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jci.org/this-month
ALSO IN THIS ISSUE:
Dissecting motor pathways in Parkinson’s disease 2
Rapid effects of acute fat intake 5
miR-27 controls Treg-mediated autoimmunity 6
Reducing toxicity in HIV reactivation strategies 6
JCI Insight 11
A summary of the most recent articles in The Journal of Clinical Investigation and JCI Insight
Scan with your mobile device for the digital version of JCI This Month.
February 2017
Kisspeptin puts love on the brain p. 1
This Month
Alejandro Aballay
Abul K. Abbas
Domenico Accili
Rexford S. Ahima
Qais Al-Awqati
Kari Alitalo
James Allison
Dario C. Altieri
Masayuki Amagai
Mark E. Anderson
Brian H. Annex
Alan Attie
Jane E. Aubin
Steven P. Balk
Michael F. Beers
John A. Belperio
Nina Bhardwaj
Morris J. Birnbaum
Joyce Bischoff
Mina J. Bissell
Craig Blackstone
Bruce R. Blazar
William A. Boisvert
Nancy Bonini
Brendan Boyce
Jonathan Bromberg
Frank C. Brosius
Hal E. Broxmeyer
Andrew Butler
Michael J. Caplan
Ruben D. Carrasco
Diego H. Castrillon
Harold Chapman
Ajay Chawla
Benjamin K. Chen
Benny J. Chen
Ju Chen
Marie-Françoise Chesselet
Vivian G. Cheung
Yongwon Choi
Thomas Clemens
Sheila Collins
Ronald G. Collman
Marco Colonna
George Cotsarelis
Shaun R. Coughlin
Christopher M. Counter
Peter D. Crompton
Tyler J. Curiel
David D’Alessio
Richard T. D’Aquila
Riccardo Dalla-Favera
Alan Daugherty
Ted Dawson
Sudhansu Dey
Harry C. Dietz III
Gianpietro Dotti
Michael Dustin
Connie J. Eaves
Dominique Eladari
Jack A. Elias
Joel K. Elmquist
Stephen G. Emerson
Jeffrey A. Engelman
Jonathan A. Epstein
Adrian Erlebacher
Joel D. Ernst
James M. Ervasti
Robert V. Farese Jr.
Eric R. Fearon
Edward A. Fisher
Susan Fisher
Richard A. Flavell
Tatiana Foroud
Velia M. Fowler
Martin Friedlander
Stephen J. Galli
J. Victor Garcia-Martinez
Alfred L. George Jr.
Stanton L. Gerson
Robert E. Gerszten
Todd Golde
Stanley Goldfarb
Larry B. Goldstein
Fred Sanford Gorelick
Kathleen J. Green
J. Timothy Greenamyre
Theresa A. Guise
David Hafler
Jonathan J. Hansen
Raymond C. Harris
Stanley L. Hazen
Peter Heeringa
Brian A. Hemmings
Meenhard Herlyn
Joachim Herz
Katherine A. High
Helen H. Hobbs
Ronald Hoffman
V. Michael Holers
Steven M. Holland
Michael J. Holtzman
Lawrence B. Holzman
Tamas L. Horvath
Gokhan S. Hotamisligil
Steven R. Houser
Scott J. Hultgren
Christopher A. Hunter
Ciro Indolfi
David E. James
William G. Kaelin Jr.
Klaus Kaestner
Mark L. Kahn
Raghu Kalluri
S. Ananth Karumanchi
Robert S. Kass
Masato Kasuga
Dontscho Kerjaschki
Sundeep Khosla
Richard N. Kitsis
Peter S. Klein
Steven Kliewer
Björn C. Knollmann
Walter J. Koch
Jay K. Kolls
Issei Komuro
Christopher D. Kontos
Murray Korc
Gary Koretzky
Calvin Kuo
Antonio La Cava
Fadi G. Lakkis
Terri Laufer
Mitchell A. Lazar
Brendan Lee
William M.F. Lee
Rudolph L. Leibel
Stanley M. Lemon
Jon D. Levine
Ross L. Levine
Klaus Ley
Richard M. Locksley
Gary Lopaschuk
Richard B. Mailman
Rama K. Mallampalli
Jack Martin
Steven O. Marx
Rodger P. McEver
Elizabeth McNally
Cornelius J. Melief
Shlomo Melmed
George Michalopoulos
Jeffrey H. Miner
Beverly Mitchell
Peter J. Mohler
Kelle Harbert Moley
Jeffery Molkentin
David D. Moore
Edward E. Morrisey
James H. Morrissey
Anthony J. Muslin
Martin G. Myers Jr.
Benjamin G. Neel
Guillermo Oliver
Eric N. Olson
Harry T. Orr
Leo E. Otterbein
William C. Parks
Warren S. Pear
Sallie R. Permar
David J. Pinsky
Edward Plow
Jeffrey Pollard
Kornelia Polyak
Catherine Postic
Josef Prchal
Alice S. Prince
Louis J. Ptáček
Luigi Puglielli
Pere Puigserver
Bali Pulendran
Ellen Puré
Susan E. Quaggin
Marlene Rabinovitch
Daniel J. Rader
Shahin Rafii
Gwendalyn J. Randolph
Barbara Rehermann
Steven L. Reiner
Sarah A. Robertson
Paul B. Rosenberg
Theodora S. Ross
Marc E. Rothenberg
Anil Rustgi
J. Evan Sadler
Junichi Sadoshima
Jose-Alain Sahel
Jean E. Schaffer
Philipp E. Scherer
Michael D. Schneider
Detlef Schuppan
Michael W. Schwartz
William K. Scott
Randy Seeley
Amita Sehgal
Clay Semenkovich
Gregg L. Semenza
John Seykora
Steven D. Shapiro
Mari Shinohara
Steven E. Shoelson
Gerald I. Shulman
Roy L. Silverstein
M. Celeste Simon
Mihaela Skobe
Journal of Clinical Investigation Consulting Editors
Lois Smith
Steven R. Smith
Susan S. Smyth
Weihong Song
Ashley L. St. John
Herman F. Staats
Jonathan S. Stamler
John R. Stanley
Colin L. Stewart
Doris Stoffers
Warren Strober
Maureen A. Su
Katalin Susztak
Catharina Svanborg
Ira Tabas
Alan R. Tall
Sakae Tanaka
Victor J. Thannickal
Andrei Thomas-Tikhonenko
Georgia D. Tomaras
Peter Tontonoz
Laurence A. Turka
Raphael H. Valdivia
Marcel R.M. van den Brink
Luc Van Kaer
Matthias von Herrath
Yisong Y. Wan
Hong Wang
David Weinstock
Jeffrey Weiser
Bart O. Williams
Joseph C. Wu
Thomas A. Wynn
Rudolf Zechner
Kang Zhang
Len Zon
Ming-Hui Zou
Weiping Zou
1j c i . o r g / t h i s - m o n t h f e b r u a r y 2 0 1 7
EditorHoward A. Rockman
Executive EditorSarah C. Jackson
Science EditorsJillian Hurst, Corinne Williams
Assistant Science EditorElyse Dankoski
Deputy EditorsGarnett Kelsoe, Bryan L. Roth
Associate EditorsSoman N. Abraham, Vann Bennett, Gerard C. Blobe, Kathleen M. Caron, Marc G. Caron, John P. Chute, Thomas M. Coffman, Anna Mae Diehl, Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard, Paul W. Noble, Jeffrey C. Rathmell, W. Kimryn Rathmell, Jonathan S. Serody, Norman Sharpless, Thomas Weber, Yiping Yang
Clinical Medicine Associate EditorsMichael A. Morse, Andrew J. Muir, Scott M. Palmer, Mark A. Stacy
Asia EditorDavid M. Virshup
Chair, Executive CouncilRobert J. Lefkowitz
BiostatisticiansCynthia Coffman, Maren Olsen
BioethicistArthur L. Caplan
Editor at LargeUshma S. Neill
ISSN 2324-7703 (print)ISSN 2325-4556 (online)
Contact the JCI and JCI Insight2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: [email protected] (JCI); [email protected] (JCI Insight)
For the full JCI online: jci.me/127/2For JCI Insight: jci.me/insight/2/1 jci.me/insight/2/2
This MonthFebruary 2017
Kisspeptin enhances limbic activity in response to sexual and emotional imagesThe peptide hormone kisspeptin is a key mediator of reproductive fitness that stimulates the secretion of gonadotropin-releasing hormone, which constitutes the first step in the hypothalamic-pituitary-gonadal axis. In this issue of the JCI, Alexander Comninos et al. examined whether kisspeptin has additional functions outside of the hypothalamus and tested kisspeptin response in the limbic system, which controls mood and emotional behavior. As shown on the cover, functional neuroimaging revealed that kisspeptin administration to healthy heterosexual men increased limbic brain activity in response to images that were sexual (red) or couple bonding related (purple). Additionally, assessment of reward, drive, and mood by psychometric measures correlated with enhanced limbic brain activity. Collectively, these results suggest that kisspeptin is a central regulator of sexual and emotional brain processing as well as fertility in humans.
