Research Focuses on the Gen- Maureen R

This Month

Surveying resident physician exposure to COVID-19 2 Alternative mechanisms underlying acute graft- versus-host disease 4 Targeting melanocortin signaling alleviates cachexia 5 Intrathecal gene therapy improves neuromuscular deterioration in canine model 6

September 2020 JCI This Month is a summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight jci.org/this-month Placental infection by SARS–CoV-2 p. 2

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

Soman N. Abraham Richard T. D'Aquila Katherine A. High Terri Laufer David J. Pinsky M. Celeste Simon John S. Adams Alan Daugherty Helen H. Hobbs Mitchell A. Lazar Edward Plow Mihaela Skobe Qais Al-Awqati Sudhansu Dey Ronald Hoffman Brendan Lee Catherine Postic Donald Small Kari Alitalo Anna Mae Diehl V. Michael Holers William M.F. Lee Alice S. Prince Lois Smith Dario C. Altieri Harry C. Dietz III Steven Holland Rudolph L. Leibel Louis J. Ptáček Akrit Sodhi Masayuki Amagai Gianpietro Dotti David Holtzman Wayne I. Lencer Luigi Puglielli Weihong Song Brian H. Annex Michael Dustin Michael J. Holtzman Jon D. Levine Pere Puigserver Ashley L. St. John M. Amin Arnaout Connie J. Eaves Lawrence B. Holzman Ross L. Levine Bali Pulendran Jonathan Stamler Alan Attie Dominique Eladari Tamas L. Horvath Klaus Ley Ellen Puré Colin L. Stewart Jane E. Aubin Joel K. Elmquist Gokhan S. Hotamisligil Rodger A. Liddle Susan E. Quaggin Doris Stoffers Michael F. Beers Stephen G. Emerson Steven R. Houser Richard Locksley Marlene Rabinovitch Warren Strober Vann Bennett Jonathan A. Epstein Ralph H. Hruban Fanxin Long Daniel J. Rader Maureen A. Su Gregory K. Bergey Adrian Erlebacher Christopher A. Hunter Gary Lopaschuk Shahin Rafii D. James Surmeier Nina Bhardwaj Joel D. Ernst David James Nigel Mackman Gwendalyn J. Randolph Katalin Susztak Morris J. Birnbaum James M. Ervasti Richard J. Jones Richard B. Mailman Jeffrey C. Rathmell Catharina Svanborg Joyce Bischoff Robert V. Farese Jr. William G. Kaelin Jr. Rama K. Mallampalli W. Kimryn Rathmell Ira Tabas Craig Blackstone Eric R. Fearon Klaus Kaestner Kieren A. Marr Barbara Rehermann Alan R. Tall Bruce R. Blazar Anthony W. Ferrante Jr. Mark L. Kahn Jack Martin Muredach P. Reilly Sakae Tanaka Gerard C. Blobe Edward A. Fisher Raghu Kalluri Steven O. Marx Jochen Reiser Victor J. Thannickal William A. Boisvert Richard A. Flavell S. Ananth Karumanchi Rodger P. McEver Ryan Riddle Andrei Thomas-Tikhonenko Nancy Bonini Alessia Fornoni David A. Kass Elizabeth McNally Sarah A. Robertson Georgia D. Tomaras Brendan Boyce Tatiana Foroud Robert S. Kass Cornelis J. Melief Howard A. Rockman Peter Tontonoz Jonathan Bromberg Martin Friedlander Masato Kasuga Shlomo Melmed Paul B. Rosenberg Laurence A. Turka Frank C. Brosius Stephen J. Galli Daniel P. Kelly George Michalopoulos Theodora S. Ross Marcel R.M. van den Brink Hal E. Broxmeyer J. Victor Garcia-Martinez Dontscho Kerjaschki Jeffrey H. Miner Marc E. Rothenberg Luc Van Kaer Michael J. Caplan Alfred L. George Jr. Sundeep Khosla Peter J. Mohler Anil Rustgi David M. Virshup Diego H. Castrillon Sharon Gerecht Richard N. Kitsis Jeffery D. Molkentin Scheherazade Sadegh-Nasseri Matthias von Herrath Harold Chapman Stanton L. Gerson Peter S. Klein David D. Moore Junichi Sadoshima Yisong Y. Wan Ajay Chawla Robert E. Gerszten Steven Kliewer Edward E. Morrisey Akira Sawa Bart O. Williams Benjamin K. Chen Todd Golde Björn C. Knollmann James H. Morrissey Jose-Alain Sahel Allan W. Wolkoff Benny J. Chen Sherita Golden Walter J. Koch Deborah M. Muoio Jean E. Schaffer Joseph C. Wu Ju Chen Stanley Goldfarb Jay K. Kolls Anthony J. Muslin Philipp E. Scherer Thomas A. Wynn Jun Chen Larry B. Goldstein Issei Komuro Martin G. Myers Jr. Michael D. Schneider Ramnik J. Xavier Marie-Françoise Chesselet Fred Sanford Gorelick Christopher D. Kontos Benjamin G. Neel Detlef Schuppan Mingzhao Xing Vivian G. Cheung Kathleen J. Green Murray Korc Paul W. Noble Amita Sehgal Yiping Yang Raymond Chung Steven K. Grinspoon Gary Koretzky Eric N. Olson Clay Semenkovich Srinivasan Yegnasubramanian Jeanne M. Clark David Hafler Stavroula Kousteni Harry T. Orr Jonathan S. Serody Mone Zaidi Sheila Collins Jonathan J. Hansen John W. Krakauer Leo E. Otterbein John Seykora Len Zon Ronald G. Collman Raymond Clement Harris Rohit N. Kulkarni Roberto Pacifici Theresa A. Shapiro Weiping Zou Marco Colonna Stanley L. Hazen Shelby Kutty Akhilesh Pandey Mari Shinohara R. Suzanne Zukin Shaun R. Coughlin Peter Heeringa Chulan Kwon William C. Parks Steven E. Shoelson Tyler J. Curiel Meenhard Herlyn Antonio La Cava Warren S. Pear Gerald I. Shulman David D'Alessio Joachim Herz Fadi G. Lakkis Sallie R. Permar Roy L. Silverstein Featured Editor This Month 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 September 2020 review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.

For the JCI Marcela V. Maus, MD, PhD, Associate Edi- Editor tor, is Director of Cellular Immunotherapy at Rexford S. Ahima the Massachusetts General Hospital (MGH) Deputy Editors Cancer Center; a member of the Center for Can- Arturo Casadevall, Gregg L. Semenza, Gordon F. Tomaselli cer Immunology and the Department of Medi- cine, Division of Hematology and Oncology, and Associate Editors Mark E. Anderson, Mary Y. Armanios, Attending Physician in the Hematopoietic Stem Nilofer S. Azad, Joel N. Blankson, William R. Bishai, Cell Transplant and Cellular Therapy Service at Robert A. Brodsky, Peter A. Calabresi, MGH; Assistant Professor at Harvard Medical Thomas L. Clemens, Franco R. D’Alessio, Ted M. Dawson, Angelo M. DeMarzo, School; Associate Member of the Broad Institute Stephen Desiderio, Mark Donowitz, of Harvard and MIT; and Associate Member of Andrew P. Feinberg, Paul M. Hassoun, the Ragon Institute of MGH, MIT, and Harvard. Her research focuses on the gen- Maureen R. Horton, Elizabeth M. Jaffee, Mariana J. Kaplan, Marikki Laiho, Charles J. Lowenstein, eration, mechanisms, and use of innovative forms of T cell engineering, including Leo Luznik, Marcela V. Maus, Timothy H. Moran, with chimeric antigen receptors, and bringing these cell therapies to the clinical Laszlo Nagy, William Nelson, Brian O’Rourke, setting. Dr. Maus is a member of the American Society for Clinical Investigation. Ben Ho Park,Jonathan D. Powell, Thomas C. Quinn, Hamid Rabb, Jean-Pierre Raufman, Stuart C. Ray, Publication highlights Linda Smith Resar, Jeffrey D. Rothstein, Jonathan Schneck, Akrit S. Sodhi, Charlotte J. Sumner, Frigault MJ, Maus MV. State of the art in CAR T cell therapy for CD19+ B cell Simeon I. Taylor, Robert G. Weiss, Sarah J. Wheelan, malignancies. J Clin Invest. 2020;130(4):1586–1594. Marsha Wills-Karp Boroughs AC, Larson RC, Choi BD, Bouffard AA, Riley LS, Schiferle E, Kulkarni AS, Editorial Advisory Group Cetrulo CL, Ting D, Blazar BR, Demehri S, Maus MV. Chimeric antigen receptor costimula- Peter Agre, Carol W. Grieder, Diane E. Griffin, Paul B. Rothman, David Valle tion domains modulate human regulatory T cell function. JCI Insight. 2019;5(8):e126194. Biostatistician Choi BD, Yu X, Castano AP, Bouffard AA, Schmidts A, Larson RC, Bailey SR, Boroughs AC, Eliseo Guallar Frigault MJ, Leick MB, Scarfò I, Cetrulo CL, Demehri S, Nahed BV, Cahill DP, Computational Biologist Wakimoto H, Curry WT, Carter BS, Maus MV. CAR-T cells secreting BiTEs circumvent Patrick Cahan antigen escape without detectable toxicity. Nat Biotechnol. 2019;37(9):1049–1058. JCI Scholars Olivia Uddin, Chirag Vasavda Frigault MJ, Dietrich J, Martinez-Lage M, Leick M, Choi BD, DeFilipp Z, Chen YB, Abramson J, Crombie J, Armand P, Nayak L, Panzini C, Riley LS, Gallagher K, Maus MV. Staff Editors Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma. Blood. Executive Editor 2019;134(11):860–866. Sarah C. Jackson Senior Science Editor Garfall AL, Stadtmauer EA, Hwang WT, Lacey SF, Melenhorst JJ, Krevvata M, Carroll MP, Corinne Williams Matsui WH, Wang Q, Dhodapkar MV, Dhodapkar K, Das R, Vogl DT, Weiss BM, Cohen AD, Science Editor Mangan PA, Ayers EC, Nunez-Cruz S, Kulikovskaya I, Davis MM, Lamontagne A, Elyse Dankoski Dengel K, Kerr ND, Young RM, Siegel DL, Levine BL, Milone MC, Maus MV, June CH. Assistant Science Editor Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation Lisa Conti for refractory multiple myeloma. JCI Insight. 2019;4(4):e127684. Editor at Large Ushma S. Neill Contact the JCI and JCI Insight The American Society for Clinical Investigation holds the rights to Editorial Intern and publishes the Journal of Clinical Investigation and JCI Insight.

