jci.org/this-month

Soluble uPAR isoform 2 mediates kidney injury 3

A vaccination strategy against EBV-driven malignancies 3

NKG2A blockade unleashes tumor-killing NK cells 4

Predicting positive outcomes in CAR T cell treatment 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 2019

Elucidating T cell subtypes in eosinophilic esophagitis p. 2

This Month

Journal of Clinical Investigation Consulting Editors

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j c i . o r g / t h i s - m o n t h m a y 2 0 1 9 1

For the JCIEditorRexford S. Ahima

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

Associate EditorsMark E. Anderson, Mary Y. Armanios, Joel N. Blankson, William R. Bishai, Robert A. Brodsky, Peter A. Calabresi, Thomas L. Clemens, Franco R. D’Alessio, Ted M. Dawson, Angelo M. DeMarzo, Stephen Desiderio, Mark Donowitz, Andrew P. Feinberg, Paul M. Hassoun, Maureen R. Horton, Elizabeth M. Jaffee, Mariana J. Kaplan, Marikki Laiho, Leo Luznik, Marcela V. Maus, Timothy H. Moran, Laszlo Nagy, William Nelson, Brian O’Rourke, Ben Ho Park, Jonathan D. Powell, Thomas C. Quinn, Hamid Rabb, Jean-Pierre Raufman, Stuart C. Ray, Linda Smith Resar, Jeffrey D. Rothstein, Jonathan Schneck, Akrit S. Sodhi, Charlotte J. Sumner, Simeon I. Taylor, Robert G. Weiss, Sarah J. Wheelan, Marsha Wills-Karp

Editorial Advisory GroupPeter Agre, Carol W. Grieder, Diane E. Griffin, Paul B. Rothman, David Valle

BiostatisticianEliseo Guallar

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JCI This Month ISSN 2324-7703 (print);ISSN 2325-4556 (online)

For the full JCI online: jci.me/129/5

This MonthMay 2019

Contact the JCI and JCI Insight2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050Email: staff@the-jci.org (JCI); staff@insight.jci.org (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.

Recent reports indicate an increase in retractions and corrections of published articles due to post-publication detection of problematic data. At the JCI, we screen three categories of data — Western blots, statistics, and images, including histology panels, flow cytometry plots, and graphs — in manuscripts prior to acceptance in an attempt to reduce post-publication actions and, hopefully, increase confidence in the papers we publish.

Between July 1, 2018, and February 5, 2019, we screened 200 papers on a clear path toward acceptance for publication. During this time, 28.5% of the papers screened were flagged for issues with statistical tests, 21% of papers had issues with blots, and 27.5% of papers had image anomalies. The most common statistical concern was a lack of accounting for multiple comparisons in the chosen analysis. Western blots were typically flagged for missing the corresponding raw images and/or use of loading controls derived from a gel different from the other samples in the figure panel. Of the papers with image issues, 89.1% had minor transgressions, such as reuse of a control image in multiple panels; 7.3% had what we consider moderate issues that required explanation of how figures were prepared; and 3.6% (2 of 200 total papers) had major issues that could not be sufficiently explained, resulting in rejection.

We believe our screening process has limited the number of post-publication corrections, which surely benefits our authors and increases our readers’ confidence in the data published by the JCI. Despite the issues that were uncovered during our screening, we believe that the majority of our authors act in good faith and are not intentionally introducing errors to the scientific literature. As manuscripts increasingly become more complicated and involve more coauthors, the chance to introduce errors increases. Authors, reviewers, editors, and readers must all guard against honest mistakes, sloppy science, and fraud. The integrity of the scientific community is on the line.

Corinne WilliamsScience Editor, The Journal of Clinical Investigation | JCI Insight

Arturo CasadevallDeputy Editor, The Journal of Clinical Investigation

Sarah JacksonExecutive Editor, The Journal of Clinical Investigation | JCI Insight

To read the complete editorial, see http://jci.me/128380

(ASCI) indicates corresponding authors who are ASCI members.

Figure errors, sloppy science, and fraud

From the Editors

j c i . o r g / t h i s - m o n t h m a y 2 0 1 92

research

Editor’s picks

on the jci cover inflammation

Isolating and interpreting tissue-resident T cell subtypes in eosinophilic esophagitis

The extensive variety in T cell subtypes reflects their participation in diverse pathological mechanisms. To date, few studies have focused on localized T cell subtypes in autoimmune and allergic disorders, in which tissue-specific imbalances may be key drivers of inflammation. The food allergic disorder eosinophilic esophagitis (EoE), driven by T cell–derived cytokines that inflame the esophageal mucosa, represents an ideal model for studying tissue-restricted T cell dysfunction. In this issue of the JCI, Ting Wen et al. identified eight distinct subtypes within 1088 tissue-resident T cells isolated from human esophageal biopsies. EoE patient samples were enriched with subtypes T7 and T8, whose phenotypes were consistent with classical Tregs and memory Th2 cells, respectively. Transcriptomic analysis revealed that T8 cells expressed the short-chain fatty acid receptor FFAR3, and further experiments corroborated the hypothesis that fatty acids are capable of stimulating local Th2-driven allergic inflammation. Walter Eckalbar and David Erle's accompanying Commentary describes the study's crucial insights into clinically relevant T cell subtypes, their transcriptomic markers and pathways, laying the groundwork for tools and models that better account for allergic disease heterogeneity. The cover image spotlights the identification of distinct T cell subtypes in disease, superimposing an isolated T cell over an inflamed eosinophilic esophageal biopsy. Image credit: Chris Woods, Ting Wen, and Marc Rothenberg.

Single-cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitisTing Wen, Bruce J. Aronow, Yrina Rochman, Mark Rochman, Kiran KC, Phil J. Dexheimer, Philip Putnam, Vincent Mukkada, Heather Foote, Kira Rehn, Sam Darko, Daniel Douek, and Marc E. Rothenberg (ASCI) http://jci.me/125917

Related CommentarySingling out Th2 cells in eosinophilic esophagitisWalter L. Eckalbar and David J. Erle http://jci.me/128479

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JCI | Research: Editor’s picks

nephrology

uPAR isoform 2 mediates kidney injury via β3 integrin/c-Src axisElevated soluble urokinase plasminogen activator receptor (suPAR) level is a risk factor for incident and progressive kidney diseases, such as focal segmental glomerulosclerosis (FSGS). While suPAR’s precise role in kidney injury remains under investigation, its interaction with β3 integrin on podocytes is one known mechanism. Changli Wei and colleagues followed up on prior observations that mice expressing suPAR isoform 2 (suPAR2) rapidly developed nephropathy. In the present study, they revealed that suPAR2 forms a dimer in solution and can be detected in the blood and urine of transgenic mice expressing this suPAR2 in adipose tissue. suPAR2 expression induced FSGS-like pathology in mouse models (see the associated image) and altered transcription of genes in immune response, wound healing, and integrin-mediated pathways. Restraining β3 integrin expression or function or inhibiting c-Src prevented renal injury in suPAR2-expressing mice. In the accompanying Commentary, Jeffrey Kopp and Jurgen Heymann highlight the therapeutic implications of a mechanism for suPAR2-driven kidney injury that is amenable to glomerular Src inhibition.

uPAR isoform 2 forms a dimer and induces severe kidney disease in miceChangli Wei, Jing Li, Brian D. Adair, Ke Zhu, Jian Cai, Michael Merchant, Beata Samelko, Zhongji Liao, Kwi Hye Koh, Nicholas J. Tardi, Ranadheer R. Dande, Shuangxin Liu, Jianchao Ma, Salvatore Dibartolo, Stefan Hägele, Vasil Peev, Salim S. Hayek, David J. Cimbaluk, Melissa Tracy, Jon Klein, Sanja Sever, Sanford J. Shattil, M. Amin Arnaout, and Jochen Reiser (ASCI) http://jci.me/124793

Related Commentaryc-Src is in the effector pathway linking uPAR and podocyte injuryJeffrey B. Kopp and Jurgen Heymann http://jci.me/127927

Heterologous priming boosts protection against EBV-driven malignancies and infection

hematology

No strategies exist to prevent or treat EBV infection, an extremely common persistent infection that drives multiple B cell and epithelial cell malignancies in immunocompromised individuals. Cytotoxic T cells targeting the EBV antigen EBNA1 have been identified as key controllers of EBV infection and EBV-associ-ated malignancies. Julia Rühl and colleagues investigated vaccine strategies to improve EBNA1-targeting CD4+ and CD8+ T cell responses. They reveal that rela-tive to adenoviral EBNA1 delivery alone, heterologous prime-boost vaccination with EBNA1-encoding adenovirus and modified vaccinia virus Ankara (MVA) vectors enhanced the expansion and maintenance of EBNA1-targeting CD8+ T cells by concomitant CD4+ T cell activation. In mouse models, a heterologous adenoviral/MVA prime-boost regimen protected against EBV-associated lymphomas. In an accompanying Commentary, Sandhya Sharma and Rayne Rouce describe this heterologous vaccination strategy as a promising intervention for EBV infection and EBV-driven malignancies.

