jci.org/this-month

Self-reactive T cells contribute to cardiac healing 2

Peptide modification improves intramuscular ASO delivery 3

DNA damage response protein coordinates kidney repair 4

Rethinking weight and diet guidelines in pregnancy 5

Vaccination-induced correlates of decreased HIV-1 risk 5

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

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November 2019

This Month

ANGPTL4 destabilizes the retinal vasculature in diabetic macular edema p. 2

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

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

BiostatisticianEliseo Guallar

Computational BiologistPatrick Cahan

JCI ScholarsJ. David Peske, Laura Sena

Staff EditorsExecutive EditorSarah C. Jackson

Senior Science EditorCorinne Williams

Science EditorElyse Dankoski

Assistant Science EditorLisa Conti

Editor at LargeUshma S. Neill

Editorial InternBouchra Taib

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

For the full JCI online: jci.me/129/11

This MonthNovember 2019

Contact the JCI and JCI Insight2015 Manchester Road, Ann 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.

(ASCI) indicates corresponding authors who are ASCI members.

The JCI’s Editorial Board is composed of peer scientists at Johns Hopkins University School of Medicine, the University of Maryland School of Medicine, and the National Institutes of Health. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the Board meets weekly to discuss manuscripts undergoing review.

Featured Editor

Nilofer S. Azad, MD, Associate Editor, is an Associate Professor of Oncology and a mem-ber of the Gastrointestinal Oncology Program within the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. Dr. Azad is the principal investigator of numerous early-phase clinical trials in solid tumors and gastrointestinal cancers. She has been a member of the National Cancer Insti-tute’s Colon Cancer Task Force and the advi-sory boards of the Biden Cancer Initiative and the Cholangiocarcinoma Foundation, among others. Her laboratory is currently investigating

drugs that work through epigenetic mechanisms, as well as epigenetic molec-ular differences in tumors that may change the efficacy of treatment, and the intersection of these agents with immunotherapy.

Publication highlights

Kurzrock R, Ball DW, Zahurak ML, Nelkin BD, Subbiah V, Ahmed S, O’Connor A, Karunsena E, Parkinson RM, Bishop JA, Ha Y, Sharma R, Gocke CD, Zinner R, Rudek MA, Sherman SI, Azad NS. A phase I trial of the VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced solid tumors and differentiated thyroid cancers. Clin Cancer Res. 2019;25(18):5475–5484.

Lee V, Wang J, Zahurak M, Gootjes E, Verheul HM, Parkinson R, Kerner Z, Sharma A, Rosner G, De Jesus-Acosta A, Laheru D, Le DT, Oganesian A, Lilly E, Brown T, Jones P, Baylin S, Ahuja N, Azad N. A Phase I trial of a guadecitabine (SGI-110) and irinotecan in metastatic colorectal cancer patients previously exposed to irinotecan. Clin Cancer Res. 2018;24(24):6160–6167.

Shroff RT, Yarchoan M, O’Connor A, Gallagher D, Zahurak ML, Rosner G, Ohaji C, Sartorius-Mergenthaler S, Parkinson R, Subbiah V, Zinner R, Azad NS. The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Br J Cancer. 2017;116(11):1402–1407.

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research

Editor’s picks

ophthalmologyon the jci cover

cardiology

Autoreactive T cells assume pro-repair roles in the infarcted heart

Elevated ANGPTL4 contributes to vascular destabilization in diabetic macular edemaAnti-VEGF treatments have become a standard of care for patients with diabetic macular edema (DME), a complication of diabetes characterized by progressive damage to the retinal vasculature, leading to vascular leakage and visual impairment. The goal of anti-VEGF therapies is to prevent the leakage of fluid from the injured blood vessels that produces edema; however, in many DME patients, anti-VEGF therapy does not substantially improve vision. In this issue of the JCI, Akrit Sodhi et al. draw upon recent observations linking angiopoietin-like 4 (ANGPTL4) to retinal hyperpermeability to explore this protein’s role in DME. Their work reveals that ANGPTL4 and VEGF work in concert to destabilize the retina’s vasculature. The researchers report that ANGPTL4 levels are increased in the aqueous fluid of DME patients and diabetic mouse models. Further, they determined that ANGPTL4’s binding to neuropilin 1 and 2 on endothelial cells disrupts vascular barriers via activation of RhoA/ROCK signaling, a mechanism that occurs in parallel to VEGF’s effects on vascular permeability. Treatment with a soluble fragment of neuropilin 1 blocked ANGPTL4-induced vascular leakage in diabetic animals, supporting a potential therapeutic avenue for interfering in ANGPTL4- mediated mechanisms in DME. This issue’s cover depicts the pathological leakage of the retinal vasculature in a patient with diabetic eye disease. Image courtesy of Wilmer Photography; modified by Isabella and Adriana Sodhi.

Angiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edemaAkrit Sodhi, Tao Ma, Deepak Menon, Monika Deshpande, Kathleen Jee, Aumreetam Dinabandhu, Jordan Vancel, Daoyuan Lu, and Silvia Montaner http://jci.me/120879

Myocardial infarction (MI) drives T cell priming and proliferation in the heart-draining lymph nodes. These MI-induced T cells include both inflammation-resolving FOXP3+ Tregs and conventional T cells, though their specific functions in cardiac repair remain unclear. Max Rieckmann and colleagues identified myosin heavy chain α (MYHCA) as a cardiac self-antigen that activates CD4+ Th cells following experimental MI. MYHCA-specific Th cells accumulated in the infarct zone and acquired Treg-like features, indicating that the injured myocardium recruits autoreactive Th cells and facilitates the conversion to pro-repair phenotypes. Hearts enriched in MYHCA-specific T cells had improved outcomes one week after experimental MI, and adoptive transfer of these cells into healthy mice did not produce pathogenic effects. The researchers further revealed the presence of CD4+ and FOXP3+ T cells in infarcted postmortem hearts. In the related Commentary, Ziad Mallat calls for further investigation of the cells’ therapeutic potential to aid in recovery from cardiac injury.

Myocardial infarction triggers cardioprotective antigen-specific T helper cell responsesMax Rieckmann, Murilo Delgobo, Chiara Gaal, Lotte Büchner, Philipp Steinau, Dan Reshef, Cristina Gil-Cruz, Ellis N. ter Horst, Malte Kircher, Theresa Reiter, Katrin G. Heinze, Hans W.M. Niessen, Paul A.J. Krijnen, Anja M. van der Laan, Jan J. Piek, Charlotte Koch, Hans-Jürgen Wester, Constantin Lapa, Wolfgang R. Bauer, Burkhard Ludewig, Nir Friedman, Stefan Frantz, Ulrich Hofmann, and Gustavo Campos Ramos http://jci.me/123859

Related CommentaryRegulating heart repair with cardiac-specific T lymphocytesZiad Mallat http://jci.me/132441

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JCI | Research: Editor’s picks

oncology

Reversing diphthamide pathway impairment restores efficacy of CD123-targeted cancer therapyTagraxofusp, a CD123-targeting therapy fused to a truncated diphtheria toxin payload, is approved for blastic plasmacytoid dendritic cell neoplasm (BPDCN) and under investigation for other hematologic cancers. The factors contributing to tagraxofusp treatment response remain unclear. Katsuhiro Togami, Timothy Pastika, Jason Stephansky, et al., determined that tagraxofusp resistance in patient-derived BPDCN and acute myeloid leukemia (AML) cells was not driven by CD123 loss. Rather, cells displayed resistance to diphtheria toxin due to methylation and downregulation

of DPH1, a critical enzyme in the diphthamide synthesis pathway. In tagraxofusp-resistant AML cells, inhibiting DNA methyltransferase rescued DPH1 expression and restored response to tagraxofusp. Further, cotreating BPDCN patient-derived xenograft models with the DNA methyltransferase inhibitor azacitidine and tagraxofusp prolonged survival relative to either treatment alone. In the related Commentary, Lukasz Gondek puts these data into clinical context, highlighting an upcoming phase I trial of azacitidine/tagraxofusp combination treatment in myeloid malignancies.

DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistanceKatsuhiro Togami, Timothy Pastika, Jason Stephansky, Mahmoud Ghandi, Amanda L. Christie, Kristen L. Jones, Carl A. Johnson, Ross W. Lindsay, Christopher L. Brooks, Anthony Letai, Jeffrey W. Craig, Olga Pozdnyakova, David M. Weinstock, Joan Montero, Jon C. Aster, Cory M. Johannessen, and Andrew A. Lane http://jci.me/128571

Related CommentaryHitting the bullseye with a nonlethal payload: resistance in CD123-positive malignanciesLukasz P. Gondek http://jci.me/132443

muscle biology

Cell-penetrating peptides improve ASO delivery and myotonic dystrophy correctionMyotonic dystrophy (DM1) is caused by CUG repeats in the DM1 protein kinase (DMPK) transcript that sequester CUG-targeting RNA binding factors within nuclear foci and lead to abnormal splicing in multiple genes. Antisense oligonucleotide (ASO) strategies have successfully reversed DM1 phenotypes in mouse models, but ASO delivery and uptake in muscle tissue remains an obstacle to clinical success. To improve drug distribution, teams led by Denis Furling and Matthew Wood collaborated to test a DM1-reversing ASO conjugated to the cell-penetrating peptide Pip6a. Low doses of the

Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and miceArnaud F. Klein, Miguel A. Varela, Ludovic Arandel, Ashling Holland, Naira Naouar, Andrey Arzumanov, David Seoane, Lucile Revillod, Guillaume Bassez, Arnaud Ferry, Dominic Jauvin, Genevieve Gourdon, Jack Puymirat, Michael J. Gait, Denis Furling, and Matthew J.A. Wood http://jci.me/128205

Related CommentaryBetter living through peptide-conjugated chemistry: next-generation antisense oligonucleotidesElizabeth M. McNally (ASCI) and Brian D. Leverson http://jci.me/131933

ASO-peptide conjugate produced long-lasting reversal of splicing defects, transcriptional alterations, and myotonia in mouse models. The conjugated ASO also corrected splicing defects and other molecular alterations present in patient-derived DM1 muscle cells (compare ASO-treated cells, left, with DM1-derived cells, right, in the associated image). In the accompanying Commentary, Elizabeth McNally and Brian Leverson outline opportunities to use peptide-conjugated ASOs in DM1 and other diseases where tissue penetration remains a barrier to successful ASO therapy.

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JCI | Research: Editor’s picks

nephrology

ATR-mediated DNA repair reduces pathological remodeling after kidney injuryMany forms of kidney injury lead to activation of the DNA damage response (DDR), which detects and mends breaks in DNA strands in coordination with the cell cycle. Following up on recent work associating kidney fibrosis with G2/M cell-cycle arrest, Seiji Kishi, Craig Brooks, Joseph Bonventre and colleagues interrogated the role of the DDR kinase ATR in pathogenic responses to kidney injury. In patients with chronic kidney disease and in cisplatin-exposed human kidney organoids, renal damage was associated with increased ATR activation (see the associated image). Ablation of ATR in renal proximal tubule cells (RPTCs) exacerbated cisplatin- or ischemia-induced kidney injury in mouse models. Following cisplatin injury, the researchers observed more RPTCs in the G2/M phase in ATR-deficient mice compared with WT mice. The accompanying Commentary by Bruce Molitoris discusses the implications of ATR’s critical role in protecting against maladaptive repair of kidney injuries.

Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responsesSeiji Kishi, Craig R. Brooks, Kensei Taguchi, Takaharu Ichimura, Yutaro Mori, Akinwande Akinfolarin, Navin Gupta, Pierre Galichon, Bertha C. Elias, Tomohisa Suzuki, Qian Wang, Leslie Gewin, Ryuji Morizane, and Joseph V. Bonventre (ASCI) http://jci.me/122313

Related CommentaryDNA damage response protects against progressive kidney diseaseBruce A. Molitoris (ASCI) http://jci.me/131171

Calcium channel Orai1 enhances Th17 cell–mediated progressive kidney injuryIL-17–expressing T helper cells (Th17 cells) contribute to delayed recovery from acute kidney injury (AKI) and its progression to chronic kidney disease. High-salt diet has been shown to reactivate Th17 cells following ischemic renal injury, driving increased fibrosis and neutrophil infiltration. Purvi Mehrotra and colleagues determined that the store-operated calcium entry channel Orai1 contributes to Th17 cell activation and maladaptive renal repair. They observed that both Orai1-expressing and Th17 cells were elevated in the peripheral blood of AKI

patients. Orai1 activity enhanced intracellular calcium flux and IL-17 expression in salt-stimulated T cells isolated from post-AKI rats. In contrast, when rats were fed a high-salt diet following AKI, Orai1 inhibition attenuated the severity of progressive renal impairment. Together, the results suggest that Orai1 expression mediates salt-driven Th17 cell activation. Sanjeev Noel’s accompanying Commentary describes the potential of Orai1 inhibitors to become interventions for the AKI–to–chronic kidney disease transition.

Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injuryPurvi Mehrotra, Michael Sturek, Javier A. Neyra, and David P. Basile http://jci.me/126108

Related CommentaryOrai1: CRACing the Th17 response in AKISanjeev Noel http://jci.me/131935

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JCI | Research: Editor’s picks

clinical medicine

Optimizing the immunogenicity of a prime-boost HIV vaccine regimenThe most effective demonstration of an HIV vaccine to date was RV144, which combined four injections of canarypox-vectored vaccine with two injections of recombinant gp120 protein (AIDSVAX B/E). Although RV144 achieved only moderate efficacy, the trial provided clues for optimizing prime-boost HIV vaccine regimens. In a phase I trial of 104 HIV-negative participants, Nadine Rouphael and colleagues investigated the safety and immunogenicity of regimens combining AIDSVAX B/E with a DNA-HIV vaccine, an immunogenic alternative to the original vectored vaccine. Whereas RV144 induced potentially protective antibody responses six months after the final injection, the DNA-HIV/protein combinations induced higher-magnitude and persistent anti-HIV antibody responses within six weeks of the initial treatment. The study also determined that immunologic responses to regimens with DNA priming/protein boosting were superior to protein priming/DNA boosting. In the accompanying Commentary, Nelson Michael supports the study’s conclusion that these regimens are safe and immunogenic, providing a rationale for a modified strategy for HIV vaccine efficacy trials.

DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trialNadine G. Rouphael, Cecilia Morgan, Shuying S. Li, Ryan Jensen, Brittany Sanchez, Shelly Karuna, Edith Swann, Magdalena E. Sobieszczyk, Ian Frank, Gregory J. Wilson, Hong-Van Tieu, Janine Maenza, Aliza Norwood, James Kobie, Faruk Sinangil, Giuseppe Pantaleo, Song Ding, M. Juliana McElrath, Stephen C. De Rosa, David C. Montefiori, Guido Ferrari, Georgia D. Tomaras, Michael C. Keefer, and the HVTN 105 Protocol Team and the NIAID HIV Vaccine Trials Network http://jci.me/128699

Related CommentarySimplified steps to heterologous prime-boost HIV vaccine development?Nelson L. Michael http://jci.me/132440

Evidence to improve nutritional and weight gain guidelines in pregnancyThe Institute of Medicine’s guidelines for weight gain and nutrition during pregnancy are not tailored to women with obesity, two-thirds of whom gain excess weight during pregnancy that poses a risk to mother and child. To improve recommendations for this group, Jasper Most and colleagues studied weight gain, caloric intake, and energy expenditure in 54 pregnant women with obesity. Their report indicates that increased caloric intake is not required to support a healthy pregnancy in the setting of obesity, contradicting current recommendations. The researchers also observed that gestational weight gain due to increased blood volume, expansion of breast tissue, and fetal mass accounted for the 5–9 kg of weight gain that is currently recommended. Thus, for women in the study, even modest increases in daily calorie consumption led to excess weight gain. Sarah Comstock’s accompanying Commentary supports using this evidence as a step toward improving maternal health guidelines.

Evidence-based recommendations for energy intake in pregnant women with obesityJasper Most, Marshall St Amant, Daniel S. Hsia, Abby D. Altazan, Diana M. Thomas, L. Anne Gilmore, Porsha M. Vallo, Robbie A. Beyl, Eric Ravussin, and Leanne M. Redman http://jci.me/130341

Related CommentaryTime to change weight gain recommendations for pregnant women with obesitySarah S. Comstock http://jci.me/131932

aids/hiv

Vaccine-induced Fcγ receptor recruitment and IgG3 linked to lower HIV-1 riskThe most recently completed HIV-1 efficacy trial, HVTN 505, did not demonstrate overall efficacy; however, there was evidence that vaccination exerted selective pressure on the infecting viruses. Led by Peter Gilbert and Georgia Tomaras, Scott Neidich, Youyi Fong, Shuying Li, et al. investigated the immune correlates of HIV-1 risk in this trial to improve the design of future vaccine regimens, focusing on antibody-mediated Fcγ receptor recruitment, antibody-dependent cellular phagocytosis, and anti-Env IgG3. Their analyses indicate that increases in all three variables were inversely correlated with HIV-1 acquisition, with antibody-mediated Fcγ receptor binding also correlating with decreased viral load. A computational analysis revealed that combined measurements of antibody and CD8+ T cells best predicted HIV-1 acquisition. In the related Commentary, Tysheena Charles and Cynthia Derdeyn highlight how insights into antibody and immune system interactions may improve the study and design of future vaccines.

