jci.org/this-month

Brown fat counteracts alcohol-impaired lipid metabolism 3

Mitochondrial content and racial disparity in cancer 4

Hypoxia-activated FoxO3 mitigates progressive kidney injury 5

Rapid antidepressant effects of mTORC1 activation 5

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

Scan for the digital version of JCI This Month.

June 2019

Bariatric surgery’s effects on bone and marrow niche p. 2

This Month

Journal of Clinical Investigation Consulting Editors

Soman N. Abraham

John S. Adams

Qais Al-Awqati

Kari Alitalo

Dario C. Altieri

Masayuki Amagai

Brian H. Annex

M. Amin Arnaout

Alan Attie

Jane E. Aubin

Michael F. Beers

Vann Bennett

Gregory K. Bergey

Nina Bhardwaj

Morris J. Birnbaum

Joyce Bischoff

Craig Blackstone

Bruce R. Blazar

Gerard C. Blobe

William A. Boisvert

Nancy Bonini

Brendan Boyce

Jonathan Bromberg

Frank C. Brosius

Hal E. Broxmeyer

Michael J. Caplan

Diego H. Castrillon

Harold Chapman

Ajay Chawla

Benjamin K. Chen

Benny J. Chen

Ju Chen

Jun Chen

Marie-Françoise Chesselet

Vivian G. Cheung

Raymond Chung

Jeanne M. Clark

Sheila Collins

Ronald G. Collman

Marco Colonna

Shaun R. Coughlin

Tyler J. Curiel

David D'Alessio

Richard T. D'Aquila

Alan Daugherty

Sudhansu Dey

Anna Mae Diehl

Harry C. Dietz III

Gianpietro Dotti

Michael Dustin

Connie J. Eaves

Dominique Eladari

Joel K. Elmquist

Stephen G. Emerson

Jonathan A. Epstein

Adrian Erlebacher

Joel D. Ernst

James M. Ervasti

Robert V. Farese Jr.

Eric R. Fearon

Anthony W. Ferrante Jr.

Edward A. Fisher

Richard A. Flavell

Alessia Fornoni

Tatiana Foroud

Martin Friedlander

Stephen J. Galli

J. Victor Garcia-Martinez

Alfred L. George Jr.

Sharon Gerecht

Stanton L. Gerson

Robert E. Gerszten

Todd Golde

Sherita Golden

Stanley Goldfarb

Larry B. Goldstein

Fred Sanford Gorelick

Kathleen J. Green

Steven K. Grinspoon

David Hafler

Jonathan J. Hansen

Raymond Clement Harris

Stanley L. Hazen

Peter Heeringa

Meenhard Herlyn

Joachim Herz

Katherine A. High

Helen H. Hobbs

Ronald Hoffman

V. Michael Holers

Steven Holland

David Holtzman

Michael J. Holtzman

Lawrence B. Holzman

Tamas L. Horvath

Gokhan S. Hotamisligil

Steven R. Houser

Ralph H. Hruban

Christopher A. Hunter

David James

Richard J. Jones

William G. Kaelin Jr.

Klaus Kaestner

Mark L. Kahn

Raghu Kalluri

S. Ananth Karumanchi

David A. Kass

Robert S. Kass

Masato Kasuga

Daniel P. Kelly

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

Stavroula Kousteni

John W. Krakauer

Rohit N. Kulkarni

Chulan Kwon

Antonio La Cava

Fadi G. Lakkis

Terri Laufer

Mitchell A. Lazar

Brendan Lee

William M.F. Lee

Rudolph L. Leibel

Wayne I. Lencer

Jon D. Levine

Ross L. Levine

Klaus Ley

Rodger A. Liddle

Richard Locksley

Fanxin Long

Gary Lopaschuk

Nigel Mackman

Richard B. Mailman

Rama K. Mallampalli

Kieren A. Marr

Jack Martin

Steven O. Marx

Rodger P. McEver

Elizabeth McNally

Cornelis J. Melief

Shlomo Melmed

George Michalopoulos

Jeffrey H. Miner

Peter J. Mohler

Jeffery D. Molkentin

David D. Moore

Edward E. Morrisey

James H. Morrissey

Deborah M. Muoio

Anthony J. Muslin

Martin G. Myers Jr.

Benjamin G. Neel

Paul W. Noble

Guillermo Oliver

Eric N. Olson

Harry T. Orr

Leo E. Otterbein

Roberto Pacifici

Akhilesh Pandey

William C. Parks

Warren S. Pear

Sallie R. Permar

David J. Pinsky

Edward Plow

Catherine Postic

Alice S. Prince

Louis J. Ptacek

Luigi Puglielli

Pere Puigserver

Bali Pulendran

Ellen Puré

Susan E. Quaggin

Marlene Rabinovitch

Daniel J. Rader

Shahin Rafii

Gwendalyn J. Randolph

Jeffrey C. Rathmell

W. Kimryn Rathmell

Barbara Rehermann

Muredach P. Reilly

Ryan Riddle

Sarah A. Robertson

Howard A. Rockman

Paul B. Rosenberg

Theodora S. Ross

Marc E. Rothenberg

Anil Rustgi

Scheherazade Sadegh-Nasseri

J. Evan Sadler

Junichi Sadoshima

Akira Sawa

Jose-Alain Sahel

Jean E. Schaffer

Philipp E. Scherer

Michael D. Schneider

Detlef Schuppan

Amita Sehgal

Clay Semenkovich

Jonathan S. Serody

John Seykora

Theresa A. Shapiro

Mari Shinohara

Steven E. Shoelson

Gerald I. Shulman

Roy L. Silverstein

M. Celeste Simon

Mihaela Skobe

Donald Small

Lois Smith

Akrit Sodhi

Weihong Song

Ashley L. St. John

Jonathan Stamler

Colin L. Stewart

Doris Stoffers

Warren Strober

Maureen A. Su

D. James Surmeier

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

Marcel R.M. van den Brink

Luc Van Kaer

David M. Virshup

Matthias von Herrath

Kathryn R. Wagner

Yisong Y. Wan

Bart O. Williams

Allan W. Wolkoff

Joseph C. Wu

Thomas A. Wynn

Ramnik J. Xavier

Mingzhao Xing

Yiping Yang

Srinivasan Yegnasubramanian

Mone Zaidi

Kang Zhang

Len Zon

Weiping Zou

R. Suzanne Zukin

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

For the JCIEditorRexford S. Ahima

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

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

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

BiostatisticianEliseo Guallar

Computational BiologistPatrick Cahan

JCI ScholarsLaura Cohen, Jared Hinkle

StaffExecutive EditorSarah C. Jackson

Senior Science EditorCorinne Williams

Science EditorElyse Dankoski

Editorial Board CoordinatorMonika Deshpande

Editor at LargeUshma S. Neill

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

For the full JCI online: jci.me/129/6

This MonthJune 2019

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

The American Society for Clinical Investigation holds the rights to and publishes the Journal of Clinical Investigation and JCI Insight. The opinions expressed herein are solely those of the authors and are not necessarily endorsed by the ASCI.

The order of authors listed on biomedical research articles is a code that conveys the importance of their contributions: the first position typically denotes the individual who performed the bulk of the work, whereas the last position denotes the person who supervised the study. Hence, author position is critically important for career advancement. As research becomes more collaborative and more complex, first author positions are sometimes shared by 2 or more individuals. However, the individual listed first in a list of “equally contributing authors” is likely to garner a greater share of recognition.

Recent studies suggest a gender bias in the ordering of equally contributing authors. In the pediatric literature, significantly fewer females head the author list, even when they contributed equally. A study of more than 3000 biomedical publications over the past 2 decades found preferences for males occupying the first author space. Both observations raise the specter of sex bias skewing how authorship order is determined.

The JCI is committed to the highest publication standards, and that includes doing what we can to reduce sex inequity and other biases. Going forward, we now will require that senior/corresponding authors state how the first author position was assigned among coauthors. By requiring increased transparency, we hope to provide more information that can be used to properly attribute credit. We do not naively believe that these requirements will solve the problem of sex bias in choosing author order, but we are hopeful that they will trigger discussions between authors and their supervisors that could lead to fairer choices.

Arturo CasadevallDeputy Editor, The Journal of Clinical Investigation

Gregg L. SemenzaDeputy Editor, The Journal of Clinical Investigation

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

Gordon TomaselliDeputy Editor, The Journal of Clinical Investigation

Rexford S. AhimaEditor In Chief, The Journal of Clinical Investigation

To read the complete editorial, see http://jci.me/128764

(ASCI) indicates corresponding authors who are ASCI members.