Heterologous prime-boost vaccination protects against EBV antigen–expressing lymphomasJulia Rühl, Carmen Citterio, Christine Engelmann, Tracey Haigh, Andrzej Dzionek, Johannes Dreyer, Rajiv Khanna, Graham S. Taylor, Joanna B. Wilson, Carol S. Leung, and Christian Münz http://jci.me/125364

Related CommentaryAre we there yet? The never-ending quest for an Epstein-Barr virus vaccineSandhya Sharma and Rayne H. Rouce http://jci.me/128370

j c i . o r g / t h i s - m o n t h m a y 2 0 1 94

JCI | Research: Editor’s picks

oncology

Deubiquitinase USP9X regulates ALDH1A3-dependent glioblastoma stem cell identityGlioblastoma remains difficult to cure in part due to the self-renewal activity and differentiation potential of glioblastoma stem cells (GSCs), which are capable of initiating recurrent and therapy-resistant tumors. Mesenchymal GSCs (MES GSCs) express the aldehyde dehydrogenase ALDH1A3 at high levels and depend on this enzyme to maintain self-renewal capabilities. A study led by Huibo Wang identifies the deubiquitinating enzyme USP9X as a crucial regulator of ALDH1A3 activity in MES GSCs. Mechanistic work revealed that USP9X directly deubiquitinates ALDH1A3, thereby reducing ALDH1 turnover and promoting high enzymatic activity that is essential for MES GSC maintenance. In xenograft models, a USP9X inhibitor enhanced ALDH1A3 degradation and impaired self-renewal and tumorigenic capacity in MES GSCs, indicating that MES GSCs are vulnerable to pharmacological USP9X inhibition. Hiroaki Wakimoto’s Commentary indicates that USP9X’s role in GSC maintenance makes it an exciting potential target in glioblastoma.

USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cellsZhengxin Chen, Hong-Wei Wang, Shuai Wang, Ligang Fan, Shuang Feng, Xiaomin Cai, Chenghao Peng, Xiaoting Wu, Jiacheng Lu, Dan Chen, Yuanyuan Chen, Wenting Wu, Daru Lu, Ning Liu, Yongping You, and Huibo Wang http://jci.me/126414

Related CommentaryDeubiquitinating ALDH1A3 key to maintaining the culprit of aggressive brain cancerHiroaki Wakimoto http://jci.me/128742

NKG2A downregulation circumvents tumor-mediated NK cell suppression

Many tumors avoid targeting by cytotoxic NK cells by overexpressing HLA-E, which suppresses antitumor activity by binding to the inhibitory NK cell receptor NKG2A. Elevated NKG2A expression on tumor-interacting NK cells has been observed in several cancers, and antibody-mediated blockade of this receptor is currently in clinical trials. Takahiro Kamiya and colleagues explored an alternative method for preventing HLA-E–mediated suppression of NK cells: they designed an scFv-based construct to prevent surface expression of NKG2A and generated NKG2A-deficient NK cells. NKG2A deficiency did not impair NK cell cytotoxicity or proliferation; rather, these modified NK cells displayed enhanced antitumor activity in vitro and in a xenograft model (see the associated image). In an accompanying Commentary, Frank Cichocki and Jeffrey Miller discuss the potential of NKG2A-modified NK cells as an adoptive cellular therapy for cancer.

Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cellsTakahiro Kamiya, See Voon Seow, Desmond Wong, Murray Robinson, and Dario Campana (ASCI) http://jci.me/123955

Related CommentarySetting traps for NKG2A gives NK cell immunotherapy a fighting chanceFrank Cichocki and Jeffrey S. Miller (ASCI) http://jci.me/128480

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JCI | Research: Editor’s picks

clinical medicineImmune signatures predict mutational subtypes of gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) segregate into subtypes based on oncogenic mutation, and these subtypes are correlated with distinct clinical and pathologic features. For instance, while GISTs harboring mutations in the proto-oncogene KIT respond well to tyrosine kinase inhibitors, many PDGFRA-mutant GISTs are resistant to these therapies. Gerardo Vitiello, Timothy Bowler, and colleagues integrated bioinformatic, immunohistochemical, and flow cytometry analyses to characterize immune infiltrate in KIT- and PDGFRA-mutant GISTs from 75 patients. Increased chemokine expression and enhanced neoepitope binding in the PDGFRA-mutant tumors suggested greater immuno-genicity compared with KIT-mutant tumors (see the accompanying image). A machine-learning approach generated immune signatures capable of distinguishing KIT-mutant from PDGFRA-mutant GISTs and predicting PD-1 and PD-L1 expression across all GIST subtypes. These insights into the immune landscapes of GIST subtypes may facilitate patient stratification and aid in the development of personalized therapies.

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumorGerardo A. Vitiello, Timothy G. Bowler, Mengyuan Liu, Benjamin D. Medina, Jennifer Q. Zhang, Nesteene J. Param, Jennifer K. Loo, Rachel L. Goldfeder, Frederic Chibon, Ferdinand Rossi, Shan Zeng, and Ronald P. DeMatteo (ASCI) http://jci.me/124108

Patient- and product-specific parameters forecast CAR T cell outcomes in leukemiaCD19-targeting CAR T cells and other immunotherapeutic strategies have exhibited remarkable efficacy in inducing remission in B cell malignancies, but these treatments are not universally effective or durable. Prospective identification of patients who are unlikely to benefit could spare these patients the substantial cost and potential toxicity of CAR T treatments. Olivia Finney and colleagues analyzed early CAR T cell engraftment and function in 43 pediatric patients enrolled in a phase I safety study of CD19-targeting CAR T cells in acute lymphoblastic leukemia. Their findings reveal that characteristics of the patient’s immune system and the CAR T cell product itself interact to influence the likelihood of achieving sustained remission and the risk of antigen-positive relapse. In the accompanying Commentary, David Barrett calls for further refinement of these predictive factors, which could lead to improved clinical decision-making in candidates for CAR T cell therapy.

CD19 CAR T cell product and disease attributes predict leukemia remission durabilityOlivia C. Finney, Hannah Brakke, Stephanie Rawlings-Rhea, Roxana Hicks, Danielle Doolittle, Marisa Lopez, Ben Futrell, Rimas J. Orentas, Daniel Li, Rebecca Gardner, and Michael C. Jensen http://jci.me/125423

Related CommentaryImproving CAR T cell immunotherapy–mediated remissions for pediatric leukemiaDavid M. Barrett http://jci.me/128743

Early immune responses anticipate immunogenic qualities of influenza vaccinationConventional intramuscular delivery of the influenza vaccine induces humoral responses but fails to amplify cytotoxic CD8+ T cell responses to influenza viruses. More effective and durable vaccine responses necessitate better coordination between humoral and cell-mediated immunity. A study led by Behazine Combadière compared responses to multiple vaccination routes in 60 healthy volunteers to evaluate differential engagement of humoral versus cytotoxic immunity. At 21 days after immunization, the researchers observed that transcutaneous and intradermal delivery were more likely to elicit vaccine-specific CD8+ T cells, whereas intramuscular delivery tended to produce elevated antibody titers. Transcriptomic analysis of volunteers’ whole blood identified innate immune gene signatures that accurately predicted the cytotoxic versus humoral quality of the immune responses within one day of immunization. These insights into early immune responses that correlate with cellular and humoral immunity provide groundwork for detailed comparisons of vaccination strategies.

Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccinationEléna Gonçalves, Olivia Bonduelle, Angèle Soria, Pierre Loulergue, Alexandra Rousseau, Marine Cachanado, Henri Bonnabau, Rodolphe Thiebaut, Nicolas Tchitchek, Sylvie Behillil, Sylvie van der Werf, Annika Vogt, Tabassome Simon, Odile Launay, and Behazine Combadière http://jci.me/125372

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JCI | Features

review

Examining the contribution of gut microbiota to graft-versus-host diseaseGraft-versus-host disease (GvHD) is a common and deadly complication of hematopoietic cell transplantation (HCT), in which donor immune cells mount an inflammatory response against the recipient’s tissues, resulting in dermatitis, hepatic dysfunction, and gastrointestinal symptoms. Immunosuppressive interventions are associated with numerous risks, and better preventive strategies will require a more comprehensive understanding of GvHD’s drivers. In this Review, David Fredricks outlines evidence from humans and animal models linking the gut microbiota to GvHD pathogenesis. He describes how preconditioning regimens and prophylactic broad-spectrum antibiotics in HCT recipients alter the balance between beneficial and deleterious bacterial populations, leaving the intestinal epithelium vulnerable to multiple sources of uncontrolled inflammation (see the accompanying image). More detailed work dissecting interactions among specific bacterial species, environmental factors, and individual patient genetics will help reveal the complex and dynamic relationship between gut microbes and GvHD risk.

The gut microbiota and graft-versus-host diseaseDavid N. Fredricks http://jci.me/125797

conversations with giants in medicine

George ChurchYou may know George Church as a founding member of the Human Genome Project, as an innovator who made personalized genome sequencing affordable, and as the father of synthetic biology. You may recall that he attempted to clone woolly mammoth genes into African elephants, made his entire genome publicly available, and founded a multitude of successful biotechnology startups. Dr. Church, who is also a professor at Harvard and MIT, is as close to a household name as geneticists come.

In an interview with JCI’s Editor-at-Large Ushma Neill, he reveals how an “extra-curricular” early-life education nurtured an interest in nature that led to his deep interest in science and mathematics. He also discusses highlights of his career and his thoughts on the ethical and privacy issues associated with human genome sequencing and manipulation. http://jci.me/128550

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Current research articles

bone biologyLkb1 deletion in periosteal mesenchymal progenitors induces osteogenic tumors through mTORC1 activationYujiao Han, Heng Feng, Jun Sun, Xiaoting Liang, Zhuo Wang, Wenhui Xing, Qinggang Dai, Yang Yang, Anjia Han, Zhanying Wei, Qing Bi, Hongbin Ji, Tiebang Kang, and Weiguo Zou http://jci.me/124590

clinical medicineInnate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination p. 5Eléna Gonçalves, Olivia Bonduelle, Angèle Soria, Pierre Loulergue, Alexandra Rousseau, Marine Cachanado, Henri Bonnabau, Rodolphe Thiebaut, Nicolas Tchitchek, Sylvie Behillil, Sylvie van der Werf, Annika Vogt, Tabassome Simon, Odile Launay, and Behazine Combadière http://jci.me/125372

CD19 CAR T cell product and disease attributes predict leukemia remission durability p. 5Olivia C. Finney, Hannah Brakke, Stephanie Rawlings-Rhea, Roxana Hicks, Danielle Doolittle, Marisa Lopez, Ben Futrell, Rimas J. Orentas, Daniel Li, Rebecca Gardner, and Michael C. Jensen http://jci.me/125423

Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumorsFangjun Chen, Zhengyun Zou, Juan Du, Shu Su, Jie Shao, Fanyan Meng, Ju Yang, Qiuping Xu, Naiqing Ding, Yang Yang, Qin Liu, Qin Wang, Zhichen Sun, Shujuan Zhou, Shiyao Du, Jia Wei, and Baorui Liu http://jci.me/99538

gastroenterologyIL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel diseaseLyssia Belarif, Richard Danger, Laetitia Kermarrec, Véronique Nerrière-Daguin, Sabrina Pengam, Tony Durand, Caroline Mary, Elise Kerdreux, Vanessa Gauttier, Aneta Kucik, Virginie Thepenier, Jerome C. Martin, Christie Chang, Adeeb Rahman, Nina Salabert-Le Guen, Cécile Braudeau, Ahmed Abidi, Grégoire David, Florent Malard, Celine Takoudju, Bernard Martinet, Nathalie Gérard, Isabelle Neveu, Michel Neunlist, Emmanuel Coron, Thomas T. MacDonald, Pierre Desreumaux, Hoa-Le Mai, Stephanie Le Bas-Bernardet, Jean-François Mosnier, Miriam Merad, Régis Josien, Sophie Brouard, Jean-Paul Soulillou, Gilles Blancho, Arnaud Bourreille, Philippe Naveilhan, Bernard Vanhove, and Nicolas Poirier http://jci.me/121668

Intestinal development and homeostasis require activation and apoptosis of diet-reactive T cellsAlexander Visekruna, Sabrina Hartmann, Yasmina Rodriguez Sillke, Rainer Glauben, Florence Fischer, Hartmann Raifer, Hans Mollenkopf, Wilhelm Bertrams, Bernd Schmeck, Matthias Klein, Axel Pagenstecher, Michael Lohoff, Ralf Jacob, Oliver Pabst, Paul William Bland, Maik Luu, Rossana Romero, Britta Siegmund, Krishnaraj Rajalingam, and Ulrich Steinhoff http://jci.me/98929

hematologyBETP degradation simultaneously targets acute myelogenous leukemic stem cells and the microenvironmentSujan Piya, Hong Mu, Seemana Bhattacharya, Philip L. Lorenzi, R. Eric Davis, Teresa McQueen, Vivian Ruvolo, Natalia Baran, Zhiqiang Wang, Yimin Qian, Craig M. Crews, Marina Konopleva, Jo Ishizawa, M. James You, Hagop Kantarjian, Michael Andreeff, and Gautam Borthakur http://jci.me/120654

Heterologous prime-boost vaccination protects against EBV antigen–expressing lymphomas p. 3Julia Rühl, Carmen Citterio, Christine Engelmann, Tracey Haigh, Andrzej Dzionek, Johannes Dreyer, Rajiv Khanna, Graham S. Taylor, Joanna B. Wilson, Carol S. Leung, and Christian Münz http://jci.me/125364

Osteogenic tumor progression

T cells within a Peyer’s patch

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Current research articles

immunologymiR-142 controls metabolic reprogramming that regulates dendritic cell activationYaping Sun, Katherine Oravecz-Wilson, Sydney Bridges, Richard McEachin, Julia Wu, Stephanie H. Kim, Austin Taylor, Cynthia Zajac, Hideaki Fujiwara, Daniel Christopher Peltier, Thomas Saunders, and Pavan Reddy (ASCI) http://jci.me/123839

Staphylococcus aureus drives expansion of low-density neutrophils in diabetic miceTaylor S. Cohen, Virginia Takahashi, Jessica Bonnell, Andrey Tovchigrechko, Raghothama Chaerkady, Wen Yu, Omari Jones-Nelson, Young Lee, Rajiv Raja, Sonja Hess, C. Kendall Stover, John J. Worthington, Mark A. Travis, and Bret R. Sellman http://jci.me/126938

IL-26 contributes to host defense against intracellular bacteriaAngeline Tilly Dang, Rosane M.B. Teles, David I. Weiss, Kislay Parvatiyar, Euzenir N. Sarno, Maria T. Ochoa, Genhong Cheng, Michel Gilliet, Barry R. Bloom, and Robert L. Modlin (ASCI) http://jci.me/99550

inflammationMembrane assembly of aquaporin-4 autoantibodies regulates classical complement activation in neuromyelitis opticaJohn Soltys, Yiting Liu, Alanna Ritchie, Scott Wemlinger, Kristin Schaller, Hannah Schumann, Gregory P. Owens, and Jeffrey L. Bennett http://jci.me/122942