Antibody Fc effector functions and IgG3 associate with decreased HIV-1 riskScott D. Neidich, Youyi Fong, Shuying S. Li, Daniel E. Geraghty, Brian D. Williamson, William Chad Young, Derrick Goodman, Kelly E. Seaton, Xiaoying Shen, Sheetal Sawant, Lu Zhang, Allan C. deCamp, Bryan S. Blette, Mengshu Shao, Nicole L. Yates, Frederick Feely, Chul-Woo Pyo, Guido Ferrari, HVTN 505 Team, Ian Frank, Shelly T. Karuna, Edith M. Swann, John R. Mascola, Barney S. Graham, Scott M. Hammer, Magdalena E. Sobieszczyk, Lawrence Corey, Holly E. Janes, M. Juliana McElrath, Raphael Gottardo, Peter B. Gilbert, and Georgia D. Tomaras http://jci.me/126391

Related CommentaryStriking a balance in an antibody network: a roadmap for HIV-1 vaccinesTysheena P. Charles and Cynthia A. Derdeyn http://jci.me/132535

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JCI | Features

viewpoint

How to fight skyrocketing prescription drug pricing in AmericaHealth care costs — including the prices of medical treatments, lab tests, hospital stays, and doctor visits — are greater in the United States than in any of the countries considered its economic peers. The staggering prices of prescription drugs command particular attention in discussions about improving US health policies. In a Viewpoint, Arthur Caplan emphasizes Americans’ right to affordably access life-saving treatments and offers serious solutions to America’s drug-pricing problems. He argues that rather than relying on piecemeal efforts to curb out-of-control prices, a consolidated federal agency should do the bargaining for drug pricing in the United States. The accompanying image, based on Leslie Thrasher’s Tipping the Scales, suggests that government has a role in moderating prescription drug costs.

Obtaining prescription drugs in America: it’s no bargainArthur L. Caplan http://jci.me/132977

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

j c i . o r g / t h i s - m o n t h n o v e m b e r 2 0 1 9 7

Current research articles

aids/hivGlycan-dependent HIV-specific neutralizing antibodies bind to cells of uninfected individualsJana Blazkova, Eric W. Refsland, Katherine E. Clarridge, Victoria Shi, J. Shawn Justement, Erin D. Huiting, Kathleen R. Gittens, Xuejun Chen, Stephen D. Schmidt, Cuiping Liu, Nicole Doria-Rose, John R. Mascola, Alonso Heredia, Susan Moir, and Tae-Wook Chun http://jci.me/125955

Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk p. 5Scott D. Neidich, Youyi Fong, Shuying S. Li, Daniel E. Geraghty, Brian D. Williamson, William Chad Young, Derrick Goodman, Kelly E. Seaton, Xiaoying Shen, Sheetal Sawant, Lu Zhang, Allan C. deCamp, Bryan S. Blette, Mengshu Shao, Nicole L. Yates, Frederick Feely, Chul-Woo Pyo, Guido Ferrari, HVTN 505 Team, Ian Frank, Shelly T. Karuna, Edith M. Swann, John R. Mascola, Barney S. Graham, Scott M. Hammer, Magdalena E. Sobieszczyk, Lawrence Corey, Holly E. Janes, M. Juliana McElrath, Raphael Gottardo, Peter B. Gilbert, and Georgia D. Tomaras http://jci.me/126391

HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapyWilliam R. McManus, Michael J. Bale, Jonathan Spindler, Ann Wiegand, Andrew Musick, Sean C. Patro, Michele D. Sobolewski, Victoria K. Musick, Elizabeth M. Anderson, Joshua C. Cyktor, Elias K. Halvas, Wei Shao, Daria Wells, Xiaolin Wu, Brandon F. Keele, Jeffrey M. Milush, Rebecca Hoh, John W. Mellors, Stephen H. Hughes, Steven G. Deeks, John M. Coffin, and Mary F. Kearney http://jci.me/126714

cardiologyMyocardial infarction triggers cardioprotective antigen-specific T helper cell responses p. 2Max Rieckmann, Murilo Delgobo, Chiara Gaal, Lotte Büchner, Philipp Steinau, Dan Reshef, Cristina Gil-Cruz, Ellis N. ter Horst, Malte Kircher, Theresa Reiter, Katrin G. Heinze, Hans W.M. Niessen, Paul A.J. Krijnen, Anja M. van der Laan, Jan J. Piek, Charlotte Koch, Hans-Jürgen Wester, Constantin Lapa, Wolfgang R. Bauer, Burkhard Ludewig, Nir Friedman, Stefan Frantz, Ulrich Hofmann, and Gustavo Campos Ramos http://jci.me/123859

Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasisBrigitte Laforest, Wenli Dai, Leonid Tyan, Sonja Lazarevic, Kaitlyn M. Shen, Margaret Gadek, Michael T. Broman, Christopher R. Weber, and Ivan P. Moskowitz (ASCI) http://jci.me/124231

clinical medicineAge-dependent SMN expression in disease-relevant tissue and implications for SMA treatmentDaniel M. Ramos, Constantin d’Ydewalle, Vijayalakshmi Gabbeta, Amal Dakka, Stephanie K. Klein, Daniel A. Norris, John Matson, Shannon J. Taylor, Phillip G. Zaworski, Thomas W. Prior, Pamela J. Snyder, David Valdivia, Christine L. Hatem, Ian Waters, Nikhil Gupte, Kathryn J. Swoboda, Frank Rigo, C. Frank Bennett, Nikolai Naryshkin, Sergey Paushkin, Thomas O. Crawford, and Charlotte J. Sumner (ASCI) http://jci.me/124120

T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical responseCorey Smith, Dillon Corvino, Leone Beagley, Sweera Rehan, Michelle A. Neller, Pauline Crooks, Katherine K. Matthews, Matthew Solomon, Laetitia Le Texier, Scott Campbell, Ross S. Francis, Daniel Chambers, and Rajiv Khanna http://jci.me/128323

DNA priming and gp120 boosting induces HIV-specific antibodies in a randomized clinical trial p. 5Nadine G. Rouphael, Cecilia Morgan, Shuying S. Li, Ryan Jensen, Brittany Sanchez, Shelly Karuna, Edith Swann, Magdalena E. Sobieszczyk, Ian Frank, Gregory J. Wilson, Hong-Van Tieu, Janine Maenza, Aliza Norwood, James Kobie, Faruk Sinangil, Giuseppe Pantaleo, Song Ding, M. Juliana McElrath, Stephen C. De Rosa, David C. Montefiori, Guido Ferrari, Georgia D. Tomaras, Michael C. Keefer, and the HVTN 105 Protocol Team and the NIAID HIV Vaccine Trials Network http://jci.me/128699

Evidence-based recommendations for energy intake in pregnant women with obesity p. 5Jasper Most, Marshall St Amant, Daniel S. Hsia, Abby D. Altazan, Diana M. Thomas, L. Anne Gilmore, Porsha M. Vallo, Robbie A. Beyl, Eric Ravussin, and Leanne M. Redman http://jci.me/130341

gastroenterologyIFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruptionVictoria Langer, Eugenia Vivi, Daniela Regensburger, Thomas H. Winkler, Maximilian J. Waldner, Timo Rath, Benjamin Schmid, Lisa Skottke, Somin Lee, Noo Li Jeon, Thomas Wohlfahrt, Viktoria Kramer, Philipp Tripal, Michael Schumann, Stephan Kersting, Claudia Handtrack, Carol I. Geppert, Karina Suchowski, Ralf H. Adams, Christoph Becker, Andreas Ramming, Elisabeth Naschberger, Nathalie Britzen-Laurent, and Michael Stürzl http://jci.me/124884

Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinomaPaul C. Moore, Jessica T. Cortez, Chester E. Chamberlain, Diana Alba, Amy C. Berger, Zoe Quandt, Alice Chan, Mickie H. Cheng, Jhoanne L. Bautista, Justin Peng, Michael S. German, Mark S. Anderson, and Scott A. Oakes (ASCI) http://jci.me/129961

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Current research articles

immunologyFOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans Qiumei Du, Larry K. Huynh, Fatma Coskun, Erika Molina, Matthew A. King, Prithvi Raj, Shaheen Khan, Igor Dozmorov, Christine M. Seroogy, Christian A. Wysocki, Grace T. Padron, Tyler R. Yates, M. Louise Markert, M. Teresa de la Morena, and Nicolai S.C. van Oers http://jci.me/127565

Increased flux through the mevalonate pathway mediates fibrotic repair without injuryJennifer L. Larson-Casey, Mudit Vaid, Linlin Gu, Chao He, Guo-Qiang Cai, Qiang Ding, Dana Davis, Taylor F. Berryhill, Landon S. Wilson, Stephen Barnes, Jeffrey D. Neighbors, Raymond J. Hohl, Kurt A. Zimmerman, Bradley K. Yoder, Ana Leda F. Longhini, Vidya Sagar Hanumanthu, Ranu Surolia, Veena B. Antony, and A. Brent Carter (ASCI) http://jci.me/127959

JMJD3 regulates CD4+ T cell trafficking by targeting actin cytoskeleton regulatory gene Pdlim4Chuntang Fu, Qingtian Li, Jia Zou, Changsheng Xing, Mei Luo, Bingnan Yin, Junjun Chu, Jiaming Yu, Xin Liu, Helen Y. Wang, and Rong-Fu Wang http://jci.me/128293