Reducing bias: accounting for the order of co–first authors

From the Editors

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

research

Editor’s picks

on the jci cover

Bariatric surgery–induced bone loss involves the bone marrow nicheBariatric surgeries reduce the stomach’s capacity and represent an effective strategy for inducing weight loss, improving glucose tolerance, and reducing cardiovascular risks in obese individuals. The metabolic benefits associated with bariatric surgery often precede weight loss and are part of a complex response to profound changes in nutrient absorption and other aspects of systemic metabolism. Bariatric surgery can also induce bone loss and increased incidence of bone fracture through mechanisms that are not entirely understood. In this issue of the JCI, Ziru Li et al. examined bone loss in a mouse model of vertical sleeve gastrectomy (VSG), the most commonly performed bariatric surgery procedure. They observed that the impairments in bone mineralization and formation that occurred within 2–4 weeks of VSG were independent of sex, body mass, and nutrition. Rather, bone loss correlated with myeloid cell expansion in the bone marrow, reduction of marrow adipose tissue, and increases in circulating neutrophils. The researchers demonstrated an important role for the neutrophil-stimulating factor G-CSF in mediating VSG’s effects on the bone marrow niche. In the accompanying Commentary, Soravis Osataphan and Mary Elizabeth Patti contextualize these insights into the pathways affected by bariatric surgery. This issue’s cover conceptualizes VSG’s effects on bone, the bone marrow niche, and circulating cells. Image credit: Ziru Li, Devika P. Bagchi, Callie A.S. Corsa, and other members of the MacDougald lab.

bone biology

Public TCRβ sequences have an advantage during human thymic selection

G-CSF partially mediates effects of sleeve gastrectomy on the bone marrow nicheZiru Li, Julie Hardij, Simon S. Evers, Chelsea R. Hutch, Sarah M. Choi, Yikai Shao, Brian S. Learman, Kenneth T. Lewis, Rebecca L. Schill, Hiroyuki Mori, Devika P. Bagchi, Steven M. Romanelli, Ki-Suk Kim, Emily Bowers, Cameron Griffin, Randy J. Seeley, Kanakadurga Singer, Darleen A. Sandoval, Clifford J. Rosen, and Ormond A. MacDougald http://jci.me/126173

autoimmunity

Diversity in T cell receptor (TCR) sequences contributes to the ability of the immune system to recognize a large number of diverse pathogens. While it is estimated that humans possess 40–100 million distinct TCR β chain (TCRβ) sequences, there is a profound degree of overlap in TCR repertoires among individuals. The thymic processes that shape the shared or “public” TCR repertoire are not well characterized. Mohsen Khosravi-Maharlooei, Aleksandar Obradovic, and colleagues developed a humanized mouse model engrafted with human fetal thymic tissue to interrogate human thymic selection in vivo. They observed that the thymus shapes the TCR repertoire using both positive and negative selection processes and that public TCRβ sequences share common properties, including shorter peptide length, reduced hydrophobicity of peptide contact residues, increased cross-reactivity, and autoreactivity, that bias in favor of positive selection and against negative selection. Antonio La Cava’s accompa-

nying Commentary unpacks this study’s insights into the thymic selection processes that favor maintenance of public TCRβ sequences in humans.

Cross-reactive public TCR sequences undergo positive selection in the human thymic repertoireMohsen Khosravi-Maharlooei, Aleksandar Obradovic, Aditya Misra, Keshav Motwani, Markus Holzl, Howard R. Seay, Susan DeWolf, Grace Nauman, Nichole Danzl, Haowei Li, Siu-hong Ho, Robert Winchester, Yufeng Shen, Todd M. Brusko, and Megan Sykes http://jci.me/124358

Related CommentaryHuman T cell repertoire: what happens in thymus does not stay in thymusAntonio La Cava http://jci.me/128371

Related CommentaryTrim the gut, lose the weight — and the boneSoravis Osataphan and Mary Elizabeth Patti (ASCI) http://jci.me/128745

j c i . o r g / t h i s - m o n t h j u n e 2 0 1 9 3

JCI | Research: Editor’s picks

metabolism

The BeAT goes on, thanks to breast milk–derived alkylglycerols

Brown fat activation counteracts alcohol’s pathogenic effects on the liverAlcohol consumption increases lipolysis and hepatic de novo lipogenesis, which contribute to liver steatosis and the risk of liver disease in heavy alcohol users. Despite alcohol’s adverse metabolic effects, moderate alcohol use is associated with protection from cardiovascular disease and metabolism disorders. Hong Shen and colleagues shed light on a brown fat–mediated process that counteracts aberrant lipid trafficking and liver injury driven by alcohol ingestion. Direct administration of alcohol into the brains of mice led to sympathetic activation of brown adipose tissue and upregulation of the thermogenic protein UCP1. UCP1-induced thermogenesis utilized fatty acids as fuel, diminishing lipid trafficking to the liver. Alcohol-activated brown fat also released adiponectin and other hepatoprotective adipokines, which

mitigated alcohol-induced liver steatosis, oxidative stress, cell death, and liver fibrosis. Seonghwan Hwang and Bin Gao detail the work’s insights into potential therapeutic targets for combating alcohol-driven liver steatosis, injury, and disease in the accompanying Commentary.

Brown fat activation mitigates alcohol-induced liver steatosis and injury in miceHong Shen, Lin Jiang, Jiandie D. Lin, M. Bishr Omary, and Liangyou Rui http://jci.me/124376

Related CommentaryHow does your fat affect your liver when you drink?Seonghwan Hwang and Bin Gao (ASCI) http://jci.me/128984

As childhood obesity reaches epidemic levels, there is a crucial need to understand the mechanisms underlying adipose tissue (AT) development. As an early source of lipids, breast milk may supply important signals to support healthy AT in infants. A study from the laboratory of Tamás Röszer indicates a role for breast milk–derived lipids called alkylglycerols in maintaining metabolically active beige AT (BeAT). In neonatal mice, alkylglycerol supplementation increased BeAT content relative to that in control-fed littermates. Moreover, human infants fed alkylglycerol-free formula experienced premature BeAT loss (see the associated image). Mechanistically, the study determined that AT macrophages metabolize alkylglycerols to platelet-activating factor (PAF), activating an IL-6/STAT3 pathway that promotes BeAT differentiation. In the accompanying Commentary, Christy Gliniak and Philipp Scherer discuss these insights into the importance of BeAT in infant development, which suggest opportunities to intervene in the development of childhood obesity.

Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophagesHaidong Yu, Sedat Dilbaz, Jonas Coßmann, Anh Cuong Hoang, Victoria Diedrich, Annika Herwig, Akiko Harauma, Yukino Hoshi, Toru Moriguchi, Kathrin Landgraf, Antje Körner, Christina Lucas, Susanne Brodesser, Lajos Balogh, Julianna Thuróczy, Gopal Karemore, Michael Scott Kuefner, Edwards A. Park, Christine Rapp, Jeffrey Bryant Travers, and Tamás Röszer http://jci.me/125646

Related CommentaryCritical lipids link breastfeeding to healthy adipose tissue in infancy and adulthoodChristy M. Gliniak and Philipp E. Scherer http://jci.me/128830

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

JCI | Research: Editor’s picks

clinical medicine

Clinical response to CAR T cell therapy in multiple myelomaChimeric antigen receptor (CAR) T cells have successfully treated B cell hematologic malignancies, providing a rationale for exploring their use in multiple myeloma. A clinical trial conducted by Adam Cohen and colleagues tested the safety and efficacy of CAR T cells targeting B cell maturation antigen (BCMA), which has been identified as a rational target for myeloma therapies in preclinical studies. The study evaluated patient-derived, BCMA-specific CAR T cells manufactured and infused into 25 subjects with relapsed/refractory multiple myeloma. CAR T cell treatment combined with lymphodepletion produced a higher response rate than the same CAR T cell treatment alone (64% vs. 44%), supporting prior observations that lymphodepletion may enhance the efficacy of adoptive cellular therapies. Serious adverse events including cytokine release syndrome and neurotoxicity suggest a level of toxicity comparable to that of CD19-targeted CAR T cells. Ivan Borrello and Philip Imus frame the study’s outcomes as important insights into designing future trials of BCMA-specific CAR T cells in myeloma in the accompanying Commentary.

B cell maturation antigen–specific CAR T cells are clinically active in multiple myelomaAdam D. Cohen, Alfred L. Garfall, Edward A. Stadtmauer, J. Joseph Melenhorst, Simon F. Lacey, Eric Lancaster, Dan T. Vogl, Brendan M. Weiss, Karen Dengel, Annemarie Nelson, Gabriela Plesa, Fang Chen, Megan M. Davis, Wei-Ting Hwang, Regina M. Young, Jennifer L. Brogdon, Randi Isaacs, Iulian Pruteanu-Malinici, Don L. Siegel, Bruce L. Levine, Carl H. June, and Michael C. Milone http://jci.me/126397

Related CommentaryBCMA CAR T cells: the winding path to successIvan Borrello and Philip H. Imus http://jci.me/128372

Tumor mitochondrial content may influence racial disparity in cancer outcomesElevated cancer mortality in African American versus European American cancer patients is often attributed to socioeconomic factors, but recent analyses associate outcome disparities in specific cancer types with biological factors. Danthasinghe Waduge Badrajee Piyarathna and colleagues performed a pan-cancer analysis of The Cancer Genome Atlas gene expression data and a second cohort of patient tumor samples to identify common biological drivers of disparate racial outcomes. Tumors from African American patients displayed elevated expression of genes associated with mitochondrial oxidative phosphorylation as well as the ERR1-PCG1α transcriptional program, which promotes mitochon-drial biogenesis. African American patient tumors also contained more mitochondria than tumors from European American patients. Jennifer Beebe-Dimmer and Kathleen Cooney speculate on the potential to use ancestry-informed markers to improve clinical decision-making in an accompanying Commentary.

