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ALSO IN THIS ISSUE:

Optogenetic blockade of ventricular arrhythmia 3

Context-specific activation of mast cell responses 4

Review Series: Hypoxia and inflammation edited by M. Celeste Simon 7

JCI Insight 12

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October 2016

Endogenous NET inhibitors p. 1

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This MonthOctober 2016

Peptide inhibitors of neutrophil extracellular trap formation

On the JCI cover

Neutrophil extracellular traps (NETs) are extracellular fibers of decon-densed chromatin generated from a specialized form of neutrophil death. NETs are thought to play a comple-mentary role in the traditional antimi-crobial activities of neutrophils, but there is also evidence that NETs con-tribute to pathological inflammation and immune-related dysfunction. Previous work has shown that NET formation is blunted in neutrophils from umbilical cord blood, possibly as an immunomodulatory mecha-nism facilitating transition from the sterile intrauterine environment. In this issue, work by Christian Yost and

colleagues identified a peptide in umbilical cord blood that inhibits NET forma-tion in neutrophils isolated from neonates and adults. By serially monitoring NET formation in premature neonates, they isolated a neonatal NET inhibitory factor (nNIF) present immediately after birth. nNIF and related peptides iden-tified by homology selectively reduced NET formation without altering other key responses in adult neutrophils. Treatment with the peptides also effectively reduced tissue damage and mortality in mouse models of E. coli–, LPS-, and CLP-induced inflammation. These findings suggest that neonatal NET-inhibi-tory peptides may have therapeutic value for blunting pathological NET formation in inflammatory conditions. The cover image shows NET formation by LPS-stimulated neutrophils isolated from a 3-day-old preterm infant. Image credit: Diana Lim.

Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formationChristian C. Yost, Hansjörg Schwertz, Mark J. Cody, Jared A. Wallace, Robert A. Campbell, Adriana Vieira-de-Abreu, Claudia V. Araujo, Sebastian Schubert, Estelle S. Harris, Jesse W. Rowley, Matthew T. Rondina, James M. Fulcher, Curry L. Koening, Andrew S. Weyrich, and Guy A. Zimmerman http://jci.me/83873

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research

Editor’s picks

Interruption of progerin–lamin A/C interactions reduces Hutchinson-Gilford progeria syndrome phenotypeHutchinson-Gilford progeria syndrome (HGPS) is a rare genetic condition characterized by the onset of rapid aging during childhood. It is caused by a mutation in the gene encoding lamin A/C that produces an alternatively spliced protein called progerin. Su-Jin Lee, Youn-Sang Jung, and colleagues observed that interactions between progerin and lamin A/C induce an abnormal formation of nuclear lamina that resembles HGPS cellular phenotypes (see the accompanying image). They then used a screening assay to identify 3 compounds that block progerin–lamin A/C binding. These compounds effectively reduced nuclear deformation and senescence markers in HGPS model cells. Moreover, one of the compounds markedly improved the progeria phenotype and lifespan in mice expressing the HGPS mutation. This work has identified a promising therapeutic approach to treating HGPS as well as other aging-related disorders.

Interruption of progerin–lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotypeSu-Jin Lee, Youn-Sang Jung, Min-Ho Yoon, So-mi Kang, Ah-Young Oh, Jee-Hyun Lee, So-Young Jun, Tae-Gyun Woo, Ho-Young Chun, Sang Kyum Kim, Kyu Jin Chung, Ho-Young Lee, Kyeong Lee, Guanghai Jin, Min-Kyun Na, Nam Chul Ha, Clea Bárcena, José M.P. Freije, Carlos López-Otín, Gyu Yong Song, and Bum-Joon Park http://jci.me/84164

agingoncology

Targeting enhanced mitochondrial function in RB1-deficient triple-negative breast cancerNo specific treatments are available for triple-negative breast cancer (TNBC), a tumor subtype that lacks expression of estrogen, progesterone, and human EGFR 2 (HER2) receptors. Although TNBC tumors frequently lose retinoblastoma 1 tumor suppressor (RB1), together with TP53, the involve-ment of RB1 in a number of cellular processes makes it difficult to target directly. The Zacksenhaus laboratory and colleagues looked at downstream pathways that are modified when both Rb1 and p53 are deleted in TNBC-like mouse tumors and determined that the combined deletion upregulates the mitochondrial protein translation (MPT) pathway. Furthermore, they identified an FDA-approved drug, tigecycline, that blocks MPT function and attenuates the growth of RB1-mutant TNBC xenografts in immune-compromised mice. These findings suggest that RB1-deficient tumor growth is driven by enhanced mitochondrial function and support the study of MPT inhibitors as a potential treatment for TNBC.

RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translationRobert A. Jones, Tyler J. Robinson, Jeff C. Liu, Mariusz Shrestha, Veronique Voisin, YoungJun Ju, Philip E.D. Chung, Giovanna Pellecchia, Victoria L. Fell, SooIn Bae, Lakshmi Muthuswamy, Alessandro Datti, Sean E. Egan, Zhe Jiang, Gustavo Leone, Gary D. Bader, Aaron Schimmer, and Eldad Zacksenhaus http://jci.me/81568

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JCI | Research: Editor’s picks

At the heart of atrial contractionCalcium-induced calcium release is a key mediator of excitation-contraction coupling in heart. Ventricular myocytes possess a high density of transverse tubules, which propagate the action potential that drives calcium release uniformly throughout the cell during each heart beat. In contrast, atrial myocytes have relatively few or no transverse tubules and are characterized by distinct calcium signatures. Stephan Lehnart and colleagues now describe a membrane structure, composed of axial tubules adjacent to sarcoplasmic reticulum membrane junctions containing ryanodine receptors (RyR2), that rapidly activates atrial myocyte contraction through central RyR2 clusters. This “super-hub” structure was shown to locally regulate calcium-induced calcium release and contractile function through constitutively increased RyR2 phosphorylation. In mice with atrial hypertrophy, atrial myocytes exhibited an increase in super-hubs and accelerated calcium release that may contribute to impaired contractile function. In the accompanying Commentary, Thomas Hund and Peter Mohler discuss how these studies provide a new understanding of the unique mechanism of excitation-contraction coupling in atrial myocytes.

