an elevated inflammatory phenotype. In nondiabetic mice, NETs decreased during atherosclerosis resolution; however, plaques

persisted in diabetic animals and were associated with increased inflammation and impaired resolution. DNase1 treatment of diabetic Ldlr–/– mice decreased NET content and macrophage inflammation within plaques, thereby promoting resolution of atherosclerosis in response to lipid lowering. Together, these results provide strong experimental evidence that NETs are a driver of increased cardiovascular risk in patients with diabetes. The cover image shows the presence of NETs (colocalization of MPO, red), H3Cit (pink), and Ly6G (green) in atherosclerotic plaques in an area also positive for macrophages.

Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic miceTatjana Josefs, Tessa J. Barrett, Emily J. Brown, Alexandra Quezada, Xiaoyun Wu, Maud Voisin, Jaume Amengual, and Edward A. Fisher http://jci.me/134796

B-type natriuretic peptide contributes to septic hypotension

Elevated levels of B-type natriuretic peptide (BNP) are associated with myocardial dysfunction in sepsis, which may be due to the effect of natriuretic signaling on cardiac output and blood pressure. However, evidence of a causal role for BNP in septic hypotension is lacking, and the mechanism driving increased BNP production in sepsis is poorly understood. Matthew Hoffman and colleagues used a cecal ligation and puncture (CLP) model of sepsis to investigate the requirement for BNP in sepsis-related hypotension. Deletion of Nppb, which encodes BNP, protected mice from a sepsis-induced decrease in end-diastolic volume (see the accompanying image) and preserved cardiac output. Treatment with a BNP-neutralizing antibody had a similar effect. BNP expression was directly driven by c-Jun binding to the Nppb promoter and could be prevented by pharmacological inhibition of JNK. Furthermore, both JNK inhibition and BNP neutralization improved survival in the CLP model. These findings advance JNK and BNP as potential therapeutic targets for septic hypotension.

B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes in septic hypotensionMatthew Hoffman, Ioannis D. Kyriazis, Alexandra Dimitriou, Santosh K. Mishra, Walter J. Koch, and Konstantinos Drosatos http://jci.me/133675

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JCI Insight | Editor’s picks

12

immunology

infectious disease

Mouse model reveals sex-specific Acinetobacter baumannii pneumonia susceptibility

Innate immune populations defend against Klebsiella pneumoniae infection

metabolism

IMPDH inhibitor mizoribine shows potential for tuberous sclerosis complexThe nucleotide synthesis enzyme inosine-5′-monophosphate dehydrogenase (IMPDH) has long been a target for immunosuppression, leading to the development of multiple IMPDH inhibitors in current clinical use. Recent studies demonstrated that blocking IMPDH may also have antitumor effects, suggesting that drugs with approved safety profiles could be repurposed as cancer therapy. Alexander Valvezan and colleagues compared the effect of two clinically used IMPDH inhibitors in mouse models of tuberous sclerosis complex (TSC). One of the inhibitors, mizoribine, selectively induced apoptosis in Tsc2–/– cells in vitro. In a xenograft tumor model, mizoribine blocked tumor growth to the same extent as rapamycin and continued to slow tumor growth even after treatment ended (see the accompanying image).

Notably, the FDA-approved IMPDH inhibitor mycophenolate mofetil did not similarly block tumor growth. These findings support the pursuit of future studies applying mizoribine to the treatment of TSC.