Kisspeptin modulates sexual and emotional brain processing in humansAlexander N. Comninos, Matthew B. Wall, Lysia Demetriou, Amar J. Shah, Sophie A. Clarke, Shakunthala Narayanaswamy, Alexander Nesbitt, Chioma Izzi-Engbeaya, Julia K. Prague, Ali Abbara, Risheka Ratnasabapathy, Victoria Salem, Gurjinder M. Nijher, Channa N. Jayasena, Mark Tanner, Paul Bassett, Amrish Mehta, Eugenii A. Rabiner, Christoph Hönigsperger, Meire Ribeiro Silva, Ole Kristian Brandtzaeg, Elsa Lundanes, Steven Ray Wilson, Rachel C. Brown, Sarah A. Thomas, Stephen R. Bloom, and Waljit S. Dhillo http://jci.me/89519
On the JCI cover
Top read JCI articles of 2016Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibitionLeonid Cherkassky, Aurore Morello, Jonathan Villena-Vargas, Yang Feng, Dimiter S. Dimitrov, David R. Jones, Michel Sadelain, and Prasad S. Adusumilli http://jci.me/83092Evaluation of direct-to-consumer low-volume lab tests in healthy adultsBrian A. Kidd, Gabriel Hoffman, Noah Zimmerman, Li Li, Joseph W. Morgan, Patricia K. Glowe, Gregory J. Botwin, Samir Parekh, Nikolina Babic, Matthew W. Doust, Gregory B. Stock, Eric E. Schadt, and Joel T. Dudley http://jci.me/86318Tumor immune profiling predicts response to anti–PD-1 therapy in human melanomaAdil I. Daud, Kimberly Loo, Mariela L. Pauli, Robert Sanchez-Rodriguez, Priscila Munoz Sandoval, Keyon Taravati, Katy Tsai, Adi Nosrati, Lorenzo Nardo, Michael D. Alvarado, Alain P. Algazi, Miguel H. Pampaloni, Iryna V. Lobach, Jimmy Hwang, Robert H. Pierce, Iris K. Gratz, Matthew F. Krummel, and Michael D. Rosenblum http://jci.me/87324Increased mitochondrial arginine metabolism supports bioenergetics in asthmaWeiling Xu, Sudakshina Ghosh, Suzy A.A. Comhair, Kewal Asosingh, Allison J. Janocha, Deloris A. Mavrakis, Carole D. Bennett, Lourdes L. Gruca, Brian B. Graham, Kimberly A. Queisser, Christina C. Kao, Samuel H. Wedes, John M. Petrich, Rubin M. Tuder, Satish C. Kalhan, and Serpil C. Erzurum http://jci.me/82925Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesityJing Cui, Yi Ding, Shu Chen, Xiaoqiang Zhu, Yichen Wu, Mingliang Zhang, Yaxin Zhao, Tong-Ruei R. Li, Ling V. Sun, Shimin Zhao, Yuan Zhuang, Weiping Jia, Lei Xue, Min Han, Tian Xu, and Xiaohui Wu http://jci.me/85676
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.
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research
Editor’s picks
neuroscience
Distinct striatal pathways contribute to therapy response in Parkinson’s disease
Selective acetylcholine modulation restores memory and extends life span in mice
Degeneration of dopamine inputs to the striatum causes loss of motor function in Parkinson’s disease. L-DOPA is an effective treatment, but it can cause uncontrol-lable movements known as L-DOPA–induced dyskinesia (LID). Cristina Alcacer and labmates dissected the circuitry underlying parkinsonian motor deficits and LID by expressing excitatory Gq-coupled DREADD receptors specifically in the two major cell types of the striatum: spiny projection neurons forming the direct or indirect pathway (dSPNs or iSPNs) of the basal ganglia. Stimulating DREADD receptors led to activation of either dSPNs or iSPNs in parkinsonian mice (see the accompanying image). Stimulation of dSPNs mimicked the therapeutic effects of L-DOPA therapy; in contrast, stimulation of iSPNs abolished them. Moreover, LID was exacerbated by
dSPN stimulation and inhibited by stimulating iSPNs. Dyskinesias resembling LID were evoked by activating dSPNs with a DREADD receptor that mimics the stimulatory effects of dopamine on these neurons. The identification of distinct and complementary roles for striatal pathways in movement pathologies may inform the design of improved therapies for Parkinson’s disease.
Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapyCristina Alcacer, Laura Andreoli, Irene Sebastianutto, Johan Jakobsson, Tim Fieblinger, and Maria Angela Cenci http://jci.me/90132
Acetylcholinesterase inhibitors are a leading treatment for symptoms of Alzheimer’s disease, some of which arise from the degeneration of acetylcholine-producing neurons. In spite of the clinical benefits of these therapies, numerous adverse effects arise from nonselective targeting of acetylcholine transmission. Work by Sophie Bradley and labmates assessed the efficacy of two highly selective allosteric modulators of the M1 muscarinic acetylcholine receptor in a mouse model of prion disease. The model showed many hallmarks of human Alzheimer’s disease, including memory deficits and progressive hippocampal neuron degeneration (see the accompanying image). Treatment with M1-selective ligands reversed memory deficits and profoundly extended the life span of the diseased mice, suggesting that similar ligands may have potential as clinical treatments for Alzheimer’s disease.
M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory lossSophie J. Bradley, Julie-Myrtille Bourgognon, Helen E. Sanger, Nicholas Verity, Adrian J. Mogg, David J. White, Adrian J. Butcher, Julie A. Moreno, Colin Molloy, Timothy Macedo-Hatch, Jennifer M. Edwards, Jurgen Wess, Robert Pawlak, David J. Read, Patrick M. Sexton, Lisa M. Broad, Joern R. Steinert, Giovanna R. Mallucci, Arthur Christopoulos, Christian C. Felder, and Andrew B. Tobin http://jci.me/87526
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JCI | Research: Editor’s picks
Intracellular calcium flux triggers secondary damage after stroke
During a stroke, cell death occurs in the brain regions directly affected by ischemia. The ischemic event also triggers spreading waves of depolarizing neurons, or peri-infarct depolarizations (PIDs), that contribute to additional damage in the tissue surrounding the primary damage site. Cordula Rakers and Gabor Petzold visualized calcium transients in a mouse model of focal ischemia and found that PIDs are accompanied by profound increases in intracellular calcium in astrocytes and neurons (see the accompanying image).