Axial tubule junctions control rapid calcium signaling in atriaSören Brandenburg, Tobias Kohl, George S.B. Williams, Konstantin Gusev, Eva Wagner, Eva A. Rog-Zielinska, Elke Hebisch, Miroslav Dura, Michael Didié, Michael Gotthardt, Viacheslav O. Nikolaev, Gerd Hasenfuss, Peter Kohl, Christopher W. Ward, W. Jonathan Lederer, and Stephan E. Lehnart http://jci.me/88241

Related CommentaryAtrial-specific pathways for control of intracellular signaling and myocyte functionThomas J. Hund and Peter J. Mohler http://jci.me/90348

Testing the translational potential of optogenetic heart defibrillationPatients at risk for ventricular arrhythmias receive heart defibrillator implants that terminate arrhythmia by delivering electrical shocks to cardiac tissue. Because electrical shocks often damage heart tissue, Tobias Bruegmann, Patrick Boyle, and colleagues explored optogenetic stimulation as a potential alternative for terminating ventricular arrhythmias. They expressed the light-sensitive cation channel channelrhodopsin-2 (ChR2) in the hearts of mice and determined that delivering single pulses of light to cardiac tissue was sufficient to terminate electrically induced arrhythmias. They further characterized the use of optogenetic stimulations in a clinically validated in silico model of human hearts, showing that ChR2-mediated

depolarization of heart tissue causes inactivation of voltage-gated sodium channels that prevents the propagation of ongoing arrhythmias. This work suggests that optogenetic defibrillation may have translational potential as a nondamaging alternative to electrical defibrillation.

Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulationsTobias Bruegmann, Patrick M. Boyle, Christoph C. Vogt, Thomas V. Karathanos, Hermenegild J. Arevalo, Bernd K. Fleischmann, Natalia A. Trayanova, and Philipp Sasse http://jci.me/88950

cardiology

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

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JCI | Research: Editor’s picks

Loss of Wiskott-Aldrich syndrome protein in Tregs exacerbates food allergy

In Wiskott-Aldrich syndrome (WAS), loss of function in the WAS protein (WASP) leads to both immunodeficiency and a predisposition to autoimmune conditions. Drawing from the observation that a high number of WAS patients experience increased sensitization to food allergens, Willem Lexmond, Jeremy Goettel, Jonathan Lyons, and coworkers investigated the link between IgE levels and food allergy in a WASP-deficient mouse model. They found that WASP-deficient mice experienced spontaneous sensitization to food antigens, particularly wheat and soy. Limiting WASP deficiency to FOXP3+ Tregs exacerbated allergic inflammation in the small intestine relative to global WASP deficiency (see the associated image), suggesting a cell-specific role for WASP in controlling inflammatory immune responses. In the accompanying Commentary, Yun Liang and Johann Gudjonsson reflect on how these findings may inform future therapeutic approaches for allergic conditions.

FOXP3+ Tregs require WASP to restrain Th2-mediated food allergyWillem S. Lexmond, Jeremy A. Goettel, Jonathan J. Lyons, Justin Jacobse, Marion M. Deken, Monica G. Lawrence, Thomas H. DiMaggio, Daniel Kotlarz, Elizabeth Garabedian, Paul Sackstein, Celeste C. Nelson, Nina Jones, Kelly D. Stone, Fabio Candotti, Edmond H.H.M. Rings, Adrian J. Thrasher, Joshua D. Milner, Scott B. Snapper, and Edda Fiebiger http://jci.me/85129

immunology

Stimuli-specific mast cell degranulation strategies associate with distinct inflammatory responsesMast cells secrete granules that perform a number of physiological and pathological functions, ranging from enhancing resistance to venoms and parasites to allergic reactions and anaphylaxis. Using dynamic imaging to follow mast cells undergoing degranula-tion, Nicolas Gaudenzio and coworkers determined that mast cells secrete granules in different temporal and spatial patterns in response to the activation

signals anti-IgE and substance P (see the associated image). Pharmacological evidence indicated that the degranulation pattern associated with anti-IgE was regulated via an IKK-β–dependent mechanism, whereas substance P–induced granule secretion was IKK-β independent. Moreover, these degranulation patterns had differential effects on granule transportation and persistence in draining lymph

nodes, suggesting a functional role for stimuli-specific mast cell responses. In the accompanying Commen-tary, Jörn Karhausen and Soman Abraham discuss the finding that mast cells produce distinct degranulation patterns in response to different stimuli.

Different activation signals induce distinct mast cell degranulation strategiesNicolas Gaudenzio, Riccardo Sibilano, Thomas Marichal, Philipp Starkl, Laurent L. Reber, Nicolas Cenac, Benjamin D. McNeil, Xinzhong Dong, Joseph D. Hernandez, Ronit Sagi-Eisenberg, Ilan Hammel, Axel Roers, Salvatore Valitutti, Mindy Tsai, Eric Espinosa, and Stephen J. Galli http://jci.me/85538

Related CommentaryHow mast cells make decisionsJörn Karhausen and Soman N. Abraham http://jci.me/90361

Related CommentaryWASP, Tregs, and food allergies — rare disease provides insight into a common problemYun Liang and Johann E. Gudjonsson http://jci.me/90198

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JCI | Research: Editor’s picks

immunology

TGF-β signaling limits CD4 T cell responses during chronic infectionChronic viral infections suppress T cell populations and functions, producing detrimental effects on immune responses to ongoing and future infections. Although increased TGF-β signaling in immune cells is associated with chronic hepatitis C and HIV infections, whether this signaling contributes to T cell suppression is not well understood. Gavin Lewis and colleagues assessed the role of TGF-β signaling in T cells in mouse models of chronic infection and CD4 T cells from HIV-infected patients. Ablating TGF-β receptor 2 enhanced CD4 T cell proliferation and differentiation and increased the expression of the cytotoxic gene program, including the transcrip-tion factor eomesodermin. Overexpres-sion of eomesodermin recapitulated the CD4 T cell phenotype, suggesting that TGF-β–dependent effects occur through suppression of this transcription factor. TGF-β also suppressed eomesodermin and cytotoxic molecules in HIV-specific CD4 T cells. Together, these data identify an eomesodermin-driven pathway that is restricted by TGF-β to limit CD4 T cell proliferation and function during chronic infections.