IMPDH inhibitors for antitumor therapy in tuberous sclerosis complexAlexander J. Valvezan, Molly C. McNamara, Spencer K. Miller, Margaret E. Torrence, John M. Asara, Elizabeth P. Henske, and Brendan D. Manning http://jci.me/135071

Acinetobacter baumannii is an emerging pathogen that exhibits versatile multidrug resistance, thus opportunistic infections with A. baumannii have a very high mortality rate. To model the disease, Sílvia Pires and colleagues intranasally infected mice with A. baumannii and noted that female mice had increased susceptibility to pneumonia, increased lethality, and greater bacterial counts than male mice. Treatment of male mice with 17β-estradiol exacerbated the pathological response to A. baumannii infection, although estradiol did not directly affect bacterial growth in vitro. While depletion of neutrophils and alveolar macrophages increased bacterial burden in both sexes, alveolar macrophage depletion disproportionately increased the bacterial burden in female mice, associated with changes in expression of mitochondrial genes, and reduced ATP production. This study reveals a metabolic function of alveolar macrophages in controlling infection in female mice and highlights the importance of modeling inflammatory diseases in both sexes.

Biological sex influences susceptibility to Acinetobacter baumannii pneumonia in miceSílvia Pires, Adeline Peignier, Jeremy Seto, Davida S. Smyth, and Dane Parker http://jci.me/132223

Carbapenem-resistant Klebsiella pneumoniae is a widespread opportunistic infection, but the host immunological responses to infection are poorly defined. In a model of pulmonary K. pneumoniae infection, Naoki Iwanaga and colleagues determined that Rag2–/–Il2rg–/– mice, which lack T, B, NK, and innate lymphoid cells, are more susceptible to infection than WT mice. However, Rag2–/– mice were not more susceptible compared with WT animals, indicating that the adaptive immune system does not determine infectivity to primary infection. Single-cell RNA-Seq of infected Rag2–/– mice revealed recruitment of IL-22+ ILC3 cells and IFN-γ+ NK cells to the lung that were critical to host resistance. The transplant rejection inhibitor FK506

decreased recruitment of the IL-22+ and IFN-γ+ populations to the lung, rendering WT mice susceptible to infection. Finally, administration of recombinant IL-22 reduced bacterial burden in FK506-treated and Rag2–/–Il2rg–/– mice. These findings support the development of host-directed immunotherapy as an adjunct treatment to antibiotics.

Host immunology and rationale immunotherapy for carbapenem-resistant Klebsiella pneumoniae infectionNaoki Iwanaga, Ivy Sandquist, Alanna Wanek, Janet McCombs, Kejing Song, and Jay K. Kolls (ASCI) http://jci.me/135591

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JCI Insight | Editor’s picks

endocrinology

Pulsatile insulin secretion alteration in humans with TCF7L2 alleleMost of the genetic variants that predispose to type 2 diabetes are thought to influence β cell function and insulin secretion. One of these is the T allele in TCF7L2, which associates with a subtle defect in insulin secretion. To determine whether abnormalities in insulin pulse characteristics could precede the development of hyperglycemia, Marcello Laurenti and colleagues studied nondiabetic individuals who were homozygous for the diabetes-associated allele at rs7903146 in the TCF7L2 locus. Peripheral C-peptide concentra-tions were used to deconvolve pulsatile insulin secretion without necessitating hepatic vein catheterization. Subjects in the TT genotype group exhibited disorderly insulin pulses during fasting. Moreover, in response to hyperglycemia, the dispersion of insulin pulse frequencies decreased in the CC genotype group but did not change in the TT group. Therefore, altered insulin pulse characteristics may be a biomarker for impaired β cell function that is detectable prior to the onset of overt glucose dysregulation.

Diabetes-associated genetic variation in TCF7L2 alters pulsatile insulin secretion in humansMarcello C. Laurenti, Chiara Dalla Man, Ron T. Varghese, James C. Andrews, Robert A. Rizza, Aleksey Matveyenko, Giuseppe De Nicolao, Claudio Cobelli, and Adrian Vella (ASCI) http://jci.me/136136

GLP-2R deficiency activates hepatic stellate cells and exacerbates murine steatohepatitisThe hormone glucagon-like peptide–2 (GLP-2) exerts proliferative and cytoprotective actions in the small bowel. The GLP-2 analog teduglutide is used clinically to decrease the requirement for parenteral nutrition in patients with short-bowel syndrome (SBS). However, the GLP-2 receptor (GLP-2R) is also detected outside the gut, raising issues of safety with GLP-2R agonists. While SBS patients are at elevated risk of hepatic steatosis and liver failure, the mechanistic effects of GLP-2 on the liver remain poorly understood. Shai Fuchs and colleagues have now shown that teduglutide treatment does not alter hepatic metabolism or inflammation in mice fed a high-fat, high-fructose, high-cholesterol (HFHC) diet.

