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Characterizing immunogenic TP53 neoantigens 2

Neuronal apoE receptors influence amyloid-β metabolism 3

CD33 ligand restrains IgE-mediated anaphylaxis 5

Platelet-derived miR-223 regulates vascular repair 5

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

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March 2019

Cingulum stimulation enhances mood during awake neurosurgery p. 2

This Month

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j c i . o r g / t h i s - m o n t h m a r c h 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, Paul B. Rothman, Diane E. Griffin, and David Valle

BiostatisticianEliseo Guallar

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

For the full JCI online: jci.me/129/3

This MonthMarch 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)

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Featured Editor

William R. Bishai, MD, PhD, Associate Editor, is Professor of Medicine in the Division of Infectious Diseases and Co-Director of the Center for Tuberculosis Research at Johns Hopkins School of Medicine. His main areas of research include mechanisms of tuberculosis pathogenesis and development of tools to combat tuberculosis, including drugs, diagnostics, and vaccines. Dr. Bishai is a member of the American Society for Clinical Investigation as well as the Association of American Physicians.

Publication highlights

Gupta S, Krug S, Pokkali S, Leanderson T, Isaacs JT, Srikrishna G, Bishai WR. Pharmacologic exhaustion of suppressor cells with tasquinimod enhances bacterial clearance during TB [published online ahead of print November 5, 2018]. Am J Respir Crit Care Med. doi: 10.1164/rccm.201805-0820LE.

Urbanowski ME, Ihms EA, Bigelow K, Kübler A, Elkington PT, Bishai WR. Repetitive aerosol exposure promotes cavitary tuberculosis and enables screening for targeted inhibitors of extensive lung destruction. J Infect Dis. 2018;218(1):53–63.

Dey RJ, Dey B, Zheng Y, Cheung LS, Zhou J, Sayre D, Kumar P, Guo H, Lamichhane G, Sintim HO, Bishai WR. Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase. Nat Chem Biol. 2017;13(2):210–217.

Ahidjo BA, Maiga MC, Ihms EA, Maiga M, Ordonez AA, Cheung LS, Beck S, Andrade BB, Jain S, Bishai WR. The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis. JCI Insight. 2016;1(14):e86017.

(ASCI) indicates corresponding authors who are ASCI members.

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

research

Editor’s picks

on the jci cover

oncology

Cingulum bundle stimulation reduces anxiety during awake neurosurgical proceduresCertain neurosurgeries must be performed on alert patients in order to continuously monitor motor, sensory, and language function. Understandably, many patients undergoing awake craniotomy experience anxiety that can make the procedure intolerable. In this issue of the JCI, Kelly Bijanki et al. describe a noteworthy observation that occurred during diagnostic intracranial electroencephalography (iEEG): low-intensity stimulation of the anterior cingulum bundle instantly improved the patient’s mood and reduced anxiety, and this stimulation was subsequently used to alleviate anxiety during her awake craniotomy for epilepsy. The cingulum bundle connects the limbic regions with prefrontal, parietal, and temporal lobes and contributes to cognitive and emotional responses. After the initial patient’s responses to the stimulation were noted, similar responses were documented in two additional patients undergoing iEEG. In an accompanying Commentary, Kelly Mills suggests that the stimulation’s anxiolytic and mood-enhancing effects, which occurred without changes in cognitive state or sedation, may make it a useful alternative to anxiolytic medications to manage patients’ tolerance of awake neurosurgical procedures. This issue’s cover depicts the position of the implanted electrode along the cingulum bundle, which is highlighted in pink. In the background, a man’s changing facial expressions represent one objective measurement of the stimulation’s effects. Image credit: Bona Kim, MA, CMI, Emory University Brain Health Center.

Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomyKelly R. Bijanki, Joseph R. Manns, Cory S. Inman, Ki Sueng Choi, Sahar Harati, Nigel P. Pedersen, Daniel L. Drane, Allison C. Waters, Rebecca E. Fasano, Helen S. Mayberg, and Jon T. Willie http://jci.me/120110

TP53 hot spot mutations are immunogenic targets for tumor-infiltrating T cells

neuroscience

Cellular immunotherapies utilizing adoptive transfer of tumor-infiltrating T cells have elicited successful clinical responses against a number of cancers. However, transferred T cells often target tumor neoantigens that are unique to an individual patient, making these cellular therapies time-consuming to develop. To identify a more broadly applicable target for cellular immunotherapies, Parisa Malekzadeh and colleagues sequenced and then screened for common immunogenic mutations in TP53, the most frequently mutated gene among all cancer types. They demonstrated that patient-derived tumor-infiltrating T cells were capable of targeting autologous TP53 “hot spot” mutations at commonly mutated positions. Further, they identified shared T cell receptors from mutation-responsive CD4+ and CD8+ T cells. Enrico Lugli, Pia Kvistborg, and Giovanni Galletti’s accompanying Commentary supports this study’s suggestion that cellular immunotherapies could be engineered to target neoantigens that are common in cancer.

Related CommentaryProbing the happy placeKelly A. Mills http://jci.me/126683

Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancersParisa Malekzadeh, Anna Pasetto, Paul F. Robbins, Maria R. Parkhurst, Biman C. Paria, Li Jia, Jared J. Gartner, Victoria Hill, Zhiya Yu, Nicholas P. Restifo, Abraham Sachs, Eric Tran, Winifred Lo, Robert P.T. Somerville, Steven A. Rosenberg, and Drew C. Deniger http://jci.me/123791

Related CommentaryCancer neoantigens targeted by adoptive T cell transfer: private no moreEnrico Lugli, Pia Kvistborg, and Giovanni Galletti http://jci.me/126295

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JCI | Research: Editor’s picks

Apolipoprotein E receptor interacts with Alzheimer’s risk allele in amyloid-β pathologyAmyloid-β accumulation in the brain precedes the development of amyloid plaques that are a diagnostic feature of Alzheimer’s disease (AD). The ε4 allele of the gene encoding apolipoprotein E (APOE4) is associated with increased AD risk, likely through an effect on amyloid-β metabolism. Masaya Tachibana, Marie-Louise Holm, and colleagues investigated the interaction of the apolipoprotein E receptor LRP1 with APOE4’s effects on amyloid pathology. In postmortem AD brains, the APOE4 allele was linked to elevated levels of insoluble amyloid-β as well as increased LRP1 expression relative to the ε3 allele (APOE3). In a mouse model of AD, APOE4-expressing mice displayed similar increases in amyloid-β deposition relative to APOE3-expressing mice; however, loss of neuronal LRP1 mitigated this increase (see the associated image). An accompanying Commentary by Michael Strickland and David Holtzman discusses these insights into mechanisms by which apolipoprotein E isoforms may differen-tially affect amyloid-β metabolism and AD risk.

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APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1Masaya Tachibana, Marie-Louise Holm, Chia-Chen Liu, Mitsuru Shinohara, Tomonori Aikawa, Hiroshi Oue, Yu Yamazaki, Yuka A. Martens, Melissa E. Murray, Patrick M. Sullivan, Kathrin Weyer, Simon Glerup, Dennis W. Dickson, Guojun Bu, and Takahisa Kanekiyo http://jci.me/124853

Related CommentaryDr. Jekyll and Mr. Hyde: ApoE explains opposing effects of neuronal LRP1Michael Strickland and David M. Holtzman http://jci.me/127578

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

JCI | Research: Editor’s picks

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Monoclonal antibody targets pathogenic IFN source in cutaneous lupus lesions

A primary antibody deficiency linked to loss of ARHGEF1Primary antibody deficiency (PAD) syndromes are characterized by failure to produce sufficient antibody responses to prevent infection. PAD is often linked to defects in B cell development, differentiation, or function, although the molecular mechanisms involved are often unclear. Amine Bouafia and colleagues identified two heterozygous loss-of-function mutations in the hematopoietic guanine nucleotide exchange factor ARHGEF1 in two siblings diagnosed with PAD. Both patients were deficient in marginal zone and memory B cells, but displayed abnormally high levels of transitional B cells and immature myeloid cells in blood. Impaired actin polymerization, prolonged AKT activation, and inefficient migration in the patients’ lymphocytes resembled the phenotype of Arhgef1-deficient mice. In the accompanying Commentary, Divij Mathew, Kimberly Kremer, and Raul Torres discuss how these findings provide insights into ARHGEF1’s role in the adaptive immune response in addition to identifying a novel cause of PAD.