Bouchra Taib 2015 Manchester Road, Ann Arbor, Michigan 48104, USA The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI. JCI This Month ISSN 2380-3029 (print) Phone: 734.222.6050 ISSN 2380-3037 (online) Email: [email protected] (JCI); (ASCI) indicates corresponding authors For the full JCI online: jci.me/130/9 [email protected] (JCI Insight) who are ASCI members.

jci.org/this-month september 2020 1 research Editor’s picks

covid-19 on the jci cover SARS–CoV-2 infection of the placenta at 22 weeks’ gestation The risks COVID-19 poses to pregnant women remain unclear, and ongoing studies are needed to determine how outcomes vary by trimester and individual patient risk factors. In this issue, Hillary Hosier, Shelli Farhadian, and colleagues present a case of SARS–CoV-2 infection of the placenta in the second trimester. This case report highlights a patient with severe COVID-19 who was admitted to the hospital at 22 weeks’ gestation with severe preeclampsia and placental abruption. The patient had a history of hypertension with a prior pregnancy that resolved with delivery. She consent- ed to termination of the pregnancy to mitigate the risk of serious maternal complications or death. Pathological examination of the placenta revealed the presence of SARS–CoV-2 primarily in syncytiotrophoblast cells at the maternal-fetal interface. The absence of placental vasculopathy distinguished the presentation in this patient from that of typical preeclampsia. The researchers hypothesized that the virus’s use of the ACE2 receptor may have precipitated preeclampsia and suggest that an individual’s predisposition to hypertensive disorders of pregnancy could be a factor in the severity of COVID-19 manifestations in pregnant women. The cover image shows immunohisto- chemical staining for SARS–CoV-2 spike protein (brown), which localized primarily within the syncytiotrophoblast cells. Image credit: Alice Lu-Culligan.

SARS–CoV-2 infection of the placenta Hillary Hosier, Shelli F. Farhadian, Raffaella A. Morotti, Uma Deshmukh, Alice Lu-Culligan, Katherine H. Campbell, Yuki Yasumoto, Chantal B.F. Vogels, Arnau Casanovas-Massana, Pavithra Vijayakumar, Bertie Geng, Camila D. Odio, John Fournier, Anderson F. Brito, Joseph R. Fauver, Feimei Liu, Tara Alpert, Reshef Tal, Klara Szigeti-Buck, Sudhir Perincheri, Christopher Larsen, Aileen M. Gariepy, Gabriela Aguilar, Kristen L. Fardelmann, Malini Harigopal, Hugh S. Taylor, Christian M. Pettker, Anne L. Wyllie, Charles Dela Cruz, Aaron M. Ring, Nathan D. Grubaugh, Albert I. Ko, Tamas L. Horvath, Akiko Iwasaki, Uma M. Reddy, and Heather S. Lipkind http://jci.me/139569

Assessing COVID-19’s impact on New York City resident physicians

During the initial emergence of the COVID-19 pandemic in the United States, New New York City COVID-19 resident physician exposure York City (NYC) was considered the epicenter of disease cases and mortality. during exponential phase of pandemic Resident physicians working in close contact with patients faced among the highest Mark P. Breazzano, Junchao Shen, Aliaa H. Abdelhakim, Lora R. Dagi Glass, risks of any health-care workers, and these risks were exacerbated by shortages in Jason D. Horowitz, Sharon X. Xie, C. Gustavo de Moraes, Alice Chen-Plotkin, personal protective equipment (PPE). Mark Breazzano and collaborators surveyed 91 and Royce W.S. Chen, on behalf of the New York City Residency Program NYC residency program directors from March 2 to April 12, 2020, to evaluate Directors COVID-19 Research Group http://jci.me/139587 COVID-19’s impact on residents and variations in PPE use. In total, 2306 residents Related Commentary and 24 specialties were represented in the survey responses. The study reveals how Toward better preparedness for the next pandemic COVID-19 risk differed among different specialties and how PPE use may have Lauren I. Shapiro, Grace R. Kajita, Julia H. Arnsten, influenced infection risk. Lauren Shapiro, Grace Kajita, Julia Arnsten, and Yaron Tomer and Yaron Tomer http://jci.me/140296 highlight how these insights may help improve preparedness in ongoing responses to the COVID-19 pandemic in the accompanying Commentary.

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cardiology

Inhibiting BET bromodomain ameliorates cardiac pathology in murine laminopathy model Cardiomyopathy and heart failure are major causes of premature death discusses how these studies support further preclinical studies of in patients with laminopathies, a group of diseases caused by mutations approaches targeting BET bromodomain in laminopathy-linked DCM. in LMNA, the gene encoding the nuclear membrane protein lamin A/C. BET bromodomain inhibition attenuates cardiac Despite a strong link between LMNA mutations and dilated cardiomyopathy phenotype in myocyte-specific lamin A/C–deficient mice (DCM), no targeted therapies exist for these patients. In this issue, Gaelle Gaelle Auguste, Leila Rouhi, Scot J. Matkovich, Cristian Coarfa, Auguste and colleagues investigated cardiac dysfunction in cardiomyocyte- Matthew J. Robertson, Grazyna Czernuszewicz, Priyatansh Gurha, specific Lmna-deficient mice, reporting a phenotype that strongly resembles and Ali J. Marian http://jci.me/135922 clinical manifestations of laminopathy-associated DCM. An analysis of differentially expressed genes predicted the involvement of bromodomain- Related Commentary containing protein 4, a transcriptional and epigenetic regulator, in this BETs that cover the spread from acquired to heritable cardiac pathology. Mice treated daily with a BET bromodomain inhibitor heart failure exhibited improvements in cardiac phenotype as well as prolonged survival Michael Alexanian and Saptarsi M. Haldar time. Michael Alexanian and Saptarsi Haldar’s accompanying Commentary http://jci.me/140304

Regulation of CaMKII activation restrains pathological cardiac stress responses Pathological remodeling of myocardial tissue after stress and injury can alter calcium homeostasis and related signaling and gene expression pathways. Calcium/ calmodulin-dependent protein kinase II (CaMKII) hyperactivation is associated with exacerbation of cardiac injury, and limiting CaMKII activity appears to reduce pathological responses to myocardial stress. Klitos Konstantinidis and colleagues identified a pathway in which MICAL1, a methionine monooxygenase, and MSRB, a methionine reductase, regulate CaMKII in the stressed heart. They show that MICAL1 and MSRB attenuate CaMKII activation by controlling the oxidation of M308, a highly conserved residue in CaMKII’s calmodulin binding site. MICAL1-deficient mice displayed increases in CaMKII activation, cardiac arrhythmia, and premature death, whereas increasing M308 oxidation appeared protective in a cellular model of arrhythmia. Together, the findings indicate a previously unknown role for MICAL proteins in calcium-sensing physiology and heart disease. Your research generates MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII more than statistics. Klitos Konstantinidis, Vassilios J. Bezzerides, Lo Lai, Holly M. Isbell, An-Chi Wei, Yuejin Wu, Meera C. Viswanathan, Ian D. Blum, Jonathan M. Granger, Get noticed. Danielle Heims-Waldron, Donghui Zhang, Elizabeth D. Luczak, Kevin R. Murphy, Fujian Lu, Daniel H. Gratz, Bruno Manta, Qiang Wang, Qinchuan Wang, Submit your work Alex L. Kolodkin, Vadim N. Gladyshev, Thomas J. Hund, William T. Pu, Mark N. Wu, today at jci.org. Anthony Cammarato, Mario A. Bianchet, Madeline A. Shea, Rodney L. Levine, and Mark E. Anderson (ASCI) http://jci.me/133181

jci.org/this-month september 2020 3 JCI | Research: Editor’s picks

transplantation Donor monocyte and resident T cell interactions contribute to graft-versus-host disease Allogeneic hematopoietic cell transplantation (alloHCT) can prolong Peripheral host T cells survive hematopoietic stem cell remission in patients with hematologic and lymphoid malignancies. transplantation and promote graft-versus-host disease However, despite careful HLA matching between donor and host, deadly Sherrie J. Divito, Anders T. Aasebø, Tiago R. Matos, Pei-Chen Hsieh, Matthew Collin, complications can occur. The acute form of graft-versus-host disease Christopher P. Elco, John T. O’Malley, Espen S. Bækkevold, Henrik Reims, (aGVHD) is believed to be predominantly mediated by donor T cells, Tobias Gedde-Dahl, Michael Hagerstrom, Jude Hilaire, John W. Lian, Edgar L. Milford, which are stimulated by host antigen-presenting cells to exert Geraldine S. Pinkus, Vincent T. Ho, Robert J. Soiffer, Haesook T. Kim, Martin C. Mihm, cytopathic effects on host tissue. Two studies in this issue describe an Jerome Ritz, Indira Guleria, Corey S. Cutler, Rachael A. Clark, Frode L. Jahnsen, alternative mechanism underlying aGVHD. Sherrie Divito, Anders Aasebø, and Thomas S. Kupper (ASCI) http://jci.me/129965 Tiago Matos, and collaborators observed that gut- and skin-resident Donor monocyte–derived macrophages promote human acute host T cells survive pretransplant conditioning regimens (see the graft-versus-host disease associated image). In a mouse model, they demonstrated that donor Laura Jardine, Urszula Cytlak, Merry Gunawan, Gary Reynolds, Kile Green, monocytes could stimulate skin-resident host T cells to produce Xiao-Nong Wang, Sarah Pagan, Maharani Paramitha, Christopher A. Lamb, GVHD-like dermatitis. In a separate study, Laura Jardine et al. identified Anna K. Long, Erin Hurst, Smeera Nair, Graham H. Jackson, Amy Publicover, donor CD11c+CD14+ monocyte–derived macrophages as the dominant Venetia Bigley, Muzlifah Haniffa, A.J. Simpson, and Matthew Collin leukocyte population in cutaneous aGVHD patients. In skin explants, the http://jci.me/133909 donor-derived macrophages stimulated cytopathic damage both independently and via effects on host T cells. The accompanying Related Commentary Commentary by James Young suggests that understanding these Alternative mechanisms that mediate graft-versus-host additional mechanisms contributing to GVHD development may open disease in allogeneic hematopoietic cell transplants new avenues for investigating prophylactic strategies. James W. Young http://jci.me/140064

Prevention of graft-versus-host disease using human CD83- targeted CAR T cells Prophylactic strategies to prevent graft-versus- presenting cells canonically associated with the Human CD83–targeted chimeric host disease (GVHD) following allogeneic development of GVHD. In mouse models, infusion antigen receptor T cells prevent and hematopoietic cell transplantation (alloHCT) of CD83-targeted CAR T cells both prevented and treat graft-versus-host disease primarily rely on calcineurin inhibitors. In addition rescued xenogenic GVHD. Further, the researchers Bishwas Shrestha, Kelly Walton, Jordan Reff, to their limited efficacy, calcineurin inhibitors may revealed that CD83 is an acute myeloid leukemia Elizabeth M. Sagatys, Nhan Tu, Justin Boucher, also interfere in beneficial effects of alloHCT. (AML) antigen and that CD83-targeted CAR T cells Gongbo Li, Tayyebb Ghafoor, Martin Felices, Bishwas Shrestha and colleagues developed a have antitumor activity against human AML cell Jeffrey S. Miller, Joseph Pidala, Bruce R. Blazar, chimeric antigen receptor (CAR) T cell targeting lines. The results support clinical investigation of Claudio Anasetti, Brian C. Betts, human CD83, an activation marker present on both CD83 CAR T cells for their protective effects against and Marco L. Davila the CD4+ T cells, and proinflammatory antigen- GVHD and efficacy against AML. http://jci.me/135754