Early adaptive immune activation detected in monozygotic twins with prodromal multiple sclerosisEduardo Beltrán, Lisa Ann Gerdes, Julia Hansen, Andrea Flierl-Hecht, Stefan Krebs, Helmut Blum, Birgit Ertl-Wagner, Frederik Barkhof, Tania Kümpfel, Reinhard Hohlfeld, and Klaus Dornmair http://jci.me/128475

infectious diseasePeritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus disseminationSelina K. Jorch, Bas G.J. Surewaard, Mokarram Hossain, Moritz Peiseler, Carsten Deppermann, Jennifer Deng, Ania Bogoslowski, Fardau van der Wal, Abdelwahab Omri, Michael J. Hickey, and Paul Kubes http://jci.me/127286

p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virusDaniel Menendez, Joyce Snipe, Jacqui Marzec, Cynthia L. Innes, Fernando P. Polack, Mauricio T. Caballero, Shepherd H. Schurman, Steven R. Kleeberger, and Michael A. Resnick http://jci.me/128626

Plasma deconvolution identifies broadly neutralizing antibodies associated with hepatitis C virus clearanceValerie J. Kinchen, Guido Massaccesi, Andrew I. Flyak, Madeleine C. Mankowski, Michelle D. Colbert, William O. Osburn, Stuart C. Ray, Andrea L. Cox, James E. Crowe Jr., and Justin R. Bailey http://jci.me/130720

metabolismHotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivationW. Brian Dalton, Eric Helmenstine, Noel Walsh, Lukasz P. Gondek, Dhanashree S. Kelkar, Abigail Read, Rachael Natrajan, Eric S. Christenson, Barbara Roman, Samarjit Das, Liang Zhao, Robert D. Leone, Daniel Shinn, Taylor Groginski, Anil K. Madugundu, Arun Patil, Daniel J. Zabransky, Arielle Medford, Justin Lee, Alex J. Cole, Marc Rosen, Maya Thakar, Alexander Ambinder, Joshua Donaldson, Amy E. DeZern, Karen Cravero, David Chu, Rafael Madero-Marroquin, Akhilesh Pandey, Paula J. Hurley, Josh Lauring, and Ben Ho Park (ASCI) http://jci.me/125022

Nuclear envelope–localized torsinA-LAP1 complex regulates hepatic VLDL secretion and steatosisJi-Yeon Shin, Antonio Hernandez-Ono, Tatyana Fedotova, Cecilia Östlund, Michael J. Lee, Sarah B. Gibeley, Chun-Chi Liang, William T. Dauer, Henry N. Ginsberg, and Howard J. Worman (ASCI) http://jci.me/129769

Regulation of hepatic mitochondrial oxidation by glucose-alanine cycling during starvation in humansKitt Falk Petersen, Sylvie Dufour, Gary W. Cline, and Gerald I. Shulman (ASCI) http://jci.me/129913

muscle biologyPeptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice p. 3Arnaud F. Klein, Miguel A. Varela, Ludovic Arandel, Ashling Holland, Naira Naouar, Andrey Arzumanov, David Seoane, Lucile Revillod, Guillaume Bassez, Arnaud Ferry, Dominic Jauvin, Genevieve Gourdon, Jack Puymirat, Michael J. Gait, Denis Furling, and Matthew J.A. Wood http://jci.me/128205

Recombinant annexin A6 promotes membrane repair and protects against muscle injuryAlexis R. Demonbreun, Katherine S. Fallon, Claire C. Oosterbaan, Elena Bogdanovic, James L. Warner, Jordan J. Sell, Patrick G. Page, Mattia Quattrocelli, David Y. Barefield, and Elizabeth M. McNally (ASCI) http://jci.me/128840

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nephrologyProximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses p. 4Seiji Kishi, Craig R. Brooks, Kensei Taguchi, Takaharu Ichimura, Yutaro Mori, Akinwande Akinfolarin, Navin Gupta, Pierre Galichon, Bertha C. Elias, Tomohisa Suzuki, Qian Wang, Leslie Gewin, Ryuji Morizane, and Joseph V. Bonventre (ASCI) http://jci.me/122313

Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury p. 4Purvi Mehrotra, Michael Sturek, Javier A. Neyra, and David P. Basile http://jci.me/126108

Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubuleFei Deng, Isha Sharma, Yingbo Dai, Ming Yang, and Yashpal S. Kanwar http://jci.me/129903

oncologyStromal integrin α11 regulates PDGFRβ signaling and promotes breast cancer progressionIrina Primac, Erik Maquoi, Silvia Blacher, Ritva Heljasvaara, Jan Van Deun, Hilde Y.H. Smeland, Annalisa Canale, Thomas Louis, Linda Stuhr, Nor Eddine Sounni, Didier Cataldo, Taina Pihlajaniemi, Christel Pequeux, Olivier De Wever, Donald Gullberg, and Agnès Noel http://jci.me/125890

cGAS/STING axis mediates a topoisomerase II inhibitor–induced tumor immunogenicityZining Wang, Jiemin Chen, Jie Hu, Hongxia Zhang, Feifei Xu, Wenzhuo He, Xiaojuan Wang, Mengyun Li, Wenhua Lu, Gucheng Zeng, Penghui Zhou, Peng Huang, Siyu Chen, Wende Li, Liang-ping Xia, and Xiaojun Xia http://jci.me/127471

Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytesAlena Gros, Eric Tran, Maria R. Parkhurst, Sadia Ilyas, Anna Pasetto, Eric M. Groh, Paul F. Robbins, Rami Yossef, Andrea Garcia-Garijo, Carlos A. Fajardo, Todd D. Prickett, Li Jia, Jared J. Gartner, Satyajit Ray, Lien Ngo, John R. Wunderllich, James C. Yang, and Steven A. Rosenberg http://jci.me/127967

DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance p. 3Katsuhiro Togami, Timothy Pastika, Jason Stephansky, Mahmoud Ghandi, Amanda L. Christie, Kristen L. Jones, Carl A. Johnson, Ross W. Lindsay, Christopher L. Brooks, Anthony Letai, Jeffrey W. Craig, Olga Pozdnyakova, David M. Weinstock, Joan Montero, Jon C. Aster, Cory M. Johannessen, and Andrew A. Lane http://jci.me/128571

ophthalmologyAngiopoietin-like 4 binds neuropilins and cooperates with VEGF to induce diabetic macular edema p. 2Akrit Sodhi, Tao Ma, Deepak Menon, Monika Deshpande, Kathleen Jee, Aumreetam Dinabandhu, Jordan Vancel, Daoyuan Lu, and Silvia Montaner http://jci.me/120879

AAV8-vectored suprachoroidal gene transfer produces widespread ocular transgene expressionKun Ding, Jikui Shen, Zibran Hafiz, Sean F. Hackett, Raquel Lima e Silva, Mahmood Khan, Valeria E. Lorenc, Daiqin Chen, Rishi Chadha, Minie Zhang, Sherri Van Everen, Nicholas Buss, Michele Fiscella, Olivier Danos, and Peter A. Campochiaro http://jci.me/129085

pulmonologyAirway epithelium–shifted mast cell infiltration regulates asthmatic inflammation via IL-33 signalingMatthew C. Altman, Ying Lai, James D. Nolin, Sydney Long, Chien-Chang Chen, Adrian M. Piliponsky, William A. Altemeier, Megan Larmore, Charles W. Frevert, Michael S. Mulligan, Steven F. Ziegler, Jason S. Debley, Michael C. Peters, and Teal S. Hallstrand http://jci.me/126402

reproductive biologyLymphatic mimicry in maternal endothelial cells promotes placental spiral artery remodelingJohn B. Pawlak, László Bálint, Lillian Lim, Wanshu Ma, Reema B. Davis, Zoltán Benyó, Michael J. Soares, Guillermo Oliver, Mark L. Kahn, Zoltán Jakus, and Kathleen M. Caron http://jci.me/120446

vascular biologyIntegrin α5β1 regulates PP2A complex assembly through PDE4D in atherosclerosisSanguk Yun, Rui Hu, Melanie E. Schwaemmle, Alexander N. Scherer, Zhenwu Zhuang, Anthony J. Koleske, David C. Pallas, and Martin A. Schwartz http://jci.me/127692