TGF-β receptor maintains CD4 T helper cell identity during chronic viral infectionsGavin M. Lewis, Ellen J. Wehrens, Lara Labarta-Bajo, Hendrik Streeck, and Elina I. Zuniga http://jci.me/87041

hematology

Sensitivity to mitochondrial-mediated apoptosis predicts chemoresistance in myeloid tumor cellsChemotherapy-resistant tumors may arise from the selective survival of chemoresistant cell subpopulations in the pretreatment tumor. Characterizing these subpopulations prior to treatment could provide important insights about the mechanisms that underlie therapeutic resistance. Patrick Bhola and colleagues hypoth-esized that tumors resistant to first-line chemotherapies for acute myeloid leukemia (AML) derive from subpopulations of cells that are insensitive to mitochondrial-mediated apoptosis prior to treatment. They developed a functional single-cell assay to determine a tumor cell’s sensitivity to mitochondrial-mediated apoptosis (see the accompanying image). They found that this sensitivity is heterogeneous among tumor cells in human AML myeloblasts. In AML patients, the most apoptosis-insensitive tumor cells were the best predictors of patient response to first-line chemotherapies. This work demonstrates a method to identify chemoresistant tumor cells prior to therapeutic intervention, which may lead to key clinical insights about chemoresistance in AML and other hematologic cancers.

Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemiaPatrick D. Bhola, Brenton G. Mar, R. Coleman Lindsley, Jeremy A. Ryan, Leah J. Hogdal, Thanh Trang Vo, Daniel J. DeAngelo, Ilene Galinsky, Benjamin L. Ebert, and Anthony Leta http://jci.me/82908

Erythroid cell–specific silencing of BCL11A induces fetal hemoglobin productionInducing fetal hemoglobin production in adults is a strategy that has recently been explored for the treatment of sickle cell disease and other β-hemoglobin–associated diseases. The fetal-to-adult hemoglobin switch in humans is regulated by BCL11A, a transcription factor that is also required for B lymphocyte development. Christian Brendel, Swaroopa Guda, and colleagues silenced BCL11A with an erythroid cell– specific microRNA-embedded shRNA and demonstrated that the treatment successfully induced fetal hemoglobin in human erythroid cells. Moreover, transplantation of Bcl11a shRNA–modified hematopoietic stem cells ameliorated the sickle-associated phenotype in a murine model of the disease. These findings suggest that inducing fetal hemoglobin using targeted shRNA knockdown of BCL11A is a potential therapy for β-hemoglobin–associated disorders.

Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotypeChristian Brendel, Swaroopa Guda, Raffaele Renella, Daniel E. Bauer, Matthew C. Canver, Young-Jo Kim, Matthew M. Heeney, Denise Klatt, Jonathan Fogel, Michael D. Milsom, Stuart H. Orkin, Richard I. Gregory, and David A. Williams http://jci.me/87885

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JCI | Research: Editor’s picks

autoimmunity

Dual defects in immune tolerance checkpoints drive organ-specific autoimmunity

Angiotensin II modulation prevents brain endothelial disruption in malariaCerebral malaria is a severe complication of malaria infection that is characterized by the disruption of endothelial cell integrity at the blood-brain barrier. Research conducted by Julio Gallego-Delgado and colleagues determined that P. falciparum–infected red blood cells (Pf-iRBC) disrupt endothelial cell junctions in a process that requires angiotensin II–mediated β-catenin activation. Using angiotensin II–specific drugs that are either currently available or in clinical development, they demonstrated that modulating angiotensin II receptors prevented Pf-iRBC–induced β-catenin activation, which prevented detachment and disruption in endothelial cells (see the accompanying image). Furthermore, these drugs reduced the incidence of cerebral malaria in a murine model. In the associated Commentary, Jens Petersen et al. discuss the therapeutic potential of targeting angiotensin II signaling as a preventive treatment for cerebral malaria.

Angiotensin receptors and β-catenin regulate brain endothelial integrity in malariaJulio Gallego-Delgado, Upal Basu-Roy, Maureen Ty, Matilde Alique, Cristina Fernandez-Arias, Alexandru Movila, Pollyanna Gomes, Ada Weinstock, Wenyue Xu, Innocent Edagha, Samuel C. Wassmer, Thomas Walther, Marta Ruiz-Ortega, and Ana Rodriguez http://jci.me/87306

Related CommentaryBreaking down brain barrier breaches in cerebral malariaJens E.V. Petersen, Thomas Lavstsen, and Alister Craig http://jci.me/90188

infectious disease

Many autoimmune diseases are linked to multiple genetic defects in immune checkpoints that underlie tolerance mechanisms. Individuals with mutations in the autoimmune regulator gene AIRE develop multiple organ-specific autoimmunity that varies in penetrance and type of tissue affected, suggesting that defects in AIRE may synergize with other checkpoint mutations to promote autoimmune disease in specific tissues. Irina Proekt and colleagues investigated whether an Aire point mutation could drive organ-specific autoimmunity when coupled to LYN deficiency. On its own, LYN deficiency is associated with systemic lupus-like phenotypes in mice. However, LYN-deficient mice expressing mutant Aire developed progressive uveitis (see the accompanying image), which was linked to the presence of retinal antigen-specific T cells that were primed by hyperactive LYN-deficient dendritic cells. Combined loss of AIRE and LYN function enabled the T cells to escape both thymic and peripheral tolerance checkpoints, leading to the destructive autoimmune response in the eye. These results provide evidence for multigenic interactions between distinct tolerance pathways in the pathogen-esis of organ-specific autoimmunity.

LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunityIrina Proekt, Corey N. Miller, Marion Jeanne, Kayla J. Fasano, James J. Moon, Clifford A. Lowell, Douglas B. Gould, Mark S. Anderson, and Anthony L. DeFranco http://jci.me/84440

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JCI Review Series

Hypoxia and inflammation

Inflammation is a primary response to injury and or infection, allow-ing the body to eliminate pathogens and/or damaged tissue and to initiate repair processes. Low oxygen levels, or hypoxia, is a key fea-ture of inflamed tissue and is due to damage to the local vasculature and increased oxygen consumption by pathogens and infiltrating immune cells. In addition to being a feature of inflammation, hypoxia also induces and regulates the inflammatory response by inducing the release of inflammatory cytokines, directing immune cell infiltra-tion, and tuning the responses of the immune cells themselves. These effects are primarily mediated by a family of hypoxia-inducible tran-scription factors (HIFs) that regulates cellular responses to inadequate oxygenation. HIFs and their regulatory factors are now emerging as therapeutic targets in a number of disease states. Reviews in this series discuss the roles of hypoxia and HIFs in the regulation of inflammatory pathways, immune cell metabolism, mucosal inflammation, the tumor microenvironment, intestinal inflammation and colorectal cancer, and recovery from radiation-induced gastrointestinal toxicity. Together, these Reviews identify a number of hypoxia-regulated processes that could potentially be targeted to modulate inflammation.