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metabolism Overnutrition weakens hypocretin/ Inhibiting melanocortin orexin system function in male mice signaling preserves The neural systems regulating energy balance evolved in a natural environment where food was scarce. Overnutrition and obesity produce adaptations in behavior and brain appetite and mass function that are likely rooted in the remodeling of associated brain circuitry. Ying Tan, in cachexia models Fu Hang, and colleagues explored the effects of diet-induced obesity on the hypocretin/ orexin (Hcrt) system, a hypothalamic hub that regulates motivated behavior, stress Cachexia is a wasting syndrome that affects a large number of responses, and cognition. Obese mice, which gained 100% of body mass or more as the patients with cancer as well as those with chronic kidney disease, HIV, result of high-fat feeding, exhibited marked weakening of the Hcrt system, observed as and other illnesses. Loss of muscle and adipose tissue in cachexia is decreases in plasticity, response to reward- and stress-related neurotransmitter driven by both reduced food intake and increased energy expenditure. signaling, and hypothalamic and hippocampal network activity. Behaviorally, these Focusing on hypothalamic melanocortin signaling, which has been impairments were linked to decreased reward seeking and altered stress-coping shown to suppress appetite and energy storage, Xinxia Zhu and strategies in the obese mice. In the accompanying Commentary, Natalie Michael and Joel colleagues evaluated the drug candidate TCMCB07, an antagonist of Elmquist suggest the Hcrt system as an important regulator of energy homeostasis that the melanocortin-4 receptor, in rat models of cachexia induced by may underlie multiple physiological and behavioral consequences of overnutrition. cancer and nephrectomy. Inhibition of central melanocortin signaling via peripheral administration of TCMCB07 increased food intake and Impaired hypocretin/orexin system alters responses to salient preserved fat and lean mass in these models. There are currently no stimuli in obese male mice effective interventions for cachexia, and these findings may represent Ying Tan, Fu Hang, Zhong-Wu Liu, Milan Stoiljkovic, Mingxing Wu, Yue Tu, Wenfei Han, an important step in treating this devastating condition. Angela M. Lee, Craig Kelley, Mihály Hajós, Lingeng Lu, Luis de Lecea, Ivan De Araujo, Marina R. Picciotto, Tamas L. Horvath, and Xiao-Bing Gao http://jci.me/130889 Melanocortin-4 receptor antagonist TCMCB07 ameliorates cancer- and chronic kidney Related Commentary disease–associated cachexia Coordination of metabolism, arousal, and reward Xinxia Zhu, Michael F. Callahan, Kenneth A. Gruber, Marek Szumowski, by orexin/hypocretin neurons and Daniel L. Marks http://jci.me/138392 Natalie J. Michael and Joel K. Elmquist http://jci.me/140585

oncology Decreased stroma associates with tumor progression in pancreatic ductal adenocarcinoma Pancreatic ductal adenocarcinoma (PDA) is a highly fibrosis was associated with enhanced tumor progres- lethal solid tumor that remains difficult to treat, in part sion. The observation that stroma can play a protective due to the PDA stroma’s suspected role in tumor role in PDA highlights the need for caution in exploring progression and therapy resistance. Extensive fibrosis is translational approaches to deplete the tumor stroma. a prominent feature of the PDA stroma, but fibrosis- Pancreatic ductal adenocarcinoma targeting approaches have failed to demonstrate progression is restrained by stromal matrix benefits in preclinical and clinical studies. Honglin Jiang Honglin Jiang, Robert J. Torphy, Katja Steiger, Henry Hongo, and colleagues now report that stroma may play a more Alexa J. Ritchie, Mark Kriegsmann, David Horst, complex role than previously appreciated in PDA Sarah E. Umetsu, Nancy M. Joseph, Kimberly McGregor, outcomes. In primary resected PDA tumors, lower Michael J. Pishvaian, Edik M. Blais, Brian Lu, Mingyu Li, stromal density correlated with shorter patient survival Michael Hollingsworth, Connor Stashko, Keith Volmar, times. Moreover, PDA metastases to liver, which Jen Jen Yeh, Valerie M. Weaver, Zhen J. Wang, correlate with worse prognosis, displayed lower stromal Margaret A. Tempero, Wilko Weichert, content than primary tumors (see the accompanying and Eric A. Collisson http://jci.me/136760 image). In a mouse model of PDA, reduced intratumoral

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neuroscience Gene therapy for Krabbe disease extends life span in canine model

Krabbe disease, also called globoid cell leukodystrophy (GLD), is a severe neurological Krabbe disease successfully treated via condition caused by mutations in the gene encoding galactosylceramidase (GALC), an enzyme monotherapy of intrathecal gene therapy that is critical for maintaining normal myelin turnover. GALC deficiency leads to pathological Allison M. Bradbury, Jessica H. Bagel, Duc Nguyen, Erik A. Lykken, accumulation of the cytotoxic lipid psychosine within the CNS and PNS. Allison Bradbury, Jill Pesayco Salvador, Xuntian Jiang, Gary P. Swain, Charles Vite, and colleagues investigated the efficacy of an intrathecal gene therapy delivering Charles A. Assenmacher, Ian J. Hendricks, Keiko Miyadera, GALC in a naturally occurring canine model of GLD. The AAV9-mediated therapy restored GALC Rebecka S. Hess, Arielle Ostrager, Patricia ODonnell, enzyme activity, normalized psychosine concentration, and improved myelination in the CNS Mark S. Sands, Daniel S. Ory, G. Diane Shelton, and PNS. Importantly, the treatment significantly increased life span in treated GLD-affected Ernesto R. Bongarzone, Steven J. Gray, and Charles H. Vite dogs. These results suggest that this GALC-targeting gene therapy may have clinical benefits in http://jci.me/133953 Krabbe disease, even in postsymptomatic patients, for whom no therapy is currently indicated.

viewpoints Collaborative Exploring the relevance of vitamin D approaches to and calcitriol beyond bone homeostasis optimizing clinical Vitamin D plays an essential role in regulating mineral absorption and skeletal homeostasis. Renal cells expressing the tightly regulated CYP27B1 enzyme convert the vitamin D metabolite research during the

25(OH)D3 to its active form, calcitriol, to mediate its protective effects on bone. However, nonrenal tissues and cells also express CYP27B1 and are capable of producing calcitriol locally COVID-19 pandemic (see the accompanying image). In this issue, Wesley Pike and Mark Meyer discuss the During the initial wave of the COVID-19 pandemic, the unresolved relevance of nonrenal calcitriol production in human health and disease. While the high rates of infection and hospitalizations that occurred outcomes of clinical trials evaluating vitamin D supplementation have been unclear, other in New York City necessitated a collaborative response studies provide evidence of a role for vitamin D and its metabolites in inflammation. Pike and between the city’s medical schools and hospitals to iden- Meyer’s Viewpoint suggests multiple avenues of research that should be considered to better tify effective therapies. A Viewpoint by Roy Gulick et al. characterize vitamin D and calcitriol’s potential effects in immunity, cardiovascular health, reviews the strategies employed by committees at Weill metabolism, cancer, and other diseases. Cornell’s and Columbia’s medical schools to prioritize clinical studies of drug candidates and convalescent The unsettled science of nonrenal calcitriol production plasma as well as the stumbling blocks encountered and its clinical relevance throughout these efforts. The discussion offers insights J. Wesley Pike and Mark B. Meyer http://jci.me/141334 into fostering a productive multidisciplinary, multi- institutional effort to conduct high-stakes clinical trials and observational studies amidst an urgent and rapidly changing public health crisis. Prioritizing clinical research studies during the COVID-19 pandemic: lessons from New York City Roy M. Gulick (ASCI), Magdalena E. Sobieszczyk, Donald W. Landry, and Anthony N. Hollenberg http://jci.me/142151