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jci.org/this-month

Tumor-resident mast cells promote anti-melanoma response 12

Fecal microbiota transplantation may introduce carcinogenic bacteria 12

Immune dysfunction underlies diabetes-associated MERS-CoV severity 12

Gene correction improves healing in recessive skin disease 13

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

November 2019

Viral oncogene drives bone loss in T cell leukemia p. 11

This Month

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Pilar Alcaide

John F. Alcorn

Maria-Luisa Alegre

Ravi K. Amaravadi

Cristian Apetrei

Rajendra S. Apte

Zoltan Arany

Hossein Ardehali

Julio Ayala

Sami J. Barmada

Alexander G. Bassuk

Vann Bennett

Sudha B. Biddinger

Jonathan S. Bogan

Laura M. Bohn

Nunzio Bottini

Sebastien G. Bouret

Jason Brenchley

Renier J. Brentjens

G.R. Scott Budinger

George A. Calin

Stephen Y. Chan

Timothy A. Chan

Yuan Chang

Benjamin K. Chen

Kang Chen

Zhou-Feng Chen

Wendy Chung

Matthew Ciorba

Janice E. Clements

Craig M. Coopersmith

George Cotsarelis

Peter A. Crawford

Lisa L. Cunningham

Jennifer Davis

Ronald P. DeMatteo

Madhav V. Dhodapkar

Elia J. Duh

Sarah K. England

Carmella Evans-Molina

Robert L. Fairchild

Eric R. Fearon

Brian Finck

John H. Fingert

Robert Flaumenhaft

Edward A. Fon

Lawrence Fong

Nikolaos G. Frangogiannis

Anthony R. French

Katherine A. Gallagher

Terrence L. Geiger

Raphaela Goldbach-Mansky

Daniel R. Goldstein

Douglas K. Graham

Johann E. Gudjonsson

Kirk Habegger

Khalid A. Hanafy

Eric B. Haura

John Cijiang He

Adam Steven Helms

Robert O. Heuckeroth

Cory M. Hogaboam

Young-Kwon Hong

Eric J. Huang

Benjamin D. Humphreys

Ken Inoki

Rajan Jain

Daniel P. Judge

J. Michelle Kahlenberg

Shingo Kajimura

Pawel Kalinski

Nobuhiko Kamada

Thomas W.H. Kay

Barbara I. Kazmierczak

Catherine E. Keegan

Hans-Peter Kiem

William Y. Kim

Frank Kirchhoff

David G. Kirsch

Jason S. Knight

Donald E. Kohan

Maria Kontaridis

Laura A. Kresty

Jongsoon Lee

Michael Lehrke

Claire E. Lewis

Mathias Lichterfeld

Rodger A. Liddle

André Lieber

Michail S. Lionakis

Ivan Maillard

Ziad Mallat

Peter Mannon

Eric Martens

Franck Mauvais-Jarvis

Linda McAllister-Lucas

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

David K. Meyerholz

Jason C. Mills

Joshua D. Milner

Satdarshan Paul Monga

Hidayatullah G. Munshi

William J. Murphy

Matthias Nahrendorf

Mary C. Nakamura

Lisa F.P. Ng

Mark Nicolls

Laura J. Niedernhofer

Una O’Doherty

S. Tiong Ong

Akira Ono

Puneet Opal

Olabisi Opeyemi

Daniel Ory

Sophie Paczesny

Rulan Parekh

Victoria N. Parikh

Mary-Elizabeth Patti

Janos Peti-Peterdi

Fernando P. Polack

Benjamin Prosser

Ling Qi

Dominic Raj

Jalees Rehman

Florian Rieder

Matthew D. Ringel

Howard A. Rockman

Steven M. Rowe

Linda C. Samuelson

Victoria L. Seewaldt

Svati H. Shah

Vijay H. Shah

Yatrik M. Shah

Vikram Shakkottai

Guo-Ping Shi

Kanakadurga Singer

Scott Soleimanpour

Rhonda F. Souza

Fayyaz S. Sutterwala

Shu Takeda

James E. Talmadge

Muneesh Tewari

John P. Thyfault

Natalie J. Torok

Stephen H. Tsang

Hubert M. Tse

Fumihiko Urano

Jolanda van der Velden

Deborah J. Veis

Charles P. Venditti

Claudio J. Villanueva

Joseph Vinetz

Stephanie M. Ware

Sing Sing Way

Kevin W. Williams

Minna Woo

Prescott G. Woodruff

Jing Yang

Tianxin Yang

Yiping Yang

Vincent B. Young

Lori M. Zeltser

Zhen Zhang

Yutong Zhao

Binhua P. Zhou

JCI Insight Consulting Editors

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For JCI InsightEditorKathleen CollinsDeputy EditorsAndrew Lieberman, Donna Martin, Pavan ReddyAssociate EditorsSharlene M. Day, Gregory R. Dressler, David A. Fox, Santhi Ganesh, John Y. Kao, Celina G. Kleer, Carey Lumeng, Lona Mody, Bethany B. Moore, Alexey Nesvizhskii, Marina Pasca di Magliano, Darleen Sandoval, Andrew Tai, Weiping ZouExecutive EditorSarah C. JacksonSenior Science EditorCorinne Williams

ASCI StaffExecutive DirectorJohn B. HawleyManaging DirectorKaren D. GuthAssociate DirectorMaya HoptmanAssociate Director, TechnologyShawn PyleProduction EditorsCatherine Ahmann, Ken Beauchamp, Molly Jean, Lara L. McCarronProduction AssistantKatherine A. BullenScientific IllustratorBruce WordenCopy EditorsClare Cross, Meredith Dimick, Barbara Fabyan, Rachel Nelson, Chet ProvodaAssociate Copy EditorsDarla Nagel, Megan ReilleyAssociate Editor, Copy and ProductionRachel BullenEditorial AssistantCady VishniacPublications CoordinatorMegan JenkinsSystem Administrator and DeveloperBryan EnglishSoftware DevelopersAustin Brewer, Jose L. JardonScience Communications SpecialistNeha AggarwalAccounts ManagerPaula KremidasAdministrative AssistantTheresa KaiserFigures CoordinatorKeith Kalinowski

This MonthNovember 2019

For JCI Insight online: jci.me/insight/4/19jci.me/insight/4/20

JCI Insight’s first Impact Factor: 6.014Read more about JCI Insight’s Impact Factor, reported in the 2018 Journal Citation Reports (June 2019): http://jci.me/muhtx

Andrew Lieberman, MD, PhD, Deputy Editor, is the Gerald D. Abrams Professor of Pathology and Director of Neuropathology at the University of Michigan Medical School. His research focuses on the mechanisms of neurodegeneration in inherited neurological disorders, including Niemann-Pick type C disease and spinal and bulbar muscular atrophy. He is a member of the American Society for Clinical Investigation.

Publication highlights

Nath SR, Yu Z, Gipson TA, Marsh GB, Yoshidome E, Robins DM, Todi SV, Housman DE, Lieberman AP. Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction. J Clin Invest. 2018;128(8):3630–3641.

Schultz ML, Krus KL, Kaushik S, Dang D, Chopra R, Qi L, Shakkottai VG, Cuervo AM, Lieberman AP. Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD. Nat Commun. 2018;9(1):3671.

Chua JP, Reddy SL, Yu Z, Giorgetti E, Montie HL, Mukherjee S, Higgins J, McEachin RC, Robins DM, Merry DE, Iñiguez-Lluhí JA, Lieberman AP. Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease. J Clin Invest. 2015;125(2):831–845.

Wang AM, Miyata Y, Klinedinst S, Peng HM, Chua JP, Komiyama T, Li X, Morishima Y, Merry DE, Pratt WB, Osawa Y, Collins CA, Gestwicki JE, Lieberman AP. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol. 2013;9(2):112–118.

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

Featured Editor

j c i . o r g / t h i s - m o n t h n o v e m b e r 2 0 1 911

Editor’s picks

on the jci insight cover bone biology

Understanding bone loss in adult T cell leukemia/lymphomaBone loss is a serious complication of adult T cell leukemia/lymphoma (ATL), an aggressive cancer caused by human T cell leukemia virus type 1 (HTLV-1). Jingyu Xiang, Daniel Rauch, Devra Huey, and colleagues investigated the role of HTLV-1 oncogenes in driving bone loss. In a humanized mouse model of ATL, the oncogene HBZ played only a minor role in the lympho proliferative disorder, but it was required for disease- induced bone loss. In human cell lines, HBZ indirectly drove overexpression of RANKL, a key factor known to regulate the development and

function of bone-resorbing osteoclasts. Furthermore, in the mouse model, treatment with denosumab, a monoclonal antibody targeting RANKL, prevented bone loss. These findings clarify the mechanism controlling bone loss in ATL and demonstrate the potential of denosumab to protect ATL patients from this compli cation. The cover image shows tartrate-resistant acid phosphatase (TRAP, pink) staining of osteo-clasts in the tibia of an HTLV-1 ΔHBZ–infected humanized mouse, which lacks the HBZ protein.

HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemiaJingyu Xiang, Daniel A. Rauch, Devra D. Huey, Amanda R. Panfil, Xiaogang Cheng, Alison K. Esser, Xinming Su, John C. Harding, Yalin Xu, Gregory C. Fox, Francesca Fontana, Takayuki Kobayashi, Junyi Su, Hemalatha Sundaramoorthi, Wing Hing Wong, Yizhen Jia, Thomas J. Rosol, Deborah J. Veis, Patrick L. Green, Stefan Niewiesk, Lee Ratner, and Katherine N. Weilbaecher (ASCI) http://jci.me/128713

metabolism

Intestinal GLP-1 does not account for improved glycemia after bariatric surgeryGlucagon-like peptide–1 (GLP-1), a hormone encoded by the preprogluca-gon (Gcg) gene, modulates systemic glucose homeostasis. The hormone is secreted from intestinal L cells in response to feeding and is believed to promote insulin secretion. Following vertical sleeve gastrectomy (VSG), a commonly performed weight-loss surgery, postprandial levels of GLP-1 rise, which may contribute to VSG-induced weight loss and improved glucose tolerance. However, recent research suggests that GLP-1 production from pancreatic islet cells, not the intestine, plays a dominant role in the effect of GLP-1 on glucose homeostasis. Ki-Suk Kim and colleagues used multiple mouse models to investigate the relevant source of GLP-1. Reactivation of Gcg specifically within the intestine normalized circulating GLP-1 in response

to a variety of nutrients and in response to VSG, supporting that the intestine is the source of systemic GLP-1 following VSG. However, intes-tine-derived GLP-1 was dispensable for glycemic improvements following the surgery. Thus, islet-derived GLP-1 may act in a paracrine manner to regulate glucose homeostasis even after bariatric surgery.