ERR1- and PGC1α-associated mitochondrial alterations correlate with pan-cancer disparity in African AmericansDanthasinghe Waduge Badrajee Piyarathna, Akhila Balasubramanian, James M. Arnold, Stacy M. Lloyd, Balasubramanyam Karanam, Patricia Castro, Michael M. Ittmann, Nagireddy Putluri, Nora Navone, Jeffrey A. Jones, Wendong Yu, Vlad C. Sandulache, Andrew G. Sikora, George Michailidis, and Arun Sreekumar http://jci.me/127579

Related CommentaryMitochondrial alterations may underlie race-specific differences in cancer risk and outcomeJennifer L. Beebe-Dimmer and Kathleen A. Cooney http://jci.me/128707insight.jci.org

Lookingfor some ATP foryour PhD?

Submit your work to JCI Insight today.

JCI Insight is the publication to

keep your future on pace with

your goals. Built upon the history

and prestige of the Journal of

Clinical Investigation, JCI Insight

recognizes your work and gives it

the attention it deserves.

j c i . o r g / t h i s - m o n t h j u n e 2 0 1 9 5

JCI | Research: Editor’s picks

neuroscience

Direct mTORC1 activation induces rapid antidepressant effects

Hypoxia-activated FoxO3 counteracts progression to chronic kidney disease

nephrology

Acute kidney injury (AKI) dramatically elevates the risk for developing chronic kidney disease (CKD). The progression from AKI to CKD is associated with failure to completely repair injured kidney tubules, leading to a persistent hypoxic state. Ling Li and colleagues provide evidence of a FoxO3-dependent adaptive response to acute hypoxia that may regulate the transition to CKD following ischemic injury. In kidney tubules, hypoxia inhibited FoxO3 degradation, while hypoxia-activated HIF-1α also promoted increased FoxO3 transcription. Both responses resulted in increased FoxO3 protein levels, stimulating an autophagic stress response that mitigated hypoxic and oxidative damage to the kidney. In a mouse model, FoxO3 loss accelerated the progression from AKI to CKD (see the associated image), supporting a protective role for FoxO3 in ischemic kidney injury. In the accompanying Commentary, Xiangchen Gu, Archana Raman, and Katalin Susztak suggest that therapies targeting FoxO3 could potentially disrupt AKI-to-CKD pathogenesis.

FoxO3 activation in hypoxic tubules prevents chronic kidney diseaseLing Li, Huimin Kang, Qing Zhang, Vivette D. D’Agati, Qais Al-Awqati, and Fangming Lin http://jci.me/122256

Related CommentaryGoing from acute to chronic kidney injury with FoxO3Xiangchen Gu, Archana Raman, and Katalin Susztak (ASCI) http://jci.me/128985

Monoamine-targeting drugs are the frontline treatment for depression, but therapeutic response requires weeks to months of treatment, and efficacy rates are low. A single subanesthetic dose of ketamine has been shown to produce rapid antidepressant effects even in treatment-resistant patients. Ketamine’s efficacy is linked to mTORC1-dependent synapse formation in the medial prefrontal cortex (mPFC), a higher-order brain area whose dysfunction is linked to depression. Taro Kato and colleagues now show that the sestrin-modulating small molecule NV-5138, a direct

activator of mTORC1 signaling, produces rapid antidepressant actions comparable to those of ketamine. Within 24 hours of administration to rats, NV-5138 produced behavioral responses consistent with antidepressant activity and increased mPFC

synaptic spine density (see the associated image). NV-5138 dosing also rapidly reversed synaptic and behavioral effects of chronic unpredictable stress. In the accompanying Commentary, Yuto Hasegawa, Xiaolei Zhu, and Atsushi Kamiya highlight the concept that directly targeting the mTORC1 pathway can produce sustained antidepressant responses.

Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activationTaro Kato, Santosh Pothula, Rong-Jian Liu, Catharine H. Duman, Rosemarie Terwilliger, George P. Vlasuk, Eddine Saiah, Seung Hahm, and Ronald S. Duman http://jci.me/126859

Related CommentaryNV-5138 as a fast-acting antidepressant via direct activation of mTORC1 signalingYuto Hasegawa, Xiaolei Zhu, and Atsushi Kamiya http://jci.me/129702

j c i . o r g / t h i s - m o n t h j u n e 2 0 1 96

JCI | Features

viewpoint

A physician-scientist’s duty to defend vaccines and combat antiscienceAs the antivaccination movement becomes more mainstream and vaccine coverage drops to below critical numbers in more areas of the United States, successfully conveying the safety and importance of vaccination has become a matter of life and death. The 555 measles cases reported to date in 2019 signal the beginning of a looming crisis: at least 100,000 children in the United States are not fully vaccinated, and parental requests for vaccination exceptions are on the rise. Peter Hotez details the history of vaccines and describes the modern “antivax” movement, which is driven by fear, misinformation, as well as political motives. The Viewpoint urges physician-scientists to engage with the public and communicate accurate information about vaccination to reverse the tide of antiscience sentiment before it is too late.

The physician-scientist: defending vaccines and combating antisciencePeter Hotez http://jci.me/129121

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

Current research articles

autoimmunityCross-reactive public TCR sequences undergo positive selection in the human thymic repertoire p. 2Mohsen Khosravi-Maharlooei, Aleksandar Obradovic, Aditya Misra, Keshav Motwani, Markus Holzl, Howard R. Seay, Susan DeWolf, Grace Nauman, Nichole Danzl, Haowei Li, Siu-hong Ho, Robert Winchester, Yufeng Shen, Todd M. Brusko, and Megan Sykes http://jci.me/124358

Anti–neurofascin-155 IgG4 antibodies prevent paranodal complex formation in vivoConstance Manso, Luis Querol, Cinta Lleixà, Mallory Poncelet, Mourad Mekaouche, Jean-Michel Vallat, Isabel Illa, and Jérôme J. Devaux http://jci.me/124694

Patrolling monocytes promote the pathogenesis of early lupus-like glomerulonephritisJeeba Kuriakose, Vanessa Redecke, Cliff Guy, Jingran Zhou, Ruiqiong Wu, Sirish K. Ippagunta, Heather Tillman, Patrick D. Walker, Peter Vogel, and Hans Häcker http://jci.me/125116

bone biologyG-CSF partially mediates effects of sleeve gastrectomy on the bone marrow niche p. 2Ziru Li, Julie Hardij, Simon S. Evers, Chelsea R. Hutch, Sarah M. Choi, Yikai Shao, Brian S. Learman, Kenneth T. Lewis, Rebecca L. Schill, Hiroyuki Mori, Devika P. Bagchi, Steven M. Romanelli, Ki-Suk Kim, Emily Bowers, Cameron Griffin, Randy J. Seeley, Kanakadurga Singer, Darleen A. Sandoval, Clifford J. Rosen, and Ormond A. MacDougald http://jci.me/126173

Macrophage-lineage TRAP+ cells recruit periosteum-derived cells for periosteal osteogenesis and regenerationBo Gao, Ruoxian Deng, Yu Chai, Hao Chen, Bo Hu, Xiao Wang, Shouan Zhu, Yong Cao, Shuangfei Ni, Mei Wan, Liu Yang, Zhuojing Luo, and Xu Cao http://jci.me/98857

cardiologymicroRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potentialLi Qiao, Shiqi Hu, Suyun Liu, Hui Zhang, Hong Ma, Ke Huang, Zhenhua Li, Teng Su, Adam Vandergriff, Junnan Tang, Tyler Allen, Phuong-Uyen Dinh, Jhon Cores, Qi Yin, Yongjun Li, and Ke Cheng http://jci.me/123135

clinical medicineB cell maturation antigen–specific CAR T cells are clinically active in multiple myeloma p. 4Adam D. Cohen, Alfred L. Garfall, Edward A. Stadtmauer, J. Joseph Melenhorst, Simon F. Lacey, Eric Lancaster, Dan T. Vogl, Brendan M. Weiss, Karen Dengel, Annemarie Nelson, Gabriela Plesa, Fang Chen, Megan M. Davis, Wei-Ting Hwang, Regina M. Young, Jennifer L. Brogdon, Randi Isaacs, Iulian Pruteanu-Malinici, Don L. Siegel, Bruce L. Levine, Carl H. June, and Michael C. Milone http://jci.me/126397