Single-cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis p. 2Ting Wen, Bruce J. Aronow, Yrina Rochman, Mark Rochman, Kiran KC, Phil J. Dexheimer, Philip Putnam, Vincent Mukkada, Heather Foote, Kira Rehn, Sam Darko, Daniel Douek, and Marc E. Rothenberg (ASCI) http://jci.me/125917

muscle biologyNontranslational function of leucyl-tRNA synthetase regulates myogenic differentiation and skeletal muscle regenerationKook Son, Jae-Sung You, Mee-Sup Yoon, Chong Dai, Jong Hyun Kim, Nidhi Khanna, Aditi Banerjee, Susan A. Martinis, Gyoonhee Han, Jung Min Han, Sunghoon Kim, and Jie Chen http://jci.me/122560

nephrologyuPAR isoform 2 forms a dimer and induces severe kidney disease in mice p. 3Changli Wei, Jing Li, Brian D. Adair, Ke Zhu, Jian Cai, Michael Merchant, Beata Samelko, Zhongji Liao, Kwi Hye Koh, Nicholas J. Tardi, Ranadheer R. Dande, Shuangxin Liu, Jianchao Ma, Salvatore Dibartolo, Stefan Hägele, Vasil Peev, Salim S. Hayek, David J. Cimbaluk, Melissa Tracy, Jon Klein, Sanja Sever, Sanford J. Shattil, M. Amin Arnaout, and Jochen Reiser (ASCI) http://jci.me/124793

neuroscienceATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegenerationTakuo Hirose, Alfredo Cabrera-Socorro, David Chitayat, Thomas Lemonnier, Olivier Féraud, Carmen Cifuentes-Diaz, Nicolas Gervasi, Cedric Mombereau, Tanay Ghosh, Loredana Stoica, Jeanne d’Arc Al Bacha, Hiroshi Yamada, Marcel A. Lauterbach, Marc Guillon, Kiriko Kaneko, Joy W. Norris, Komudi Siriwardena, Susan Blasér, Jérémie Teillon, Roberto Mendoza-Londono, Marion Russeau, Julien Hadoux, Sadayoshi Ito, Pierre Corvol, Maria G. Matheus, Kenton R. Holden, Kohji Takei, Valentina Emiliani, Annelise Bennaceur-Griscelli, Charles E. Schwartz, Genevieve Nguyen, and Matthias Groszer http://jci.me/79990

Myoblasts undergo differentiation

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Flip issue to read JCI Insight content.

oncologyAspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2Serena Lucotti, Camilla Cerutti, Magali Soyer, Ana M. Gil-Bernabé, Ana L. Gomes, Philip D. Allen, Sean Smart, Bostjan Markelc, Karla Watson, Paul C. Armstrong, Jane A. Mitchell, Timothy D. Warner, Anne J. Ridley, and Ruth J. Muschel http://jci.me/121985

Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusionChristopher R. McEvoy, Huiling Xu, Kortnye Smith, Dariush Etemadmoghadam, Huei San Leong, David Y. Choong, David J. Byrne, Amir Iravani, Sophie Beck, Linda Mileshkin, Richard W. Tothill, David D. Bowtell, Bindi M. Bates, Violeta Nastevski, Judy Browning, Anthony H. Bell, Chloe Khoo, Jayesh Desai, Andrew P. Fellowes, Stephen B. Fox, and Owen W.J. Prall http://jci.me/123089

Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells p. 4Takahiro Kamiya, See Voon Seow, Desmond Wong, Murray Robinson, and Dario Campana (ASCI) http://jci.me/123955

USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells p. 4Zhengxin Chen, Hong-Wei Wang, Shuai Wang, Ligang Fan, Shuang Feng, Xiaomin Cai, Chenghao Peng, Xiaoting Wu, Jiacheng Lu, Dan Chen, Yuanyuan Chen, Wenting Wu, Daru Lu, Ning Liu, Yongping You, and Huibo Wang http://jci.me/126414

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor p. 5Gerardo A. Vitiello, Timothy G. Bowler, Mengyuan Liu, Benjamin D. Medina, Jennifer Q. Zhang, Nesteene J. Param, Jennifer K. Loo, Rachel L. Goldfeder, Frederic Chibon, Ferdinand Rossi, Shan Zeng, and Ronald P. DeMatteo (ASCI) http://jci.me/124108

pulmonologyYap/Taz regulate alveolar regeneration and resolution of lung inflammationRyan LaCanna, Daniela Liccardo, Peggy Zhang, Lauren Tragesser, Yan Wang, Tongtong Cao, Harold A. Chapman, Edward E. Morrisey, Hao Shen, Walter J. Koch, Beata Kosmider, Marla R. Wolfson, and Ying Tian http://jci.me/125014

Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylationTingting Weng, Junsuk Ko, Chioniso P. Masamha, Zheng Xia, Yu Xiang, Ning-yuan Chen, Jose G. Molina, Scott Collum, Tinne C. Mertens, Fayong Luo, Kemly Philip, Jonathan Davies, Jingjing Huang, Cory Wilson, Rajarajan A. Thandavarayan, Brian A. Bruckner, Soma S.K. Jyothula, Kelly A. Volcik, Lei Li, Leng Han, Wei Li, Shervin Assassi, Harry Karmouty-Quintana, Eric J. Wagner, and Michael R. Blackburn http://jci.me/122106

Lymph node metastatic tumor

Myofibroblasts in fibrotic lung tissue

jci.org/this-month

CXCR3 ligands guide pathogenic T cells to the failing heart 11

Chimeric antigen receptors improve Treg homing and function 12

Anti–IFN-γ prevents paraneoplastic cerebellar degeneration in mouse model 12

Mucin-targeting glycopolymer ameliorates cystic fibrosis manifestations 13

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

May 2019

PGC1α-mediated lysosomal biogenesis protects the kidney p. 10

This Month

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Christopher M. Adams

Maria-Luisa Alegre

Ravi K. Amaravadi

John K. Amory

Jennifer H. Anolik

Cristian Apetrei

Rajendra S. Apte

Zoltan Arany

Hossein Ardehali

Kenneth I. Ataga

Joseph Bass

Alexander G. Bassuk

Antonio C. Bianco

Jonathan S. Bogan

Laura M. Bohn

Nunzio Bottini

Sebastien G. Bouret

Jason Brenchley

Renier J. Brentjens

G.R. Scott Budinger

George A. Calin

Stephen Chan

Timothy Chan

Yuan Chang

Zhou-Feng Chen

Keith A. Choate

Wendy Chung

Craig M. Coopersmith

George Cotsarelis

Peter Crawford

Lisa L. Cunningham

Ronald P. DeMatteo

Elia J. Duh

Sarah K. England

Mark W. Feinberg

John H. Fingert

Robert Flaumenhaft

Edward A. Fon

Lawrence Fong

Nikolaos G. Frangogiannis

Anthony R. French

Terrence L. Geiger

Noyan Gokce

Raphaela Goldbach-Mansky

Daniel R. Goldstein

Douglas K. Graham

Khalid A. Hanafy

Eric B. Haura

John Cijiang He

Robert O. Heuckeroth

Cory M. Hogaboam

Young-Kwon Hong

Benjamin D. Humphreys

Ken Inoki

Shingo Kajimura

Pawel Kalinski

John Y. Kao

Michael G. Kaplitt

Thomas W.H. Kay

Barbara I. Kazmierczak

Hans-Peter Kiem

William Y. Kim

David G. Kirsch

Claire E. Lewis

Mathias Lichterfeld

André Lieber

Michail S. Lionakis

Carey N. Lumeng

Ivan Maillard

Ziad Mallat

Peter Mannon

Franck Mauvais-Jarvis

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

David K. Meyerholz

Jason C. Mills

Joshua D. Milner

Satdarshan (Paul) Singh Monga

Hidayatullah G. Munshi

Matthias Nahrendorf

Mary Nakamura

Lisa F.P. Ng

Mark Nicolls

Laura J. Niedernhofer

S. Tiong Ong

Puneet Opal

Daniel Ory

Sophie Paczesny

Stephanie T. Page

Mary-Elizabeth Patti

Janos Peti-Peterdi

Fernando P. Polack

Matthew D. Ringel

Steven M. Rowe

Svati H. Shah

Vijay H. Shah

Alice T. Shaw

Rhonda F. Souza

Fayyaz S. Sutterwala

Shu Takeda

Natalie J. Torok

Stephen H. Tsang

Ellie Tzima

Fumihiko Urano

Deborah J. Veis

Charles P. Venditti

Joseph M. Vinetz

Sing Sing Way

Bernd Wollnik

Minna Woo

Prescott G. Woodruff

Lori M. Zeltser

Yutong Zhao

Binhua P. Zhou

JCI Insight Consulting Editors

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For JCI InsightEditorHoward A. RockmanAssociate EditorsVann Bennett, Rodger A. Liddle, Yiping YangExecutive EditorSarah C. JacksonScience EditorCorinne Williams

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On the JCI Insight cover

This MonthMay 2019

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Submit your work to JCI Insight today.