However, GLP-2R–deficient mice exhibited increased hepatic Oil Red O staining (see accompanying image) and exacerbated hepatic inflammation. GLP-2R localized specifically to the hepatic stellate cells (HSCs), and GLP-2R–deficient mice displayed signs of HSC activation. These data indicate a role for GLP-2R in hepatic adaptation to nutrient excess and link GLP-2R signaling to HSC activity.

Loss of Glp2r signaling activates hepatic stellate cells and exacerbates diet-induced steatohepatitis in miceShai Fuchs, Bernardo Yusta, Laurie L. Baggio, Elodie M. Varin, Dianne Matthews, and Daniel J. Drucker (ASCI) http://jci.me/136907

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Current articles

Soluble (pro)renin receptor treats metabolic syndrome in mice with diet-induced obesity via interaction with PPARγFei Wang, Renfei Luo, Chang-Jiang Zou, Shiying Xie, Kexin Peng, Long Zhao, Kevin T. Yang, Chuanming Xu, and Tianxin Yang http://jci.me/128061

Vascularized composite allotransplantation combined with costimulation blockade induces mixed chimerism and reveals intrinsic tolerogenic potentialByoung Chol Oh, Georg J. Furtmüller, Madeline L. Fryer, Yinan Guo, Franka Messner, Johanna Krapf, Stefan Schneeberger, Damon S. Cooney, W.P. Andrew Lee, Giorgio Raimondi, and Gerald Brandacher http://jci.me/128560

Antibody response patterns in chikungunya febrile phase predict protection versus progression to chronic arthritisKaustuv Nayak, Vineet Jain, Manpreet Kaur, Naushad Khan, Kamalvishnu Gottimukkala, Charu Aggarwal, Rohit Sagar, Shipra Gupta, Ramesh Chandra Rai, Kritika Dixit, Mohammad Islamuddin, Wajihul Hasan Khan, Anil Verma, Deepti Maheshwari, Yadya M. Chawla, Elluri Seetharami Reddy, Harekrushna Panda, Pragati Sharma, Priya Bhatnagar, Prabhat Singh, Siva Raghavendhar B, Ashok Kumar Patel, Vinod H. Ratageri, Anmol Chandele, Pratima Ray, and Kaja Murali-Krishna http://jci.me/130509

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptorsPaul Dembny, Andrew G. Newman, Manvendra Singh, Michael Hinz, Michal Szczepek, Christina Krüger, Robert Adalbert, Omar Dzaye, Thorsten Trimbuch, Thomas Wallach, Gunnar Kleinau, Katja Derkow, Bernhard C. Richard, Carola Schipke, Claus Scheidereit, Harald Stachelscheid, Douglas Golenbock, Oliver Peters, Michael Coleman, Frank L. Heppner, Patrick Scheerer, Victor Tarabykin, Klemens Ruprecht, Zsuzsanna Izsvák, Jens Mayer, and Seija Lehnardt http://jci.me/131093

NFATC4 promotes quiescence and chemotherapy resistance in ovarian cancerAlexander J. Cole, Mangala Iyengar, Santiago Panesso-Gómez, Patrick O’Hayer, Daniel Chan, Greg M. Delgoffe, Katherine M. Aird, Euisik Yoon, Shoumei Bai, and Ronald J. Buckanovich (ASCI) http://jci.me/131486