ERR1- and PGC1α-associated mitochondrial alterations correlate with pan-cancer disparity in African Americans p. 4Danthasinghe Waduge Badrajee Piyarathna, Akhila Balasubramanian, James M. Arnold, Stacy M. Lloyd, Balasubramanyam Karanam, Patricia Castro, Michael M. Ittmann, Nagireddy Putluri, Nora Navone, Jeffrey A. Jones, Wendong Yu, Vlad C. Sandulache, Andrew G. Sikora, George Michailidis, and Arun Sreekumar http://jci.me/127579

endocrinologyCB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized miceKun Zhang, Qi Yang, Le Yang, Yan-jiao Li, Xin-shang Wang, Yu-jiao Li, Rui-li Dang, Shao-yu Guan, Yan-yan Guo, Ting Sun, Yu-mei Wu, An Liu, Yan Zhang, Shui-bing Liu, and Ming-gao Zhao http://jci.me/123689

j c i . o r g / t h i s - m o n t h j u n e 2 0 1 98

endocrinologyDexamethasone-induced Krüppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemiaAnfang Cui, Heng Fan, Yinliang Zhang, Yujie Zhang, Dong Niu, Shuainan Liu, Quan Liu, Wei Ma, Zhufang Shen, Lian Shen, Yanling Liu, Huabing Zhang, Yuan Xue, Ying Cui, Qinghua Wang, Xinhua Xiao, Fude Fang, Jichun Yang, Qinghua Cui, and Yongsheng Chang http://jci.me/66062

gastroenterologyProtein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent mannerMarianne R. Spalinger, Thomas S.B. Schmidt, Marlene Schwarzfischer, Larissa Hering, Kirstin Atrott, Silvia Lang, Claudia Gottier, Annelies Geirnaert, Christophe Lacroix, Xuezhi Dai, David J. Rawlings, Andrew C. Chan, Christian von Mering, Gerhard Rogler, and Michael Scharl http://jci.me/123263

hematologySecreted nuclear protein DEK regulates hematopoiesis through CXCR2 signalingMaegan L. Capitano, Nirit Mor-Vaknin, Anjan K. Saha, Scott Cooper, Maureen Legendre, Haihong Guo, Rafael Contreras-Galindo, Ferdinand Kappes, Maureen A. Sartor, Christopher T. Lee, Xinxin Huang, David M. Markovitz, and Hal E. Broxmeyer http://jci.me/127460

metabolismThe gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin systemKhalil Bouyakdan, Hugo Martin, Fabienne Liénard, Lionel Budry, Bouchra Taib, Demetra Rodaros, Chloé Chrétien, Éric Biron, Zoé Husson, Daniela Cota, Luc Pénicaud, Stephanie Fulton, Xavier Fioramonti, and Thierry Alquier http://jci.me/123454

Brown fat activation mitigates alcohol-induced liver steatosis and injury in mice p. 3Hong Shen, Lin Jiang, Jiandie D. Lin, M. Bishr Omary, and Liangyou Rui http://jci.me/124376

Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages p. 3Haidong Yu, Sedat Dilbaz, Jonas Coßmann, Anh Cuong Hoang, Victoria Diedrich, Annika Herwig, Akiko Harauma, Yukino Hoshi, Toru Moriguchi, Kathrin Landgraf, Antje Körner, Christina Lucas, Susanne Brodesser, Lajos Balogh, Julianna Thuróczy, Gopal Karemore, Michael Scott Kuefner, Edwards A. Park, Christine Rapp, Jeffrey Bryant Travers, and Tamás Röszer http://jci.me/125646

nephrologyFoxO3 activation in hypoxic tubules prevents chronic kidney disease p. 5Ling Li, Huimin Kang, Qing Zhang, Vivette D. D’Agati, Qais Al-Awqati, and Fangming Lin http://jci.me/122256

Stiripentol protects against calcium oxalate nephrolithiasis and ethylene glycol poisoningMarine Le Dudal, Léa Huguet, Joëlle Perez, Sophie Vandermeersch, Elise Bouderlique, Ellie Tang, Carole Martori, Nicole Chemaly, Rima Nabbout, Jean-Philippe Haymann, Vincent Frochot, Laurent Baud, Georges Deschênes, Michel Daudon, and Emmanuel Letavernier http://jci.me/99822

neuroscienceInhibiting pathologically active ADAM10 rescues synaptic and cognitive decline in Huntington’s diseaseElena Vezzoli, Ilaria Caron, Francesca Talpo, Dario Besusso, Paola Conforti, Elisa Battaglia, Elisa Sogne, Andrea Falqui, Lara Petricca, Margherita Verani, Paola Martufi, Andrea Caricasole, Alberto Bresciani, Ottavia Cecchetti, Pia Rivetti di Val Cervo, Giulio Sancini, Olaf Riess, Hoa Nguyen, Lisa Seipold, Paul Saftig, Gerardo Biella, Elena Cattaneo, and Chiara Zuccato http://jci.me/120616

Current research articles

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

Heroin addiction engages negative emotional learning brain circuits in ratsStephanie A. Carmack, Robin J. Keeley, Janaina C.M. Vendruscolo, Emily G. Lowery-Gionta, Hanbing Lu, George F. Koob, Elliot A. Stein, and Leandro F. Vendruscolo http://jci.me/125534

Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation p. 5Taro Kato, Santosh Pothula, Rong-Jian Liu, Catharine H. Duman, Rosemarie Terwilliger, George P. Vlasuk, Eddine Saiah, Seung Hahm, and Ronald S. Duman http://jci.me/126859

oncologyOncolytic virotherapy for small-cell lung cancer induces immune infiltration and prolongs survivalPatrick Kellish, Daniil Shabashvili, Masmudur M. Rahman, Akbar Nawab, Maria V. Guijarro, Min Zhang, Chunxia Cao, Nissin Moussatche, Theresa Boyle, Scott Antonia, Mary Reinhard, Connor Hartzell, Michael Jantz, Hiren J. Mehta, Grant McFadden, Frederic J. Kaye (ASCI), and Maria Zajac-Kaye http://jci.me/121323

Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balanceChaoyun Pan, Lingtao Jin, Xu Wang, Yuancheng Li, Jaemoo Chun, Austin C. Boese, Dan Li, Hee-Bum Kang, Guojing Zhang, Lu Zhou, Georgia Z. Chen, Nabil F. Saba, Dong M. Shin, Kelly R. Magliocca, Taofeek K. Owonikoko, Hui Mao, Sagar Lonial, and Sumin Kang http://jci.me/124550

Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targetsAnne Monette, Antigoni Morou, Nadia A. Al-Banna, Louise Rousseau, Jean-Baptiste Lattouf, Sara Rahmati, Tomas Tokar, Jean-Pierre Routy, Jean-François Cailhier, Daniel E. Kaufmann, Igor Jurisica, and Réjean Lapointe http://jci.me/125301

Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosisPatricia Santofimia-Castaño, Yi Xia, Wenjun Lan, Zhengwei Zhou, Can Huang, Ling Peng, Philippe Soubeyran, Adrián Velázquez-Campoy, Olga Abián, Bruno Rizzuti, José L. Neira, and Juan Iovanna http://jci.me/127223

pulmonologyLymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damageHasina Outtz Reed, Liqing Wang, Jarrod Sonett, Mei Chen, Jisheng Yang, Larry Li, Petra Aradi, Zoltan Jakus, Jeanine D’Armiento, Wayne W. Hancock, and Mark L. Kahn (ASCI) http://jci.me/125044

transplantationPosttransplantation cyclophosphamide prevents graft-versus-host disease by inducing alloreactive T cell dysfunction and suppressionLucas P. Wachsmuth, Michael T. Patterson, Michael A. Eckhaus, David J. Venzon, Ronald E. Gress, and Christopher G. Kanakry http://jci.me/124218

Ferroptotic cell death and TLR4/Trif signaling initiate neutrophil recruitment after heart transplantationWenjun Li, Guoshuai Feng, Jason M. Gauthier, Inessa Lokshina, Ryuji Higashikubo, Sarah Evans, Xinping Liu, Adil Hassan, Satona Tanaka, Markus Cicka, Hsi-Min Hsiao, Daniel Ruiz-Perez, Andrea Bredemeyer, Richard W. Gross, Douglas L. Mann, Yulia Y. Tyurina, Andrew E. Gelman, Valerian E. Kagan, Andreas Linkermann, Kory J. Lavine, and Daniel Kreisel (ASCI) http://jci.me/126428

vascular biologyRhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activityMasashi Mukohda, Shi Fang, Jing Wu, Larry N. Agbor, Anand R. Nair, Stella-Rita C. Ibeawuchi, Chunyan Hu, Xuebo Liu, Ko-Ting Lu, Deng-Fu Guo, Deborah R. Davis, Henry L. Keen, Frederick W. Quelle, and Curt D. Sigmund http://jci.me/123462

Flip issue to read JCI Insight content.