(ASCI) indicates corresponding authors who are ASCI members.

PGC1α induces TFEB-driven lysosomal biogenesis to counteract cisplatin nephrotoxicity

Damaged mitochondria release free radicals and other apoptotic mediators, thereby promoting cell death in response to stress. Kidney impairment is prevalent among individuals with monogenic mitochondrial diseases; however, recent studies have identified a renal-protective role for the mitochondrial biogenesis factor PGC1α, which increases mitochondrial mass. In this issue, Matthew Lynch, Mei Tran, Kenneth Ralto, and colleagues explored the effects of kidney tubular cell–specific KO and overexpression of PGC1α on the response

to cisplatin nephrotoxicity and determined that PGC1α is protective against acute kidney injury in this setting. Cisplatin was shown to dampen mitophagy, an effect that was counteracted by PGC1α. Cisplatin-mediated alterations of autophagy pathways were not restored by PGC1α. Instead, PGC1α was shown to regulate lysosomal biogenesis via induction of the transcription factor TFEB. TFEB depletion or inhibition of lysosome formation not only counteracted the cisplatin-protective effects of PGC1α, but actually exacerbated cisplatin-induced nephrotoxicity in mice overexpressing PGC1α. Together, these results identify cisplatin-dependent alterations of mitophagy as drivers of nephrotoxicity and reveal that PGC1α protects against cisplatin via induction of TFEB and increased lysosome formation. The cover image shows increased lysosomal mass (red) and lysosome fusion with autophagosomes (green) in a cross-section of a PGC1α-overexpressing kidney proximal tubule following cisplatin treatment, imaged using structured illumination microscopy. Mitochondria, magenta; nuclei, blue.

TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistanceMatthew R. Lynch, Mei T. Tran, Kenneth M. Ralto, Zsuzsanna K. Zsengeller, Vinod Raman, Swati S. Bhasin, Nuo Sun, Xiuying Chen, Daniel Brown, Ilsa I. Rovira, Kensei Taguchi, Craig R. Brooks, Isaac E. Stillman, Manoj K. Bhasin, Toren Finkel, and Samir M. Parikh (ASCI) http://jci.me/126749

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Editor’s picks

cardiology

CXCR3 ligands attract pathogenic T cells to the failing heartHeart failure arises from a variety of pathological conditions that result in inefficient blood-pumping capacity. Mice and humans exhibit an increase in CXCR3-binding chemokines in association with heart failure; however, the source of these chemokines and a direct role of these ligands in Th1 cell recruitment to the failing heart have not been fully established. Njabulo Ngwenyama, Ane Salvador, and colleagues now show that CXCR3+ T cells infiltrate murine and human hearts in response to pressure overload and that loss of CXCR3 expression on T cells prevents adverse cardiac remodeling in a murine model (see the accompanying image). Cardiac myeloid cells and fibroblasts were determined to be the source of CXCR3 ligands CXCL9 and CXCL10, which promote CXCR3-dependent adhesion of Th1 cells to ICAM-1 under shear conditions. Together, these results identify CXCR3-dependent recruitment of Th1 cells to the failing heart as a driver of adverse remodeling.

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunctionNjabulo Ngwenyama, Ane M. Salvador, Francisco Velázquez, Tania Nevers, Alexander Levy, Mark Aronovitz, Andrew D. Luster, Gordon S. Huggins, and Pilar Alcaide http://jci.me/125527

endocrinology

Liver-targeted insulin restores balance to muscle and hepatic glucose controlThe liver is a major site of action for glucose homeostasis, as it both produces and stores glucose in response to metabolic cues. Subcutaneous delivery of insulin has been an essential strategy for restoring glucose homeostasis in individuals with diabetes; however, this administration route may not be ideal, as it does not replicate endogenous release and liver targeting. Dale Edgerton and colleagues investigated different insulin delivery routes — peripheral and hepatic portal vein delivery — in dogs after fasting and after feeding. Portal vein delivery resulted in equal glucose

uptake in liver and muscle, while peripheral delivery impaired liver glucose metabolism and markedly increased glucose uptake in muscle, potentially increasing hypoglycemic risk and leading to other hazards. Altering the dose of peripheral insulin did not restore the balance of glucose metabolism in muscle and liver; however, peripheral delivery of a hepato-preferential insulin analog did. Cumulatively, these results suggest that liver-targeted insulin may better recapitulate the actions of endogenous insulin on glucose metabolism compared with periphery- limited formulations.

Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin deliveryDale S. Edgerton, Melanie Scott, Ben Farmer, Phillip E. Williams, Peter Madsen, Thomas Kjeldsen, Christian L. Brand, Christian Fledelius, Erica Nishimura, and Alan D. Cherrington http://jci.me/126974

j c i . o r g / t h i s - m o n t h m a y 2 0 1 9

JCI Insight | Editor’s picks

12

autoimmunity

Targeting IFN-γ protects model mice from paraneoplastic cerebellar degenerationParaneoplastic neurological disorders are rare diseases characterized by immune-mediated neuronal cell degeneration associated with the generation of antibodies that target neuronal antigens that are aberrantly expressed by tumor cells. Paraneoplastic cerebellar degeneration (PCD) is characterized by selective loss of Purkinje neurons and high titers of antibodies that target Purkinje- specific proteins. Using a recently developed murine PCD model, Lidia Yshii and colleagues characterized cerebellum-infiltrating T cells and identified α4 integrin and IFN-γ as potential therapeutic targets. Treatment of PCD model mice with an anti–α4 integrin antibody at the onset of neurological

symptoms did not impact disease development; however, anti–IFN-γ antibody was protective (see the accompanying image). These results indicate that IFN-γ from cerebellum-invading T cells is a driver of PCD that has potential to be therapeutically targeted.

IFN-γ is a therapeutic target in paraneoplastic cerebellar degenerationLidia Yshii, Béatrice Pignolet, Emilie Mauré, Mandy Pierau, Monika Brunner-Weinzierl, Oliver Hartley, Jan Bauer, and Roland Liblau http://jci.me/127001

CD28-containing chimeric antigen receptors enhance Treg functionTregs are important regulators of the immune response, as they suppress excessive inflammation, promote self-antigen tolerance, and maintain tissue integrity. Adoptive transfer of polyclonal Tregs can improve tolerance, reduce graft-versus-host disease, and ameliorate autoimmune disease; therefore, antigen-specific, long-lived Tregs have potential to enhance these beneficial features. Angela Boroughs and colleagues generated and characterized primary human Tregs modified with tissue-homing chimeric antigen receptors (CARs) harboring different costimulatory domains, which affected CAR-Treg phenotype and function. Specifically, the costimulatory domain did not affect tissue homing or FoxP3 expression; however, CD28 maintained CAR-Treg suppressor function, while 4-1BB did not. Moreover, CD28 CAR-Tregs potently inhibited effector T cell–mediated graft

rejection in a skin xenograft model (see the accompanying image). The results of this study provide evidence that CD28 CAR-Tregs promote tissue-specific immune suppression and support further exploration of these cells for clinical use.

Chimeric antigen receptor costimulation domains modulate human regulatory T cell functionAngela C. Boroughs, Rebecca C. Larson, Bryan D. Choi, Amanda A. Bouffard, Lauren S. Riley, Erik Schiferle, Anupriya S. Kulkarni, Curtis L. Cetrulo, David Ting, Bruce R. Blazar, Shadmehr Demehri, and Marcela V. Maus http://jci.me/126194

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JCI Insight | Editor’s picks

pulmonology

Glycopolymer-mediated improvement of cystic fibrosis mucus ameliorates diseaseProgressive lung dysfunction in patients with cystic fibrosis (CF) is linked to increased mucus viscosity and hampered mucociliary clearance. CF mucus structure is markedly different from that in individuals without the disease; therefore, strategies that alter mucus structure, which consists of a mucin backbone, may have therapeutic potential. Courtney Fernandez-Petty and colleagues evaluated the effect of the mucin-interacting glycopolymer poly (acetyl, arginyl) glucosamine (PAAG) on disease in multiple CF models. In a murine CF model, oral PAAG delivery dramatically improved distal intestinal obstruction syndrome and increased survival. Inhalation of nebulized PAAG improved mucociliary transport in CF rats and cleared mucus plugging, thereby reducing obstruction, in a ferret CF model (see the accompanying image). Together, these results demonstrate that PAAG improves CF mucus quality and support further evaluation of PAAG for treating CF and other mucus diseases.