Loss of ARHGEF1 causes a human primary antibody deficiencyAmine Bouafia, Sébastien Lofek, Julie Bruneau, Loïc Chentout, Hicham Lamrini, Amélie Trinquand, Marie-Céline Deau, Lucie Heurtier, Véronique Meignin, Capucine Picard, Elizabeth Macintyre, Olivier Alibeu, Marc Bras, Thierry Jo Molina, Marina Cavazzana, Isabelle André-Schmutz, Anne Durandy, Alain Fischer, Eric Oksenhendler, and Sven Kracker http://jci.me/120572

Related CommentaryARHGEF1 deficiency reveals Gα13-associated GPCRs are critical regulators of human lymphocyte functionDivij Mathew, Kimberly N. Kremer, and Raul M. Torres http://jci.me/125893

immunology

Systemic lupus erythematosus (SLE) is character-ized by autoantibody production, chronic inflamma-tion, and pathologic activation of multiple proinflam-matory pathways, notably the type I IFN pathway. Plasmacytoid dendritic cells (pDCs), which produce large amounts of type I IFN, are considered a promising therapeutic target. Richard Furie and colleagues evaluated the safety and tolerability of a pDC-targeting monoclonal antibody (BIIB059) in 54 healthy volunteers and 12 SLE patients. BIIB059 was designed to bind to the pDC receptor BDCA2 and thereby limit type I IFN production. BIIB059 administration was well tolerated and resulted in favorable pharmacokinetic and pharmacodynamic profiles in healthy and SLE subjects. In SLE patients, a single dose of BIIB059 decreased expression of blood IFN response genes, normalized IFN activity, reduced inflammatory infiltrates in skin lesions, and decreased skin disease activity. Yashaar Chaichian,

Daniel J. Wallace, and Michael Weisman’s accompa-nying Commentary supports further study of BIIB059 as an intervention in SLE.

Monoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosusRichard Furie, Victoria P. Werth, Joseph F. Merola, Lauren Stevenson, Taylor L. Reynolds, Himanshu Naik, Wenting Wang, Romy Christmann, Agnes Gardet, Alex Pellerin, Stefan Hamann, Pavan Auluck, Catherine Barbey, Parul Gulati, Dania Rabah, and Nathalie Franchimont http://jci.me/124466

Related CommentaryA promising approach to targeting type 1 IFN in systemic lupus erythematosusYashaar Chaichian, Daniel J. Wallace, and Michael H. Weisman http://jci.me/127101

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JCI | Research: Editor’s picks

CD33 targeting suppresses mast cell–mediated anaphylaxis during antigen presentation

Platelet delivery of miR-223 regulates proliferative phase of arterial repair

immunology

Anaphylaxis is a severe allergic response that is initiated when allergen-specific IgE binds to its receptor on mast cells, triggering degranulation. Allergen immunotherapy can desensitize mast cell activation by exposing the patient to escalating doses of allergen; however, because of intolerable side effects, many patients discontinue treatment before reaching the therapeutic dose. Shiteng Duan and colleagues identified the mast cell receptor CD33 as a potential target for suppressing anaphylactic responses to antigen presentation. They show that antigen- presenting liposomes also bearing the high-affinity CD33 ligand CD33L suppressed allergen-induced mast cell activation. In a mouse model of anaphylaxis, the CD33L-bearing liposomes similarly inhibited mast cell activation and produced allergen-specific desensitization that lasted for several days. Finally, activating CD33 in human mast cells prevented IgE-mediated broncho-constriction in human lung tissue. In an accompanying Commentary, Stephen Galli outlines the evidence supporting CD33-mediated mast cell suppression as a potential strategy for treating severe allergic disease.