jci.org/this-month

TNF-α and IL-9 have potential as biomarkers of acute interstitial nephritis 12

Targeting human endotrophin ameliorates malignant phenotypes 12

An improved mouse model of coronary artery disease 13

Long-term safety and efficacy of CD19-targeted CAR T cells for relapsed/refractory CLL 13

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

June 2019

Loss of cAMP gating of HCN2 channels induces generalized seizures p. 10

This Month

j c i . o r g / t h i s - m o n t h j u n e 2 0 1 917

Christopher M. Adams

Maria-Luisa Alegre

Ravi K. Amaravadi

John K. Amory

Jennifer H. Anolik

Cristian Apetrei

Rajendra S. Apte

Zoltan Arany

Hossein Ardehali

Kenneth I. Ataga

Joseph Bass

Alexander G. Bassuk

Antonio C. Bianco

Jonathan S. Bogan

Laura M. Bohn

Nunzio Bottini

Sebastien G. Bouret

Jason Brenchley

Renier J. Brentjens

G.R. Scott Budinger

George A. Calin

Stephen Chan

Timothy Chan

Yuan Chang

Zhou-Feng Chen

Keith A. Choate

Wendy Chung

Craig M. Coopersmith

George Cotsarelis

Peter Crawford

Lisa L. Cunningham

Ronald P. DeMatteo

Elia J. Duh

Sarah K. England

Mark W. Feinberg

John H. Fingert

Robert Flaumenhaft

Edward A. Fon

Lawrence Fong

Nikolaos G. Frangogiannis

Anthony R. French

Terrence L. Geiger

Noyan Gokce

Raphaela Goldbach-Mansky

Daniel R. Goldstein

Douglas K. Graham

Khalid A. Hanafy

Eric B. Haura

John Cijiang He

Robert O. Heuckeroth

Cory M. Hogaboam

Young-Kwon Hong

Benjamin D. Humphreys

Ken Inoki

Shingo Kajimura

Pawel Kalinski

John Y. Kao

Michael G. Kaplitt

Thomas W.H. Kay

Barbara I. Kazmierczak

Hans-Peter Kiem

William Y. Kim

David G. Kirsch

Claire E. Lewis

Mathias Lichterfeld

André Lieber

Michail S. Lionakis

Carey N. Lumeng

Ivan Maillard

Ziad Mallat

Peter Mannon

Franck Mauvais-Jarvis

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

David K. Meyerholz

Jason C. Mills

Joshua D. Milner

Satdarshan (Paul) Singh Monga

Hidayatullah G. Munshi

Matthias Nahrendorf

Mary Nakamura

Lisa F.P. Ng

Mark Nicolls

Laura J. Niedernhofer

S. Tiong Ong

Puneet Opal

Daniel Ory

Sophie Paczesny

Stephanie T. Page

Mary-Elizabeth Patti

Janos Peti-Peterdi

Fernando P. Polack

Matthew D. Ringel

Steven M. Rowe

Svati H. Shah

Vijay H. Shah

Alice T. Shaw

Rhonda F. Souza

Fayyaz S. Sutterwala

Shu Takeda

Natalie J. Torok

Stephen H. Tsang

Ellie Tzima

Fumihiko Urano

Deborah J. Veis

Charles P. Venditti

Joseph M. Vinetz

Sing Sing Way

Bernd Wollnik

Minna Woo

Prescott G. Woodruff

Lori M. Zeltser

Yutong Zhao

Binhua P. Zhou

JCI Insight Consulting Editors

j c i . o r g / t h i s - m o n t h j u n e 2 0 1 9 10

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

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

For JCI Insight online: jci.me/insight/4/9jci.me/insight/4/10

On the JCI Insight cover

This MonthJune 2019

Make your 18-hour days count.

Submit your work to JCI Insight today.

(ASCI) indicates corresponding authors who are ASCI members.

cAMP-dependent HCN2 activation regulates thalamic circuit behavior

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are expressed in the brain and heart, where they respond to signal-mediated changes in cAMP. There are 4 members of this family, all of which are expressed in the brain but only partially overlap. HCNs have been proposed to regulate thalamic firing, as HCN dysfunction has been observed in epilepsy models. In this issue, Verena Hammelmann and colleagues analyzed mice

harboring a form of HCN2 that is unable to bind cAMP (HCN2EA). HCN2EA mice exhibited impairments in visual learning and generalized seizures that originated from the thalamus, as well as altered sleep. cAMP gating of HCN2 was determined to regulate the transition between burst and tonic modes of firing in thalamic dorsal-lateral geniculate (dLGN) and ventrobasal (VB) nuclei. Moreover, VB-specific HCN2 deletion resulted in generalized seizures, further confirming the role of this channel in controlling consciousness. Together, these results reveal an essential function of cAMP-mediated regulation of HCN2 in burst control and support exploration of this channel as a target for thalamic epileptogenesis. The cover image shows HCN2 (red) expression at dendritic spines (MAP2, green) in WT primary neurons.

Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizuresVerena Hammelmann, Marc Sebastian Stieglitz, Henrik Hülle, Karim Le Meur, Jennifer Kass, Manuela Brümmer, Christian Gruner, René Dominik Rötzer, Stefanie Fenske, Jana Hartmann, Benedikt Zott, Anita Lüthi, Saskia Spahn, Markus Moser, Dirk Isbrandt, Andreas Ludwig, Arthur Konnerth, Christian Wahl-Schott, and Martin Biel http://jci.me/126418

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

Editor’s picks

immunology

Club cell–mediated lung repair is critical for transplant tolerance

Self-tolerance leaves holes in the B cell repertoire

Bronchiolitis obliterans syndrome (BOS) is a major obstacle for lung transplantation that results from progression of obliterans bronchiolitis (OB), which is characterized by formation of airway-blocking fibrotic occlusions. Drivers of OB are poorly understood, and strategies to limit and/or reverse disease are lacking. As club cells are important mediators of lung repair and homeostasis, Zhiyi Liu and colleagues developed mouse models to evaluate the role of these cells in transplant tolerance. Ablation of club cells in mice that received syngeneic transplants resulted in transient injury that was rapidly repaired in response to club cell reconstitution. Conversely, club cell ablation in allograft recipients resulted in a severe BOS-like phenotype (see the accompanying image), with high-grade inflammation and recognition of alloantigens and lung-restricted self-antigens. Depletion of CD8+ T cells from allograft recipients restored club cell–mediated repair and prevented OB (see image). These results reveal a critical role for club cells in maintaining lung transplant tolerance and provide a model of OB.

An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplantsZhiyi Liu, Fuyi Liao, Davide Scozzi, Yuka Furuya, Kaitlyn N. Pugh, Ramsey Hachem, Delphine L. Chen, Marlene Cano, Jonathan M. Green, Alexander S. Krupnick, Daniel Kreisel, Anne Karina T. Perl, Howard J. Huang, Steven L. Brody, and Andrew E. Gelman http://jci.me/124732

Tolerance checkpoint–mediated removal and/or inactivation of self-reactive B cells is critical for prevention of autoimmune disease. B cells that recognize foreign antigens with similarity to self-antigens can also be eliminated, thereby creating “holes” in the B cell repertoire that have potential to be exploited by pathogens. Akiko Watanabe and colleagues evaluated the human B cell receptor (BCR) repertoire in healthy subjects and patients with the autoimmune disease systemic lupus eryth-

ematosus (SLE) before and after the second tolerance checkpoint. In healthy donors, the majority of transitional B cells that recognized foreign antigens also recognized self-antigens (foreign+self), and this population dramatically decreased after maturation. In SLE patients, who lack the second checkpoint, the frequency of these foreign+self B cells was unchanged. These results indicate that cross-reactivity between foreign and self-antigens is relatively common and that removal of foreign+self

B cells that recognize microbial pathogens may alter protection against infection.

Self-tolerance curtails the B cell repertoire to microbial epitopesAkiko Watanabe, Kuei-Ying Su, Masayuki Kuraoka, Guang Yang, Alexander E. Reynolds, Aaron G. Schmidt, Stephen C. Harrison, Barton F. Haynes, E. William St. Clair, and Garnett Kelsoe http://jci.me/122551

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

JCI Insight | Editor’s picks

12

vascular biology

Cytosolic PLA2–targeting drug reduces vascular calcificationEndothelial dysfunction is a hallmark of cardiovascular disease (CVD) that ultimately leads to thrombosis and vascular occlusion. Despite the fact that it is a leading cause of death worldwide, there has been a paucity of promising drug targets to prevent and/or minimize CVD. Joost Schanstra, Trang Luong, Manousos Makridakis, Sophie Van Linthout, and colleagues evaluated the arterial proteome of patients with advanced- and early-stage CVD to identify a CVD-associated signature with potential to be targeted by bioactive small molecules. Of the candidate drugs, the cytosolic phospholipase A2 (cPLA2) inhibitor AACOCF3 was a top candidate to reverse in silico the proteomic signature of advanced CVD, as cPLA2 was notably increased in these patients. In a murine cholecalciferol- overload model of CVD, AACOF3 reduced vascular calcification via inhibition of osteoinductive signal-ing. In addition to identifying a CVD drug candidate, these results support application of proteomic signatures in drug-repurposing approaches to identify drug candidates for other complex diseases.

Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatmentJoost P. Schanstra, Trang T.D. Luong, Manousos Makridakis, Sophie Van Linthout, Vasiliki Lygirou, Agnieszka Latosisnska, Ioana Alesutan, Beate Boehme, Nadeshda Schelski, Dirk Von Lewinski, William Mullen, Stuart Nicklin, Christian Delles, Guylène Feuillet, Colette Denis, Florian Lang, Burkert Pieske, Jean-Loup Bascands, Harald Mischak, Jean-Sebastien Saulnier-Blache, Jakob Voelkl, Antonia Vlahou, and Julie Klein http://jci.me/125638

endocrinology

Exploration of human endotrophin as a therapeutic breast cancer targetThe C-terminal cleavage product of collagen VIα3, endotrophin (ETP), is highly expressed in adipose tissue and promotes tumor progression, metastatic growth, and fibrosis in murine breast cancer models. Dawei Bu and colleagues now show that recombinant human ETP promotes chemoresistance, epithelial-mesenchymal transition, and angiogenesis in human breast cancer and endothelial cells and serves as a macrophage chemoattractant. ETP was present in human plasma and was shown to circulate at higher levels in breast cancer patients. The authors developed neutralizing monoclonal antibodies against human ETP, which inhibited tumor growth and enhanced cisplatin sensitivity in mice harboring human tumor cell lesions. These results support human ETP as therapeutic target for breast cancer and provide tools for exploring ETP as a target for human fibrotic diseases.

Human endotrophin as a driver of malignant tumor growthDawei Bu, Clair Crewe, Christine M. Kusminski, Ruth Gordillo, Alexandra L. Ghaben, Min Kim, Jiyoung Park, Hui Deng, Wei Xiong, Xiao-Zheng Liu, Per Eystein Lønning, Nils Halberg, Adan Rios, Yujun Chang, Anneliese Gonzalez, Ningyan Zhang, Zhiqiang An, and Philipp E. Scherer http://jci.me/125094

Urine TNF-α and IL-9 levels may improve acute interstitial nephritis diagnosisAcute interstitial nephritis (AIN) is an immune-mediated tubulointerstitial injury that is linked to medications, infection, and other allergic reactions. While AIN is treatable, it requires biopsy to diagnose, and untreated disease accounts for approximately 15% of acute kidney disease (AKD) cases. Dennis Moledina and colleagues collected and analyzed biopsy samples, along with blood and urine, of AKD patients from two medical centers. Of the 218 participants, 32 were diagnosed with AIN. Patients with AIN had higher levels of TNF-α and IL-9 in urine than other AKD patients. Moreover, addition of urine TNF-α and IL-9 levels, along with clinical variables, such as blood eosinophils, leukocyturia, and proteinuria, was shown to improve prebiopsy AIN diagnosis. These results support the inclusion of urine TNF-α and IL-9 levels to discriminate AIN from other AKDs.

Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritisDennis G. Moledina, F. Perry Wilson, Jordan S. Pober, Mark A. Perazella, Nikhil Singh, Randy L. Luciano, Wassim Obeid, Haiqun Lin, Michael Kuperman, Gilbert W. Moeckel, Michael Kashgarian, Lloyd G. Cantley, and Chirag R. Parikh (ASCI) http://jci.me/127456

nephrology

j c i . o r g / t h i s - m o n t h j u n e 2 0 1 913

JCI Insight | Editor’s picks

cardiology

Transverse aortic constriction promotes coronary artery disease in ApoE-deficient miceMurine models of atherosclerosis recapitulate several aspects of human disease, including high plasma cholesterol levels and lesion formation in the aortic root; however, these lesions seldom progress to rupture, and, furthermore, atherosclerosis is not observed in the coronary arteries, which is the major site of human plaque formation. Recently, transverse aortic constriction (TAC) was shown to induce coronary lesions in apolipoprotein E–deficient (ApoE-deficient) mice. Alice Marino and colleagues further characterized this model and demonstrated that myocardial events, including myocardial infarction, manifest in the majority of mice as the result of coronary plaque thrombosis and/or occlusion (see the accompanying image). Cumulatively, the results of these studies reveal that the TAC ApoE-deficient model recapitulates important aspects of human disease and indicate that this model has potential as an important tool for studying drivers of coronary lesion formation and rupture.

Pressure overload leads to coronary plaque formation, progression, and myocardial events in ApoE–/– miceAlice Marino, Yi Zhang, Luisa Rubinelli, Maria Antonietta Riemma, James E. Ip, and Annarita Di Lorenzo http://jci.me/128220

clinical trials

Long-term trial supports CD19-targeted CAR T cells for relapsed/refractory CLLPatients with chronic lymphocytic leukemia (CLL) exhibit variable responses to standard combination chemotherapy. While some patients achieve complete remission (CR), the majority of patients have relapsed or refractory (R/R) disease. Short-term trials of autologous CD19-targeted chimeric antigen-expressing T cells (CAR T cells) have shown favorable safety and tolerability profiles. Now, Mark Geyer and colleagues report safety data and clinical outcomes during a long-term follow-up of a small cohort of patients with R/R CLL treated with

second-generation CD19-targeted CAR T cells (19–28z CAR T cells). Most patients also received conditioning chemotherapy prior to 19–28z CAR T cell therapy. Cytokine release syndrome was observed in all patients, but high-grade neurological events were rare. Three CLL patients who had received conditioning chemotherapy achieved durable CR and remained progression free. Overall, these data indicate that 19–28z CAR T cell therapy after chemotherapy conditioning is well tolerated and can result in CR for a subset of patients with R/R CLL.

Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLLMark B. Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J. Purdon, Meier Hsu, Sean M. Devlin, M. Lia Palomba, Elizabeth Halton, Yvette Bernal, Dayenne G. van Leeuwen, Michel Sadelain, Jae H. Park, and Renier J. Brentjens (ASCI) http://jci.me/122627

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

Current articles

Conjugated bile acids attenuate allergen-induced airway inflammation and hyperresposiveness by inhibiting UPR transducersEmily M. Nakada, Nirav R. Bhakta, Bethany R. Korwin-Mihavics, Amit Kumar, Nicolas Chamberlain, Sierra R. Bruno, David G. Chapman, Sidra M. Hoffman, Nirav Daphtary, Minara Aliyeva, Charles G. Irvin, Anne E. Dixon, Prescott G. Woodruff, Shantu Amin, Matthew E. Poynter, Dhimant H. Desai, and Vikas Anathy http://jci.me/98101

Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2Faith H. Brennan, Trisha Jogia, Ellen R. Gillespie, Linda V. Blomster, Xaria X. Li, Bianca Nowlan, Gail M. Williams, Esther Jacobson, Geoff W. Osborne, Frederic A. Meunier, Stephen M. Taylor, Kate E. Campbell, Kelli P.A. MacDonald, Jean-Pierre Levesque, Trent M. Woodruff, and Marc J. Ruitenberg http://jci.me/98254

Prior beta blocker treatment decreases leukocyte responsiveness to injuryLaurel A. Grisanti, Claudio de Lucia, Toby P. Thomas, Aron Stark, John T. Strony, Valerie D. Myers, Remus Beretta, Daohai Yu, Celestino Sardu, Raffaele Marfella, Erhe Gao, Steven R. Houser, Walter J. Koch, Eman A. Hamad, and Douglas G. Tilley http://jci.me/99485

TRPA1-expressing lamina propria mesenchymal cells regulate colonic motilityYanjing Yang, Shenglan Wang, Kimiko Kobayashi, Yongbiao Hao, Hirosato Kanda, Takashi Kondo, Yoko Kogure, Hiroki Yamanaka, Satoshi Yamamoto, Junxiang Li, Hiroto Miwa, Koichi Noguchi, and Yi Dai http://jci.me/122402

Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL p. 13Mark B. Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J. Purdon, Meier Hsu, Sean M. Devlin, M. Lia Palomba, Elizabeth Halton, Yvette Bernal, Dayenne G. van Leeuwen, Michel Sadelain, Jae H. Park, and Renier J. Brentjens (ASCI) http://jci.me/122627

Neuronal activity in vivo enhances functional myelin repairFernando C. Ortiz, Chloé Habermacher, Mariana Graciarena, Pierre-Yves Houry, Akiko Nishiyama, Brahim Nait Oumesmar, and María Cecilia Angulo http://jci.me/123434

An obligatory role for club cells in preventing obliterative bronchiolitis in lung transplants p. 11Zhiyi Liu, Fuyi Liao, Davide Scozzi, Yuka Furuya, Kaitlyn N. Pugh, Ramsey Hachem, Delphine L. Chen, Marlene Cano, Jonathan M. Green, Alexander S. Krupnick, Daniel Kreisel, Anne Karina T. Perl, Howard J. Huang, Steven L. Brody, and Andrew E. Gelman http://jci.me/124732