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucusCourtney M. Fernandez-Petty, Gareth W. Hughes, Hannah L. Bowers, John D. Watson, Bradley H. Rosen, Stacy M. Townsend, Carlo Santos, Caroline E. Ridley, Kengyeh K. Chu, Susan E. Birket, Yao Li, Hui Min Leung, Marina Mazur, Bryan A. Garcia, T. Idil Apak Evans, Emily Falk Libby, Heather Hathorne, Justin Hanes, Guillermo J. Tearney, John P. Clancy, John F. Engelhardt, William E. Swords, David J. Thornton, William P. Wiesmann, Shenda M. Baker, and Steven M. Rowe (ASCI) http://jci.me/125954

immunology

Aberrant inflammation linked to pediatric refractory epilepsyEpilepsy is a disorder characterized by unprovoked seizures that begin in childhood. Anticonvulsants improve seizure control for the majority of patients; however, a subset of patients have drug-refractory epilepsy (RE), the drivers of which are poorly understood. Pavanish Kumar and colleagues analyzed the immune response in a cohort of pediatric RE patients and compared RE-associated immune profiles with those of healthy controls and a cohort of age-matched children with autoimmune encephalitis (AIE). Patients with RE and AIE had similar immune profiles characterized by a predominance of IL-17–producing T cell subsets. RE also associated with alterations in NK cell subsets. Moreover, immune cell network analysis revealed loss of regulatory mechanisms, thereby resulting in a proinflammatory state in RE and AIE. Together, these results indicate that RE results from systemic inflammation and that strategies to restore immune balance may be beneficial to this patient population.

Proinflammatory IL-17 pathways dominate the architecture of the immunome in pediatric refractory epilepsyPavanish Kumar, Derrick Chan Wei Shih, Amanda Lim, Bhairav Paleja, Simon Ling, Lai Li Yun, Su Li Poh, Adeline Ngoh, Thaschawee Arkachaisri, Joo Guan Yeo, and Salvatore Albani http://jci.me/126337

aids/hiv

Common actinic keratosis treatment reactivates latent HIVActinic keratosis (AK) is a precancerous skin lesion that can progress to squamous cell carcinoma (SCC). There is an increased incidence of SCC in HIV-positive individuals. Topical administration of ingenol mebutate gel effectively clears AK lesions; however, it has also been shown to reactive latent HIV in CD4+ T cells. As the in vivo consequences of ingenol mebutate–induced HIV reactivation have not been fully explored, Guochun Jiang and colleagues analyzed the effect of topical ingenol mebutate gel treatment of AK in a small cohort of HIV-infected individuals on antiretroviral therapy (ART). Ingenol mebutate effectively eliminated AK, with limited alterations of immune activation in the periphery or skin. However, there was evidence of localized HIV latency reversal, including complete transcription, in skin biopsies after treatment. Cumulatively, these results support ingenol mebutate for treating AK in HIV-positive individuals and support further exploration of this compound for disrupting HIV latency.

Disruption of latent HIV in vivo during the clearance of actinic keratosis by ingenol mebutateGuochun Jiang, Emanual Maverakis, Michelle Y. Cheng, Maher M. Elsheikh, Claire Deleage, Gema Méndez-Lagares, Michiko Shimoda, Steven A. Yukl, Dennis J. Hartigan-O’Connor, George R. Thompson III, Jacob D. Estes, Joseph K. Wong, and Satya Dandekar http://jci.me/126027

j c i . o r g / t h i s - m o n t h m a y 2 0 1 9 14

Current articles

IL-1 receptor antagonist therapy mitigates placental dysfunction and perinatal injury following Zika virus infectionJun Lei, Meghan S. Vermillion, Bei Jia, Han Xie, Li Xie, Michael W. McLane, Jeanne S. Sheffield, Andrew Pekosz, Amanda Brown, Sabra L. Klein, and Irina Burd http://jci.me/122678

C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosisRunhong Han, Shuai Hu, Weisong Qin, Jinsong Shi, Qin Hou, Xia Wang, Xiaodong Xu, Minchao Zhang, Caihong Zeng, Zhihong Liu, and Hao Bao http://jci.me/122912

Vimentin intermediate filament assembly regulates fibroblast invasion in fibrogenic lung injuryRanu Surolia, Fu Jun Li, Zheng Wang, Huashi Li, Kevin Dsouza, Vinoy Thomas, Sergey Mirov, Dolores Pérez-Sala, Mohammad Athar, Victor J. Thannickal, and Veena B. Antony http://jci.me/123253

Site-1 protease–derived soluble (pro)renin receptor targets vasopressin receptor 2 to enhance urine concentrating capabilityFei Wang, Chuanming Xu, Renfei Luo, Kexin Peng, Nirupama Ramkumar, Shiying Xie, Xiaohan Lu, Long Zhao, Chang-Jiang Zuo, Donald E. Kohan, and Tianxin Yang http://jci.me/124174

Dietary unsaturated fat increases HDL metabolic pathways involving apoE favorable to reverse cholesterol transportAllyson M. Morton, Jeremy D. Furtado, Carlos O. Mendivil, and Frank M. Sacks http://jci.me/124620

Definition of a multiple myeloma progenitor population in mice driven by enforced expression of XBP1sJoshua Kellner, Caroline Wallace, Bei Liu, and Zihai Li (ASCI) http://jci.me/124698

Senescence cell–associated extracellular vesicles serve as osteoarthritis disease and therapeutic markersOk Hee Jeon, David R. Wilson, Cristina C. Clement, Sona Rathod, Christopher Cherry, Bonita Powell, Zhenghong Lee, Ahmad M. Khalil, Jordan J. Green, Judith Campisi, Laura Santambrogio, Kenneth W. Witwer, and Jennifer H. Elisseeff http://jci.me/125019

The STING ligand cGAMP potentiates the efficacy of vaccine-induced CD8+ T cellsAlice Gutjahr, Laura Papagno, Francesco Nicoli, Tomohiro Kanuma, Nozomi Kuse, Mariela Pires Cabral-Piccin, Nicolas Rochereau, Emma Gostick, Thierry Lioux, Eric Perouzel, David A. Price, Masafumi Takiguchi, Bernard Verrier, Takuya Yamamoto, Stéphane Paul, and Victor Appay http://jci.me/125107

Interleukin-27 promotes CD8+ T cell reconstitution following antibody-mediated lymphoablationKatayoun Ayasoufi, Daniel B. Zwick, Ran Fan, Suheyla Hasgur, Michael Nicosia, Victoria Gorbacheva, Karen S. Keslar, Booki Min, Robert L. Fairchild, and Anna Valujskikh http://jci.me/125489

CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction p. 11Njabulo Ngwenyama, Ane M. Salvador, Francisco Velázquez, Tania Nevers, Alexander Levy, Mark Aronovitz, Andrew D. Luster, Gordon S. Huggins, and Pilar Alcaide http://jci.me/125527

Exogenous sickle erythrocytes combined with vascular disruption trigger disseminated tumor vaso-occlusion and lung tumor regressionChiao-Wang Sun, Li-Chen Wu, Mamta Wankhede, Dezhi Wang, Jutta Thoerner, Lawrence Woody, Brian S. Sorg, Tim M. Townes, and David S. Terman (ASCI) http://jci.me/125535