6 jci.org/this-month september 2020 Current research articles bone biology Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin Darja Andreev, Mengdan Liu, Daniela Weidner, Katerina Kachler, Maria Faas, Anika Grüneboom, Ursula Schlötzer-Schrehardt, Luis E. Muñoz, Ulrike Steffen, Bettina Grötsch, Barbara Killy, Gerhard Krönke, Andreas M. Luebke, Andreas Niemeier, Falk Wehrhan, Roland Lang, Georg Schett, and Aline Bozec http://jci.me/134214 cardiology MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII p. 3 Klitos Konstantinidis, Vassilios J. Bezzerides, Lo Lai, Holly M. Isbell, An-Chi Wei, Yuejin Wu, Meera C. Viswanathan, Ian D. Blum, Jonathan M. Granger, Danielle Heims-Waldron, Donghui Zhang, Elizabeth D. Luczak, Kevin R. Murphy, Fujian Lu, Daniel H. Gratz, Bruno Manta, Qiang Wang, Qinchuan Wang, Alex L. Kolodkin, Vadim N. Gladyshev, Thomas J. Hund, William T. Pu, Mark N. Wu, Anthony Cammarato, Mario A. Bianchet, Madeline A. Shea, Rodney L. Levine, and Mark E. Anderson (ASCI) http://jci.me/133181 Auxiliary trafficking subunit GJA1-20k protects connexin-43 from degradation and limits ventricular arrhythmias Shaohua Xiao, Daisuke Shimura, Rachel Baum, Diana M. Hernandez, Sosse Agvanian, Yoshiko Nagaoka, Makoto Katsumata, Paul D. Lampe, Andre G. Kleber, TingTing Hong, Robin M. Shaw (ASCI) http://jci.me/134682 BET bromodomain inhibition attenuates cardiac phenotype in myocyte-specific lamin A/C–deficient mice p. 3 Gaelle Auguste, Leila Rouhi, Scot J. Matkovich, Cristian Coarfa, Matthew J. Robertson, Grazyna Czernuszewicz, Priyatansh Gurha, and Ali J. Marian http://jci.me/135922 covid-19 Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent Alessio Mazzoni, Lorenzo Salvati, Laura Maggi, Manuela Capone, Anna Vanni, Michele Spinicci, Jessica Mencarini, Roberto Caporale, Benedetta Peruzzi, Alberto Antonelli, Michele Trotta, Lorenzo Zammarchi, Luca Ciani, Leonardo Gori, Chiara Lazzeri, Andrea Matucci, Alessandra Vultaggio, Oliviero Rossi, Fabio Almerigogna, Paola Parronchi, Paolo Fontanari, Federico Lavorini, Adriano Peris, Gian Maria Rossolini, Alessandro Bartoloni, Sergio Romagnani, Francesco Liotta, Francesco Annunziato, and Lorenzo Cosmi http://jci.me/138554 SARS–CoV-2 infection of the placenta p. 2 Hillary Hosier, Shelli F. Farhadian, Raffaella A. Morotti, Uma Deshmukh, Alice Lu-Culligan, Katherine H. Campbell, Yuki Yasumoto, Chantal B.F. Vogels, Arnau Casanovas-Massana, Pavithra Vijayakumar, Bertie Geng, Camila D. Odio, John Fournier, Anderson F. Brito, Joseph R. Fauver, Feimei Liu, Tara Alpert, Reshef Tal, Klara Szigeti-Buck, Sudhir Perincheri, Christopher Larsen, Aileen M. Gariepy, Gabriela Aguilar, Kristen L. Fardelmann, Malini Harigopal, Hugh S. Taylor, Christian M. Pettker, Anne L. Wyllie, Charles Dela Cruz, Aaron M. Ring, Nathan D. Grubaugh, Albert I. Ko, Tamas L. Horvath, Akiko Iwasaki, Uma M. Reddy, and Heather S. Lipkind http://jci.me/139569 New York City COVID-19 resident physician exposure during exponential phase of pandemic p. 2 Mark P. Breazzano, Junchao Shen, Aliaa H. Abdelhakim, Lora R. Dagi Glass, Jason D. Horowitz, Sharon X. Xie, C. Gustavo de Moraes, Alice Chen-Plotkin, and Royce W.S. Chen, on behalf of the New York City Residency Program Directors COVID-19 Research Group http://jci.me/139587 Early safety indicators of COVID-19 convalescent plasma in 5000 patients Michael J. Joyner, R. Scott Wright, DeLisa Fairweather, Jonathon W. Senefeld, Katelyn A. Bruno, Stephen A. Klassen, Rickey E. Carter, Allan M. Klompas, Chad C. Wiggins, John R.A. Shepherd, Robert F. Rea, Emily R. Whelan, Andrew J. Clayburn, Matthew R. Spiegel, Patrick W. Johnson, Elizabeth R. Lesser, Sarah E. Baker, Kathryn F. Larson, Juan G. Ripoll, Kylie J. Andersen, David O. Hodge, Katie L. Kunze, Matthew R. Buras, Matthew N.P. Vogt, Vitaly Herasevich, Joshua J. Dennis, Riley J. Regimbal, Philippe R. Bauer, Janis E. Blair, Camille M. Van Buskirk, Jeffrey L. Winters, James R. Stubbs, Nigel S. Paneth, Nicole C. Verdun, Peter Marks, and Arturo Casadevall http://jci.me/140200 dermatology 3D model of harlequin ichthyosis reveals inflammatory therapeutic targets Florence Enjalbert, Priya Dewan, Matthew P. Caley, Eleri M. Jones, Mary A. Morse, David P. Kelsell, Anton J. Enright, and Edel A. O’Toole http://jci.me/132987 hiv/aids Filgotinib suppresses HIV-1–driven gene transcription by inhibiting HIV-1 splicing and T cell activation Yang-Hui Jimmy Yeh, Katharine M. Jenike, Rachela M. Calvi, Jennifer Chiarella, Rebecca Hoh, Steven G. Deeks, and Ya-Chi Ho http://jci.me/137371 immunology Long noncoding RNA H19X is a key mediator of TGF-β–driven fibrosis Elena Pachera, Shervin Assassi, Gloria A. Salazar, Mara Stellato, Florian Renoux, Adam Wunderlin, Przemyslaw Blyszczuk, Robert Lafyatis, Fina Kurreeman, Jeska de Vries-Bouwstra, Tobias Messemaker, Carol A. Feghali-Bostwick, Gerhard Rogler, Wouter T. van Haaften, Gerard Dijkstra, Fiona Oakley, Maurizio Calcagni, Janine Schniering, Britta Maurer, Jörg H.W. Distler, Gabriela Kania, Mojca Frank-Bertoncelj, and Oliver Distler http://jci.me/135439

jci.org/this-month september 2020 7 Current research articles

Bruton’s tyrosine kinase inhibition effectively protects against human IgE-mediated anaphylaxis Melanie C. Dispenza, Rebecca A. Krier-Burris, Krishan D. Chhiba, Bradley J. Undem, Piper A. Robida, and Bruce S. Bochner (ASCI) http://jci.me/138448 infectious disease Anti–influenza H7 human antibody targets antigenic site in hemagglutinin head domain interface Jinhui Dong, Iuliia Gilchuk, Sheng Li, Ryan Irving, Matthew T. Goff, Hannah L. Turner, Andrew B. Ward, Robert H. Carnahan, and James E. Crowe Jr. (ASCI) http://jci.me/136032 FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages Arielle M. Bryan, Jeehyun Karen You, Travis McQuiston, Cristina Lazzarini, Zhijuan Qiu, Brian Sheridan, Barbara Nuesslein-Hildesheim, and Maurizio Del Poeta (ASCI) http://jci.me/136068 inflammation β-Glucan–induced reprogramming of human macrophages inhibits NLRP3 inflammasome activation in cryopyrinopathies Giorgio Camilli, Mathieu Bohm, Alícia Corbellini Piffer, Rachel Lavenir, David L. Williams, Benedicte Neven, Gilles Grateau, Sophie Georgin-Lavialle, and Jessica Quintin http://jci.me/134778 TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations Paarth B. Dodhiawala, Namrata Khurana, Daoxiang Zhang, Yi Cheng, Lin Li, Qing Wei, Kuljeet Seehra, Hongmei Jiang, Patrick M. Grierson, Andrea Wang-Gillam, and Kian-Huat Lim http://jci.me/137660 Salt generates antiinflammatory Th17 cells but amplifies pathogenicity in proinflammatory cytokine microenvironments Julia Matthias, Sylvia Heink, Felix Picard, Julia Zeiträg, Anna Kolz, Ying-Yin Chao, Dominik Soll, Gustavo P. de Almeida, Elke Glasmacher, Ilse D. Jacobsen, Thomas Riedel, Anneli Peters, Stefan Floess, Jochen Huehn, Dirk Baumjohann, Magdalena Huber, Thomas Korn, and Christina E. Zielinski http://jci.me/137786 metabolism Impaired hypocretin/orexin system alters responses to salient stimuli in obese male mice p. 5 Ying Tan, Fu Hang, Zhong-Wu Liu, Milan Stoiljkovic, Mingxing Wu, Yue Tu, Wenfei Han, Angela M. Lee, Craig Kelley, Mihály Hajós, Lingeng Lu, Luis de Lecea, Ivan De Araujo, Marina R. Picciotto, Tamas L. Horvath, and Xiao-Bing Gao http://jci.me/130889 Melanocortin-4 receptor antagonist TCMCB07 ameliorates cancer- and chronic kidney disease– associated cachexia p. 5 Xinxia Zhu, Michael F. Callahan, Kenneth A. Gruber, Marek Szumowski, and Daniel L. Marks http://jci.me/138392 muscle biology Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction Lin Liu, Chenyun Ding, Tingting Fu, Zhenhua Feng, Ji-Eun Lee, Liwei Xiao, Zhisheng Xu, Yujing Yin, Qiqi Guo, Zongchao Sun, Wanping Sun, Yan Mao, Likun Yang, Zheng Zhou, Danxia Zhou, Leilei Xu, Zezhang Zhu, Yong Qiu, Kai Ge, and Zhenji Gan http://jci.me/136155 nephrology p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease Zhengwei Ma, Lin Li, Man J. Livingston, Dongshan Zhang, Qingsheng Mi, Ming Zhang, Han-Fei Ding, Yuqing Huo, Changlin Mei, and Zheng Dong http://jci.me/135536 Methylation in pericytes after acute injury promotes chronic kidney disease Yu-Hsiang Chou, Szu-Yu Pan, Yu-Han Shao, Hong-Mou Shih, Shi-Yao Wei, Chun-Fu Lai, Wen-Chih Chiang, Claudia Schrimpf, Kai-Chien Yang, Liang-Chuan Lai, Yung-Ming Chen, Tzong-Shinn Chu, and Shuei-Liong Lin http://jci.me/135773 neuroscience Krabbe disease successfully treated via monotherapy of intrathecal gene therapy p. 6 Allison M. Bradbury, Jessica H. Bagel, Duc Nguyen, Erik A. Lykken, Jill Pesayco Salvador, Xuntian Jiang, Gary P. Swain, Charles A. Assenmacher, Ian J. Hendricks, Keiko Miyadera, Rebecka S. Hess, Arielle Ostrager, Patricia ODonnell, Mark S. Sands, Daniel S. Ory, G. Diane Shelton, Ernesto R. Bongarzone, Steven J. Gray, and Charles H. Vite http://jci.me/133953 Tau is not necessary for amyloid-beta–induced synaptic and memory impairments Daniela Puzzo, Elentina K. Argyrousi, Agnieszka Staniszewski, Hong Zhang, Elisa Calcagno, Elisa Zuccarello, Erica Acquarone, Mauro Fa’, Domenica D. Li Puma, Claudio Grassi, Luciano D’Adamio, Nicholas M. Kanaan, Paul E. Fraser, and Ottavio Arancio http://jci.me/137040