Signal regulatory protein α protects podocytes through promotion of autophagic activityLimin Li, Ying Liu, Shan Li, Rong Yang, Caihong Zeng, Weiwei Rong, Hongwei Liang, Mingchao Zhang, Xiaodong Zhu, Koby Kidder, Yuan Liu, Zhihong Liu, and Ke Zen http://jci.me/124747

Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2–interacting proteinSivareddy Kotla, Hang Thi Vu, Kyung Ae Ko, Yin Wang, Masaki Imanishi, Kyung-Sun Heo, Yuka Fujii, Tamlyn N. Thomas, Young Jin Gi, Hira Mazhar, Jesus Paez-Mayorga, Ji-Hyun Shin, Yunting Tao, Carolyn J. Giancursio, Jan L.M. Medina, Jack Taunton, Aldos J. Lusis, John P. Cooke, Keigi Fujiwara, Nhat-Tu Le, and Jun-ichi Abe http://jci.me/124867

Human endotrophin as a driver of malignant tumor growth p. 12Dawei Bu, Clair Crewe, Christine M. Kusminski, Ruth Gordillo, Alexandra L. Ghaben, Min Kim, Jiyoung Park, Hui Deng, Wei Xiong, Xiao-Zheng Liu, Per Eystein Lønning, Nils Halberg, Adan Rios, Yujun Chang, Anneliese Gonzalez, Ningyan Zhang, Zhiqiang An, and Philipp E. Scherer http://jci.me/125094

Distinct amino acid and lipid perturbations characterize acute versus chronic malariaRegina Joice Cordy, Rapatbhorn Patrapuvich, Loukia N. Lili, Monica Cabrera-Mora, Jung-Ting Chien, Gregory K. Tharp, Manoj Khadka, Esmeralda V.S. Meyer, Stacey A. Lapp, Chester J. Joyner, AnaPatricia Garcia, Sophia Banton, ViLinh Tran, Viravarn Luvira, Siriwan Rungin, Teerawat Saeseu, Nattawan Rachaphaew, Suman B. Pakala, Jeremy D. DeBarry, MaHPIC Consortium, Jessica C. Kissinger, Eric A. Ortlund, Steven E. Bosinger, John W. Barnwell, Dean P. Jones, Karan Uppal, Shuzhao Li, Jetsumon Sattabongkot, Alberto Moreno, and Mary R. Galinski http://jci.me/125156

B lymphocytes protect islet β cells in diabetes-prone NOD mice treated with imatinibChristopher S. Wilson, Jason M. Spaeth, Jay Karp, Blair T. Stocks, Emilee M. Hoopes, Roland W. Stein, and Daniel J. Moore http://jci.me/125317

Sclerostin inhibition alleviates breast cancer–induced bone metastases and muscle weaknessEric Hesse, Saskia Schröder, Diana Brandt, Jenny Pamperin, Hiroaki Saito, and Hanna Taipaleenmäki http://jci.me/125543

Increased attrition of memory T cells during sepsis requires 2B4Jianfeng Xie, Ching-wen Chen, Yini Sun, Sonia J. Laurie, Wenxiao Zhang, Shunsuke Otani, Gregory S. Martin, Craig M. Coopersmith, and Mandy L. Ford http://jci.me/126030

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancerVictoria H. Cruz, Emily N. Arner, Wenting Du, Alberto E. Bremauntz, and Rolf A. Brekken http://jci.me/126117

VIPergic neurons of the infralimbic and prelimbic cortices control palatable food intake through separate cognitive pathwaysBrandon A. Newmyer, Ciarra M. Whindleton, Peter M. Klein, Mark P. Beenhakker, Marieke K. Jones, and Michael M. Scott http://jci.me/126283

Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritisMaarten M. Steinz, Malin Persson, Bejan Aresh, Karl Olsson, Arthur J. Cheng, Emma Ahlstrand, Mats Lilja, Tommy R. Lundberg, Eric Rullman, Kristina Ängeby Möller, Katalin Sandor, Sofia Ajeganova, Takashi Yamada, Nicole Beard, Björn C.G. Karlsson, Pasi Tavi, Ellinor Kenne, Camilla I. Svensson, Dilson E. Rassier, Roger Karlsson, Ran Friedman, Thomas Gustafsson, and Johanna T. Lanner http://jci.me/126347

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

Current articles

B cell profiling in malaria reveals expansion and remodeling of CD11c+ B cell subsetsChristopher Sundling, Caroline Rönnberg, Victor Yman, Muhammad Asghar, Peter Jahnmatz, Tadepally Lakshmikanth, Yang Chen, Jaromir Mikes, Mattias N. Forsell, Klara Sondén, Adnane Achour, Petter Brodin, Kristina E.M. Persson, and Anna Färnert http://jci.me/126492

PP2A enables IL-2 signaling by preserving IL-2Rβ chain expression during Treg developmentAmir Sharabi, Hao Li, Isaac R. Kasper, Wenliang Pan, Esra Meidan, Maria G. Tsokos, Vaishali R. Moulton, and George C. Tsokos http://jci.me/126294

Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures p. 10Verena Hammelmann, Marc Sebastian Stieglitz, Henrik Hülle, Karim Le Meur, Jennifer Kass, Manuela Brümmer, Christian Gruner, René Dominik Rötzer, Stefanie Fenske, Jana Hartmann, Benedikt Zott, Anita Lüthi, Saskia Spahn, Markus Moser, Dirk Isbrandt, Andreas Ludwig, Arthur Konnerth, Christian Wahl-Schott, and Martin Biel http://jci.me/126418

Deficiency of Socs3 leads to brain-targeted experimental autoimmune encephalomyelitis via enhanced neutrophil activation and ROS productionZhaoqi Yan, Wei Yang, Luke Parkitny, Sara A. Gibson, Kevin S. Lee, Forrest Collins, Jessy S. Deshane, Wayne Cheng, Amy S. Weinmann, Hairong Wei, Hongwei Qin, and Etty N. Benveniste http://jci.me/126520

Differential transcriptome and development of human peripheral plasma cell subsetsSwetha Garimilla, Doan C. Nguyen, Jessica L. Halliley, Christopher Tipton, Alexander F. Rosenberg, Christopher F. Fucile, Celia L. Saney, Shuya Kyu, Denise Kaminski, Yu Qian, Richard H. Scheuermann, Greg Gibson, Iñaki Sanz, and F. Eun-Hyung Lee http://jci.me/126732

Circulating cell death biomarker TRAIL is associated with increased organ dysfunction in sepsisEdward J. Schenck, Kevin C. Ma, David R. Price, Thomas Nicholson, Clara Oromendia, Eliza Rose Gentzler, Elizabeth Sanchez, Rebecca M. Baron, Laura E. Fredenburgh, Jin-Won Huh, Ilias I. Siempos, and Augustine M.K. Choi (ASCI) http://jci.me/127143

Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipientsEverett H. Meyer, Ginna Laport, Bryan Xie, Kate MacDonald, Kartoosh Heydari, Bita Sahaf, Sai-Wen Tang, Jeanette Baker, Randall Armstrong, Keri Tate, Cynthia Tadisco, Sally Arai, Laura Johnston, Robert Lowsky, Lori Muffly, Andrew R. Rezvani, Judith Shizuru, Wen-Kai Weng, Kevin Sheehan, David Miklos, and Robert S. Negrin http://jci.me/127244

Detection of circulating extracellular mRNAs by modified small-RNA-sequencing analysisKemal M. Akat, Youngmin A. Lee, Arlene Hurley, Pavel Morozov, Klaas E.A. Max, Miguel Brown, Kimberly Bogardus, Anuoluwapo Sopeyin, Kai Hildner, Thomas G. Diacovo, Markus F. Neurath, Martin Borggrefe, and Thomas Tuschl http://jci.me/127317

Patterns of ANA+ B cells for SLE patient stratificationJolien Suurmond, Yemil Atisha-Fregoso, Ashley N. Barlev, Silvia A. Calderon, Meggan C. Mackay, Cynthia Aranow, and Betty Diamond http://jci.me/127885

Pressure overload leads to coronary plaque formation, progression, and myocardial events in ApoE–/– mice p. 13Alice Marino, Yi Zhang, Luisa Rubinelli, Maria Antonietta Riemma, James E. Ip, and Annarita Di Lorenzo http://jci.me/128220

Self-tolerance curtails the B cell repertoire to microbial epitopes p. 11Akiko Watanabe, Kuei-Ying Su, Masayuki Kuraoka, Guang Yang, Alexander E. Reynolds, Aaron G. Schmidt, Stephen C. Harrison, Barton F. Haynes, E. William St. Clair, and Garnett Kelsoe http://jci.me/122551

An endogenous peptide marker differentiates SOD1 stability and facilitates pharmacodynamic monitoring in SOD1 amyotrophic lateral sclerosisIlya Gertsman, Joanne Wuu, Melissa McAlonis-Downes, Majid Ghassemian, Karen Ling, Frank Rigo, Frank Bennett, Michael Benatar, Timothy M. Miller, and Sandrine Da Cruz http://jci.me/122768