In astrocytes, intracellular elevations in calcium were mediated by the inositol triphosphate receptor IP3R2. Loss of IP3R2 attenuated PID-related calcium transients in astrocytes and neurons, leading to decreases in PID frequency, increased neuronal survival, and smaller infarct volume after focal ischemia. These findings highlight the concept that targeting astroglial calcium pathways may be a potential therapeutic approach to mitigate ongoing injury after stroke.
PET imaging of olfactory neurons enables monitoring of neurological diseaseOlfactory sensory neurons undergo neurogenesis throughout the adult life span. Because this neuronal population exhibits high levels of neuron turnover, noninvasive quantification of the nasal neuron population could provide important insights related to the diagnosis and progression of neurodevelop-mental and neurodegenerative diseases. Genevieve
Van de Bittner and colleagues assessed GV1-57, a PET radiotracer that specifically binds to mature olfactory sensory neurons and quantifies their population. GV1-57 detected neuron generation during rodent postnatal development and neuron degeneration in rodent models of aging and neurodegenerative disease (see the associated image). Moreover, the
PET radiotracer maintained saturable binding in nonhuman primate nasal epithelium, providing proof of concept for its translation to human imaging in a clinical setting. In the accompanying Commentary, Helene Benveniste, Yuri Lazebnik, and Nora Volkow discuss this tracer’s potential as a prototype for visualizing and characterizing olfactory neurogenesis.
Nasal neuron PET imaging quantifies neuron generation and degenerationGenevieve C. Van de Bittner, Misha M. Riley, Luxiang Cao, Janina Ehses, Scott P. Herrick, Emily L. Ricq, Hsiao-Ying Wey, Michael J. O’Neill, Zeshan Ahmed, Tracey K. Murray, Jaclyn E. Smith, Changning Wang, Frederick A. Schroeder, Mark W. Albers, and Jacob M. Hooker http://jci.me/89162
Related CommentarySeeing how we smellHelene Benveniste, Yuri Lazebnik, and Nora D. Volkow http://jci.me/91305
Astrocytic calcium release mediates peri-infarct depolarizations in a rodent stroke modelCordula Rakers and Gabor C. Petzold http://jci.me/89354
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JCI | Research: Editor’s picks
cardiology
Regulating cardiomyocyte proliferation during heart developmentAs the heart develops, maturing myocytes undergo cell cycle withdrawal as their proliferative capacity is reduced. Failure to undergo cell cycle withdrawal can lead to life-threatening heart diseases, including ventricular noncompaction, which is associated with overproliferation of trabecular myocytes. The growth factor receptor ERBB2 is critical in cardiomyocyte proliferation and is downregu-lated at the end of cardiac development. New work by Maretoshi Hirai and colleagues identified the endocytic adaptor proteins NUMB and NUMBL as essential mediators of ERBB2 signaling in maturing cardiomyocytes. In the absence of NUMB and NUMBL, mice exhibited sustained ERBB2 signaling that was associated with overproliferation of trabecular cardiomyocytes (see the accompanying image). Further study determined that NUMB/NUMBL interactions mediate endosomal degradation of ERBB2 through interactions with the Ras-related protein Rab7. In NUMB/NUMBL-deficient cells, consequent activation of ERBB2 led to aberrant activation of STAT5 and YAP1. These findings provide insight into mechanisms that critically control cardiac development and influence developmental heart diseases.
Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradationMaretoshi Hirai, Yoh Arita, C. Jane McGlade, Kuo-Fen Lee, Ju Chen, and Sylvia M. Evans http://jci.me/91081
hematology
Inflammatory environment drives risk of graft-versus-host disease in leukemia patientsDonor T cells engrafted into patients with leukemia evoke a graft-versus-leukemia (GVL) response by targeting malignant tissue, but donor T cells can also attack healthy tissue, leading to life-threatening graft-versus-host disease (GVHD). GVHD risk is reduced when grafts are depleted of T cells before transplantation and patients receive a postponed infusion of donor lymphocytes. Work performed by Cornelis van Bergen and coworkers examined T cell responses in patients who developed GVL without GVHD. They observed that transplantation success in these patients corresponded to lower T cell response magnitude and diversity for minor histocompat-ibility antigens (MiHAs). Although T cells recognized similar types of MiHAs in patients who developed GVHD, T cells in non-GVHD patients more selectively targeted hematopoietic cells. These findings support the
concept that a delay between engraftment and lymphocyte infusion may help donor T cells evade inflammatory environments that promote GVHD, favoring more selective GVL reactivity.
Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell responseCornelis A.M. van Bergen, Simone A.P. van Luxemburg-Heijs, Liesbeth C. de Wreede, Matthijs Eefting, Peter A. von dem Borne, Peter van Balen, Mirjam H.M. Heemskerk, Arend Mulder, Fransiscus H.J. Claas, Marcelo A. Navarrete, Wilhelmina M. Honders, Caroline E. Rutten, Hendrik Veelken, Inge Jedema, Constantijn J.M. Halkes, Marieke Griffioen, and J.H. Frederik Falkenburg http://jci.me/86175
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JCI | Research: Editor’s picks
metabolism
SUMOylation of nuclear receptor LRH-1 regulates lipogenesis in the liverImbalances in liver metabolism can lead to the hepatic fat accumula-tion that is characteristic of nonalcoholic fatty liver disease (NAFLD). Although sterol element binding protein 1 (SREBP-1) and the nuclear receptor liver receptor homolog 1 (LRH-1) are known to regulate liver metabolism, their interplay in lipogenesis is not well defined. Sokrates Stein, Vera Lemos, and colleagues investigated how posttranslational modification of LRH-1 contributes to development of NAFLD. Fasting-refeeding experiments in mice expressing a SUMOylation-defective LRH-1 showed increased hepatic processing of SREBP-1 and enhanced expression of SREBP-1 target genes. They determined that defective LRH-1 SUMOylation induced elevated expression of the oxysterol binding protein–related protein OSBPL3, which in turn promoted SREBP-1 processing and led to increased lipogenesis. Moreover, in high-fat-, high-sucrose-fed mice, the aberrant post trans-lational processing of LRH-1 drove the development of NAFLD in an OSBPL3-dependent manner, identifying a potential target for the treatment or prevention of this disease.
Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver diseaseSokrates Stein, Vera Lemos, Pan Xu, Hadrien Demagny, Xu Wang, Dongryeol Ryu, Veronica Jimenez, Fatima Bosch, Thomas F. Lüscher, Maaike H. Oosterveer, and Kristina Schoonjans http://jci.me/85499
Hypothalamic Gsα imprinting underlies obesity associated with maternal Gsα mutations
A single episode of high-fat intake alters liver metabolismDiets high in saturated fat are associated with the development of nonalcoholic fatty liver disease and insulin resistance, but the initial effects of fat intake on metabolic pathways are not well described. A study by Michael Roden’s laboratory investigated how an acute episode of saturated fat intake that was equivalent to a rich meal affected insulin sensitivity, hepatic glucose metabolism, and lipid metabolism in humans and mice. They found that acute fat intake led to immediate increases in hepatic fat accumu-lation and altered hepatic metabolism. The treatment also induced insulin resistance and increased circulating levels of triglycerides and glucagon. In the accompanying Commentary, Elizabeth Parks, Hannele Yki-Järvinen, and Meredith Hawkins highlight the contribution of rapid responses to fat intake to the development of metabolic diseases.