Glycemic effect of pancreatic preproglucagon in mouse sleeve gastrectomyKi-Suk Kim, Chelsea R. Hutch, Landon Wood, Irwin J. Magrisso, Randy J. Seeley, and Darleen A. Sandoval http://jci.me/129452

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JCI Insight | Editor’s picks

12

microbiology infectious disease

Unintended consequences of fecal transplantsFecal microbiota transplantation (FMT) is a life-saving treatment for individuals with recurrent C. difficile infection and is being explored as a treatment for other disorders, including ulcerative colitis. However, the long-term consequences of FMT are understudied, and FMT donors are not currently screened for all potentially carcinogenic bacterial species. Julia Drewes and colleagues collected samples from 11 pediatric patients with recurrent C. difficile infection and their FMT donors, and followed the patients for up to six months after FMT. In four cases, transmission of potentially carcinogenic bacterial species from donor to recipient was observed. Whole genome sequencing of the bacterial isolates from one patient confirmed that transmission occurred from donor to recipient, rather than from an environmental source. Conversely, two other patients demonstrated reduction or clearance of carcinogenic species after transplant. This study indicates that additional studies of the long-term outcomes of FMT are needed and that more extensive screening of FMT donors could be beneficial.

Transmission and clearance of potential procarcinogenic bacteria during fecal microbiota transplantation for recurrent Clostridioides difficileJulia L. Drewes, Alina Corona, Uriel Sanchez, Yunfan Fan, Suchitra K. Hourigan, Melissa Weidner, Sarah D. Sidhu, Patricia J. Simner, Hao Wang, Winston Timp, Maria Oliva-Hemker, and Cynthia L. Sears http://jci.me/130848

Diabetes worsens respiratory illness due to a dysregulated immune responseMiddle East respiratory syndrome coronavirus (MERS-CoV) is a severe respiratory infection that emerged in Saudi Arabia in 2012 and caused more than 800 deaths. Epidemiological studies identified comorbid illnesses, particularly diabetes, as risk factors for more severe or lethal outcome of MERS-CoV infection. Kristen Kulcsar and colleagues investigated the connection between diabetes and MERS-CoV in a mouse model, and discovered that although viral replication did not differ between diabetic and control mice, diabetic mice exhibited a delayed and prolonged inflammatory response in the lung. Diabetic mice had lower levels of inflammatory cytokines and fewer inflammatory macrophages and T cells. These results indicate that the increased severity of MERS-CoV infection in patients with comorbid diabetes is due to immune dysregulation.

Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infectionKirsten A. Kulcsar, Christopher M. Coleman, Sarah E. Beck, and Matthew B. Frieman http://jci.me/131774

immunology

Tumor-resident mast cells have potential as melanoma treatment targetImmune checkpoint inhibitors, such as anti–CTLA-4 and anti–PD-1, have emerged as powerful tools in the fight against cancer. However, a paradox predicts patient responses: those who develop adverse events related to the immunotherapy, such as colitis, are more likely to experience tumor regression. Susanne Kaesler and colleagues discovered that in patients with colitis, LPS leakage from the intestine activated a proinflammatory program. In a mouse model of melanoma, LPS activated mast cells in the tumor micro environment, which in turn secreted CXCL10 to recruit tumor-infiltrating T cells (TILs) to mediate regression of the tumor. TIL recruitment and melanoma control required CXCL10 expression in mast cells. In humans, spontaneous tumor regression correlated with mast cell infiltration (see the accompanying image),

and CXCL10 was a biomarker of improved patient survival. These data indicate the potential of targeting immune cells in the tumor microenvironment, such as mast cells, to improve current cancer therapies.

Targeting tumor-resident mast cells for effective anti-melanoma immune responsesSusanne Kaesler, Florian Wölbing, Wolfgang Eberhard Kempf, Yuliya Skabytska, Martin Köberle, Thomas Volz, Tobias Sinnberg, Teresa Amaral, Sigrid Möckel, Amir Yazdi, Gisela Metzler, Martin Schaller, Karin Hartmann, Benjamin Weide, Claus Garbe, Hans-Georg Rammensee, Martin Röcken, and Tilo Biederman http://jci.me/125057

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JCI Insight | Editor’s picks

dermatology

cardiology

Gene correction therapy shows promise for genetic skin disease

Coronary artery disease is not linked to increased epicardial adipose inflammationEpicardial adipose tissue (EAT) is a visceral fat deposit around the heart that increases in size proportionally with obesity. Previous studies in patients with coronary artery disease (CAD) reported that EAT exhibits higher expression of inflammatory genes and a denser inflammatory cell infiltrate than subcutaneous adipose tissue, leading to the hypothesis that inflammation of EAT may contribute to CAD. To determine whether this is the case, Timothy Fitzgibbons and colleagues compared the gene expression profile of EAT isolated from 13 patients with CAD to that of 13 patients without CAD. Although EAT had higher levels of inflammatory gene expression than subcutaneous adipose tissue as expected, there was no difference in inflammatory gene expression or macrophage infiltration between the EAT of cases and controls (see the accompanying image). In contrast, CAD was associated with decreased antiinflammatory gene expression in EAT. This indicates that the adipose tissue depot, rather than disease status, is the greatest determinant of gene expression pattern.

Coronary disease is not associated with robust alterations in inflammatory gene expression in human epicardial fatTimothy P. Fitzgibbons, Nancy Lee, Khanh-Van Tran, Sara Nicoloro, Mark Kelly, Stanley K.C. Tam, and Michael P. Czech http://jci.me/124859

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable skin disorder character-ized by recurrent and chronic wounds. It is caused by loss of function of COL7A1, which results in a lack of type VII collagen (C7). A team led by Jean Tang performed a phase 1/2a clinical trial to test the safety and efficacy of gene-corrected cell therapy for RDEB patients. Keratinocytes were isolated from seven patients, and then transduced with a retrovirus carrying full-length human COL7A1. The cells

were grown into epidermal sheets, grafted onto six wound sites on each patient, and followed over several years. Treated wounds showed markedly improved healing compared with untreated wounds (see accompanying image), and patients experienced less pain at treated sites with healing. Moreover, C7 expression persisted for at least two years. The approach was safe, with no serious adverse effects reported. This study supports the use of gene-corrected cell therapy for RDEB.

Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosaShaundra Eichstadt, Melissa Barriga, Anusha Ponakala, Claudia Teng, Ngon T. Nguyen, Zurab Siprashvili, Jaron Nazaroff, Emily S. Gorell, Albert S. Chiou, Lisa Taylor, Phuong Khuu, Douglas R. Keene, Kerri Rieger, Rohit K. Khosla, Louise K. Furukawa, H. Peter Lorenz, M. Peter Marinkovich, and Jean Y. Tang http://jci.me/130554

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Current articlesTargeting tumor-resident mast cells for effective anti-melanoma immune responses p. 12Susanne Kaesler, Florian Wölbing, Wolfgang Eberhard Kempf, Yuliya Skabytska, Martin Köberle, Thomas Volz, Tobias Sinnberg, Teresa Amaral, Sigrid Möckel, Amir Yazdi, Gisela Metzler, Martin Schaller, Karin Hartmann, Benjamin Weide, Claus Garbe, Hans-Georg Rammensee, Martin Röcken, and Tilo Biedermann http://jci.me/125057

miR-486 is modulated by stretch and increases ventricular growthStephan Lange, Indroneal Banerjee, Katrina Carrion, Ricardo Serrano, Louisa Habich, Rebecca Kameny, Luisa Lengenfelder, Nancy Dalton, Rudolph Meili, Emma Börgeson, Kirk Peterson, Marco Ricci, Joy Lincoln, Majid Ghassemian, Jeffery Fineman, Juan C. del Álamo, and Vishal Nigam http://jci.me/125507

Siglec-8 antibody reduces eosinophils and mast cells in a transgenic mouse model of eosinophilic gastroenteritisBradford A. Youngblood, Emily C. Brock, John Leung, Rustom Falahati, Bruce S. Bochner, Henrik S. Rasmussen, Kathryn Peterson, Christopher Bebbington, and Nenad Tomasevic http://jci.me/126219