Hypoxia-inducible factors: key regulators of myeloid cells during inflammationNan Lin and M. Celeste Simon http://jci.me/84426

Dr. M. Celeste Simon is the scientific director of the Abramson Family Cancer Research Institute and a professor in the Department of Cell and Developmental Biology at the University of Penn-sylvania Perelman School of Medicine. She obtained her PhD in Biochemistry from Rockefeller University in 1985 and conducted postdoctoral research in the lab of Dr. Stuart Orkin, using mouse embryonic stem cells to study hematopoietic development. She became an investigator of the Howard Hughes Medical Institute in 1994. Dr. Simon showed that the transcription factor PU.1 is essential for the development of different immune cell lineages. She then turned her attention to the role of oxygen availability in regulating hematopoiesis and angiogenesis and demonstrated that HIFs are required for proper development of blood cells, blood vessels, the placenta, and the heart in the developing embryo. Currently, her laboratory studies cancer cell metabolism, tumor immunology, metastasis, and cellular responses to oxygen deprivation.

A role for oxygen sensing in inflammationSeries Editor: M. Celeste Simon

The impact of hypoxia on tumor-associated macrophagesAnne-Theres Henze and Massimiliano Mazzone http://jci.me/84427

Oxygen metabolism and barrier regulation in the intestinal mucosaLouise E. Glover, J. Scott Lee, and Sean P. Colgan http://jci.me/84429

Hypoxia-inducible factors: a central link between inflammation and cancerDaniel Triner and Yatrik M. Shah http://jci.me/84430

HIF1α and metabolic reprogramming in inflammationSarah E. Corcoran and Luke A.J. O’Neill http://jci.me/84431

Reducing radiation-induced gastrointestinal toxicity — the role of the PHD/HIF axisMonica M. Olcina and Amato J. Giaccia http://jci.me/84432

Hypoxia-dependent regulation of inflammatory pathways in immune cellsCormac T. Taylor, Glen Doherty, Padraic G. Fallon, and Eoin P. Cummins http://jci.me/84433

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JCI | Features

review

Key advancements toward β cell replacement in diabetesType 1 and type 2 diabetes lead to loss of pancreatic β cells, and strategies for replacing these cells are being explored as a way to compensate for insulin deficiency in these diseases. Two major approaches aim at restoring insulin production in diabetic patients: implantation of β cells via encapsulated devices (see the accompanying image) and induction of β cell regeneration. In this month’s issue of the JCI, Jacqueline Benthuysen, Andrea Carrano, and Maike Sander review the recent progress related to each approach, focusing in particular on advances in β cell replication strategies, which have the potential to regenerate β cells through transdifferentia-tion or by promoting the expansion of existing cells.

Advances in β cell replacement and regeneration strategies for treating diabetesJacqueline Benthuysen, Andrea C. Carrano, and Maike Sander http://jci.me/87439

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agingInterruption of progerin–lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype p. 2Su-Jin Lee, Youn-Sang Jung, Min-Ho Yoon, So-mi Kang, Ah-Young Oh, Jee-Hyun Lee, So-Young Jun, Tae-Gyun Woo, Ho-Young Chun, Sang Kyum Kim, Kyu Jin Chung, Ho-Young Lee, Kyeong Lee, Guanghai Jin, Min-Kyun Na, Nam Chul Ha, Clea Bárcena, José M.P. Freije, Carlos López-Otín, Gyu Yong Song, and Bum-Joon Park http://jci.me/84164

autoimmunityLYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity p. 6Irina Proekt, Corey N. Miller, Marion Jeanne, Kayla J. Fasano, James J. Moon, Clifford A. Lowell, Douglas B. Gould, Mark S. Anderson, and Anthony L. DeFranco http://jci.me/84440

cardiologyAxial tubule junctions control rapid calcium signaling in atria p. 3Sören Brandenburg, Tobias Kohl, George S.B. Williams, Konstantin Gusev, Eva Wagner, Eva A. Rog-Zielinska, Elke Hebisch, Miroslav Dura, Michael Didié, Michael Gotthardt, Viacheslav O. Nikolaev, Gerd Hasenfuss, Peter Kohl, Christopher W. Ward, W. Jonathan Lederer, and Stephan E. Lehnart http://jci.me/88241

Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations p. 3Tobias Bruegmann, Patrick M. Boyle, Christoph C. Vogt, Thomas V. Karathanos, Hermenegild J. Arevalo, Bernd K. Fleischmann, Natalia A. Trayanova, and Philipp Sasse http://jci.me/88950

hematologyFunctionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia p. 5Patrick D. Bhola, Brenton G. Mar, R. Coleman Lindsley, Jeremy A. Ryan, Leah J. Hogdal, Thanh Trang Vo, Daniel J. DeAngelo, Ilene Galinsky, Benjamin L. Ebert, and Anthony Letai http://jci.me/82908

Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemiaYanli Jin, Jingfeng Zhou, Fang Xu, Bei Jin, Lijing Cui, Yun Wang, Xin Du, Juan Li, Peng Li, Ruibao Ren, and Jingxuan Pan http://jci.me/85239

Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapiesMarco Ruella, David M. Barrett, Saad S. Kenderian, Olga Shestova, Ted J. Hofmann, Jessica Perazzelli, Michael Klichinsky, Vania Aikawa, Farzana Nazimuddin, Miroslaw Kozlowski, John Scholler, Simon F. Lacey, Jan J. Melenhorst, Jennifer J.D. Morrissette, David A. Christian, Christopher A. Hunter, Michael Kalos, David L. Porter, Carl H. June, Stephan A. Grupp, and Saar Gill http://jci.me/87366

Lineage-specific BCL11A knockdown circumvents toxicities and reverses sickle phenotype p. 5Christian Brendel, Swaroopa Guda, Raffaele Renella, Daniel E. Bauer, Matthew C. Canver, Young-Jo Kim, Matthew M. Heeney, Denise Klatt, Jonathan Fogel, Michael D. Milsom, Stuart H. Orkin, Richard I. Gregory, and David A. Williams http://jci.me/87885