8 jci.org/this-month september 2020 Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice Kevin M. Huang, Alix F. Leblanc, Muhammad Erfan Uddin, Ji Young Kim, Mingqing Chen, Eric D. Eisenmann, Alice A. Gibson, Yang Li, Kristen W. Hong, Duncan DiGiacomo, Sherry H. Xia, Paola Alberti, Alessia Chiorazzi, Stephen N. Housley, Timothy C. Cope, Jason A. Sprowl, Jing Wang, Charles L. Loprinzi, Anne Noonan, Maryam B. Lustberg, Guido Cavaletti, Navjot Pabla, Shuiying Hu, and Alex Sparreboom http://jci.me/136796 Impact of TREM2R47H variant on tau pathology–induced gliosis and neurodegeneration Maud Gratuze, Cheryl E.G. Leyns, Andrew D. Sauerbeck, Marie-Kim St.-Pierre, Monica Xiong, Nayeon Kim, Javier Remolina Serrano, Marie-Ève Tremblay, Terrance T. Kummer, Marco Colonna, Jason D. Ulrich, and David M. Holtzman (ASCI) http://jci.me/138179 oncology FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease Susana Garcia-Recio, Aatish Thennavan, Michael P. East, Joel S. Parker, Juan M. Cejalvo, Joseph P. Garay, Daniel P. Hollern, Xiaping He, Kevin R. Mott, Patricia Galván, Cheng Fan, Sara R. Selitsky, Alisha R. Coffey, David Marron, Fara Brasó-Maristany, Octavio Burgués, Joan Albanell, Federico Rojo, Ana Lluch, Eduardo Martinez de Dueñas, Jeffery M. Rosen, Gary L. Johnson, Lisa A. Carey, Aleix Prat, and Charles M. Perou http://jci.me/130323 γ9δ2T cell diversity and the receptor interface with tumor cells Anna Vyborova, Dennis X. Beringer, Domenico Fasci, Froso Karaiskaki, Eline van Diest, Lovro Kramer, Aram de Haas, Jasper Sanders, Anke Janssen, Trudy Straetemans, Daniel Olive, Jeanette Leusen, Lola Boutin, Steven Nedellec, Samantha L. Schwartz, Michael J. Wester, Keith A. Lidke, Emmanuel Scotet, Diane S. Lidke, Albert J.R. Heck, Zsolt Sebestyen, and Jürgen Kuball http://jci.me/132489 Myeloid signature reveals immune contexture and predicts the prognosis of hepatocellular carcinoma Chong Wu, Jie Lin, Yulan Weng, Dan-Ni Zeng, Jing Xu, Shufeng Luo, Li Xu, Mingyu Liu, Qiaomin Hua, Chao-Qun Liu, Jin-Qing Li, Jing Liao, Cheng Sun, Jian Zhou, Min-Shan Chen, Chao Liu, Zhenhong Guo, Shi-Mei Zhuang, Jin-Hua Huang, and Limin Zheng http://jci.me/135048 Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix p. 5 Honglin Jiang, Robert J. Torphy, Katja Steiger, Henry Hongo, Alexa J. Ritchie, Mark Kriegsmann, David Horst, Sarah E. Umetsu, Nancy M. Joseph, Kimberly McGregor, Michael J. Pishvaian, Edik M. Blais, Brian Lu, Mingyu Li, Michael Hollingsworth, Connor Stashko, Keith Volmar, Jen Jen Yeh, Valerie M. Weaver, Zhen J. Wang, Margaret A. Tempero, Wilko Weichert, and Eric A. Collisson http://jci.me/136760 Chemotherapy-induced S100A10 recruits KDM6A to facilitate OCT4-mediated breast cancer stemness Haiquan Lu, Yangyiran Xie, Linh Tran, Jie Lan, Yongkang Yang, Naveena L. Murugan, Ru Wang, Yueyang J. Wang, and Gregg L. Semenza (ASCI) http://jci.me/138577 ophthalmology PRICKLE3 linked to ATPase biogenesis manifested Leber’s hereditary optic neuropathy Jialing Yu, Xiaoyang Liang, Yanchun Ji, Cheng Ai, Junxia Liu, Ling Zhu, Zhipeng Nie, Xiaofen Jin, Chenghui Wang, Juanjuan Zhang, Fuxin Zhao, Shuang Mei, Xiaoxu Zhao, Xiangtian Zhou, Minglian Zhang, Meng Wang, Taosheng Huang, Pingping Jiang, and Min-Xin Guan http://jci.me/134965 transplantation Peripheral host T cells survive hematopoietic stem cell transplantation and promote graft-versus-host disease p. 4 Sherrie J. Divito, Anders T. Aasebø, Tiago R. Matos, Pei-Chen Hsieh, Matthew Collin, Christopher P. Elco, John T. O’Malley, Espen S. Bækkevold, Henrik Reims, Tobias Gedde-Dahl, Michael Hagerstrom, Jude Hilaire, John W. Lian, Edgar L. Milford, Geraldine S. Pinkus, Vincent T. Ho, Robert J. Soiffer, Haesook T. Kim, Martin C. Mihm, Jerome Ritz, Indira Guleria, Corey S. Cutler, Rachael A. Clark, Frode L. Jahnsen, and Thomas S. Kupper (ASCI) http://jci.me/129965 Donor monocyte–derived macrophages promote human acute graft-versus-host disease p. 4 Laura Jardine, Urszula Cytlak, Merry Gunawan, Gary Reynolds, Kile Green, Xiao-Nong Wang, Sarah Pagan, Maharani Paramitha, Christopher A. Lamb, Anna K. Long, Erin Hurst, Smeera Nair, Graham H. Jackson, Amy Publicover, Venetia Bigley, Muzlifah Haniffa, A.J. Simpson, and Matthew Collin http://jci.me/133909 Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease p. 4 Bishwas Shrestha, Kelly Walton, Jordan Reff, Elizabeth M. Sagatys, Nhan Tu, Justin Boucher, Gongbo Li, Tayyebb Ghafoor, Martin Felices, Jeffrey S. Miller, Joseph Pidala, Bruce R. Blazar, Claudio Anasetti, Brian C. Betts, and Marco L. Davila http://jci.me/135754 vascular biology 12(S)-HETE mediates diabetes-induced endothelial dysfunction by activating intracellular endothelial cell TRPV1 Mandy Otto, Clarissa Bucher, Wantao Liu, Melanie Müller, Tobias Schmidt, Marina Kardell, Marvin Noel Driessen, Jan Rossaint, Eric R. Gross, and Nana-Maria Wagner http://jci.me/136621 Flip issue to read JCI Insight content.

jci.org/this-month september 2020 9 This Month FATP2 promotes diabetic kidney disease p. 11

September 2020 JCI This Month is a summary of the Compartment-specific analysis reveals PDAC heterogeneity 13 most recent articles in Characterization of B cell memory in C. difficile infection 13 The Journal of Clinical Investigation and JCI Insight Pathogenic ACTG2 variant alters filament bundle structure 12 jci.org/this-month JCI Insight Consulting Editors

Pilar Alcaide Brian Finck Claire E. Lewis Florian Rieder John F. Alcorn John H. Fingert Mathias Lichterfeld Matthew D. Ringel Maria-Luisa Alegre Robert Flaumenhaft Rodger A. Liddle Howard A. Rockman Ravi K. Amaravadi Edward A. Fon André Lieber Steven M. Rowe Cristian Apetrei Lawrence Fong Michail S. Lionakis Linda C. Samuelson Rajendra S. Apte Nikolaos G. Frangogiannis Ivan Maillard Victoria L. Seewaldt Zoltan Arany Anthony R. French Ziad Mallat Svati H. Shah Hossein Ardehali Katherine A. Gallagher Peter Mannon Vijay H. Shah Julio Ayala Terrence L. Geiger Eric Martens Vikram Shakkottai Sami J. Barmada Raphaela Goldbach-Mansky Franck Mauvais-Jarvis Guo-Ping Shi Alexander G. Bassuk Douglas K. Graham Linda McAllister-Lucas Kanakadurga Singer Vann Bennett Johann E. Gudjonsson Dermot P.B. McGovern Natasha Snider Sudha B. Biddinger Kirk Habegger Borna Mehrad Scott Soleimanpour Jonathan S. Bogan Khalid A. Hanafy Ingo K. Mellinghoff Rhonda F. Souza Laura M. Bohn Eric B. Haura David K. Meyerholz Fayyaz S. Sutterwala Nunzio Bottini John Cijiang He Jason C. Mills Shu Takeda Sebastien G. Bouret Adam Steven Helms Joshua D. Milner James E. Talmadge Jason Brenchley Robert O. Heuckeroth Satdarshan Paul Monga Muneesh Tewari Renier J. Brentjens Cory M. Hogaboam Hidayatullah G. Munshi John P. Thyfault G.R. Scott Budinger Young-Kwon Hong William J. Murphy Natalie J. Torok George A. Calin Eric J. Huang Matthias Nahrendorf Stephen H. Tsang Stephen Y. Chan Benjamin D. Humphreys Mary C. Nakamura Hubert M. Tse Timothy A. Chan Ken Inoki Patrick Nana-Sinkam Fumihiko Urano Yuan Chang Rajan Jain Lisa F.P. Ng Jolanda van der Velden Benjamin K. Chen Daniel P. Judge Mark Nicolls Deborah J. Veis Kang Chen J. Michelle Kahlenberg Laura J. Niedernhofer Charles P. Venditti Zhou-Feng Chen Shingo Kajimura Una O’Doherty Claudio J. Villanueva Wendy Chung Pawel Kalinski S. Tiong Ong Joseph Vinetz Matthew Ciorba Nobuhiko Kamada Akira Ono Stephanie M. Ware Janice E. Clements Thomas W.H. Kay Puneet Opal Sing Sing Way Craig M. Coopersmith Barbara I. Kazmierczak Olabisi Opeyemi Kevin W. Williams George Cotsarelis Catherine E. Keegan Daniel Ory Minna Woo Peter A. Crawford Hans-Peter Kiem Sophie Paczesny Prescott G. Woodruff Lisa L. Cunningham William Y. Kim Rulan Parekh Jing Yang Jennifer Davis Frank Kirchhoff Victoria N. Parikh Tianxin Yang Ronald P. DeMatteo David G. Kirsch Mary-Elizabeth Patti Yiping Yang Madhav V. Dhodapkar Jason S. Knight Janos Peti-Peterdi Vincent B. Young Elia J. Duh Donald E. Kohan Fernando P. Polack Lori M. Zeltser Sarah K. England Maria Kontaridis Benjamin Prosser Zhen Zhang Carmella Evans-Molina Laura A. Kresty Ling Qi Yutong Zhao Robert L. Fairchild Jongsoon Lee Dominic Raj Binhua P. Zhou Eric R. Fearon Michael Lehrke Jalees Rehman

17 Featured Editor This Month 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 September 2020 of manuscripts directly submitted to JCI Insight, evaluate all transferred manuscripts, and meet weekly to discuss manuscripts under review.