Acute dietary fat intake initiates alterations in energy metabolism and insulin resistanceElisa Álvarez Hernández, Sabine Kahl, Anett Seelig, Paul Begovatz, Martin Irmler, Yuliya Kupriyanova, Bettina Nowotny, Peter Nowotny, Christian Herder, Cristina Barosa, Filipa Carvalho, Jan Rozman, Susanne Neschen, John G. Jones, Johannes Beckers, Martin Hrabě de Angelis, and Michael Roden http://jci.me/89444
Related CommentaryOut of the frying pan: dietary saturated fat influences nonalcoholic fatty liver diseaseElizabeth Parks, Hannele Yki-Järvinen, and Meredith Hawkins http://jci.me/92407
Inactivating mutations in the G protein Gsα lead to obesity and insulin resistance, but only when the inactivation occurs on the maternal allele. CNS-mediated regulation of sympathetic nervous system activity drives the phenotype of Gsα maternal imprinting, but the specific pathways involved are not known. Min Chen, Yogendra Shrestha, and coworkers showed that deletion of the maternal allele encoding Gsα in the dorsomedial nucleus of the hypothalamus (DMH) recapitulated the obesity and reduced energy expendi-ture associated with nonspecific maternal Gsα inactivation. DMH-specific loss of Gsα signaling also impaired brown adipose tissue activation (see the accompanying image) without compromising physiologic responses to cold temperatures. These findings suggest that obesity associated with maternal Gsα imprinting is driven by reductions in brown adipose activation via pathways that originate in the DMH.
Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutationsMin Chen, Yogendra B. Shrestha, Brandon Podyma, Zhenzhong Cui, Benedetta Naglieri, Hui Sun, Thuy Ho, Eric A. Wilson, Yong-Qi Li, Oksana Gavrilova, and Lee S. Weinstein http://jci.me/88622
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JCI | Research: Editor’s picks
autoimmunity
miR-27 is a key regulator of Treg-mediated immunological tolerance
muscle biology
Dysregulation of AMPK and mTORC1 signaling drives dystrophic muscle pathologyIn myotonic dystrophy type I (DM1), CTG repeats in the gene encoding dystrophia myotonica protein kinase lead to splicing defects that predominantly affect skeletal muscle. Recently, aberrations in the pathways that control muscle homeostasis have been linked to DM1 pathology, suggesting that components of these pathways may be potential targets for treating this disease. In this issue, Marielle Brockhoff and coworkers demonstrate that AMPK and mTORC1 signaling pathways were dysregulated in muscle tissue in a mouse model of DM1. This was accompa-nied by perturbation in the autophagic flux in muscle from DM1 mice and in muscle cells from DM1 patients. In DM1 mice, pharmacological approaches targeting AMPK improved muscle function, promoted nuclear
foci dispersion (see the accompanying image), and reduced mis-splicing of chloride channel 1 transcripts, whereas approaches targeting the mTORC1 pathway reduced myotonia without improving pathological splicing. These findings identify AMPK and mTORC1 pathways as potential therapeutic targets for treating certain aspects of DM1.
Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type IMarielle Brockhoff, Nathalie Rion, Kathrin Chojnowska, Tatiana Wiktorowicz, Christopher Eickhorst, Beat Erne, Stephan Frank, Corrado Angelini, Denis Furling, Markus A. Rüegg, Michael Sinnreich, and Perrine Castets http://jci.me/89616
aids/hiv
Rapamycin tones down the toxicity of HIV-1 reactivation strategiesAlthough HIV-1–infected patients can achieve successful disease management on antiretroviral therapies, the HIV-1 virus persists in a latent reservoir in resting memory T cells. Reactivation of HIV-1 can enable more complete eradication of the infection, but current strategies for global T cell activation are considered too toxic for therapeutic applications. Alyssa Martin and colleagues evaluated a combined strategy of T cell activation and immunosuppression using the mTOR inhibitor rapamycin
in T cells isolated from HIV-1–infected individuals. Rapamycin treatment reduced proinflammatory cytokine release and other indices of toxicity without abrogating HIV-1 reactivation in activated T cells or impairing immune recognition of infected cells. In contrast, a different immunomodulator, cyclosporine, robustly inhibited HIV-1 reactivation when combined with T cell activation. These findings indicate that rapamycin could be used to mitigate the toxicity of strategies targeting the HIV-1 latent reservoir.
Rapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicityAlyssa R. Martin, Ross A. Pollack, Adam Capoferri, Richard F. Ambinder, Christine M. Durand, and Robert F. Siliciano http://jci.me/89552
Many hematopoietic malignancies and autoimmune diseases are associated with dysregulation of miRs, which play an important role in regulating immune development and function. In patients with multiple sclerosis, elevated levels of miR-27 in T cells have been associated with inhibition of Th2 immunity and increases in pathogenic Th1 responses. Leilani Cruz and colleagues observed that T cell–specific overexpression of miR-27
led to dysregulation of Th1 responses and an autoim-mune phenotype in mice. They discovered that this phenotype arose from disruptions in Treg differentiation and function and that miR-27 regulated the expression of several genes that are important for Treg biology. These findings indicate that miR-27 regulates multiple aspects of Treg development and activity and plays a key role in establishing immunological tolerance.
Excessive expression of miR-27 impairs Treg-mediated immunological toleranceLeilani O. Cruz, Somaye Sadat Hashemifar, Cheng-Jang Wu, Sunglim Cho, Duc T. Nguyen, Ling-Li Lin, Aly Azeem Khan, and Li-Fan Lu http://jci.me/88415
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JCI | Features
conversations with giants in medicine
Eric OlsonEric Olson’s pivotal research in the field of molecular biology has uncovered the mechanisms that control cardiac and skeletal muscle development. His current work focuses on finding new treatments for muscular dystrophies, potential regenerative approaches for cardiac and skeletal muscle, and the role of epigenetic mechanisms as regulators of muscle development. Dr. Olson currently holds the Annie and Willie Nelson Professorship in Stem Cell Research at the University of Texas Southwestern Medical Center and is himself a talented musician. This month, in a conversation with JCI Editor at Large Ushma Neill, he discusses how creativity and a love of discovery have driven his career in science and what it was like to meet Willie Nelson. http://jci.me/92059
reviews
Examining the pathways that stimulate cardiac regeneration
Age-related shifts in circadian rhythm can disrupt health and longevityThe circadian system uses light cues to coordinate cellular, physiological, and behavioral processes with the 24-hour day and night cycle. The superchiasmatic nucleus in the brain is respon-sible for maintaining the circadian rhythms that influence when we sleep, wake, and eat. These rhythms also affect immune system function and metabolic pathways. As we age, circadian rhythms become fragmented, leading to detrimental effects on sleep and other aspects of health. In this issue, Suzanne Hood and Shimon Amir review the evidence that age-related changes in circadian rhythms and sleep substantially affect cognitive function, waking activity, and immunity. They also discuss potential approaches for re-entraining the circadian system to improve health outcomes in the aging population.