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cellsSisi Deng, Zhichen Sun, Jian Qiao, Yong Liang, Longchao Liu, Chunbo Dong, Aijun Shen, Yang Wang, Hong Tang, Yang-Xin Fu, and Hua Peng http://jci.me/132000

Congenital myasthenic syndrome–associated agrin variants affect clustering of acetylcholine receptors in a domain-specific mannerBisei Ohkawara, XinMing Shen, Duygu Selcen, Mohammad Nazim, Vera Bril, Mark A. Tarnopolsky, Lauren Brady, Sae Fukami, Anthony A. Amato, Uluc Yis, Kinji Ohno, and Andrew G. Engel http://jci.me/132023

Biological sex influences susceptibility to Acinetobacter baumannii pneumonia in mice p. 12Sílvia Pires, Adeline Peignier, Jeremy Seto, Davida S. Smyth, and Dane Parker http://jci.me/132223

Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD3 bispecific antibodyKarin Staflin, Christina L. Zuch de Zafra, Leah K. Schutt, Vanessa Clark, Fiona Zhong, Maria Hristopoulos, Robyn Clark, Ji Li, Mary Mathieu, Xiaocheng Chen, Jennifer Johnston, Justin Low, Ryan Ybarra, Dionysos Slaga, Jihong Yang, Meric Ovacik, Noël O. Dybdal, Klara Totpal, Melissa R. Junttila, Diego Ellerman, Genee Lee, Mark S. Dennis, Rodney Prell, and Teemu T. Junttila http://jci.me/133757

Neutrophil extracellular traps promote macrophage inflammation and impair atherosclerosis resolution in diabetic mice p. 11Tatjana Josefs, Tessa J. Barrett, Emily J. Brown, Alexandra Quezada, Xiaoyun Wu, Maud Voisin, Jaume Amengual, and Edward A. Fisher http://jci.me/134796

Interstitial microRNA miR-214 attenuates inflammation and polycystic kidney disease progressionRonak Lakhia, Matanel Yheskel, Andrea Flaten, Harini Ramalingam, Karam Aboudehen, Silvia Ferrè, Laurence Biggers, Abheepsa Mishra, Christopher Chaney, Darren P. Wallace, Thomas Carroll, Peter Igarashi (ASCI), and Vishal Patel http://jci.me/133785

Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney diseaseKevin T. Bush, Prabhleen Singh, and Sanjay K. Nigam (ASCI) http://jci.me/133817

The C5a/C5aR2 axis promotes renal inflammation and tissue damageTing Zhang, Kun-yi Wu, Ning Ma, Ling-lin Wei, Malgorzata Garstka, Wuding Zhou, and Ke Li http://jci.me/134081

Leptin receptor–expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in miceWenwen Cheng, Ermelinda Ndoka, Chelsea Hutch, Karen Roelofs, Andrew MacKinnon, Basma Khoury, Jack Magrisso, Ki Suk Kim, Christopher J. Rhodes, David P. Olson, Randy J. Seeley, Darleen Sandoval, and Martin G. Myers Jr. (ASCI) http://jci.me/134359

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Current articles

Pancreatic tropism of metastatic renal cell carcinomaNirmish Singla, Zhiqun Xie, Ze Zhang, Ming Gao, Qurratulain Yousuf, Oreoluwa Onabolu, Tiffani McKenzie, Vanina Toffessi Tcheuyap, Yuanqing Ma, Jacob Choi, Renee McKay, Alana Christie, Oscar Reig Torras, Isaac A. Bowman, Vitaly Margulis, Ivan Pedrosa, Christopher Przybycin, Tao Wang, Payal Kapur, Brian Rini, and James Brugarolas (ASCI) http://jci.me/134564