For JCI Insight Carey Lumeng, MD, PhD, Editor Associate Editor, is the Frederick Kathleen Collins G.L. Huetwell Professor for the Cure Deputy Editors and Prevention of Birth Defects Andrew Lieberman, Donna Martin, Pavan Reddy and Professor in the Department Associate Editors Sharlene M. Day, Gregory R. Dressler, David A. Fox, of Pediatrics and Molecular and Santhi Ganesh, John Y. Kao, Nobuhiko Kamada, Integrative Physiology at the Celina G. Kleer, Carey Lumeng, Lona Mody, Bethany B. Moore, Marina Pasca di Magliano, University of Michigan Medical Subramaniam Pennathur, Darleen Sandoval, School. Dr. Lumeng also serves as Yatrik M. Shah, Andrew Tai, Weiping Zou Associate Director of the University Executive Editor Sarah C. Jackson of Michigan Medical Scientist Senior Science Editor Training Program. Dr. Lumeng’s Corinne Williams research centers on inflammatory Computational Biologist mechanisms that relate to obesity-associated diseases and metabolic diseases, Alexey Nesvizhskii with a focus on the function of adipose tissue leukocytes. ASCI Staff Executive Director John B. Hawley Publication highlights Managing Director Karen D. Guth Zamarron BF, Porsche CE, Luan D, Lucas HR, Mergian TA, Associate Director Maya Hoptman Martinez-Santibanez G, Cho KW, DelProposto JL, Geletka LM, Muir LA, Production Editors Catherine Ahmann, Ken Beauchamp, Molly Jean, Lara L. McCarron Singer K, Lumeng CN. Weight regain in formerly obese mice hastens Production Assistant Samantha Smith development of hepatic steatosis due to impaired adipose tissue function. Scientific Illustrator Bruce Worden Obesity. 2020;28(6):1086–1097. Senior Copy Editor Rachel Nelson Russo L, Muir L, Geletka L, Delproposto J, Baker N, Flesher C, O’Rourke R, Copy Editors Clare Cross, Meredith Dimick, Barbara Fabyan, Chet Provoda Lumeng CN. Cholesterol 25-hydroxylase (CH25H) as a promoter of adipose Associate Copy Editors tissue inflammation in obesity and diabetes. Mol Metab. 2020;39:100983. Darla Nagel, Megan Reilley Associate Editor, Copy and Production Muir LA, Kiridena S, Griffin C, DelProposto JB, Geletka L, Rachel Bullen Martinez-Santibañez G, Zamarron BF, Lucas H, Singer K, O’Rourke RW, Editorial Assistant Cady Vishniac Lumeng CN. Rapid adipose tissue expansion triggers unique proliferation Accounts Manager Paula Kremidas and lipid accumulation profiles in adipose tissue macrophages. J Leukoc Biol. Author Services Manager Megan Jenkins 2018;103(4): 615–628. Author Services Representatives Katherine A. Bullen, Keith Kalinowski Zamarron BF, Mergian TA, Cho KW, Martinez-Santibanez G, Luan D, Singer K, Executive Administrator Theresa Kaiser DelProposto JL, Geletka LM, Muir LA, Lumeng CN. Macrophage proliferation Science Communications Specialist Neha Aggarwal sustains adipose tissue inflammation in formerly obese mice. Diabetes. Program Manager Ashley Haston 2017;66(2):392–406. Senior Engineer and Technical Lead Cho KW, Zamarron BF, Muir LA, Singer K, Porsche CE, DelProposto JB, Austin Brewer Senior Engineer, Systems and Analytics Geletka LM, Meyer KA, O’Rourke RW, Lumeng CN. Adipose tissue dendritic Bryan English cells are independent contributors to obesity-induced inflammation and insulin Software Developer Jose L. Jardon resistance. J Immunol. 2016;197(9):3650–3661. Web Developer Tran Ngoc For JCI Insight online: (ASCI) indicates corresponding authors who are ASCI members. jci.me/insight/5/15 jci.me/insight/5/16 jci.org/this-month september 2020 10 Editor’s picks

nephrology on the jci insight cover Fatty acid transport protein-2 exacerbates diabetic kidney disease

Diabetic kidney disease (DKD) is one of the most prevalent causes of end-stage renal disease and a devastating complication of diabetes. Tubular atrophy and interstitial fibrosis are among the most reliable markers of DKD progression; however, the drivers of these processes are not fully understood. Using murine models of obesity and DKD, Shenaz Khan and colleagues evaluated the contribution of albumin-bound fatty acids to tubular atrophy via lipotoxicity. In DKD-prone mice, fatty acid transport protein-2 (FATP2) deletion normalized glomerular filtration rate, reduced albuminuria, improved histo pathology, and increased life span. In addition to improving kidney function, FATP2 deficiency improved glucose control. The results of this study demonstrate a pathogenetic role for FATP2 in DKD. The Masson’s trichrome–stained section in the cover image shows the presence of interstitial fibrosis, fibroblasts, tubular vacuoles, and glomerulosclerosis in a murine model of DKD. FATP2 deficiency ameliorates these manifestations. Fatty acid transport protein-2 regulates glycemic control and diabetic kidney disease progression Shenaz Khan, Robert Gaivin, Caroline Abramovich, Michael Boylan, Jorge Calles, and Jeffrey R. Schelling http://jci.me/136845

endocrinology Dipeptidyl peptidase-4 effects on triglyceride excursion are compartment dependent

People with type 2 diabetes have elevated triglyceride levels after a meal, inhibition increased GLP-1 but had no effect on triglyceride levels in older which can have long-term effects on cardiovascular health. Glucoregulatory or HFD-fed WT mice. Together, these results point toward compartment- agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, can reduce specific effects of DPP-4 inhibition and indicate an uncoupling of DPP-4 postprandial triglycerides, though it is not clear how this effect is action from glucose homeostasis and triglyceride excursion. mediated. Elodie Varin and colleagues generated mice lacking DPP-4 Hematopoietic cell– versus enterocyte-derived globally and in specific cell compartments and evaluated the effects on dipeptidyl peptidase-4 differentially regulates lipid metabolism. Systemic and concurrent endothelial and hematopoietic triglyceride excursion in mice cell–specificDpp4 deletion improved lipid tolerance in both young and old Elodie M. Varin, Antonio A. Hanson, Jacqueline L. Beaudry, My-Anh Nguyen, mice, with hematopoietic cells playing a key role in triglyceride modulation. Xiemin Cao, Laurie L. Baggio, Erin E. Mulvihill, and Daniel J. Drucker (ASCI) However, enterocyte-specific Dpp4 deletion exacerbated triglyceride http://jci.me/140418 excursion in response to a high-fat diet (HFD). Moreover, chemical DPP-4

11 jci.org/this-month september 2020 JCI Insight | Editor’s picks

gastroenterology Visceral myopathy–associated ACTG2 alters filament bundle structure Visceral myopathy is characterized by bowel, bladder, and uterine Pseudo-obstruction–inducing ACTG2R257C alters actin dysfunction as a result of smooth muscle cell weakness. This condition is organization and function commonly linked to the R257C variant of actin γ 2, smooth muscle Sohaib Khalid Hashmi, Vasia Barka, Changsong Yang, Sabine Schneider, (ACTG2R257C); however, the pathogenic effects of this variant have not been Tatyana M. Svitkina, and Robert O. Heuckeroth (ASCI) fully elucidated. Sohaib Hashmi and colleagues evaluated the effects of http://jci.me/140604 overexpression of both ACTG2WT and ACTG2R257C variants in primary human intestinal smooth muscle cells (HISMCs). Compared with ACTG2WT, expression of ACTG2R257C reduced the volume, length, and branching of ACTG2-containing filament bundles (see the accompanying image) in HISMCs, without affecting total levels of F-actin. While the ACTG2R257C variant did not affect collagen gel contraction by cells, ACTG2R257C- expressing HISMCs were more migratory and spread farther than ACTG2WT-expressing cells. These observa- tions point toward altered filament bundle structure in disease development.

cardiology Exertion-triggered sudden cardiac death syndrome caused by loss-of-function RYR2 duplication Typically, pathogenic variants in the RYR2 gene, which encodes the type 2 cardiac ryanodine receptor (RyR2)/ calcium release channel (CRC), cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, a team led by Michael Ackerman discovered a syndrome called CRC deficiency syndrome linked to a RYR2 duplication variant responsible for the exertion-related sudden cardiac deaths of several Amish children and young adults. Now, David Tester, John Kim, and colleagues have created a patient-specific, reengineered heart cell model of this syndrome with induced pluripotent stem cell cardiomyocytes (iPSC-CMs) derived from 2 unrelated patients and have functionally characterized this RYR2 duplication variant. In contrast to CPVT-causing mutations, this RYR2 duplication variant causes a profound, biogenic loss of the CRC/RyR2 (see the accompanying image) and dysfunctional Ca2+ handling. Although there was no difference in baseline Ca2+ handling compared with normal iPSC-CMs, stimulation of patient-derived iPSC-CMs with isoproterenol increased the arrhythmic activity significantly, which could in turn be reduced by nadolol, propranolol, and flecainide. Molecular characterization of the calcium release channel deficiency syndrome David J. Tester, CS John Kim, Samantha K. Hamrick, Dan Ye, Bailey J. O’Hare, Hannah M. Bombei, Kristi K. Fitzgerald, Carla M. Haglund-Turnquist, Dianne L. Atkins, Luis A. Ochoa Nunez, Ian Law, Joel Temple, and Michael J. Ackerman (ASCI) http://jci.me/135952

jci.org/this-month september 2020 12 JCI Insight | Editor’s picks

oncology Characterization of compartment-specific differences between pancreatic ductal adenocarcinomas Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high stromal in the tumor compartment, and inhibition of EPHA2 reduced PDAC cell content, which contributes to tumorigenesis and metastasis and creates an migration and proliferation. Together, these results identify compartment- immunosuppressive environment. Given the complexity of the tumor specific differences in PDAC that are missed by bulk tumor analysis that have microenvironment, the development of effective therapies has been challeng- potential to be therapeutically targeted. ing. Tessa Le Large and colleagues used laser-capture microdissection (LCM) to Microdissected pancreatic cancer proteomes reveal tumor isolate discrete areas of samples from patients with PDAC and used a mass heterogeneity and therapeutic targets spectrometry approach to characterize proteome differences. Compartment- Tessa Y.S. Le Large, Giulia Mantini, Laura L. Meijer, Thang V. Pham, Niccola Funel, specific analysis revealed that bulk tumor analysis masks tumor-derived Nicole C.T. van Grieken, Bart Kok, Jaco Knol, Hanneke W.M. van Laarhoven, proteins, thereby obscuring potential diagnostic and prognostic markers. CALB2 Sander R. Piersma, Connie R. Jimenez, G. Kazemier, Elisa Giovannetti, was identified and validated as a tumor-specific marker, while COL11A1 was and Maarten F. Bijlsma http://jci.me/138290 shown to be stroma specific. The receptor tyrosine kinase EPHA2 was identified

CD28 costimulation restores renal cell immunology carcinoma–infiltrating lymphocyte metabolism and function Limited B cell memory The tumor microenvironment has profound response to C. difficile influence over T cell activation and function. In particular, suppression of metabolic reprogramming infection may underlie of T cells within tumors markedly dampens effector functions. Kathryn Beckermann and colleagues recurrence characterized metabolic pathways involved in Clostridioides difficile infection (CDI) of the intestinal activation and function of CD8+ tumor-infiltrating tract can result in life-threatening symptoms. Moreover, lymphocytes (TILs) isolated from renal cell carcino- CDI is refractory to antibiotic therapy and has a high mas (RCCs). TCR stimulation alone resulted in limited rate of reinfection, suggesting lack of a strong adaptive activation; however, CD28 costimulation enhanced immune response to this pathogen. Hemangi Shah and activation, function, and proliferation, which was colleagues evaluated isolated memory B cells specific linked to increased glycolysis and mitochondrial for the C. difficile toxin TcdB from individuals with a oxidative metabolism. In response to TCR and CD28 history of CDI. While TcdB-specific memory B cell– costimulation, RCC CD8+ TIL mitochondria displayed encoded antibodies exhibited somatic hypermutation, enhanced fusion (see the accompanying image), isotype class switch was limited. Isolated monoclonal higher membrane potential, and increased mitochondrial mass, which, along with TIL TcdB antibodies had low-to-moderate affinity for the activation and function, were dependent on glucose metabolism. Cumulatively, this work toxin and limited neutralization capacity. These results indicates that enhancing glycolysis and mitochondrial fitness via CD28 costimuation, in indicate that inadequate memory B cell responses conjunction with checkpoint blockade, has potential as a therapeutic strategy to enhance against C. difficile may underlie recurrent disease. TIL activity in RCC. Human C. difficile toxin–specific CD28 costimulation drives tumor-infiltrating T cell glycolysis memory B cell repertoires encode poorly to promote inflammation neutralizing antibodies Kathryn E. Beckermann, Rachel Hongo, Xiang Ye, Kirsten Young, Katie Carbonell, Hemangi B. Shah, Kenneth Smith, Edgar J. Scott II, Diana C. Contreras Healey, Peter J. Siska, Sierra Barone, Caroline E. Roe, Christof C. Smith, Jason L. Larabee, Judith A. James, Jimmy D. Ballard, Benjamin G. Vincent, Frank M. Mason, Jonathan M. Irish, W. Kimryn Rathmell (ASCI), and Mark L. Lang http://jci.me/138137 and Jeffrey C. Rathmell http://jci.me/138729