The aging clock: circadian rhythms and later lifeSuzanne Hood and Shimon Amir http://jci.me/90328
Limited therapeutic options are available to patients with advanced cardiovascular disease. As heart failure often results from cardiomyocyte death, regenerative approaches to replace lost cardiomyocytes have the potential to dramati-cally improve disease prognosis. Although most adult mammalian cardiomyocytes lose the ability to proliferate, the regenerative programs initiated in zebrafish and neonatal mice have
provided clues about potential targets for stimulating growth in mature cardiac tissue. Ravi Karra and Ken Poss describe the latest findings and challenges in the field of cardiac regenerative medicine. They discuss the pathways that respond to injury in zebrafish and neonatal mouse cardiac tissue as well as the possibility of targeting these pathways to stimulate regeneration in the adult heart.
Redirecting cardiac growth mechanisms for therapeutic regenerationRavi Karra and Kenneth D. Poss http://jci.me/89786
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aids/hivRapamycin-mediated mTOR inhibition uncouples HIV-1 latency reversal from cytokine-associated toxicity p. 6Alyssa R. Martin, Ross A. Pollack, Adam Capoferri, Richard F. Ambinder, Christine M. Durand, and Robert F. Siliciano http://jci.me/89552
autoimmunityExcessive expression of miR-27 impairs Treg-mediated immunological tolerance p. 6Leilani O. Cruz, Somaye Sadat Hashemifar, Cheng-Jang Wu, Sunglim Cho, Duc T. Nguyen, Ling-Li Lin, Aly Azeem Khan, and Li-Fan Lu http://jci.me/88415
cardiologyAdaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation p. 4Maretoshi Hirai, Yoh Arita, C. Jane McGlade, Kuo-Fen Lee, Ju Chen, and Sylvia M. Evans http://jci.me/91081
cell biologyFluorescent aminoglycosides reveal intracellular trafficking routes in mechanosensory hair cellsDale W. Hailey, Robert Esterberg, Tor H. Linbo, Edwin W. Rubel, and David W. Raible http://jci.me/85052
gastroenterologyOrphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formationDaniel O. Kechele, R. Eric Blue, Bailey Zwarycz, Scott T. Espenschied, Amanda T. Mah, Marni B. Siegel, Charles M. Perou, Shengli Ding, Scott T. Magness, P. Kay Lund, and Kathleen M. Caron http://jci.me/87588
Matriptase-mediated cleavage of EpCAM destabilizes claudins and dysregulates intestinal epithelial homeostasisChuan-Jin Wu, Xu Feng, Michael Lu, Sohshi Morimura, and Mark C. Udey http://jci.me/88428
hematologySelective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response p. 4Cornelis A.M. van Bergen, Simone A.P. van Luxemburg-Heijs, Liesbeth C. de Wreede, Matthijs Eefting, Peter A. von dem Borne, Peter van Balen, Mirjam H.M. Heemskerk, Arend Mulder, Fransiscus H.J. Claas, Marcelo A. Navarrete, Wilhelmina M. Honders, Caroline E. Rutten, Hendrik Veelken, Inge Jedema, Constantijn J.M. Halkes, Marieke Griffioen, and J.H. Frederik Falkenburg http://jci.me/86175
Versatile humanized niche model enables study of normal and malignant human hematopoiesisAnder Abarrategi, Katie Foster, Ashley Hamilton, Syed A. Mian, Diana Passaro, John Gribben, Ghulam Mufti, and Dominique Bonnet http://jci.me/89364
BCL-W has a fundamental role in B cell survival and lymphomagenesisClare M. Adams, Annette S. Kim, Ramkrishna Mitra, John K. Choi, Jerald Z. Gong, and Christine M. Eischen http://jci.me/89486
Current research articles
Aberrant YAP1 localization
GPR182 in kidney
9j c i . o r g / t h i s - m o n t h f e b r u a r y 2 0 1 7
metabolismImpaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease p. 5Sokrates Stein, Vera Lemos, Pan Xu, Hadrien Demagny, Xu Wang, Dongryeol Ryu, Veronica Jimenez, Fatima Bosch, Thomas F. Lüscher, Maaike H. Oosterveer, and Kristina Schoonjans http://jci.me/85499
Mechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosisRachel J. Perry, Liang Peng, Abudukadier Abulizi, Lynn Kennedy, Gary W. Cline, and Gerald I. Shulman http://jci.me/88477
Gsα deficiency in the dorsomedial hypothalamus underlies obesity associated with Gsα mutations p. 5Min Chen, Yogendra B. Shrestha, Brandon Podyma, Zhenzhong Cui, Benedetta Naglieri, Hui Sun, Thuy Ho, Eric A. Wilson, Yong-Qi Li, Oksana Gavrilova, and Lee S. Weinstein http://jci.me/88622
Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance p. 5Elisa Álvarez Hernández, Sabine Kahl, Anett Seelig, Paul Begovatz, Martin Irmler, Yuliya Kupriyanova, Bettina Nowotny, Peter Nowotny, Christian Herder, Cristina Barosa, Filipa Carvalho, Jan Rozman, Susanne Neschen, John G. Jones, Johannes Beckers, Martin Hrabě de Angelis, and Michael Roden http://jci.me/89444
muscle biologyTargeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I p. 6Marielle Brockhoff, Nathalie Rion, Kathrin Chojnowska, Tatiana Wiktorowicz, Christopher Eickhorst, Beat Erne, Stephan Frank, Corrado Angelini, Denis Furling, Markus A. Rüegg, Michael Sinnreich, and Perrine Castets http://jci.me/89616
neuroscienceM1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss p. 2Sophie J. Bradley, Julie-Myrtille Bourgognon, Helen E. Sanger, Nicholas Verity, Adrian J. Mogg, David J. White, Adrian J. Butcher, Julie A. Moreno, Colin Molloy, Timothy Macedo-Hatch, Jennifer M. Edwards, Jurgen Wess, Robert Pawlak, David J. Read, Patrick M. Sexton, Lisa M. Broad, Joern R. Steinert, Giovanna R. Mallucci, Arthur Christopoulos, Christian C. Felder, and Andrew B. Tobin http://jci.me/87526
Nasal neuron PET imaging quantifies neuron generation and degeneration p. 3Genevieve C. Van de Bittner, Misha M. Riley, Luxiang Cao, Janina Ehses, Scott P. Herrick, Emily L. Ricq, Hsiao-Ying Wey, Michael J. O’Neill, Zeshan Ahmed, Tracey K. Murray, Jaclyn E. Smith, Changning Wang, Frederick A. Schroeder, Mark W. Albers, and Jacob M. Hooker http://jci.me/89162
Astrocytic calcium release mediates peri-infarct depolarizations in a rodent stroke model p. 3Cordula Rakers and Gabor C. Petzold http://jci.me/89354
Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathyNigel A. Calcutt, Darrell R. Smith, Katie Frizzi, Mohammad Golam Sabbir, Subir K. Roy Chowdhury, Teresa Mixcoatl-Zecuatl, Ali Saleh, Nabeel Muttalib, Randy Van der Ploeg, Joseline Ochoa, Allison Gopaul, Lori Tessler, Jürgen Wess, Corinne G. Jolivalt, and Paul Fernyhough http://jci.me/88321Adult sensory neurons
AICAR-treated muscle
Lrh1-mutant liver lipids
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JCI | Current research articles
neuroscienceKisspeptin modulates sexual and emotional brain processing in humans p. 1Alexander N. Comninos, Matthew B. Wall, Lysia Demetriou, Amar J. Shah, Sophie A. Clarke, Shakunthala Narayanaswamy, Alexander Nesbitt, Chioma Izzi-Engbeaya, Julia K. Prague, Ali Abbara, Risheka Ratnasabapathy, Victoria Salem, Gurjinder M. Nijher, Channa N. Jayasena, Mark Tanner, Paul Bassett, Amrish Mehta, Eugenii A. Rabiner, Christoph Hönigsperger, Meire Ribeiro Silva, Ole Kristian Brandtzaeg, Elsa Lundanes, Steven Ray Wilson, Rachel C. Brown, Sarah A. Thomas, Stephen R. Bloom, and Waljit S. Dhillo http://jci.me/89519
Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy p. 2Cristina Alcacer, Laura Andreoli, Irene Sebastianutto, Johan Jakobsson, Tim Fieblinger, and Maria Angela Cenci http://jci.me/90132