Current research articles

Sarcoplasmic reticulum junctions

Immune synapse formation

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immunologyFoxp3+ Tregs require WASP to restrain Th2-mediated food allergy p. 4Willem S. Lexmond, Jeremy A. Goettel, Jonathan J. Lyons, Justin Jacobse, Marion M. Deken, Monica G. Lawrence, Thomas H. DiMaggio, Daniel Kotlarz, Elizabeth Garabedian, Paul Sackstein, Celeste C. Nelson, Nina Jones, Kelly D. Stone, Fabio Candotti, Edmond H.H.M. Rings, Adrian J. Thrasher, Joshua D. Milner, Scott B. Snapper, and Edda Fiebiger http://jci.me/85129

ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cellsChandra Sekhar Boddupalli, Shiny Nair, Simon M. Gray, Heba N. Nowyhed, Rakesh Verma, Joanna A. Gibson, Clara Abraham, Deepak Narayan, Juan Vasquez, Catherine C. Hedrick, Richard A. Flavell, Kavita M. Dhodapkar, Susan M. Kaech, and Madhav V. Dhodapkar http://jci.me/85329

Different activation signals induce distinct mast cell degranulation strategies p. 4Nicolas Gaudenzio, Riccardo Sibilano, Thomas Marichal, Philipp Starkl, Laurent L. Reber, Nicolas Cenac, Benjamin D. McNeil, Xinzhong Dong, Joseph D. Hernandez, Ronit Sagi-Eisenberg, Ilan Hammel, Axel Roers, Salvatore Valitutti, Mindy Tsai, Eric Espinosa, and Stephen J. Galli http://jci.me/85538

A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeletonErin Janssen, Mira Tohme, Mona Hedayat, Marion Leick, Sudha Kumari, Narayanaswamy Ramesh, Michel J. Massaad, Sumana Ullas, Veronica Azcutia, Christopher C. Goodnow, Katrina L. Randall, Qi Qiao, Hao Wu, Waleed Al-Herz, Dianne Cox, John Hartwig, Darrell J. Irvine, Francis W. Luscinskas, and Raif S. Geha http://jci.me/85774

Cognate HLA absence in trans diminishes human NK cell educationVanessa Landtwing, Ana Raykova, Gaetana Pezzino, Vivien Béziat, Emanuela Marcenaro, Claudine Graf, Alessandro Moretta, Riccarda Capaul, Andrea Zbinden, Guido Ferlazzo, Karl-Johan Malmberg, Obinna Chijioke, and Christian Münz http://jci.me/86923

TGF-β receptor maintains CD4 T helper cell identity during chronic viral infections p. 5Gavin M. Lewis, Ellen J. Wehrens, Lara Labarta-Bajo, Hendrik Streeck, and Elina I. Zuniga http://jci.me/87041

NLRC4 suppresses melanoma tumor progression independently of inflammasome activationAnn M. Janowski, Oscar R. Colegio, Emma E. Hornick, Jennifer M. McNiff, Matthew D. Martin, Vladimir P. Badovinac, Lyse A. Norian, Weizhou Zhang, Suzanne L. Cassel, and Fayyaz S. Sutterwala http://jci.me/86953

Aging promotes acquisition of naive-like CD8+ memory T cell traits and enhanced functionalitiesJens Eberlein, Bennett Davenpor, Tom Nguyen, Francisco Victorino, Kelsey Haist, Kevin Jhun, Anis Karimpour-Fard, Lawrence Hunter, Ross Kedl, Eric T. Clambey, and Dirk Homann http://jci.me/88546

Current research articles

Intestinal mast cells

Metastatic melanoma

T cell actin foci

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infectious diseaseAngiotensin receptors and β-catenin regulate brain endothelial integrity in malaria p. 6Julio Gallego-Delgado, Upal Basu-Roy, Maureen Ty, Matilde Alique, Cristina Fernandez-Arias, Alexandru Movila, Pollyanna Gomes, Ada Weinstock, Wenyue Xu, Innocent Edagha, Samuel C. Wassmer, Thomas Walther, Marta Ruiz-Ortega, and Ana Rodriguez http://jci.me/87306

inflammationNeonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation p. 1Christian C. Yost, Hansjörg Schwertz, Mark J. Cody, Jared A. Wallace, Robert A. Campbell, Adriana Vieira-de-Abreu, Claudia V. Araujo, Sebastian Schubert, Estelle S. Harris, Jesse W. Rowley, Matthew T. Rondina, James M. Fulcher, Curry L. Koening, Andrew S. Weyrich, and Guy A. Zimmerman http://jci.me/83873

metabolismInhibition of apolipoprotein B synthesis stimulates endoplasmic reticulum autophagy that prevents steatosisDonna M. Conlon, Tiffany Thomas, Tatyana Fedotova, Antonio Hernandez-Ono, Gilbert Di Paolo, Robin B. Chan, Kelly Ruggles, Sarah Gibeley, Jing Liu, and Henry N. Ginsberg http://jci.me/86028

oncologyTelomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expressionEkta Khattar, Pavanish Kumar, Chia Yi Liu, Semih Can Akıncılar, Anandhkumar Raju, Manikandan Lakshmanan, Julien Jean Pierre Maury, Yu Qiang, Shang Li, Ern Yu Tan, Kam M. Hui, Ming Shi, Yuin Han Loh, and Vinay Tergaonkar http://jci.me/86042

RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation p. 2Robert A. Jones, Tyler J. Robinson, Jeff C. Liu, Mariusz Shrestha, Veronique Voisin, YoungJun Ju, Philip E.D. Chung, Giovanna Pellecchia, Victoria L. Fell, SooIn Bae, Lakshmi Muthuswamy, Alessandro Datti, Sean E. Egan, Zhe Jiang, Gustavo Leone, Gary D. Bader, Aaron Schimmer, and Eldad Zacksenhaus http://jci.me/81568

stem cellsCOUP-TFII regulates satellite cell function and muscular dystrophyXin Xie, Sophia Y. Tsai, and Ming-Jer Tsai http://jci.me/87414

Endothelial cell rupture

Dystrophic muscle

RB1-deficient tumor

Hepatic triglycerides

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JCI Insight is a new peer-reviewed journal dedicated to biomedical research, ranging from preclinical to clinical studies.More information: http://jci.me/insinf or editors@insight.jci.org

Editor’s picks

Antifibrotic pirfenidone exacerbates lung damage in a murine tuberculosis model

Alveolar epithelial cell telomere dysfunction induces pulmonary fibrosis in mice

pulmonology

Pirfenidone is an antifibrotic drug that was recently approved for the treatment of idiopathic pulmonary fibrosis (IPF), which is character-ized by lung inflammation and fibrosis. As tuberculosis (TB) is also characterized by lung inflammation and fibrosis, Bintou Ahidjo and colleagues tested whether pirfenidone could be used as an adjunctive therapy during antimicrobial treatment of TB to reduce inflammatory lung damage and accelerate treatment response in a murine model of chronic TB. Surprisingly, pirfenidone reduced bacterial clearance, increased relapse rates, and exacerbated pulmonary cavitation compared with standard treatment (see the accompanying image). These findings indicate that patients treated with pirfenidone or other antifibrotic agents should be monitored for TB infection.