Alteration of myocardial GRK2 produces a global metabolic phenotypeBenjamin P. Woodall, Kenneth S. Gresham, Meryl A. Woodall, Mesele-Christina Valenti, Alessandro Cannavo, Jessica Pfleger, J. Kurt Chuprun, Konstantinos Drosatos, and Walter J. Koch http://jci.me/123848

Aged marrow macrophages expand platelet-biased hematopoietic stem cells via interleukin-1BBenjamin J. Frisch, Corey M. Hoffman, Sarah E. Latchney, Mark W. LaMere, Jason Myers, John Ashton, Allison J. Li, Jerry Saunders II, James Palis, Archibald S. Perkins, Amanda McCabe, Julianne N.P. Smith, Kathleen E. McGrath, Fatima Rivera-Escalera, Andrew McDavid, Jane L. Liesveld, Vyacheslav A. Korshunov, Michael R. Elliott, Katherine C. MacNamara, Michael W. Becker, and Laura M. Calvi (ASCI) http://jci.me/124213

An effective mouse model for adoptive cancer immunotherapy targeting neoantigensKen-ichi Hanada, Zhiya Yu, Gabrielle R. Chappell, Adam S. Park, and Nicholas P. Restifo http://jci.me/124405

Contractile and hemodynamic forces coordinate Notch1b-mediated outflow tract valve formationJeffrey J. Hsu, Vijay Vedula, Kyung In Baek, Cynthia Chen, Junjie Chen, Man In Chou, Jeffrey Lam, Shivani Subhedar, Jennifer Wang, Yichen Ding, Chih-Chiang Chang, Juhyun Lee, Linda L. Demer, Yin Tintut, Alison L. Marsden, and Tzung K. Hsiai (ASCI) http://jci.me/124460

Bmal1 deletion in mice facilitates adaptation to disrupted light/dark conditionsGuangrui Yang, Lihong Chen, Jiayang Zhang, Baoyin Ren, and Garret A. FitzGerald (ASCI) http://jci.me/125133

j c i . o r g / t h i s - m o n t h j u n e 2 0 1 9 16

Gene suppressing therapy for Pelizaeus-Merzbacher disease using artificial microRNAHeng Li, Hironori Okada, Sadafumi Suzuki, Kazuhisa Sakai, Hitomi Izumi, Yukiko Matsushima, Noritaka Ichinohe, Yu-ichi Goto, Takashi Okada, and Ken Inoue http://jci.me/125052

Systems biology identifies cytosolic PLA2 as a target in vascular calcification treatment p. 12Joost P. Schanstra, Trang T.D. Luong, Manousos Makridakis, Sophie Van Linthout, Vasiliki Lygirou, Agnieszka Latosisnska, Ioana Alesutan, Beate Boehme, Nadeshda Schelski, Dirk Von Lewinski, William Mullen, Stuart Nicklin, Christian Delles, Guylène Feuillet, Colette Denis, Florian Lang, Burkert Pieske, Jean-Loup Bascands, Harald Mischak, Jean-Sebastien Saulnier-Blache, Jakob Voelkl, Antonia Vlahou, and Julie Klein http://jci.me/125638

Cullin-3–dependent deregulation of ACTN1 represents a pathogenic mechanism in nemaline myopathyJordan Blondelle, Kavya Tallapaka, Jane T. Seto, Majid Ghassemian, Madison Clark, Jenni M. Laitila, Adam Bournazos, Jeffrey D. Singer, and Stephan Lange http://jci.me/125665

Chronic immune barrier dysregulation among women with a history of violence victimizationAlison Swaims-Kohlmeier, Lisa B. Haddad, Tiger Zheng-Rong Li, Kathryn A. Brookmeyer, James M. Baker, Cathy Spatz Widom, James C. Lamousin, Kai-Hua Chi, Cheng Y. Chen, Ellen N. Kersh, Jeffrey A. Johnson, Melissa M. Herbst-Kralovetz, Matthew Hogben, Igho Ofotokun, and Jacob E. Kohlmeier http://jci.me/126097

TLR9/MyD88/TRIF signaling activates host immune inhibitory CD200 in Leishmania infectionIsmael P. Sauter, Katerine G. Madrid, Josiane B. de Assis, Anderson Sá-Nunes, Ana C. Torrecilhas, Daniela I. Staquicini, Renata Pasqualini, Wadih Arap (ASCI), and Mauro Cortez http://jci.me/126207

Single-cell transcriptomics–based MacSpectrum reveals macrophage activation signatures in diseasesChuan Li, Antoine Menoret, Cullen Farragher, Zhengqing Ouyang, Christopher Bonin, Paul Holvoet, Anthony T. Vella, and Beiyan Zhou http://jci.me/126453

Blocking IL-10 receptor signaling ameliorates Mycobacterium tuberculosis infection during influenza-induced exacerbationSarah Ring, Lars Eggers, Jochen Behrends, Adam Wutkowski, Dominik Schwudke, Andrea Kröger, Alexandra Maximiliane Hierweger, Christoph Hölscher, Gülsah Gabriel, and Bianca Schneider http://jci.me/126533

Prohibitin promotes dedifferentiation and is a potential therapeutic target in neuroblastomaIan C. MacArthur, Yi Bei, Heathcliff Dorado Garcia, Michael V. Ortiz, Joern Toedling, Filippos Klironomos, Jana Rolff, Angelika Eggert, Johannes H. Schulte, Alex Kentsis, and Anton G. Henssen http://jci.me/127130

ERK1/2 signaling induces skeletal muscle slow fiber-type switching and reduces muscular dystrophy disease severityJustin G. Boyer, Vikram Prasad, Taejeong Song, Donghoon Lee, Xing Fu, Kelly M. Grimes, Michelle A. Sargent, Sakthivel Sadayappan, and Jeffery D. Molkentin http://jci.me/127356

Erythropoietin inhibits SGK1-dependent Th17 cell induction and Th17 cell–dependent kidney diseaseChiara Donadei, Andrea Angeletti, Chiara Cantarelli, Vivette D. D’Agati, Gaetano La Manna, Enrico Fiaccadori, Julian K. Horwitz, Huabao Xiong, Chiara Guglielmo, Susan Hartzell, Joren C. Madsen, Umberto Maggiore, Peter S. Heeger, and Paolo Cravedi http://jci.me/127428

Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis p. 12Dennis G. Moledina, F. Perry Wilson, Jordan S. Pober, Mark A. Perazella, Nikhil Singh, Randy L. Luciano, Wassim Obeid, Haiqun Lin, Michael Kuperman, Gilbert W. Moeckel, Michael Kashgarian, Lloyd G. Cantley, and Chirag R. Parikh (ASCI) http://jci.me/127456

Phase I trial of the single-chain urokinase intrapleural LTI-01 in complicated parapneumonic effusions or empyemaLutz Beckert, Ben Brockway, Graham Simpson, Anne Marie Southcott, Y.C. Gary Lee, Najib Rahman, Richard W. Light, Steven Shoemaker, John Gillies, Andrey A. Komissarov, Galina Florova, Timothy Ochran, William Bradley, Harrison Ndetan, Karan P. Singh, Krishna Sarva, and Steven Idell http://jci.me/127470

Biomarkers of endothelial activation/dysfunction distinguish subgroups of Ugandan patients with sepsis and differing mortality risksDanielle V. Clark, Patrick Banura, Karen Bandeen-Roche, W. Conrad Liles, Kevin C. Kain, W. Michael Scheld, William J. Moss, and Shevin T. Jacob http://jci.me/127623

Parkin does not prevent accelerated cardiac aging in mitochondrial DNA mutator miceBenjamin P. Woodall, Amabel M. Orogo, Rita H. Najor, Melissa Q. Cortez, Eileen R. Moreno, Hongxia Wang, Ajit S. Divakaruni, Anne N. Murphy, and Åsa B. Gustafsson http://jci.me/127713

Polycomb repressive complex 2 is a critical mediator of allergic inflammationChristine R. Keenan, Nadia Iannarella, Alexandra L. Garnham, Alexandra C. Brown, Richard Y. Kim, Jay C. Horvat, Philip M. Hansbro, Stephen L. Nutt, and Rhys S. Allan http://jci.me/127745

Intraislet glucagon signaling is critical for maintaining glucose homeostasisLu Zhu, Diptadip Dattaroy, Jonathan Pham, Lingdi Wang, Luiz F. Barella, Yinghong Cui, Kenneth J. Wilkins, Bryan L. Roth, Ute Hochgeschwender, Franz M. Matschinsky, Klaus H. Kaestner, Nicolai M. Doliba, and Jürgen Wess http://jci.me/127994

Titin mutation associated with responsiveness to checkpoint blockades in solid tumorsQingzhu Jia, Jun Wang, Ning He, Ji He, and Bo Zhu http://jci.me/127901 Flip issue to read JCI content.