vascular biologyCarbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesisSungwoon Lee, Seung-Sik Rho, Hyojin Park, Jeong Ae Park, Jihye Kim, In-Kyu Lee, Gou Young Koh, Naoki Mochizuki, Young-Myeong Kim, and Young-Guen Kwon http://jci.me/85145
Blood pressure–associated polymorphism controls ARHGAP42 expression via serum response factor DNA bindingXue Bai, Kevin D. Mangum, Rachel A. Dee, George A. Stouffer, Craig R. Lee, Akinyemi Oni-Orisan, Cam Patterson, Jonathan C. Schisler, Anthony J. Viera, Joan M. Taylor, and Christopher P. Mack http://jci.me/88899
MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosisBishuang Cai, Edward B. Thorp, Amanda C. Doran, Brian E. Sansbury, Mat J.A.P. Daemen, Bernhard Dorweiler, Matthew Spite, Gabrielle Fredman, and Ira Tabas http://jci.me/90520
Retinal VEGFR-3
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Editor’s picks
Top read JCI Insight articles of 2016The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effectsHidekazu Itamura, Takero Shindo, Isao Tawara, Yasushi Kubota, Ryusho Kariya, Seiji Okada, Krishna V. Komanduri, and Shinya Kimura http://jci.me/86331
Elimination of p19ARF-expressing cells enhances pulmonary function in miceMichihiro Hashimoto, Azusa Asai, Hiroyuki Kawagishi, Ryuta Mikawa, Yuji Iwashita, Kazuki Kanayama, Kazushi Sugimoto, Tadashi Sato, Mitsuo Maruyama, and Masataka Sugimoto http://jci.me/87732
Zika virus productively infects primary human placenta-specific macrophagesKellie Ann Jurado, Michael K. Simoni, Zhonghua Tang, Ryuta Uraki, Jesse Hwang, Sarah Householder, Mingjie Wu, Brett D. Lindenbach, Vikki M. Abrahams, Seth Guller, and Erol Fikrig http://jci.me/88461
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
A wearable artificial kidney for patients with end-stage renal diseaseVictor Gura, Matthew B. Rivara, Scott Bieber, Raj Munshi, Nancy Colobong Smith, Lori Linke, John Kundzins, Masoud Beizai, Carlos Ezon, Larry Kessler, and Jonathan Himmelfarb http://jci.me/86397
Kappa opioid receptors mediate multiple protective processes in posttraumatic cartilage degeneration
bone biology
Opioid-like drugs, which primarily mediate their effects through three classic opioid receptors, are commonly used to treat patients with osteoarthritis. Recent efforts to develop nonaddictive opioids have centered on the kappa opioid receptor (KOR), as KOR agonists do not typically exhibit addictive properties; however, the precise role of this receptor in the skeletal system has not been completely elucidated. Using a murine model of osteoarthritis, Ling Wu and colleagues demonstrated that KOR-deficient mice exhibit accelerated injury-induced cartilage degeneration compared with WT mice (see the accompanying image), suggesting a protective effect of KOR signaling. Mechanistic studies revealed that KOR activation increased the expression of anabolic enzymes, increased joint lubrication, and inhibited cartilage catabolism and degeneration mediated by proinflammatory cytokines. These findings indicate that KOR agonists may elicit a multifactorial protective response to protect against cartilage degeneration after injury.
Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degenerationLing Wu, Shu Zhang, Ruzanna Shkhyan, Siyoung Lee, Francesca Gullo, Claire D. Eliasberg, Frank A. Petrigliano, Kai Ba, Jing Wang, Yunfeng Lin, and Denis Evseenko http://jci.me/88553
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vascular biology
JCI Insight | Editor’s picks
Quantitative noninvasive imaging of lymphatic transport
MeCP2 overexpression hypersensitizes mice to lethal influenza infection
The lymphatic vasculature maintains fluid homeostasis, regulates transport of macromolecules from the interstitium to the blood, and modulates immunity within tissues. Lymphatic function is disturbed in a number of pathological conditions, necessitating the development of techniques to measure lymphatic flow. Steven Proulx and colleagues report the use of an interstitially injected 40-kDa PEGylated near-infrared (NIR) dye conjugate, P40D800, to measure lymphatic function in mice. The NIR dye was taken up specifically by the lymphatic
vasculature, eventually appearing in the blood circulation, where it could be visualized in a superficial vein. This method was able to quantify changes in lymphatic transport in murine models of impaired lymphatic flow, including decreased transport in aged or anesthetized mice (see the accompanying image). Moreover, the NIR dye had sufficient sensitivity for the measurement of lymphatic transport from the peritoneal cavity, allowing for assessment of lymphatic transport in organs that cannot be imaged using current techniques.
Quantitative measurement of lymphatic function in mice by noninvasive near-infrared imaging of a peripheral veinSteven T. Proulx, Qiaoli Ma, Diana Andina, Jean-Christophe Leroux, and Michael Detmar http://jci.me/90861
Overexpression of methyl-CpG-binding protein 2 (MeCP2) causes the severe neuro developmental disorder MeCP2 duplication syndrome, which is also characterized by chronic, severe respira-tory infections. James Cronk and colleagues investigated the role of MeCP2 in the response to influenza infection. They found that expression of MeCP2 at 3 to 5 times the normal level in mice resulted in hypersensitivity to influenza infection that was character-ized by multiple complications such as high levels of neutrophils, cortico-sterones, and cytokines; defects in adaptive immunity; and pulmonary hemorrhage (see the accompanying image). Interestingly, bone marrow
transplant after irradiation did not improve survival, indicating that the cells mediating the increased morbidity and mortality were insensitive to radiation. These findings indicate that MeCP2 overexpression affects multiple compartments to render the response to infection ineffective.
infectious disease
Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing miceJames C. Cronk, Jasmin Herz, Taeg S. Kim, Antoine Louveau, Emily K. Moser, Ashish K. Sharma, Igor Smirnov, Kenneth S. Tung, Thomas J. Braciale, and Jonathan Kipnis http://jci.me/88257
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JCI Insight | Editor’s picks
oncology
Anti-SIRPα antibodies impair tumor development by promoting cellular phagocytosisThe tumor microenvironment plays a critical role in regulating tumor initiation and progression as well as shaping interactions between tumor cells and immune cells, allowing tumor cells to evade elimination by the immune system. Signal- regulatory protein α (SIRPα) is expressed on macrophages and inhibits phagocytosis of target cells through interactions with CD47 expressed on target cells. Tadahiko Yanagita and colleagues found that SIRPα is highly expressed in human renal cell carcinoma and melanoma (see the accompanying image). Using immunocompetent syngeneic murine models of these diseases, they demonstrated that administration of an anti-SIRPα antibody that blocks the SIRPα-CD47 interaction impaired tumor formation via direct induction of antibody-dependent cellular phagocytosis and abrogation of antiphagocytic signaling mediated by CD47 ligation of SIRPα. These findings suggest that anti-SIRPα antibodies should be studied further as a cancer immunotherapy.