The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosisBintou A. Ahidjo, Mariama C. Maiga, Elizabeth A. Ihms, Mamoudou Maiga, Alvaro A. Ordonez, Laurene S. Cheung, Sarah Beck, Bruno B. Andrade, Sanjay Jain, and William R. Bishai http://jci.me/86017

In idiopathic pulmonary fibrosis (IPF) patients, type II alveolar epithelial cells (AECs) have shortened telomeres, but it is unclear how telomere dysfunction contributes to lung fibrosis. Ram Naikawadi and colleagues examined the effects of telomere shortening in type II AECs in mice by inducing AEC-specific deletion of telomeric repeat binding factor (Trf1), which protects the ends of telomeres. After 2 weeks, TRF1-deficient mice exhibited a DNA damage response in type II AECs and increased susceptibil-ity to influenza virus. Over a 9-month period, Trf1 deletion resulted in shortened telomeres; spontaneous lung remodeling (see the accompanying image) characterized by increased numbers of type II AECs and smooth muscle actin–expressing mesenchymal cells and collagen deposition; accumulation of senescent AECs; and death. In contrast, Trf1 deletion in collagen-expressing cells caused pulmonary edema, but not fibrosis. These studies demonstrate that telomere dysfunction in type II AECs is sufficient to cause progressive lung fibrosis in the absence of injury, similar to the disease progression seen in IPF patients.

Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosisRam P. Naikawadi, Supparerk Disayabutr, Benat Mallavia, Matthew L. Donne, Gary Green, Janet L. La, Jason R. Rock, Mark R. Looney, and Paul J. Wolters http://jci.me/86704

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JCI Insight | Editor’s picks

A miRNA signature for infantile hemangioma

vascular biology

Glymphatics mediate CNS clearance of adeno-associated viral vectors

neuroscience

Infantile hemangiomas (IHs) are benign vascular tumors occurring in 4%–5% of infants. These tumors involute spontaneously or in response to propranolol; however, they resemble other vascular anomalies and cannot be definitively diagnosed without biopsy. Because microRNAs (miRNAs) are critical regulators of vascular development, Graham Strub and colleagues assayed miRNAs from IH tumor tissue, IH patient plasma, non-IH vascular anomalies, and controls. They identified a miRNA cluster, known as C19MC, that is specifically upregulated in IH tumor endothelial cells and detectable in IH patient plasma. Importantly, circulating C19MC miRNAs decreased in parallel with IH tumor regression but rebounded with tumor regrowth. These results suggest that plasma C19MC miRNAs could be used to diagnose and monitor IH treatment. Additionally, C19MC miRNAs may be important in IH pathogenesis, as their knowns targets include genes encoding inhibitors of cell growth and proliferation.

Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangiomaGraham M. Strub, Andrew L. Kirsh, Mark E. Whipple, Winston P. Kuo, Rachel B. Keller, Raj P. Kapur, Mark W. Majesky, and Jonathan A. Perkins http://jci.me/88856

Recombinant adeno-associated viral (AAV) vectors are currently being evaluated in clinical gene therapy trials for the treatment of neurological diseases. These therapeutic modalities have been hampered by variability in AAV vector delivery, efficiency, and gene expression, and a better understanding of the mechanisms governing AAV vector transport in the brain could guide improvements of these therapeutic strategies. Giridhar Murlidharan and colleagues investigated the role of glymphatic fluid transport in the clearance of AAV vectors in the brain. Astrocytic aquaporin-4 (AQP4) is essential for glymphatic clearance of interstitial solutes. Murlidharan and colleagues found that aged mice exhibited altered localization of neuronal AQP4, which was correlated with greater AAV vector retention, compared with that in young mice. Further, AQP4-deficient mice had greater AAV transduction efficiency and vector spread compared with WT mice (see the accompanying image). These findings indicate that age-related changes in glymphatic flux influence AAV vector spread and efficiency, potentially altering treatment outcomes.

Glymphatic fluid transport controls paravascular clearance of AAV vectors from the brainGiridhar Murlidharan, Andrew Crowther, Rebecca A. Reardon, Juan Song, and Aravind Asokan http://jci.me/88034

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JCI Insight | Editor’s picks

oncology

Platelet α6β1 integrin leads cancer cells to the lungsMetastasis is the leading cause of cancer-related death, and there is growing evidence that platelets aid in the dissemination of cancer cells. Elmina Mammadova-Bach and colleagues showed that platelet α6β1 integrin participates in tumor metastasis by promoting interactions with tumor cells. Platelet-specific deletion of α6β1 integrin decreased lung metastasis after injection of tumor cells intravenously or into the mammary fat pad (see the accompanying image). Mechanis-tically, Mammadova-Bach and colleagues showed that the tumor cell disintegrin ADAM9 serves as a receptor for platelet α6β1 integrin. This interaction promoted platelet activation and tumor cell extravasation. Importantly, antibody-

mediated blockade of α6β1 integrin inhibited tumor metastasis in murine models of breast cancer and melanoma. These findings suggest that disruption of tumor/platelet interactions could prevent metastasis.

Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell–derived ADAM9Elmina Mammadova-Bach, Paola Zigrino, Camille Brucker, Catherine Bourdon, Monique Freund, Adèle De Arcangelis, Scott I. Abrams, Gertaud Orend, Christian Gachet, and Pierre Henri Mangin http://jci.me/88245

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The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis p. 12Bintou A. Ahidjo, Mariama C. Maiga, Elizabeth A. Ihms, Mamoudou Maiga, Alvaro A. Ordonez, Laurene S. Cheung, Sarah Beck, Bruno B. Andrade, Sanjay Jain, and William R. Bishai http://jci.me/86017

T cell responses to human platelet antigen–1a involve a unique form of indirect allorecognition

Maria Therese Ahlen, Anne Husebekk, Ida Løken Killie, Bjørn Skogen, and Tor Brynjar Stuge http://jci.me/86558

Analysis of cystic fibrosis–associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseasesCarleen M. Sabusap, Wei Wang, Carmel M. McNicholas, W. Joon Chung, Lianwu Fu, Hui Wen, Marina Mazur, Kevin L. Kirk, James F. Collawn, Jeong S. Hong, and Eric J. Sorscher http://jci.me/86581

Telomere dysfunction in alveolar epithelial cells causes lung remodeling and fibrosis p. 12Ram P. Naikawadi, Supparerk Disayabutr, Benat Mallavia, Matthew L. Donne, Gary Green, Janet L. La, Jason R. Rock, Mark R. Looney, and Paul J. Wolters http://jci.me/86704

IL1RL1 asthma risk variants regulate airway type 2 inflammationErin D. Gordon, Joe Palandra, Agata Wesolowska-Andersen, Lando Ringel, Cydney L. Rios, Marrah E. Lachowicz-Scroggins, Louis Z. Sharp, Jamie L. Everman, Hannah J. MacLeod, Jae W. Lee, Robert J. Mason, Michael A. Matthay, Richard T. Sheldon, Michael C. Peters, Karl H. Nocka, John V. Fahy, and Max A. Seibold http://jci.me/87871

Glymphatic fluid transport controls paravascular clearance of AAV vectors from the brain p. 13Giridhar Murlidharan, Andrew Crowther, Rebecca A. Reardon, Juan Song, and Aravind Asokan http://jci.me/88034

Platelet integrin α6β1 controls lung metastasis through direct binding to cancer cell–derived ADAM9 p. 14

Elmina Mammadova-Bach, Paola Zigrino, Camille Brucker, Catherine Bourdon, Monique Freund, Adèle De Arcangelis, Scott I. Abrams, Gertaud Orend, Christian Gachet, and Pierre Henri Mangin http://jci.me/88245

Lack of immunoediting in murine pancreatic cancer reversed with neoantigenRebecca A. Evans, Mark S. Diamond, Andrew J. Rech, Timothy Chao, Max W. Richardson, Jeffrey H. Lin, David L. Bajor, Katelyn T. Byrne, Ben Z. Stanger, James L. Riley, Nune Markosyan, Rafael Winograd, and Robert H. Vonderheide http://jci.me/88328

In vivo disruption of latent HSV by designer endonuclease therapyMartine Aubert, Emily A. Madden, Michelle Loprieno, Harshana S. DeSilva Feelixge, Laurence Stensland, Meei-Li Huang, Alexander L. Greninger, Pavitra Roychoudhury, Nixon Niyonzima, Thuy Nguyen, Amalia Magaret, Roman Galleto, Daniel Stone, and Keith R. Jerome http://jci.me/88468

CFTR gene transfer with AAV improves early cystic fibrosis pig phenotypesBenjamin Steines, David D. Dickey, Jamie Bergen, Katherine J.D.A. Excoffon, John R. Weinstein, Xiaopeng Li, Ziying Yan,

Mahmoud H. Abou Alaiwa, Viral S. Shah, Drake C. Bouzek, Linda S. Powers, Nicholas D. Gansemer, Lynda S. Ostedgaard, John F. Engelhardt, David A. Stoltz, Michael J. Welsh, Patrick L. Sinn, David V. Schaffer, and Joseph Zabner http://jci.me/88728

HSV-infected neuronal cultures

AAV vector spread

Current research articles

Tuberculosis-infected lung

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Current research articles

Lentiviral-mediated phenotypic correction of cystic fibrosis pigsAshley L. Cooney, Mahmoud H. Abou Alaiwa, Viral S. Shah, Drake C. Bouzek, Mallory R. Stroik, Linda S. Powers, Nick D. Gansemer, David K. Meyerholz, Michael J. Welsh, David A. Stoltz, Patrick L. Sinn, and Paul B. McCray Jr. http://jci.me/88730

A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility geneYonghe Ding, Pamela A. Long, J. Martijn Bos, Yu-Huan Shih, Xiao Ma, Rhianna S. Sundsbak, Jianhua Chen, Yiwen Jiang, Liqun Zhao, Xinyang Hu, Jianan Wang, Yongyong Shi, Michael J. Ackerman, Xueying Lin, Stephen C. Ekker, Margaret M. Redfield, Timothy M. Olson, and Xiaolei Xu http://jci.me/88797

Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma p. 13

Graham M. Strub, Andrew L. Kirsh, Mark E. Whipple, Winston P. Kuo, Rachel B. Keller, Raj P. Kapur, Mark W. Majesky, and Jonathan A. Perkins http://jci.me/88856

Enhanced protective antibody to a mutant meningococcal factor H-binding protein with low-factor H bindingDan M. Granoff, Serena Giuntini, Flor A. Gowans, Eduardo Lujan, Kelsey Sharkey, and Peter T. Beernink http://jci.me/88907

Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with agingJennifer J. DuPont, Amy McCurley, Ana P. Davel, Joseph McCarthy, Shawn B. Bender, Kwangseok Hong, Yan Yang, Jeung-Ki Yoo, Mark Aronovitz, Wendy E. Baur, Demetra D. Christou, Michael A. Hill, and Iris Z. Jaffe http://jci.me/88942

Multi-parametric profiling of non–small-cell lung cancers reveals distinct immunophenotypesPatrick H. Lizotte, Elena V. Ivanova, Mark M. Awad, Robert E. Jones, Lauren Keogh, Hongye Liu, Ruben Dries, Christina Almonte, Grit S. Herter-Sprie, Abigail Santos, Nora B. Feeney, Cloud P. Paweletz, Meghana M. Kulkarni, Adam J. Bass, Anil K. Rustgi, Guo-Cheng Yuan, Donald W. Kufe, Pasi A. Jänne, Peter S. Hammerman, Lynette M. Sholl, F. Stephen Hodi, William G. Richards, Raphael Bueno, Jessie M. English, Mark A. Bittinger, and Kwok-Kin Wong http://jci.me/89014

Diphtheria toxin–mediated ablation of lymphatic endothelial cells results in progressive lymphedemaJason C. Gardenier, Geoffrey E. Hespe, Raghu P. Kataru, Ira L. Savetsky, Jeremy S. Torrisi, Gabriela D. García Nores, Joseph J. Dayan, David Chang, Jamie Zampell, Inés Martínez-Corral, Sagrario Ortega, and Babak J. Mehrara http://jci.me/84095