MAGI1 as a link between endothelial activation and ER stress drives atherosclerosisJun-ichi Abe, Kyung Ae Ko, Sivareddy Kotla, Yin Wang, Jesus Paez-Mayorga, Ik Jae Shin, Masaki Imanishi, Hang Thi Vu, Yunting Tao, Miguel M. Leiva-Juarez, Tamlyn N. Thomas, Jan L. Medina, Jong Hak Won, Yuka Fujii, Carolyn J. Giancursio, Elena McBeath, Ji-Hyun Shin, Liliana Guzman, Rei J. Abe, Jack Taunton, Naoki Mochizuki, William Faubion, John P. Cooke, Keigi Fujiwara, Scott E. Evans, and Nhat-Tu Le http://jci.me/125570

Iron-deficiency anemia reduces cardiac contraction by downregulating RyR2 channels and suppressing SERCA pump activityYu Jin Chung, Antao Luo, Kyung Chan Park, Aminah A. Loonat, Samira Lakhal-Littleton, Peter A. Robbins, and Pawel Swietach http://jci.me/125618

Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx miceRussell G. Rogers, Mario Fournier, Lizbeth Sanchez, Ahmed G. Ibrahim, Mark A. Aminzadeh, Michael I. Lewis, and Eduardo Marbán (ASCI) http://jci.me/125754

Disruption of latent HIV in vivo during the clearance of actinic keratosis by ingenol mebutate p. 13Guochun Jiang, Emanual Maverakis, Michelle Y. Cheng, Maher M. Elsheikh, Claire Deleage, Gema Méndez-Lagares, Michiko Shimoda, Steven A. Yukl, Dennis J. Hartigan-O’Connor, George R. Thompson III, Jacob D. Estes, Joseph K. Wong, and Satya Dandekar http://jci.me/126027

Chromatin remodeler HELLS maintains glioma stem cells through E2F3 and MYCGuoxin Zhang, Zhen Dong, Briana C. Prager, Leo J.K. Kim, Qiulian Wu, Ryan C. Gimple, Xiuxing Wang, Shideng Bao, Petra Hamerlik, and Jeremy N. Rich (ASCI) http://jci.me/126140

Altered X-chromosome inactivation in T cells may promote sex-biased autoimmune diseasesCamille M. Syrett, Bam Paneru, Donavon Sandoval-Heglund, Jianle Wang, Sarmistha Banerjee, Vishal Sindhava, Edward M. Behrens, Michael Atchison, and Montserrat C. Anguera http://jci.me/126751

Stem cell–derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetesMohammad Haque, Fengyang Lei, Xiaofang Xiong, Jugal Kishore Das, Xingcong Ren, Deyu Fang, Shahram Salek-Ardakani, Jin-Ming Yang, and Jianxun Song http://jci.me/126471

IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration p. 12Lidia Yshii, Béatrice Pignolet, Emilie Mauré, Mandy Pierau, Monika Brunner-Weinzierl, Oliver Hartley, Jan Bauer, and Roland Liblau http://jci.me/127001

j c i . o r g / t h i s - m o n t h m a y 2 0 1 915

Current articles

Cardiac hypertrophy and arrhythmia in mice induced by a mutation in ryanodine receptor 2Francisco J. Alvarado, J. Martijn Bos, Zhiguang Yuchi, Carmen R. Valdivia, Jonathan J. Hernández, Yan-Ting Zhao, Dawn S. Henderlong, Yan Chen, Talia R. Booher, Cherisse A. Marcou, Filip Van Petegem, Michael J. Ackerman, and Héctor H. Valdivia http://jci.me/126544

Osteoporosis and skeletal dysplasia caused by pathogenic variants in SGMS2Minna Pekkinen, Paulien A. Terhal, Lorenzo D. Botto, Petra Henning, Riikka E. Mäkitie, Paul Roschger, Amrita Jain, Matthijs Kol, Matti A. Kjellberg, Eleftherios P. Paschalis, Koen van Gassen, Mary Murray, Pinar Bayrak-Toydemir, Maria K. Magnusson, Judith Jans, Mehran Kausar, John C. Carey, Pentti Somerharju, Ulf H. Lerner, Vesa M. Olkkonen, Klaus Klaushofer, Joost C.M. Holthuis, and Outi Mäkitie http://jci.me/126180

Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapyLillian Sun, Paul E. Clavijo, Yvette Robbins, Priya Patel, Jay Friedman, Sarah Greene, Rita Das, Chris Silvin, Carter Van Waes, Lucas A. Horn, Jeffrey Schlom, Claudia Palena, Dean Maeda, John Zebala, and Clint T. Allen http://jci.me/126853

Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery p. 11Dale S. Edgerton, Melanie Scott, Ben Farmer, Phillip E. Williams, Peter Madsen, Thomas Kjeldsen, Christian L. Brand, Christian Fledelius, Erica Nishimura, and Alan D. Cherrington http://jci.me/126974

CD91 on dendritic cells governs immunosurveillance of nascent, emerging tumorsAbigail L. Sedlacek, Theodore P. Younker, Yu Jerry Zhou, Lisa Borghesi, Tatiana Shcheglova, Ion I. Mandoiu, and Robert J. Binder http://jci.me/127239

Classical and intermediate monocytes scavenge non-transferrin-bound iron and damaged erythrocytesDavid Haschka, Verena Petzer, Florian Kocher, Christoph Tschurtschenthaler, Benedikt Schaefer, Markus Seifert, Sieghart Sopper, Thomas Sonnweber, Clemens Feistritzer, Tara L. Arvedson, Heinz Zoller, Reinhard Stauder, Igor Theurl, Guenter Weiss, and Piotr Tymoszuk http://jci.me/98867

Human duct cells contribute to β cell compensation in insulin resistanceErcument Dirice, Dario F. De Jesus, Sevim Kahraman, Giorgio Basile, Raymond W.S. Ng, Abdelfattah El Ouaamari, Adrian Kee Keong Teo, Shweta Bhatt, Jiang Hu, and Rohit N. Kulkarni (ASCI) http://jci.me/99576

UCP1 expression–associated gene signatures of human epicardial adipose tissueKanta Chechi, Jinchu Vijay, Pierre Voisine, Patrick Mathieu, Yohan Bossé, Andre Tchernof, Elin Grundberg, and Denis Richard http://jci.me/123618

Single-cell RNA sequencing identifies TGF-β as a key regenerative cue following LPS-induced lung injuryKent A. Riemondy, Nicole L. Jansing, Peng Jiang, Elizabeth F. Redente, Austin E. Gillen, Rui Fu, Alyssa J. Miller, Jason R. Spence, Anthony N. Gerber, Jay R. Hesselberth, and Rachel L. Zemans http://jci.me/123637

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activationMichael Rehman, Simone Vodret, Luca Braga, Corrado Guarnaccia, Fulvio Celsi, Giulia Rossetti, Valentina Martinelli, Tiziana Battini, Carlin Long, Kristina Vukusic, Tea Kocijan, Chiara Collesi, Nadja Ring, Natasa Skoko, Mauro Giacca, Giannino Del Sal, Marco Confalonieri, Marcello Raspa, Alessandro Marcello, Michael P. Myers, Sergio Crovella, Paolo Carloni, and Serena Zacchigna http://jci.me/123987

Human antibody response to Zika targets type-specific quaternary structure epitopesMatthew H. Collins, Huy A. Tu, Ciara Gimblet-Ochieng, Guei-Jiun Alice Liou, Ramesh S. Jadi, Stefan W. Metz, Ashlie Thomas, Benjamin D. McElvany, Edgar Davidson, Benjamin J. Doranz, Yaoska Reyes, Natalie M. Bowman, Sylvia Becker-Dreps, Filemón Bucardo, Helen M. Lazear, Sean A. Diehl, and Aravinda M. de Silva http://jci.me/124588

Disruption of embryonic ROCK signaling reproduces the sarcomeric phenotype of hypertrophic cardiomyopathyKate E. Bailey, Guy A. MacGowan, Simon Tual-Chalot, Lauren Phillips, Timothy J. Mohun, Deborah J. Henderson, Helen M. Arthur, Simon D. Bamforth, and Helen M. Phillips http://jci.me/125172

Repression of AXL expression by AP-1/JNK blockage overcomes resistance to PI3Ka therapyMai Badarni, Manu Prasad, Noa Balaban, Jonathan Zorea, Ksenia Yagodayev, Joshua Ben-Zion, Anat Bahat Dinur, Reidar Grénman, Barak Rotblat, Limor Cohen, and Moshe Elkabets http://jci.me/125341