Aberrant cell migration contributes to defective airway epithelial repair in childhood wheezeThomas Iosifidis, Erika N. Sutanto, Alysia G. Buckley, Laura Coleman, Erin E. Gill, Amy H. Lee, Kak-Ming Ling, Jessica Hillas, Kevin Looi, Luke W. Garratt, Kelly M. Martinovich, Nicole C. Shaw, Samuel T. Montgomery, Elizabeth Kicic-Starcevich, Yuliya V. Karpievitch, Peter Le Souëf, Ingrid A. Laing, Shyan Vijayasekaran, Francis J. Lannigan, Paul J. Rigby, Robert E.W. Hancock, Darryl A. Knight, Stephen M. Stick, Anthony Kicic, Western Australian Epithelial Research Program (WAERP), and Australian Respiratory Epithelium Consortium (AusREC) http://jci.me/133125

Multimodal immune phenotyping of maternal peripheral blood in normal human pregnancyRichard Apps, Yuri Kotliarov, Foo Cheung, Kyu Lee Han, Jinguo Chen, Angélique Biancotto, Ashley Babyak, Huizhi Zhou, Rongye Shi, Lisa Barnhart, Sharon M. Osgood, Yasmine Belkaid, Steven M. Holland, John S. Tsang, and Christa S. Zerbe http://jci.me/134838

Diabetes-associated genetic variation in TCF7L2 alters pulsatile insulin secretion in humans p. 13Marcello C. Laurenti, Chiara Dalla Man, Ron T. Varghese, James C. Andrews, Robert A. Rizza, Aleksey Matveyenko, Giuseppe De Nicolao, Claudio Cobelli, and Adrian Vella (ASCI) http://jci.me/136136

IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex p. 12Alexander J. Valvezan, Molly C. McNamara, Spencer K. Miller, Margaret E. Torrence, John M. Asara, Elizabeth P. Henske, and Brendan D. Manning http://jci.me/135071

Multiexon deletion alleles of ATF6 linked to achromatopsiaEun-Jin Lee, Wei-Chieh Jerry Chiang, Heike Kroeger, Chloe Xiaoke Bi, Daniel L. Chao, Dorota Skowronska-Krawczyk, Rebecca R. Mastey, Stephen H. Tsang, Leon Chea, Kyle Kim, Scott R. Lambert, Julia M.D. Grandjean, Britta Baumann, Isabelle Audo, Susanne Kohl, Anthony T. Moore, R. Luke Wiseman, Joseph Carroll, and Jonathan H. Lin (ASCI) http://jci.me/136041

Irreversible JNK1-JUN inhibition by JNK-IN-8 sensitizes pancreatic cancer to 5-FU/FOLFOX chemotherapyMatthew B. Lipner, Xianlu L. Peng, Chong Jin, Yi Xu, Yanzhe Gao, Michael P. East, Naim U. Rashid, Richard A. Moffitt, Silvia G. Herrera Loeza, Ashley B. Morrison, Brian T. Golitz, Cyrus Vaziri, Lee M. Graves, Gary L. Johnson, and Jen Jen Yeh (ASCI) http://jci.me/129905

B-type natriuretic peptide is upregulated by c-Jun N-terminal kinase and contributes in septic hypotension p. 11Matthew Hoffman, Ioannis D. Kyriazis, Alexandra Dimitriou, Santosh K. Mishra, Walter J. Koch, and Konstantinos Drosatos http://jci.me/133675

Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsisElisabeth Zechendorf, Caroline E. O’Riordan, Lara Stiehler, Natalie Wischmeyer, Fausto Chiazza, Debora Collotta, Bernd Denecke, Sabrina Ernst, Gerhard Müller-Newen, Sina M. Coldewey, Bianka Wissuwa, Massimo Collino, Tim-Philipp Simon, Tobias Schuerholz, Christian Stoppe, Gernot Marx, Christoph Thiemermann, and Lukas Martin http://jci.me/131571