Arterial injury induces a multistage reparative process during which vascular smooth muscle cells (VSMCs) dedifferentiate, repopulate the damaged area, and finally return to a quiescent state. Prolonged VSMC proliferation can lead to intimal hyperplasia and restenosis, which are observed more frequently in diabetic individuals. While activated platelets are known to influence VSMC dedifferentiation via release of PDGF and cytokines, a study by Zhi Zeng and colleagues highlights their contribution to the timely resolution of the proliferative phase. In coculture experiments and in vivo lineage-tracing studies, they observed that the return to quiescence required VSMCs to internalize activated platelets (see the associated image). Horizontal transfer of miR-223 from internalized platelets inhibited PDGFRβ expression in VSMCs, inducing the latter’s switch to a quiescent phenotype. Noting an observation that uncontrolled glucose levels depress miR-223 expres-

sion, Elena Dolmatova and Kathy Griendling’s accompanying Commen-tary speculates on potentially targetable mechanisms underlying increased risk of restenosis in patients with diabetes.

Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repairZhi Zeng, Luoxing Xia, Xuejiao Fan, Allison C. Ostriker, Timur Yarovinsky, Meiling Su, Yuan Zhang, Xiangwen Peng, Yi Xie, Lei Pi, Xiaoqiong Gu, Sookja Kim Chung, Kathleen A. Martin, Renjing Liu, John Hwa, and Wai Ho Tang http://jci.me/124508

Related CommentaryPlatelet microRNAs and vascular injuryElena V. Dolmatova and Kathy K. Griendling http://jci.me/127580

vascular biology

CD33 recruitment inhibits IgE-mediated anaphylaxis and desensitizes mast cells to allergenShiteng Duan, Cynthia J. Koziol-White, William F. Jester Jr., Corwin M. Nycholat, Matthew S. Macauley, Reynold A. Panettieri Jr., and James C. Paulson (ASCI) http://jci.me/125456

Related CommentaryRecruiting CD33 on mast cells to inhibit IgE-mediated mast cell–dependent anaphylaxisStephen J. Galli (ASCI) http://jci.me/127100

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JCI | Features

viewpoints

reviews

Clashing perspectives on the future of precision medicine

Examining the autoimmune mechanisms contributing to encephalitis disorders and epilepsyRecent insights into the autoimmune basis of several encephalitis disorders have increased interest in potential autoimmune mechanisms underlying seizures and epilepsy. Several seizure-linked disorders, including Rasmussen’s encephalitis, are linked to immune responses to neuronal antibodies (see the accompanying image), and a number of drug-resistant epilepsies are accompanied by elevated levels of cytotoxic T cells and inflammatory molecules in the CNS. However, a review by Christian Geis, Jesus Planagumà, Mar Carreño, Francesc Graus, and Josep Dalmau urges prudence in differentiating between autoimmune epilepsy and the occurrence of seizures linked to autoimmune disease: while patients with autoimmune encephalitis disorders may experience a seizure, many do not go on to develop true epilepsy. This Review outlines a range of mechanisms by which CNS inflammation, neuronal hyperexcitability, and long-term synaptic dysfunction act in combination or independently to contribute to epileptogenesis.

Autoimmune seizures and epilepsyChristian Geis, Jesus Planagumà, Mar Carreño, Francesc Graus, and Josep Dalmau http://jci.me/125178

Tissue-targeting strategies propel synthetic nucleic acid drug discoveryRecent FDA approvals of RNA-targeting treatments for Duchenne’s muscular dystrophy, spinal muscular atrophy, and other diseases highlight the potential of antisense oligonucleotides (ASOs) as therapeutic strategies. Successful development of ASO-based therapies for other diseases will be enhanced, in part, by ongoing advances in the ability to selectively deliver these drugs to specific tissues. Tissue targeting provides an opportunity to increase treatment potency, improve pharmacokinetic profile, and reduce toxicity of an ASO-based therapy. In this Review, Punit Seth, Michael Tanowitz, and Frank Bennett describe a variety of strategies that facilitate ASO delivery, including chemical modifications, conjugation to tissue-specific receptors or ligands, and encapsulation in lipid nanoparticles. Advances in tissue-specific targeting may also facilitate noninvasive ASO delivery to the CNS and other protected tissues.