Displacement analysis of myocardial mechanical deformation (DIAMOND) reveals segmental susceptibility to doxorubicin-induced injury and regenerationJunjie Chen, Yichen Ding, Michael Chen, Jonathan Gau, Nelson Jen, Chadi Nahal, Sally Tu, Cynthia Chen, Steve Zhou, Chih-Chiang Chang, Jintian Lyu, Xiaolei Xu, Tzung K. Hsiai, and René R. Sevag Packard http://jci.me/125362

DNA-encoded bispecific T cell engagers and antibodies present long-term antitumor activityAlfredo Perales-Puchalt, Elizabeth K. Duperret, Xue Yang, Patricia Hernandez, Krzysztof Wojtak, Xizhou Zhu, Seang-Hwan Jung, Edgar Tello-Ruiz, Megan C. Wise, Luis J. Montaner, Kar Muthumani, and David B. Weiner http://jci.me/126086

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Epigenetic loss of the endoplasmic reticulum–associated degradation inhibitor SVIP induces cancer cell metabolic reprogrammingPere Llinàs-Arias, Margalida Rosselló-Tortella, Paula López-Serra, Montserrat Pérez-Salvia, Fernando Setién, Silvia Marin, Juan P. Muñoz, Alexandra Junza, Jordi Capellades, María E. Calleja-Cervantes, Humberto J. Ferreira, Manuel Castro de Moura, Marina Srbic, Anna Martínez-Cardús, Carolina de la Torre, Alberto Villanueva, Marta Cascante, Oscar Yanes, Antonio Zorzano, Catia Moutinho, and Manel Esteller http://jci.me/125888

A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus p. 13Courtney M. Fernandez-Petty, Gareth W. Hughes, Hannah L. Bowers, John D. Watson, Bradley H. Rosen, Stacy M. Townsend, Carlo Santos, Caroline E. Ridley, Kengyeh K. Chu, Susan E. Birket, Yao Li, Hui Min Leung, Marina Mazur, Bryan A. Garcia, T. Idil Apak Evans, Emily Falk Libby, Heather Hathorne, Justin Hanes, Guillermo J. Tearney, John P. Clancy, John F. Engelhardt, William E. Swords, David J. Thornton, William P. Wiesmann, Shenda M. Baker, and Steven M. Rowe (ASCI) http://jci.me/125954

Chimeric antigen receptor costimulation domains modulate human regulatory T cell function p. 12Angela C. Boroughs, Rebecca C. Larson, Bryan D. Choi, Amanda A. Bouffard, Lauren S. Riley, Erik Schiferle, Anupriya S. Kulkarni, Curtis L. Cetrulo, David Ting, Bruce R. Blazar, Shadmehr Demehri, and Marcela V. Maus http://jci.me/126194

Myelin repair stimulated by CNS-selective thyroid hormone actionMeredith D. Hartley, Tania Banerji, Ian J. Tagge, Lisa L. Kirkemo, Priya Chaudhary, Evan Calkins, Danielle Galipeau, Mitra D. Shokat, Margaret J. DeBell, Shelby Van Leuven, Hannah Miller, Gail Marracci, Edvinas Pocius, Tapasree Banerji, Skylar J. Ferrara, J. Matthew Meinig, Ben Emery, Dennis Bourdette, and Thomas S. Scanlan http://jci.me/126329

Proinflammatory IL-17 pathways dominate the architecture of the immunome in pediatric refractory epilepsy p. 13Pavanish Kumar, Derrick Chan Wei Shih, Amanda Lim, Bhairav Paleja, Simon Ling, Lai Li Yun, Su Li Poh, Adeline Ngoh, Thaschawee Arkachaisri, Joo Guan Yeo, and Salvatore Albani http://jci.me/126337

Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibodyNoriko Makita, Takao Ando, Junichiro Sato, Katsunori Manaka, Koji Mitani, Yasuko Kikuchi, Takayoshi Niwa, Masanori Ootaki, Yuko Takeba, Naoki Matsumoto, Atsushi Kawakami, Toshihisa Ogawa, Masaomi Nangaku, and Taroh Iiri http://jci.me/126449

Predicting breast cancer response to neoadjuvant chemotherapy based on tumor vascular features in needle biopsiesTerisse A. Brocato, Ursa Brown-Glaberman, Zhihui Wang, Reed G. Selwyn, Colin M. Wilson, Edward F. Wyckoff, Lesley C. Lomo, Jennifer L. Saline, Anupama Hooda-Nehra, Renata Pasqualini, Wadih Arap (ASCI), C. Jeffrey Brinker, and Vittorio Cristini http://jci.me/126518

Identification of epitopes in ovalbumin that provide insights for cancer neoepitopesSukrut Hemant Karandikar, John Sidney, Alessandro Sette, Mark Joseph Selby, Alan Jerry Korman, and Pramod Kumar Srivastava http://jci.me/127882

TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance p. 10Matthew R. Lynch, Mei T. Tran, Kenneth M. Ralto, Zsuzsanna K. Zsengeller, Vinod Raman, Swati S. Bhasin, Nuo Sun, Xiuying Chen, Daniel Brown, Ilsa I. Rovira, Kensei Taguchi, Craig R. Brooks, Isaac E. Stillman, Manoj K. Bhasin, Toren Finkel, and Samir M. Parikh (ASCI) http://jci.me/126749

Autophagy links antimicrobial activity with antigen presentation in Langerhans cellsAngeline Tilly Dang, Rosane M.B. Teles, Phillip T. Liu, Aaron Choi, Annalisa Legaspi, Euzenir N. Sarno, Maria T. Ochoa, Kislay Parvatiyar, Genhong Cheng, Michel Gilliet, Barry R. Bloom, and Robert L. Modlin (ASCI) http://jci.me/126955

Faulty oxygen sensing disrupts angiomotin function in trophoblast cell migration and predisposes to preeclampsiaAbby Farrell, Sruthi Alahari, Leonardo Ermini, Andrea Tagliaferro, Michael Litvack, Martin Post, and Isabella Caniggia http://jci.me/127009

Identification of rare HIV-1–infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppressionAndrea Lisco, Chun-Shu Wong, Silvia Lucena Lage, Itzchak Levy, Jason Brophy, Jeffrey Lennox, Maura Manion, Megan V. Anderson, Yolanda Mejia, Christopher Grivas, Harry Mystakelis, Peter D. Burbelo, Ainhoa Perez-Diez, Adam Rupert, Craig A. Martens, Sarah L. Anzick, Caryn Morse, Shanna Chan, Claire Deleage, and Irini Sereti http://jci.me/127113

The effect of BPIFA1/SPLUNC1 genetic variation on its expression and function in asthmatic airway epitheliumNiccolette Schaefer, Xingnan Li, Max A. Seibold, Nizar N. Jarjour, Loren C. Denlinger, Mario Castro, Andrea M. Coverstone, W. Gerald Teague, Jonathan Boomer, Eugene R. Bleecker, Deborah A. Meyers, Wendy C. Moore, Gregory A. Hawkins, John Fahy, Brenda R. Phillips, David T. Mauger, Azzeddine Dakhama, Shaan Gellatly, Nicole Pavelka, Reena Berman, Y. Peter Di, Sally E. Wenzel, and Hong Wei Chu http://jci.me/127237

The female-biased factor VGLL3 drives cutaneous and systemic autoimmunityAllison C. Billi, Mehrnaz Gharaee-Kermani, Joseph Fullmer, Lam C. Tsoi, Brett D. Hill, Dennis Gruszka, Jessica Ludwig, Xianying Xing, Shannon Estadt, Sonya J. Wolf, Syed Monem Rizvi, Celine C. Berthier, Jeffrey B. Hodgin, Maria A. Beamer, Mrinal K. Sarkar, Yun Liang, Ranjitha Uppala, Shuai Shao, Chang Zeng, Paul W. Harms, Monique E. Verhaegen, John J. Voorhees, Fei Wen, Nicole L. Ward, Andrzej A. Dlugosz, J. Michelle Kahlenberg, and Johann E. Gudjonsson http://jci.me/127291

Blood-retina barrier failure and vision loss in neuron-specific degenerationElena Ivanova, Nazia M. Alam, Glen T. Prusky, and Botir T. Sagdullaev http://jci.me/126747

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