Cardiovascular response to small-molecule APJ activationBrandon Ason, Yinhong Chen, Qi Guo, Kimberly M. Hoagland, Ray W. Chui, Mark Fielden, Weston Sutherland, Rhonda Chen, Ying Zhang, Shirley Mihardja, Xiaochuan Ma, Xun Li, Yaping Sun, Dongming Liu, Khanh Nguyen, Jinghong Wang, Ning Li, Sridharan Rajamani, Yusheng Qu, BaoXi Gao, Andrea Boden, Vishnu Chintalgattu, Jim R. Turk, Joyce Chan, Liaoyuan A. Hu, Paul Dransfield, Jonathan Houze, Jingman Wong, Ji Ma, Vatee Pattaropong, Murielle M. Véniant, Hugo M. Vargas, Gayathri Swaminath, and Aarif Y. Khakoo http://jci.me/132898

Phenotypic and functional translation of IL1RL1 locus polymorphisms in lung tissue and asthmatic airway epitheliumMichael A. Portelli, F. Nicole Dijk, Maria E. Ketelaar, Nick Shrine, Jenny Hankinson, Sangita Bhaker, Néomi S. Grotenboer, Ma’en Obeidat, Amanda P. Henry, Charlotte K. Billington, Dominick Shaw, Simon R. Johnson, Zara E.K. Pogson, Andrew Fogarty, Tricia M. McKeever, David C. Nickle, Yohan Bossé, Maarten van den Berge, Alen Faiz, Sharon Brouwer, Judith M. Vonk, Paul de Vos, Corry-Anke Brandsma, Cornelius J. Vermeulen, Amisha Singapuri, Liam G. Heaney, Adel H. Mansur, Rekha Chaudhuri, Neil C. Thomson, John W. Holloway, Gabrielle A. Lockett, Peter H. Howarth, Robert Niven, Angela Simpson, John D. Blakey, Martin D. Tobin, Dirkje S. Postma, Ian P. Hall, Louise V. Wain, Martijn C. Nawijn, Christopher E. Brightling, Gerard H. Koppelman, and Ian Sayers http://jci.me/132446

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Control of PTH secretion by the TRPC1 ion channelMarta Onopiuk, Bonnie Eby, Vasyl Nesin, Peter Ngo, Megan Lerner, Caroline M. Gorvin, Victoria J. Stokes, Rajesh V. Thakker, Maria Luisa Brandi, Wenhan Chang, Mary Beth Humphrey, Leonidas Tsiokas, and Kai Lau http://jci.me/132496

Glucose in the hypothalamic paraventricular nucleus regulates GLP-1 releaseYue Ma, Risheka Ratnasabapathy, Ivan De Backer, Chioma Izzi-Engbeaya, Marie-Sophie Nguyen-Tu, Joyceline Cuenco, Ben Jones, Christopher D. John, Brian Y.H. Lam, Guy A. Rutter, Giles S.H. Yeo, Waljit S. Dhillo, and James Gardiner http://jci.me/132760

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host diseaseKatiri J. Snyder, Nina C. Zitzer, Yandi Gao, Hannah K. Choe, Natalie E. Sell, Lotus Neidemire-Colley, Anora Ignaci, Charuta Kale, Raymond D. Devine, Maria G. Abad, Maciej Pietrzak, Min Wang, Hong Lin, Yang W. Zhang, Gregory K. Behbehani, Jane E. Jackman, Ramiro Garzon, Kris Vaddi, Robert A. Baiocchi, and Parvathi Ranganathan http://jci.me/131099

Intercalated cell BKα subunit is required for flow-induced K+ secretionRolando Carrisoza-Gaytan, Evan C. Ray, Daniel Flores, Allison L. Marciszyn, Peng Wu, Leah Liu, Arohan R. Subramanya, WenHui Wang, Shaohu Sheng, Lubika J. Nkashama, Jingxin Chen, Edwin K. Jackson, Stephanie M. Mutchler, Szilvia Heja, Donald E. Kohan, Lisa M. Satlin, and Thomas R. Kleyman http://jci.me/130553