The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in miceMarielle Breau, Amal Houssaini, Larissa Lipskaia, Shariq Abid, Emmanuelle Born, Elisabeth Marcos, Gabor Czibik, Aya Attwe, Delphine Beaulieu, Alberta Palazzo, Jean-Michel Flaman, Brigitte Bourachot, Guillaume Collin, Jeanne Tran Van Nhieu, David Bernard, Fatima Mechta-Grigoriou, and Serge Adnot http://jci.me/127647

Donor and host B7-H4 expression negatively regulates acute graft-versus-host disease lethalityAsim Saha, Patricia A. Taylor, Christopher J. Lees, Angela Panoskaltsis-Mortari, Mark J. Osborn, Colby J. Feser, Govindarajan Thangavelu, Wolfgang Melchinger, Yosef Refaeli, Geoffrey R. Hill, David H. Munn, William J. Murphy, Jonathan S. Serody, Ivan Maillard, Katharina Kreymborg, Marcel van den Brink, Chen Dong, Shuyu Huang, Xingxing Zang, James P. Allison, Robert Zeiser, and Bruce R. Blazar (ASCI) http://jci.me/127716

Fetal exposure to the maternal microbiota in humans and miceNoelle Younge, Jessica R. McCann, Julie Ballard, Catherine Plunkett, Suhail Akhtar, Félix Araújo-Pérez, Amy Murtha, Debra Brandon, and Patrick C. Seed http://jci.me/127806

TAFI deficiency causes maladaptive vascular remodeling after hemophilic joint bleedingTine Wyseure, Tingyi Yang, Jenny Y. Zhou, Esther J. Cooke, Bettina Wanko, Merissa Olmer, Ruchi Agashe, Yosuke Morodomi, Niels Behrendt, Martin Lotz, John Morser, Annette von Drygalski, and Laurent O. Mosnier http://jci.me/128379

HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia p. 11Jingyu Xiang, Daniel A. Rauch, Devra D. Huey, Amanda R. Panfil, Xiaogang Cheng, Alison K. Esser, Xinming Su, John C. Harding, Yalin Xu, Gregory C. Fox, Francesca Fontana, Takayuki Kobayashi, Junyi Su, Hemalatha Sundaramoorthi, Wing Hing Wong, Yizhen Jia, Thomas J. Rosol, Deborah J. Veis, Patrick L. Green, Stefan Niewiesk, Lee Ratner, and Katherine N. Weilbaecher (ASCI) http://jci.me/128713

Activity of hippocampal adult-born neurons regulates alcohol withdrawal seizuresDaehoon Lee, Balu Krishnan, Hai Zhang, Hee Ra Park, Eun Jeoung Ro, Yu-Na Jung, and Hoonkyo Suh http://jci.me/128770

KIAA0317 regulates pulmonary inflammation through SOCS2 degradationTravis B. Lear, Alison C. McKelvey, John W. Evankovich, Shristi Rajbhandari, Tiffany A. Coon, Sarah R. Dunn, James D. Londino, Bryan J. McVerry, Yingze Zhang, Eleanor Valenzi, Christine L. Burton, Rachael Gordon, Sebastien Gingras, Karina C. Lockwood, Michael J. Jurczak, Robert Lafyatis, Mark J. Shlomchik, Yuan Liu, and Bill B. Chen http://jci.me/129110

Loss of smooth muscle CYB5R3 amplifies angiotensin II–induced hypertension by increasing sGC heme oxidationBrittany G. Durgin, Scott A. Hahn, Heidi M. Schmidt, Megan P. Miller, Neha Hafeez, Ilka Mathar, Daniel Freitag, Peter Sandner, and Adam C. Straub http://jci.me/129183

Molecular determinants of response to high-dose androgen therapy in prostate cancerMichael D. Nyquist, Alexandra Corella, Osama Mohamad, Ilsa Coleman, Arja Kaipainen, Daniel A. Kuppers, Jared M. Lucas, Patrick J. Paddison, Stephen R. Plymate, Peter S. Nelson, and Elahe A. Mostaghel http://jci.me/129715

Resident memory CD8+ T cells within cancer islands mediate survival in breast cancer patientsColt A. Egelston, Christian Avalos, Travis Y. Tu, Anthony Rosario, Roger Wang, Shawn Solomon, Gayathri Srinivasan, Michael S. Nelson, Yinghui Huang, Min Hui Lim, Diana L. Simons, Ting-Fang He, John H. Yim, Laura Kruper, Joanne Mortimer, Susan Yost, Weihua Guo, Christopher Ruel, Paul H. Frankel, Yuan Yuan, and Peter P. Lee (ASCI) http://jci.me/130000

Linked dual-class HIV resistance mutations are associated with treatment failureValerie F. Boltz, Wei Shao, Michael J. Bale, Elias K. Halvas, Brian Luke, James A. McIntyre, Robert T. Schooley, Shahin Lockman, Judith S. Currier, Fred Sawe, Evelyn Hogg, Michael D. Hughes, Mary F. Kearney, John M. Coffin, and John W. Mellors http://jci.me/130118

Antisense regulation of atrial natriuretic peptide expressionSelvi Celik, Mardjaneh Karbalaei Sadegh, Michael Morley, Carolina Roselli, Patrick T. Ellinor, Thomas Cappola, J. Gustav Smith, and Olof Gidlöf http://jci.me/130978

Phase 1/2a clinical trial of gene-corrected autologous cell therapy for recessive dystrophic epidermolysis bullosa p. 13Shaundra Eichstadt, Melissa Barriga, Anusha Ponakala, Claudia Teng, Ngon T. Nguyen, Zurab Siprashvili, Jaron Nazaroff, Emily S. Gorell, Albert S. Chiou, Lisa Taylor, Phuong Khuu, Douglas R. Keene, Kerri Rieger, Rohit K. Khosla, Louise K. Furukawa, H. Peter Lorenz, M. Peter Marinkovich, and Jean Y. Tang http://jci.me/130554

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Current articles

Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinomaHaiquan Lu, Yang Lu, Yangyiran Xie, Songbo Qiu, Xinqun Li, and Zhen Fan http://jci.me/131106

Transmission and clearance of potential procarcinogenic bacteria during fecal microbiota transplantation for recurrent Clostridioides difficile p. 12Julia L. Drewes, Alina Corona, Uriel Sanchez, Yunfan Fan, Suchitra K. Hourigan, Melissa Weidner, Sarah D. Sidhu, Patricia J. Simner, Hao Wang, Winston Timp, Maria Oliva-Hemker, and Cynthia L. Sears http://jci.me/130848

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancerQiong Li, Yali Chen, Daoxiang Zhang, Julie Grossman, Lin Li, Namrata Khurana, Hongmei Jiang, Patrick M. Grierson, John Herndon, David G. DeNardo, Grant A. Challen, Jingxia Liu, Marianna B. Ruzinova, Ryan C. Fields, and Kian-Huat Lim http://jci.me/130867

Roux-en-Y gastric bypass surgery progressively alters radiologic measures of hypothalamic inflammation in obese patientsMohammed K. Hankir, Michael Rullmann, Florian Seyfried, Sven Preusser, Sindy Poppitz, Stefanie Heba, Konstantinos Gousias, Jana Hoyer, Tatjana Schütz, Arne Dietrich, Karsten Müller, and Burkhard Pleger http://jci.me/131329

Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryasTeresa Vanessa Fiorentino, Francesca Casiraghi, Alberto M. Davalli, Giovanna Finzi, Stefano La Rosa, Paul B. Higgins, Gregory A. Abrahamian, Alessandro Marando, Fausto Sessa, Carla Perego, Rodolfo Guardado-Mendoza, Subhash Kamath, Andrea Ricotti, Paolo Fiorina, Giuseppe Daniele, Ana M. Paez, Francesco Andreozzi, Raul A. Bastarracea, Anthony G. Comuzzie, Amalia Gastaldelli, Alberto O. Chavez, Eliana S. Di Cairano, Patrice Frost, Livio Luzi, Edward J. Dick, Glenn A. Halff, Ralph A. DeFronzo, and Franco Folli http://jci.me/93091

Muscarinic receptors promote pacemaker fate at the expense of secondary conduction system tissue in zebrafishMartina S. Burczyk, Martin D. Burkhalter, Teresa Casar Tena, Laurel A. Grisanti, Michael Kauk, Sabrina Matysik, Cornelia Donow, Monika Kustermann, Melanie Rothe, Yinghong Cui, Farah Raad, Svenja Laue, Allessandra Moretti, Wolfram-H. Zimmermann, Jürgen Wess, Michael Kühl, Carsten Hoffmann, Douglas G. Tilley, and Melanie Philipp http://jci.me/121971

Mss51 deletion enhances muscle metabolism and glucose homeostasis in miceYazmin I. Rovira Gonzalez, Adam L. Moyer, Nicolas J. LeTexier, August D. Bratti, Siyuan Feng, Congshan Sun, Ting Liu, Jyothi Mula, Pankhuri Jha, Shama R. Iyer, Richard Lovering, Brian O’Rourke, Hye Lim Noh, Sujin Suk, Jason K. Kim, George K. Essien Umanah, and Kathryn R. Wagner (ASCI) http://jci.me/122247

Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesisKarl Katholnig, Birgit Schütz, Stephanie D. Fritsch, David Schörghofer, Monika Linke, Nyamdelger Sukhbaatar, Julia M. Matschinger, Daniela Unterleuthner, Martin Hirtl, Michaela Lang, Merima Herac, Andreas Spittler, Andreas Bergthaler, Gernot Schabbauer, Michael Bergmann, Helmut Dolznig, Markus Hengstschläger, Mark A. Magnuson, Mario Mikula, and Thomas Weichhart http://jci.me/124164

A role for placental kisspeptin in β cell adaptation to pregnancyJames E. Bowe, Thomas G. Hill, Katharine F. Hunt, Lorna I.F. Smith, Sian J.S. Simpson, Stephanie A. Amiel, and Peter M. Jones http://jci.me/124540

Coronary disease is not associated with robust alterations in inflammatory gene expression in human epicardial fat p. 13Timothy P. Fitzgibbons, Nancy Lee, Khanh-Van Tran, Sara Nicoloro, Mark Kelly, Stanley K.C. Tam, and Michael P. Czech http://jci.me/124859

CD83 orchestrates immunity toward self and non-self in dendritic cellsAndreas B. Wild, Lena Krzyzak, Katrin Peckert, Lena Stich, Christine Kuhnt, Alina Butterhof, Christine Seitz, Jochen Mattner, Niklas Grüner, Maximilian Gänsbauer, Martin Purtak, Didier Soulat, Thomas H. Winkler, Lars Nitschke, Elisabeth Zinser, and Alexander Steinkasserer http://jci.me/126246

miR-511-3p protects against cockroach allergen–induced lung inflammation by antagonizing CCL2Danh C. Do, Jie Mu, Xia Ke, Karan Sachdeva, Zili Qin, Mei Wan, Faoud T. Ishmael, and Peisong Gao http://jci.me/126832

DNA replication in progenitor cells and epithelial regeneration after lung injury requires the oncoprotein MDM2Shilpa Singh, Catherine A. Vaughan, Christopher Rabender, Ross Mikkelsen, Sumitra Deb, and Swati Palit Deb http://jci.me/128194

Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imagingCurt Mazur, Berit Powers, Kenneth Zasadny, Jenna M. Sullivan, Hemi Dimant, Fredrik Kamme, Jacob Hesterman, John Matson, Michael Oestergaard, Marc Seaman, Robert W. Holt, Mohammed Qutaish, Ildiko Polyak, Richard Coelho, Vijay Gottumukkala, Carolynn M. Gaut, Marc Berridge, Nazira J. Albargothy, Louise Kelly, Roxana O. Carare, Jack Hoppin, Holly Kordasiewicz, Eric E. Swayze, and Ajay Verma http://jci.me/129240

Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndromeGiovanni A. Carosso, Leandros Boukas, Jonathan J. Augustin, Ha Nam Nguyen, Briana L. Winer, Gabrielle H. Cannon, Johanna D. Robertson, Li Zhang, Kasper D. Hansen, Loyal A. Goff, and Hans T. Bjornsson http://jci.me/129375

Glycemic effect of pancreatic preproglucagon in mouse sleeve gastrectomy p. 11Ki-Suk Kim, Chelsea R. Hutch, Landon Wood, Irwin J. Magrisso, Randy J. Seeley, and Darleen A. Sandoval http://jci.me/129452

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Precocious chondrocyte differentiation disrupts skeletal growth in Kabuki syndrome miceJill A. Fahrner, Wan-Ying Lin, Ryan C. Riddle, Leandros Boukas, Valerie B. DeLeon, Sheetal Chopra, Susan E. Lad, Teresa Romeo Luperchio, Kasper D. Hansen, and Hans T. Bjornsson http://jci.me/129380

Progenitor-derived human endothelial cells evade alloimmunity by CRISPR/Cas9-mediated complete ablation of MHC expressionJonathan Merola, Melanie Reschke, Richard W. Pierce, Lingfeng Qin, Susann Spindler, Tania Baltazar, Thomas D. Manes, Francesc Lopez-Giraldez, Guangxin Li, Laura G. Bracaglia, Catherine Xie, Nancy Kirkiles-Smith, W. Mark Saltzman, Gregory T. Tietjen, George Tellides, and Jordan S. Pober http://jci.me/129739

PD-1hiCXCR5– T peripheral helper cells promote B cell responses in lupus via MAF and IL-21Alexandra V. Bocharnikov, Joshua Keegan, Vanessa S. Wacleche, Ye Cao, Chamith Y. Fonseka, Guoxing Wang, Eric S. Muise, Kelvin X. Zhang, Arnon Arazi, Gregory Keras, Zhihan J. Li, Yujie Qu, Michael F. Gurish, Accelerating Medicines Partnership (AMP) RA/SLE Network, Michelle Petri, Jill P. Buyon, Chaim Putterman, David Wofsy, Judith A. James, Joel M. Guthridge, Betty Diamond, Jennifer H. Anolik, Matthew F. Mackey, Stephen E. Alves, Peter A. Nigrovic, Karen H. Costenbader, Michael B. Brenner, James A. Lederer, and Deepak A. Rao http://jci.me/130062

MicroRNA-7a overexpression in VMH restores the sympathoadrenal response to hypoglycemiaRahul Agrawal, Griffin Durupt, Dinesh Verma, Michael Montgomery, Adriana Vieira-de Abreu, Casey Taylor, Sankar Swaminathan, and Simon J. Fisher (ASCI) http://jci.me/130521

Region-specific parasympathetic nerve remodeling in the left atrium contributes to creation of a vulnerable substrate for atrial fibrillationGeorg Gussak, Anna Pfenniger, Lisa Wren, Mehul Gilani, Wenwei Zhang, Shin Yoo, David A. Johnson, Amy Burrell, Brandon Benefield, Gabriel Knight, Bradley P. Knight, Rod Passman, Jeffrey J. Goldberger, Gary Aistrup, J. Andrew Wasserstrom, Yohannes Shiferaw, and Rishi Arora http://jci.me/130532

Efficient ADCC killing of meningioma by avelumab and a high-affinity natural killer cell line, haNKAmber J. Giles, Shuyu Hao, Michelle Padget, Hua Song, Wei Zhang, John Lynes, Victoria Sanchez, Yang Liu, Jinkyu Jung, Xiaoyu Cao, Rika Fujii, Randy Jensen, David Gillespie, Jeffrey Schlom, Mark R. Gilbert, Edjah K. Nduom, Chunzhang Yang, John H. Lee, Patrick Soon-Shiong, James W. Hodge, and Deric M. Park http://jci.me/130688

βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac functionNehal J. Patel, Drew M. Nassal, Amara D. Greer-Short, Sathya D. Unudurthi, Benjamin W. Scandling, Daniel Gratz, Xianyao Xu, Anuradha Kalyanasundaram, Vadim V. Fedorov, Federica Accornero, Peter J. Mohler, Keith J. Gooch, and Thomas J. Hund http://jci.me/131046

Alveolar macrophage secretion of vesicular SOCS3 represents a platform for lung cancer therapeuticsJennifer M. Speth, Loka R. Penke, Joseph D. Bazzill, Kyung Soo Park, Rafael Gil de Rubio, Daniel J. Schneider, Hideyasu Ouchi, James J. Moon, Venkateshwar G. Keshamouni, Rachel L. Zemans, Vibha N. Lama, Douglas A. Arenberg, and Marc Peters-Golden (ASCI) http://jci.me/131340

STAT6/Arg1 promotes microglia/macrophage efferocytosis and inflammation resolution in stroke miceWei Cai, Xuejiao Dai, Jie Chen, Jingyan Zhao, Mingyue Xu, Lili Zhang, Boyu Yang, Wenting Zhang, Marcelo Rocha, Toshimasa Nakao, Julia Kofler, Yejie Shi, R. Anne Stetler, Xiaoming Hu, and Jun Chen http://jci.me/131355

Activation of pruritogenic TGR5, MrgprA3, and MrgprC11 on colon-innervating afferents induces visceral hypersensitivityJoel Castro, Andrea M. Harrington, TinaMarie Lieu, Sonia Garcia-Caraballo, Jessica Maddern, Gudrun Schober, Tracey O’Donnell, Luke Grundy, Amanda L. Lumsden, Paul Miller, Andre Ghetti, Martin S. Steinhoff, Daniel P. Poole, Xinzhong Dong, Lin Chang, Nigel W. Bunnett, and Stuart M. Brierley http://jci.me/131712

Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection p. 12Kirsten A. Kulcsar, Christopher M. Coleman, Sarah E. Beck, and Matthew B. Frieman http://jci.me/131774

perspectivesThe national MD-PhD program outcomes study: Relationships between medical specialty, training duration, research effort, and career pathsLawrence F. Brass (ASCI) and Myles H. Akabas http://jci.me/133009

The national MD-PhD program outcomes study: Outcomes variation by sex, race, and ethnicityMyles H. Akabas and Lawrence F. Brass (ASCI) http://jci.me/133010

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