13 jci.org/this-month september 2020 Current articles

Plasminogen regulates mesenchymal stem cell–mediated tissue repair after ischemia through Cyr61 activation Hao Duan, Zhenqiang He, Maohuan Lin, Yanling Wang, Fan Yang, R. Alan Mitteer, Hyun-Jun Kim, Eujing Yeo, Hongyu Han, Ling Qin, Yi Fan, and Yanqing Gong http://jci.me/131376 MEK activation modulates glycolysis and supports suppressive myeloid cells in TNBC Derek A. Franklin, Joe T. Sharick, Paula I. Ericsson-Gonzalez, Violeta Sanchez, Phillip T. Dean, Susan R. Opalenik, Stefano Cairo, Jean-Gabriel Judde, Michael T. Lewis, Jenny C. Chang, Melinda E. Sanders, Rebecca S. Cook, Melissa C. Skala, Jennifer Bordeaux, Jehovana Orozco Bender, Christine Vaupel, Gary Geiss, Douglas Hinerfeld, and Justin M. Balko http://jci.me/134290 DOCK8 is essential for LFA-1–dependent positioning of T follicular helper cells in germinal centers Erin Janssen, Mira Tohme, Jordan Butts, Sophie Giguere, Peter T. Sage, Francisco E. Velázquez, Christy Kam, Elena Milin, Mrinmoy Das, Ali Sobh, Salem Al-Tamemi, Francis W. Luscinskas, Facundo Batista, and Raif S. Geha (ASCI) http://jci.me/134508 Shock waves promote spinal cord repair via TLR3 Can Gollmann-Tepeköylü, Felix Nägele, Michael Graber, Leo Pölzl, Daniela Lobenwein, Jakob Hirsch, Angela An, Regina Irschick, Bernhard Röhrs, Christian Kremser, Hubert Hackl, Rosalie Huber, Serena Venezia, David Hercher, Helga Fritsch, Nikolaos Bonaros, Nadia Stefanova, Ivan Tancevski, Dirk Meyer, Michael Grimm, and Johannes Holfeld http://jci.me/134552 Arrestin domain containing 3 promotes Helicobacter pylori–associated gastritis by regulating protease-activated receptor 1 Yu-gang Liu, Yong-sheng Teng, Zhi-guo Shan, Ping Cheng, Chuan-jie Hao, Yi-pin Lv, Fang-yuan Mao, Shi-ming Yang, Weisan Chen, Yong-liang Zhao, Nan You, Quan-ming Zou, and Yuan Zhuang http://jci.me/135849 Gene therapy for alpha 1-antitrypsin deficiency with an oxidant-resistant human alpha 1-antitrypsin Meredith L. Sosulski, Katie M. Stiles, Esther Z. Frenk, Fiona M. Hart, Yuki Matsumura, Bishnu P. De, Stephen M. Kaminsky, and Ronald G. Crystal (ASCI) http://jci.me/135951 Molecular characterization of the calcium release channel deficiency syndrome p. 12 David J. Tester, CS John Kim, Samantha K. Hamrick, Dan Ye, Bailey J. O’Hare, Hannah M. Bombei, Kristi K. Fitzgerald, Carla M. Haglund-Turnquist, Dianne L. Atkins, Luis A. Ochoa Nunez, Ian Law, Joel Temple, and Michael J. Ackerman (ASCI) http://jci.me/135952 M3 muscarinic acetylcholine receptor–reactive Th17 cells in primary Sjögren’s syndrome Authors Saori Abe, Hiroto Tsuboi, Hanae Kudo, Hiromitsu Asashima, Yuko Ono, Fumika Honda, Hiroyuki Takahashi, Mizuki Yagishita, Shinya Hagiwara, Yuya Kondo, Isao Matsumoto, and Takayuki Sumida http://jci.me/135982 Key driver genes as potential therapeutic targets in renal allograft rejection Zhengzi Yi, Karen L. Keung, Li Li, Min Hu, Bo Lu, Leigh Nicholson, Elvira Jimenez-Vera, Madhav C. Menon, Chengguo Wei, Stephen Alexander, Barbara Murphy, Philip J. O’Connell, and Weijia Zhang http://jci.me/136220 Erythromycin inhibits neutrophilic inflammation and mucosal disease by upregulating DEL-1 Tomoki Maekawa, Hikaru Tamura, Hisanori Domon, Takumi Hiyoshi, Toshihito Isono, Daisuke Yonezawa, Naoki Hayashi, Naoki Takahashi, Koichi Tabeta, Takeyasu Maeda, Masataka Oda, Athanasios Ziogas, Vasileia Ismini Alexaki, Triantafyllos Chavakis, Yutaka Terao, and George Hajishengallis http://jci.me/136706 Fatty acid transport protein-2 regulates glycemic control and diabetic kidney disease progression p. 11 Shenaz Khan, Robert Gaivin, Caroline Abramovich, Michael Boylan, Jorge Calles, and Jeffrey R. Schelling http://jci.me/136845 C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling Alexander J.T. Wood, Arlette M. Vassallo, Marie-Hélène Ruchaud-Sparagano, Jonathan Scott, Carmelo Zinnato, Carmen Gonzalez-Tejedo, Kamal Kishore, Clive S. D’Santos, A. John Simpson, David K. Menon, Charlotte Summers, Edwin R. Chilvers, Klaus Okkenhaug, and Andrew Conway Morris http://jci.me/137029 Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes Heike Weidner, Ulrike Baschant, Franziska Lademann, Maria G. Ledesma Colunga, Ekaterina Balaian, Christine Hofbauer, Barbara M. Misof, Paul Roschger, Stéphane Blouin, William G. Richards, Uwe Platzbecker, Lorenz C. Hofbauer, and Martina Rauner http://jci.me/137062 Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines Jae-Sung Yi, Sravan Perla, Liz Enyenihi, and Anton M. Bennett http://jci.me/137753 Implementing cell-free DNA of pancreatic cancer patient–derived organoids for personalized oncology Zahra Dantes, Hsi-Yu Yen, Nicole Pfarr, Christof Winter, Katja Steiger, Alexander Muckenhuber, Alexander Hennig, Sebastian Lange, Thomas Engleitner, Rupert Öllinger, Roman Maresch, Felix Orben, Irina Heid, Georgios Kaissis, Kuangyu Shi, Geoffrey Topping, Fabian Stögbauer, Matthias Wirth, Katja Peschke, Aristeidis Papargyriou, Massoud Rezaee-Oghazi, Karin Feldmann, Arlett P.G. Schäfer, Raphela Ranjan, Clara Lubeseder-Martellato, Daniel E. Stange, Thilo Welsch, Marc Martignoni, Güralp O. Ceyhan, Helmut Friess, Alexander Herner, Lucia Liotta, Matthias Treiber, Guido von Figura, Mohamed Abdelhafez, Peter Klare, Christoph Schlag, Hana Algül, Jens Siveke, Rickmer Braren, Gregor Weirich, Wilko Weichert, Dieter Saur, Roland Rad, Roland M. Schmid, Günter Schneider, and Maximilian Reichert http://jci.me/137809