Adjuvanted multi-epitope vaccines protect HLA-A*1101 transgenic mice against Toxoplasma gondii

Kamal El Bissati, Aziz Chentoufi, Paulette A. Krishack, Ying Zhou, Stuart Woods, Jitender P. Dubey, Lo Vang, Joseph Lykins, Kate E. Broderick, Ernest Mui, Yasuhiro Suzuki, Qila Sa, Stephanie Bi, Nestor Cardona, Shiv K. Verma, Laura Frazeck, Catherine A. Reardon, John Sidney, Jeff Alexander, Alessandro Sette, Tom Vedvick, Chris Fox, Jeffrey A. Guderian, Steven Reed, Craig W. Roberts, and Rima McLeod http://jci.me/85955

Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesiaVincent A. Jourdain, Chris C. Tang, Florian Holtbernd, Christian Dresel, Yoon Young Choi, Yilong Ma, Vijay Dhawan, and David Eidelberg http://jci.me/86615

Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host diseaseLaëtitia Le Texier, Katie E. Lineburg, Benjamin Cao, Cameron McDonald-Hyman, Lucie Leveque-El Mouttie, Jemma Nicholls, Michelle Melino, Blessy C. Nalkurthi, Kylie A. Alexander, Bianca Teal, Stephen J. Blake, Fernando Souza-Fonseca-Guimaraes, Christian R. Engwerda, Rachel D. Kuns, Steven W. Lane, Michele Teng, Charis Teh, Daniel Gray, Andrew D. Clouston, Susan K. Nilsson, Bruce R. Blazar, Geoffrey R. Hill, and Kelli P.A. MacDonald http://jci.me/86850

DNAJB6 in ER stress

Lymphatic regeneration

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Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complicationsKelli M. Sas, Pradeep Kayampilly, Jaeman Byun, Viji Nair, Lucy M. Hinder, Junguk Hur, Hongyu Zhang, Chengmao Lin, Nathan R. Qi, George Michailidis, Per-Henrik Groop, Robert G. Nelson, Manjula Darshi, Kumar Sharma, Jeffrey R. Schelling, John R. Sedor, Rodica Pop-Busui, Joel M. Weinberg, Scott A. Soleimanpour, Steven F. Abcouwer, Thomas W. Gardner, Charles F. Burant, Eva L. Feldman, Matthias Kretzler, Frank C. Brosius III, and Subramaniam Pennathur http://jci.me/86976

A ferret model of COPD-related chronic bronchitisS. Vamsee Raju, Hyunki Kim, Stephen A. Byzek, Li Ping Tang, John E. Trombley, Patricia Jackson, Lawrence Rasmussen, J. Michael Wells, Emily Falk Libby, Erik Dohm, Lindy Winter, Sharon L. Samuel, Kurt R. Zinn, J. Edwin Blalock, Trenton R. Schoeb, Mark T. Dransfield, and Steven M. Rowe http://jci.me/87536

MUTYH promotes oxidative microglial activation and inherited retinal degeneration

Shunji Nakatake, Yusuke Murakami, Yasuhiro Ikeda, Noriko Morioka, Takashi Tachibana, Kohta Fujiwara, Noriko Yoshida, Shoji Notomi, Toshio Hisatomi, Shigeo Yoshida, Tatsuro Ishibashi, Yusaku Nakabeppu, and Koh-Hei Sonoda http://jci.me/87781

PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal diseaseZakariae Bram, Estelle Louiset, Bruno Ragazzon, Sylvie Renouf, Julien Wils, Céline Duparc, Isabelle Boutelet, Marthe Rizk-Rabin, Rossella Libé, Jacques Young, Dennis Carson, Marie-Christine Vantyghem, Eva Szarek, Antoine Martinez, Constantine A. Stratakis, Jérôme Bertherat, and Hervé Lefebvre http://jci.me/87958

Bladder catheterization increases susceptibility to infection that can be prevented by prophylactic antibiotic treatmentMatthieu Rousseau, H.M. Sharon Goh, Sarah Holec, Matthew L. Albert, Rohan B.H. Williams, Molly A. Ingersoll, and Kimberly A. Kline http://jci.me/88178

A xenograft model of macrophage activation synd rome amenable to anti-CD33 and anti–IL-6R treatmentMark Wunderlich, Courtney Stockman, Mahima Devarajan, Navin Ravishankar, Christina Sexton, Ashish R. Kumar, Benjamin Mizukawa, and James C. Mulloy http://jci.me/88181

One-time injection of AAV8 encoding urocortin 2 provides long term resolution of insulin resistanceMei Hua Gao, Dimosthenis Giamouridis, N. Chin Lai, Evelyn Walenta, Vivian Almeida Paschoal, Young Chul Kim, Atsushi Miyanohara, Tracy Guo, Min Liao, Li Liu, Zhen Tan, Theodore P. Ciaraldi, Simon Schenk, Aditi Bhargava, Da Young Oh, and H. Kirk Hammond http://jci.me/88322

Cell type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosyMegan S. Inkeles, Rosane M.B. Teles, Delila Pouldar, Priscila R. Andrade, Cressida A. Madigan, David Lopez, Mike Ambrose, Mahdad Noursadeghi, Euzenir N. Sarno, Thomas H. Rea, Maria T. Ochoa, M. Luisa Iruela-Arispe, William R. Swindell, Tom H.M. Ottenhoff, Annemieke Geluk, Barry R. Bloom, Matteo Pellegrini, and Robert L. Modlin http://jci.me/88843

Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areataMilène Kennedy Crispin, Justin M. Ko, Brittany G. Craiglow, Shufeng Li, Gautam Shankar, Jennifer R. Urban, James C. Chen, Jane E. Cerise, Ali Jabbari, Mårten C.G. Winge, M. Peter Marinkovich, Angela M. Christiano, Anthony E. Oro, and Brett A. King http://jci.me/89776

Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areataJulian Mackay-Wiggan, Ali Jabbari, Nhan Nguyen, Jane E. Cerise, Charlotte Clark, Grace Ulerio, Megan Furniss, Roger Vaughan, Angela M. Christiano, and Raphael Clynes http://jci.me/89790

Fatty liver

Mucus-expressing cells

http://www.biolegend.com/veri/jci