MicroRNA-148a facilitates inflammatory dendritic cell differentiation and autoimmunity by targeting MAFBYao Meng, Jun Li, Zhizhong Ye, Zhihua Yin, Qing Sun, Zhuojun Liao, Guanhua Li, Jun Deng, Lu Liu, Yuqing Yu, Li Wu, Haibo Zhou, and Nan Shen http://jci.me/133721

Altered calcium handling produces reentry-promoting action potential alternans in atrial fibrillation–remodeled heartsTao Liu, Feng Xiong, Xiao-Yan Qi, Jiening Xiao, Louis Villeneuve, Issam Abu-Taha, Dobromir Dobrev, Congxin Huang, and Stanley Nattel http://jci.me/133754

Prognostic and predictive value of an immune infiltration signature in diffuse lower-grade gliomasLai-Rong Song, Jian-Cong Weng, Cheng-Bei Li, Xu-Lei Huo, Huan Li, Shu-Yu Hao, Zhen Wu, Liang Wang, Da Li, and Jun-Ting Zhang http://jci.me/133811

CX3CR1–CD8+ T cells are critical in antitumor efficacy but functionally suppressed in the tumor microenvironmentTakayoshi Yamauchi, Toshifumi Hoki, Takaaki Oba, Hidehito Saito, Kristopher Attwood, Michael S. Sabel, Alfred E. Chang, Kunle Odunsi, and Fumito Ito http://jci.me/133920

Pancreas tissue slices from organ donors enable in situ analysis of type 1 diabetes pathogenesisJulia K. Panzer, Helmut Hiller, Christian M. Cohrs, Joana Almaça, Stephen J. Enos, Maria Beery, Sirlene Cechin, Denise M. Drotar, John R. Weitz, Jorge Santini, Mollie K. Huber, Mirza Muhammad Fahd Qadir, Ricardo L. Pastori, Juan Domínguez-Bendala, Edward A. Phelps, Mark A. Atkinson, Alberto Pugliese, Alejandro Caicedo, Irina Kusmartseva, and Stephan Speier http://jci.me/134525

Prehospital plasma is associated with distinct biomarker expression following injuryDanielle S. Gruen, Joshua B. Brown, Francis X. Guyette, Yoram Vodovotz, Pär I. Johansson, Jakob Stensballe, Derek A. Barclay, Jinling Yin, Brian J. Daley, Richard S. Miller, Brian G. Harbrecht, Jeffrey A. Claridge, Herb A. Phelan, Matthew D. Neal, Brian S. Zuckerbraun, Timothy R. Billiar, Jason L. Sperry, and PAMPer study group http://jci.me/135350

Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development Weiping Su, Guanqiao Liu, Xiaonan Liu, Yangying Zhou, Qi Sun, Gehua Zhen, Xiao Wang, Yihe Hu, Peisong Gao, Shadpour Demehri, Xu Cao, and Mei Wan http://jci.me/135446

Loss of Glp2r signaling activates hepatic stellate cells and exacerbates diet-induced steatohepatitis in mice p. 13Shai Fuchs, Bernardo Yusta, Laurie L. Baggio, Elodie M. Varin, Dianne Matthews, and Daniel J. Drucker (ASCI) http://jci.me/136907

Host immunology and rationale immunotherapy for carbapenem-resistant Klebsiella pneumoniae infection p. 12Naoki Iwanaga, Ivy Sandquist, Alanna Wanek, Janet McCombs, Kejing Song, and Jay K. Kolls (ASCI) http://jci.me/135591

Commensal bacteria stimulate antitumor responses via T cell cross-reactivityCatherine A. Bessell, Ariel Isser, Jonathan J. Havel, Sangyun Lee, David R. Bell, John W. Hickey, Worarat Chaisawangwong, Joan Glick Bieler, Raghvendra Srivastava, Fengshen Kuo, Tanaya Purohit, Ruhong Zhou, Timothy A. Chan, and Jonathan P. Schneck http://jci.me/135597

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