jci.org/this-month september 2020 14 Current articles

Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma Marie-Julie Nokin, Elodie Darbo, Camille Travert, Benjamin Drogat, Aurélie Lacouture, Sonia San José, Nuria Cabrera, Béatrice Turcq, Valérie Prouzet-Mauleon, Mattia Falcone, Alberto Villanueva, Haiyun Wang, Michael Herfs, Miguel Mosteiro, Pasi A. Jänne, Jean-Louis Pujol, Antonio Maraver, Mariano Barbacid, Ernest Nadal, David Santamaría, and Chiara Ambrogio http://jci.me/137869 Synchronization of mothers and offspring promotes tolerance and limits allergy Kathryn A. Knoop, Keely G. McDonald, Paige E. Coughlin, Devesha H. Kulkarni, Jenny K. Gustafsson, Brigida Rusconi, Vini John, I. Malick Ndao, Avraham Beigelman, Misty Good, Barbara B. Warner, Charles O. Elson, Chyi-Song Hsieh, Simon P. Hogan, Phillip I. Tarr, and Rodney D. Newberry http://jci.me/137943 Microdissected pancreatic cancer proteomes reveal tumor heterogeneity and therapeutic targets p. 13 Tessa Y.S. Le Large, Giulia Mantini, Laura L. Meijer, Thang V. Pham, Niccola Funel, Nicole C.T. van Grieken, Bart Kok, Jaco Knol, Hanneke W.M. van Laarhoven, Sander R. Piersma, Connie R. Jimenez, G. Kazemier, Elisa Giovannetti, and Maarten F. Bijlsma http://jci.me/138290 Polymorphonuclear myeloid-derived suppressor cells limit antigen cross-presentation by dendritic cells in cancer Alessio Ugolini, Vladimir A. Tyurin, Yulia Y. Tyurina, Evgenii N. Tcyganov, Laxminarasimha Donthireddy, Valerian E. Kagan, Dmitry I. Gabrilovich, and Filippo Veglia http://jci.me/138581 Multiple system atrophy pathology is associated with primary Sjögren’s syndrome Kyle S. Conway, Sandra Camelo-Piragua, Amanda Fisher-Hubbard, William R. Perry, Vikram G. Shakkottai, and Sriram Venneti http://jci.me/138619 BET bromodomain proteins regulate transcriptional reprogramming in genetic dilated cardiomyopathy Andrew Antolic, Hiroko Wakimoto, Zhe Jiao, Joshua M. Gorham, Steven R. DePalma, Madeleine E. Lemieux, David A. Conner, Da Young Lee, Jun Qi, Jonathan G. Seidman, James E. Bradner, Jonathan D. Brown, Saptarsi M. Haldar, Christine E. Seidman, and Michael A. Burke http://jci.me/138687 The value of genotypic and imaging information to predict functional and structural outcomes in ADPKD Sravanthi Lavu, Lisa E. Vaughan, Sarah R. Senum, Timothy L. Kline, Arlene B. Chapman, Ronald D. Perrone, Michal Mrug, William E. Braun, Theodore I. Steinman, Frederic F. Rahbari-Oskoui, Godela M. Brosnahan, Kyongtae T. Bae, Douglas Landsittel, Fouad T. Chebib, Alan S.L. Yu, Vicente E. Torres, the HALT PKD and CRISP Study Investigators, and Peter C. Harris http://jci.me/138724 Selective inhibition of mTORC1 in tumor vessels increases antitumor immunity Shan Wang, Ariel Raybuck, Eileen Shiuan, Sung Hoon Cho, Qingfei Wang, Dana M. Brantley-Sieders, Deanna Edwards, Margaret M. Allaman, James Nathan, Keith T. Wilson, David DeNardo, Siyuan Zhang, Rebecca Cook, Mark Boothby, and Jin Chen http://jci.me/139237 Patient ancestry significantly contributes to molecular heterogeneity of systemic lupus erythematosus Michelle D. Catalina, Prathyusha Bachali, Anthony E. Yeo, Nicholas S. Geraci, Michelle A. Petri, Amrie C. Grammer, and Peter E. Lipsky http://jci.me/140380 The impact of antidiabetic treatment on human hypothalamic infundibular neurons and microglia Martin J.T. Kalsbeek, Samantha E.C. Wolff, Nikita L. Korpel, Susanne E. la Fleur, Johannes A. Romijn, Eric Fliers, Andries Kalsbeek, Dick F. Swaab, Inge Huitinga, Elly M. Hol, and Chun-Xia Yi http://jci.me/133868 Polycystin-1 regulates ARHGAP35-dependent centrosomal RhoA activation and ROCK signaling Andrew J. Streets, Philipp P. Prosseda, and Albert C.M. Ong http://jci.me/135385 Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates pituitary growth hormone production Jaemeun Lee, Kyungchan Kim, Jae Hyun Cho, Jin Young Bae, Timothy P. O’Leary, James D. Johnson, Yong Chul Bae, and Eun-Kyoung Kim http://jci.me/135412 Elevating EGFR-MAPK program by a nonconventional Cdc42 enhances intestinal epithelial survival and regeneration Xiao Zhang, Sheila Bandyopadhyay, Leandro Pires Araujo, Kevin Tong, Juan Flores, Daniel Laubitz, Yanlin Zhao, George Yap, Jingren Wang, Qingze Zou, Ronaldo Ferraris, Lanjing Zhang, Wenwei Hu, Edward M. Bonder, Pawel R. Kiela, Robert Coffey, Michael P. Verzi, Ivaylo I. Ivanov, and Nan Gao http://jci.me/135923 Kynurenines link chronic inflammation to functional decline and physical frailty Reyhan Westbrook, Tae Chung, Jacqueline Lovett, Chris Ward, Humberto Joca, Huanle Yang, Mohammed Khadeer, Jing Tian, Qian-Li Xue, Anne Le, Luigi Ferrucci, Ruin Moaddel, Rafa de Cabo, Ahmet Hoke, Jeremy Walston, and Peter M. Abadir http://jci.me/136091 Phenotypic heterogeneity of neurofibromatosis type 1 in a large international registry Mika M. Tabata, Shufeng Li, Pamela Knight, Annette Bakker, and Kavita Y. Sarin http://jci.me/136262 Ovarian granulosa cell tumor characterization identifies FOXL2 as an immunotherapeutic target Stefano Pierini, Janos L. Tanyi, Fiona Simpkins, Erin George, Mireia Uribe-Herranz, Ronny Drapkin, Robert Burger, Mark A. Morgan, and Andrea Facciabene http://jci.me/136773 All-cause mortality in metabolically healthy individuals was not predicted by overweight and obesity Qiuyue Tian, Anxin Wang, Yingting Zuo, Shuohua Chen, Haifeng Hou, Wei Wang, Shouling Wu, and Youxin Wang http://jci.me/136982 Fluid-electrolyte homeostasis requires histone deacetylase function Kelly A. Hyndman, Joshua S. Speed, Luciano D. Mendoza, John M. Allan, Jackson Colson, Randee Sedaka, Chunhua Jin, Hyun Jun Jung, Samir El-Dahr, David M. Pollock, and Jennifer S. Pollock http://jci.me/137792

15 jci.org/this-month september 2020 Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action Junmei Cairns, James N. Ingle, Tanda M. Dudenkov, Krishna R. Kalari, Erin E. Carlson, Jie Na, Aman U. Buzdar, Mark E. Robson, Matthew J. Ellis, Paul E. Goss, Lois E. Shepherd, Barbara Goodnature, Matthew P. Goetz, Richard M. Weinshilboum, Hu Li, Mehrab Ghanat Bari, and Liewei Wang (ASCI) http://jci.me/137571 Lipid mediators and biomarkers associated with type 1 diabetes development Alexander J. Nelson, Daniel J. Stephenson, Robert N. Bone, Christopher L. Cardona, Margaret A. Park, Ying G. Tusing, Xiaoyong Lei, George Kokotos, Christina L. Graves, Clayton E. Mathews, Joanna Kramer, Martin J. Hessner, Charles E. Chalfant, and Sasanka Ramanadham http://jci.me/138034 Human C. difficile toxin–specific memory B cell repertoires encode poorly neutralizing antibodies p. 13 Hemangi B. Shah, Kenneth Smith, Edgar J. Scott II, Jason L. Larabee, Judith A. James, Jimmy D. Ballard, and Mark L. Lang http://jci.me/138137 Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta Nara Liessi, Emanuela Pesce, Clarissa Braccia, Sine Mandrup Bertozzi, Alessandro Giraudo, Tiziano Bandiera, Nicoletta Pedemonte, and Andrea Armirotti http://jci.me/138722 CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation p. 13 Kathryn E. Beckermann, Rachel Hongo, Xiang Ye, Kirsten Young, Katie Carbonell, Diana C. Contreras Healey, Peter J. Siska, Sierra Barone, Caroline E. Roe, Christof C. Smith, Benjamin G. Vincent, Frank M. Mason, Jonathan M. Irish, W. Kimryn Rathmell (ASCI), and Jeffrey C. Rathmell http://jci.me/138729 Homozygous G650del nexilin variant causes cardiomyopathy in mice Canzhao Liu, Simone Spinozzi, Wei Feng, Ze’e Chen, Lunfeng Zhang, Siting Zhu, Tongbin Wu, Xi Fang, Kunfu Ouyang, Sylvia M. Evans, and Ju Chen http://jci.me/138780 Reduced left atrial cardiomyocyte PITX2 and elevated circulating BMP10 predict atrial fibrillation after ablation Jasmeet S. Reyat, Winnie Chua, Victor R. Cardoso, Anika Witten, Peter M. Kastner, S. Nashitha Kabir, Moritz F. Sinner, Robin Wesselink, Andrew P. Holmes, Davor Pavlovic, Monika Stoll, Stefan Kääb, Georgios V. Gkoutos, Joris R. de Groot, Paulus Kirchhof, and Larissa Fabritz http://jci.me/139179 Developmental changes in myocardial B cells mirror changes in B cells associated with different organs Cibele Rocha-Resende, Wei Yang, Wenjun Li, Daniel Kreisel, Luigi Adamo, and Douglas L. Mann (ASCI) http://jci.me/139377 Curative in vivo hematopoietic stem cell gene therapy of murine thalassemia using large regulatory elements Hongjie Wang, Aphrodite Georgakopoulou, Chang Li, Zhinan Liu, Sucheol Gil, Ashvin Bashyam, Evangelia Yannaki, Achilles Anagnostopoulos, Amit Pande, Zsuzsanna Izsvák, Thalia Papayannopoulou, and André Lieber (ASCI) http://jci.me/139538 IL18–containing 5-gene signature distinguishes histologically identical dermatomyositis and lupus erythematosus skin lesions Lam C. Tsoi, Mehrnaz Gharaee-Kermani, Celine C. Berthier, Tori Nault, Grace A. Hile, Shannon N. Estadt, Matthew T. Patrick, Rachael Wasikowski, Allison C. Billi, Lori Lowe, Tamra J. Reed, Johann E. Gudjonsson, and J. Michelle Kahlenberg http://jci.me/139558 Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease Génesis Vega, Anita Guequén, Amber R. Philp, Ambra Gianotti, Llilian Arzola, Manuel Villalón, Olga Zegarra-Moran, Luis J.V. Galietta, Marcus A. Mall, and Carlos A. Flores http://jci.me/140076 Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD Lindsay T. Fourman, James M. Billingsley, George Agyapong, Shannan J. Ho Sui, Meghan N. Feldpausch, Julia Purdy, Isabel Zheng, Chelsea S. Pan, Kathleen E. Corey, Martin Torriani, David E. Kleiner, Colleen M. Hadigan, Takara L. Stanley, Raymond T. Chung, and Steven K. Grinspoon (ASCI) http://jci.me/140134 Risk-associated alterations in marrow T cells in pediatric leukemia Jithendra Kini Bailur, Samuel S. McCachren, Katherine Pendleton, Juan C. Vasquez, Hong Seo Lim, Alyssa Duffy, Deon B. Doxie, Akhilesh Kaushal, Connor Foster, Deborah DeRyckere, Sharon Castellino, Melissa L. Kemp, Peng Qiu, Madhav V. Dhodapkar (ASCI), and Kavita M. Dhodapkar http://jci.me/140179 Hematopoietic cell– versus enterocyte-derived dipeptidyl peptidase-4 differentially regulates triglyceride excursion in mice p. 11 Elodie M. Varin, Antonio A. Hanson, Jacqueline L. Beaudry, My-Anh Nguyen, Xiemin Cao, Laurie L. Baggio, Erin E. Mulvihill, and Daniel J. Drucker (ASCI) http://jci.me/140418 CD47 prevents the elimination of diseased fibroblasts in scleroderma Tristan Lerbs, Lu Cui, Megan E. King, Tim Chai, Claire Muscat, Lorinda Chung, Ryanne Brown, Kerri Rieger, Tyler Shibata, and Gerlinde Wernig http://jci.me/140458 Pseudo-obstruction–inducing ACTG2R257C alters actin organization and function p. 12 Sohaib Khalid Hashmi, Vasia Barka, Changsong Yang, Sabine Schneider, Tatyana M. Svitkina, and Robert O. Heuckeroth (ASCI) http://jci.me/140604 review The complement system in COVID-19: friend and foe? Anuja Java, Anthony J. Apicelli, M. Kathryn Liszewski, Ariella Coler-Reilly, John P. Atkinson, Alfred H.J. Kim, Flip issue to read JCI content. and Hrishikesh S. Kulkarni http://jci.me/140711

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