Selective tissue targeting of synthetic nucleic acid drugsPunit P. Seth, Michael Tanowitz, and C. Frank Bennett http://jci.me/125228

Two Viewpoints in this issue address the achievements and future of precision medicine. The article by Michael Joyner and Nigel Paneth reflects on the aims of the Human Genome Project, which promised to deliver insights that would improve genetic disease, diagnostics, pharmacogenomics, preventive medicine, and gene therapy within our lifetimes. They argue that our current awareness of the limitations of precision medicine should inspire the medical community to reprioritize its investments in projects that may better meet our nation’s health needs. On the other hand, Antony Rosen and Scott Zeger take the view that precision medicine methods provide an opportunity to enhance clinical decision-making by integrating improvements in biological measurements, computational power, and connectivity. Their article reimagines precision medicine beyond “big data” and “deep learning,” describing the need to develop infrastructure and health systems that can optimize its clinical potential.

Related ArticlesPromises, promises, and precision medicineMichael J. Joyner and Nigel Paneth http://jci.me/126119

Precision medicine: discovering clinically relevant and mechanistically anchored disease subgroups at scaleAntony Rosen (ASCI) and Scott L. Zeger http://jci.me/126120

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Current research articles

aids/hivMucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody responseYongjun Sui, George K. Lewis, Yichuan Wang, Kurt Berckmueller, Blake Frey, Amiran Dzutsev, Diego Vargas-Inchaustegui, Venkatramanan Mohanram, Thomas Musich, Xiaoying Shen, Anthony DeVico, Timothy Fouts, David Venzon, James Kirk, Robert C. Waters, James Talton, Dennis Klinman, John Clements, Georgia D. Tomaras, Genoveffa Franchini, Marjorie Robert-Guroff, Giorgio Trinchieri, Robert C. Gallo, and Jay A. Berzofsky http://jci.me/122110

Intact HIV-1 proviruses accumulate at distinct chromosomal positions during prolonged antiretroviral therapyKevin B. Einkauf, Guinevere Q. Lee, Ce Gao, Radwa Sharaf, Xiaoming Sun, Stephane Hua, Samantha M.Y. Chen, Chenyang Jiang, Xiaodong Lian, Fatema Z. Chowdhury, Eric S. Rosenberg, Tae-Wook Chun, Jonathan Z. Li, Xu G. Yu, and Mathias Lichterfeld (ASCI) http://jci.me/124291

autoimmunityReduced expression of phosphatase PTPN2 promotes pathogenic conversion of Tregs in autoimmunityMattias N.D. Svensson, Karen M. Doody, Benjamin J. Schmiedel, Sourya Bhattacharyya, Bharat Panwar, Florian Wiede, Shen Yang, Eugenio Santelli, Dennis J. Wu, Cristiano Sacchetti, Ravindra Gujar, Gregory Seumois, William B. Kiosses, Isabelle Aubry, Gisen Kim, Piotr Mydel, Shimon Sakaguchi, Mitchell Kronenberg, Tony Tiganis, Michel L. Tremblay, Ferhat Ay, Pandurangan Vijayanand, and Nunzio Bottini (ASCI) http://jci.me/123267

microRNA-142–mediated repression of phosphodiesterase 3B critically regulates peripheral immune toleranceNelomi Anandagoda, Joanna C.D. Willis, Arnulf Hertweck, Luke B. Roberts, Ian Jackson, M. Refik Gökmen, Richard G. Jenner, Jane K. Howard, and Graham M. Lord http://jci.me/124725

bone biologySubchondral bone osteoclasts induce sensory innervation and osteoarthritis painShouan Zhu, Jianxi Zhu, Gehua Zhen, Yihe Hu, Senbo An, Yusheng Li, Qin Zheng, Zhiyong Chen, Ya Yang, Mei Wan, Richard Leroy Skolasky, Yong Cao, Tianding Wu, Bo Gao, Mi Yang, Manman Gao, Julia Kuliwaba, Shuangfei Ni, Lei Wang, Chuanlong Wu, David Findlay, Holger K. Eltzschig, Hong Wei Ouyang, Janet Crane, Feng-Quan Zhou, Yun Guan, Xinzhong Dong, and Xu Cao http://jci.me/121561

gastroenterologyEndogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammationJonathan T. Busada, Sivapriya Ramamoorthy, Derek W. Cain, Xiaojiang Xu, Donald N. Cook, and John A. Cidlowski http://jci.me/123233