Anti-SIRPα antibodies as a potential new tool for cancer immunotherapyTadahiko Yanagita, Yoji Murata, Daisuke Tanaka, Sei-ichiro Motegi, Eri Arai, Edwin Widyanto Daniwijaya, Daisuke Hazama, Ken Washio, Yasuyuki Saito, Takenori Kotani, Hiroshi Ohnishi, Per-Arne Oldenborg, Noel Verjan Garcia, Masayuki Miyasaka, Osamu Ishikawa, Yae Kanai, Takahide Komori, and Takashi Matozaki http://jci.me/89140
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Current research articles
A xenogeneic-free system generating functional human gut organoids from pluripotent stem cellsHajime Uchida, Masakazu Machida, Takumi Miura, Tomoyuki Kawasaki, Takuya Okazaki, Kengo Sasaki, Seisuke Sakamoto, Noriaki Ohuchi, Mureo Kasahara, Akihiro Umezawa, and Hidenori Akutsu http://jci.me/86492
IFITM1 targets HIV-1 latently infected cells for antibody-dependent cytolysisRui André Saraiva Raposo, Miguel de Mulder Rougvie, Dominic Paquin-Proulx, Phillip M. Brailey, Vinicius D. Cabido, Paul M. Zdinak, Allison S. Thomas, Szu-han Huang, Greta A. Beckerle, Richard B. Jones, and Douglas F. Nixon http://jci.me/85811
Kappa opioid receptor signaling protects cartilage tissue against posttraumatic degeneration p. 11Ling Wu, Shu Zhang, Ruzanna Shkhyan, Siyoung Lee, Francesca Gullo, Claire D. Eliasberg, Frank A. Petrigliano, Kai Ba, Jing Wang, Yunfeng Lin, and Denis Evseenko http://jci.me/88553
Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy p. 13Tadahiko Yanagita, Yoji Murata, Daisuke Tanaka, Sei-ichiro Motegi, Eri Arai, Edwin Widyanto Daniwijaya, Daisuke Hazama, Ken Washio, Yasuyuki Saito, Takenori Kotani, Hiroshi Ohnishi, Per-Arne Oldenborg, Noel Verjan Garcia, Masayuki Miyasaka, Osamu Ishikawa, Yae Kanai, Takahide Komori, and Takashi Matozaki http://jci.me/89140
Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboliMargaret F. Bennewitz, Maritza A. Jimenez, Ravi Vats, Egemen Tutuncuoglu, Jude Jonassaint, Gregory J. Kato, Mark T. Gladwin, and Prithu Sundd http://jci.me/89761
Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activationJack D. Stopa, Donna Neuberg, Maneka Puligandla, Bruce Furie, Robert Flaumenhaft, and Jeffrey I. Zwicker http://jci.me/89373
Protection against Plasmodium falciparum malaria by PfSPZ VaccineJudith E. Epstein, Kristopher M. Paolino, Thomas L. Richie, Martha Sedegah, Alexandra Singer, Adam J. Ruben, Sumana Chakravarty, April Stafford, Richard C. Ruck, Abraham G. Eappen, Tao Li, Peter F. Billingsley, Anita Manoj, Joana C. Silva, Kara Moser, Robin Nielsen, Donna Tosh, Susan Ciccatelli, Harini Ganeshan, Jessica Case, Debbie Padilla, Silas Davidson, Lindsey Garver, Elizabeth Savarino, Tooba Murshedkar, Anusha Gunasekera, Patrick S. Twomey, Sharina Reyes, James E. Moon, Eric R. James, Natasha KC, Minglin Li, Esteban Abot, Arnel Belmonte, Kevin Hauns, Maria Belmonte, Jun Huang, Carlos Vasquez, Shon Remich, Mary Carrington, Yonas Abebe, Amy Tillman, Bradley Hickey, Jason Regules, Eileen Villasante, B. Kim Lee Sim, and Stephen L. Hoffman http://jci.me/89154
Vps34 regulates myofibril proteostasis to prevent hypertrophic cardiomyopathyHirotaka Kimura, Satoshi Eguchi, Junko Sasaki, Keiji Kuba, Hiroki Nakanishi, Shunsuke Takasuga, Masakazu Yamazaki, Akiteru Goto, Hiroyuki Watanabe, Hiroshi Itoh, Yumiko Imai, Akira Suzuki, Noboru Mizushima, and Takehiko Sasaki http://jci.me/89462
Ectonucleotidase CD39-driven control of postinfarction myocardial repair and ruptureNadia R. Sutton, Takanori Hayasaki, Matthew C. Hyman, Anuli C. Anyanwu, Hui Liao, Danica Petrovic-Djergovic, Linda Badri, Amy Baek, Natalie Walker, Keigo Fukase, Yogendra Kanthi, Scott H. Visovatti, Ellen L. Horste, Jessica J. Ray, Sascha N. Goonewardena, and David J. Pinsky http://jci.me/89504
Neutrophil-platelet aggregate
Gut organoid E-cadherin
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Quantitative measurement of lymphatic function in mice by noninvasive near-infrared imaging of a peripheral vein p. 12Steven T. Proulx, Qiaoli Ma, Diana Andina, Jean-Christophe Leroux, and Michael Detmar http://jci.me/90861
Kruppel-like factor4 regulates PRDM1 expression through binding to an autoimmune risk alleleSu Hwa Jang, Helen Chen, Peter K. Gregersen, Betty Diamond, and Sun Jung Kim http://jci.me/89569
Metastasis regulation by PPARD expression in cancer cellsXiangsheng Zuo, Weiguo Xu, Min Xu, Rui Tian, Micheline J. Moussalli, Fei Mao, Xiaofeng Zheng, Jing Wang, Jeffrey S. Morris, Mihai Gagea, Cathy Eng, Scott Kopetz, Dipen M. Maru, Asif Rashid, Russell Broaddus, Daoyan Wei, Mien-Chie Hung, Anil K. Sood, and Imad Shureiqi http://jci.me/91419
A patient-derived-xenograft platform to study BRCA-deficient ovarian cancersErin George, Hyoung Kim, Clemens Krepler, Brandon Wenz, Mehran Makvandi, Janos L. Tanyi, Eric Brown, Rugang Zhang, Patricia Brafford, Stephanie Jean, Robert H. Mach, Yiling Lu, Gordon B. Mills, Meenhard Herlyn, Mark Morgan, Xiaochen Zhang, Robert Soslow, Ronny Drapkin, Neil Johnson, Ying Zheng, George Cotsarelis, Katherine L. Nathanson, and Fiona Simpkins http://jci.me/89760
Oxidized CaMKII promotes asthma through the activation of mast cellsJingjing Qu, Danh C. Do, Yufeng Zhou, Elizabeth Luczak, Wayne Mitzner, Mark E. Anderson, and Peisong Gao http://jci.me/90139
GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistanceRuby Kuang, Arman Jahangiri, Smita Mascharak, Alan Nguyen, Ankush Chandra, Patrick M. Flanigan, Garima Yagnik,
Jeffrey R. Wagner, Michael De Lay, Diego Carrera, Brandyn A. Castro, Josie Hayes, Maxim Sidorov, Jose Luiz Izquierdo Garcia, Pia Eriksson, Sabrina Ronen, Joanna Phillips, Annette Molinaro, Suneil Koliwad, and Manish K. Aghi http://jci.me/88815
Deletion of p22phox-dependent oxidative stress in the hypothalamus protects against obesity by modulating β3-adrenergic mechanismsHeinrich E. Lob, Jiunn Song, Chansol Hurr, Alvin Chung, Colin N. Young, Allyn L. Mark, and Robin L. Davisson http://jci.me/87094
Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage developmentReena J. Popat, Seran Hakki, Alpesh Thakker, Alice M. Coughlan, Julie Watson, Mark A. Little, Corinne M. Spickett, Paul Lavender, Behdad Afzali, Claudia Kemper, and Michael G. Robson http://jci.me/87379
Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivoAlison Xiaoqiao Xie, Jakovin J. Lee, and Ken D. McCarthy http://jci.me/90565
Transient stimulation expands superior antitumor T cells for adoptive therapyYuki Kagoya, Munehide Nakatsugawa, Toshiki Ochi, Yuchen Cen, Tingxi Guo, Mark Anczurowski, Kayoko Saso, Marcus O. Butler, and Naoto Hirano http://jci.me/89580
Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunctionAli Hashemi Gheinani, Bernhard Kiss, Felix Moltzahn, Irene Keller, Rémy Bruggmann, Hubert Rehrauer, Catharine Aquino Fournier, Fiona C. Burkhard, and Katia Monastyrskaya http://jci.me/89560
Mast cell extravasation
Diaphragm lymphatics
Schwann cells
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JCI Insight | Current research articles
Influenza A induces dysfunctional immunity and death in MeCP2-overexpressing mice p. 12James C. Cronk, Jasmin Herz, Taeg S. Kim, Antoine Louveau, Emily K. Moser, Ashish K. Sharma, Igor Smirnov, Kenneth S. Tung, Thomas J. Braciale, and Jonathan Kipnis http://jci.me/88257
Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadthEnrique Martin-Gayo, Jacqueline Cronin, Taylor Hickman, Zhengyu Ouyang, Madelene Lindqvist, Kellie E. Kolb, Julian Schulze zur Wiesch, Rafael Cubas, Filippos Porichis, Alex K. Shalek, Jan van Lunzen, Elias K. Haddad, Bruce D. Walker, Daniel E. Kaufmann, Mathias Lichterfeld, and Xu G. Yu http://jci.me/89574
Prostatic compensation of the vitamin D axis in African American menZachary Richards, Ken Batai, Rachael Farhat, Ebony Shah, Andrew Makowski, Peter H. Gann, Rick Kittles, and Larisa Nonn http://jci.me/91054
CD44 expression in endothelial colony-forming cells regulates neurovascular trophic effectSusumu Sakimoto, Valentina Marchetti, Edith Aguilar, Kelsey Lee, Yoshihiko Usui, Salome Murinello,
Felicitas Bucher, Jennifer K. Trombley, Regis Fallon, Ravenska Wagey, Carrie Peters, Elizabeth L. Scheppke, Peter D. Westenskow, and Martin Friedlander http://jci.me/89906
3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugsRanu Surolia, Fu Jun Li, Zheng Wang, Huashi Li, Gang Liu, Yong Zhou, Tracy Luckhardt, Sejong Bae, Rui-ming Liu, Sunad Rangarajan, Joao de Andrade, Victor J. Thannickal, and Veena B. Antony http://jci.me/91377
Repair after nephron ablation reveals limitations of neonatal neonephrogenesisFlorian Tögel, M. Todd Valerius, Benjamin S. Freedman, Rossella Latrino, Mor Grinstein, and Joseph V. Bonventre http://jci.me/88848
Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinibJan A. Burger, Kelvin W. Li, Michael J. Keating, Mariela Sivina, Ahmed M. Amer, Naveen Garg, Alessandra Ferrajoli,
Xuelin Huang, Hagop Kantarjian, William G. Wierda, Susan O’Brien, Marc K. Hellerstein, Scott M. Turner, Claire L. Emson, Shih-Shih Chen, Xiao-Jie Yan, Dominik Wodarz, and Nicholas Chiorazzi http://jci.me/89904
Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertensionPin-I Chen, Aiqin Cao, Kazuya Miyagawa, Nancy F. Tojais, Jan K. Hennigs, Caiyun G. Li, Nathaly M. Sweeney, Audrey S. Inglis, Lingli Wang, Dan Li, Matthew Ye, Brian J. Feldman, and Marlene Rabinovitch http://jci.me/90427
Myocardial microRNAs associated with reverse remodeling in human heart failureCarmen C. Sucharov, David P. Kao, J. David Port, Anis Karimpour-Fard, Robert A. Quaife, Wayne Minobe, Karin Nunley, Brian D. Lowes, Edward M. Gilbert, and Michael R. Bristow http://jci.me/89169
Prostate epithelium megalin
Kidney lineage tracing
Christopher M. Adams
Maria-Luisa Alegre
Ravi K. Amaravadi
John K. Amory
Jennifer H. Anolik
Cristian Apetrei
Rajendra S. Apte
Zoltan Arany
Hossein Ardehali
Kenneth I. Ataga
Joseph Bass
Alexander G. Bassuk
Antonio C. Bianco
Jonathan S. Bogan
Laura M. Bohn
Nunzio Bottini
Sebastien G. Bouret
Jason Brenchley
Renier J. Brentjens
G.R. Scott Budinger
George A. Calin
Stephen Chan
Yuan Chang
Zhou-Feng Chen
Keith A. Choate
Wendy Chung
Craig M. Coopersmith
George Cotsarelis
Peter Crawford
Lisa L. Cunningham
Ronald P. DeMatteo
Elia J. Duh
Sarah K. England
Mark W. Feinberg
John H. Fingert
Robert Flaumenhaft
Edward A. Fon
Lawrence Fong
Nikolaos G. Frangogiannis
Anthony R. French
Terrence L. Geiger
Noyan Gokce
Raphaela Goldbach-Mansky
Daniel R. Goldstein
Douglas K. Graham
Khalid A. Hanafy
Eric B. Haura
John Cijiang He
Robert O. Heuckeroth
Cory M. Hogaboam
Young-Kwon Hong
Benjamin D. Humphreys
Ken Inoki
Shingo Kajimura
Pawel Kalinski
John Y. Kao
Mariana J. Kaplan
Michael G. Kaplitt
Barbara I. Kazmierczak
Hans-Peter Kiem
William Y. Kim
David G. Kirsch
Mathias Lichterfeld
André Lieber
Michail S. Lionakis
Carey N. Lumeng
Leo Luznik
Ivan Maillard
Ziad Mallat
Peter Mannon
Franck Mauvais-Jarvis
Dermot P.B. McGovern
Borna Mehrad
Ingo K. Mellinghoff
Jason C. Mills
Joshua D. Milner
Satdarshan (Paul) Singh Monga
Hidayatullah G. Munshi
Matthias Nahrendorf
Mary Nakamura
Lisa F.P. Ng
Mark Nicolls
Laura J. Niedernhofer
Deborah V. Novack
S. Tiong Ong
Puneet Opal
Daniel Ory
Sophie Paczesny
Stephanie T. Page
Mary-Elizabeth Patti
Janos Peti-Peterdi
Fernando P. Polack
Matthew D. Ringel
Steven M. Rowe
Svati H. Shah
Vijay H. Shah
Alice T. Shaw
Rhonda F. Souza
Fayyaz S. Sutterwala
Shu Takeda
Natalie J. Torok
Stephen H. Tsang
Ellie Tzima
Mark C. Udey
Fumihiko Urano
Charles P. Venditti
Joseph M. Vinetz
Sing Sing Way
Bernd Wollnik
Minna Woo
Prescott G. Woodruff
Lori M. Zeltser
Yutong Zhao
Binhua P. Zhou
JCI Insight Consulting Editors