hematologySingle-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancerAlexandra A. Soukup, Ye Zheng, Charu Mehta, Jun Wu, Peng Liu, Miao Cao, Inga Hofmann, Yun Zhou, Jing Zhang, Kirby D. Johnson, Kyunghee Choi, Sunduz Keles, and Emery H. Bresnick http://jci.me/122694

immunologyLoss of ARHGEF1 causes a human primary antibody deficiency p. 4Amine Bouafia, Sébastien Lofek, Julie Bruneau, Loïc Chentout, Hicham Lamrini, Amélie Trinquand, Marie-Céline Deau, Lucie Heurtier, Véronique Meignin, Capucine Picard, Elizabeth Macintyre, Olivier Alibeu, Marc Bras, Thierry Jo Molina, Marina Cavazzana, Isabelle André-Schmutz, Anne Durandy, Alain Fischer, Eric Oksenhendler, and Sven Kracker http://jci.me/120572

Immune synapses between mast cells and γδ T cells limit viral infectionChinmay Kumar Mantri and Ashley L. St. John http://jci.me/122530

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Current research articles

immunologyMonoclonal antibody targeting BDCA2 ameliorates skin lesions in systemic lupus erythematosus p. 4Richard Furie, Victoria P. Werth, Joseph F. Merola, Lauren Stevenson, Taylor L. Reynolds, Himanshu Naik, Wenting Wang, Romy Christmann, Agnes Gardet, Alex Pellerin, Stefan Hamann, Pavan Auluck, Catherine Barbey, Parul Gulati, Dania Rabah, and Nathalie Franchimont http://jci.me/124466

CD33 recruitment inhibits IgE-mediated anaphylaxis and desensitizes mast cells to allergen p. 5Shiteng Duan, Cynthia J. Koziol-White, William F. Jester Jr., Corwin M. Nycholat, Matthew S. Macauley, Reynold A. Panettieri Jr., and James C. Paulson (ASCI) http://jci.me/125456

Antigen delivery targeted to tumor-associated macrophages overcomes tumor immune resistanceDaisuke Muraoka, Naohiro Seo, Tae Hayashi, Yoshiro Tahara, Keisuke Fujii, Isao Tawara, Yoshihiro Miyahara, Kana Okamori, Hideo Yagita, Seiya Imoto, Rui Yamaguchi, Mitsuhiro Komura, Satoru Miyano, Masahiro Goto, Shin-ichi Sawada, Akira Asai, Hiroaki Ikeda, Kazunari Akiyoshi, Naozumi Harada, and Hiroshi Shiku http://jci.me/97642

Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in miceKate Smith-Jackson, Yi Yang, Harriet Denton, Isabel Y. Pappworth, Katie Cooke, Paul N. Barlow, John P. Atkinson, M. Kathryn Liszewski, Matthew C. Pickering, David Kavanagh, H. Terence Cook, and Kevin J. Marchbank http://jci.me/99296

infectious diseaseDynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitisNeil R.H. Stone, Johanna Rhodes, Matthew C. Fisher, Sayoki Mfinanga, Sokoine Kivuyo, Joan Rugemalila, Ella Shtifman Segal, Leor Needleman, Síle F. Molloy, June Kwon-Chung, Thomas S. Harrison, William Hope, Judith Berman, and Tihana Bicanic http://jci.me/124516

nephrologyPTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney diseaseYajuan Li, Qingsong Hu, Chunlai Li, Ke Liang, Yu Xiang, Heidi Hsiao, Tina K. Nguyen, Peter K. Park, Sergey D. Egranov, Chandrashekar R. Ambati, Nagireddy Putluri, David H. Hawke, Leng Han, Mien-Chie Hung, Farhad R. Danesh, Liuqing Yang, and Chunru Lin http://jci.me/121987

Podocyte histone deacetylase activity regulates murine and human glomerular diseasesKazunori Inoue, Geliang Gan, Maria Ciarleglio, Yan Zhang, Xuefei Tian, Christopher E. Pedigo, Corey Cavanaugh, Janet Tate, Ying Wang, Elizabeth Cross, Marwin Groener, Nathan Chai, Zhen Wang, Amy Justice, Zhenhai Zhang, Chirag R. Parikh, Francis P. Wilson, and Shuta Ishibe http://jci.me/124030

neuroscienceCingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy p. 2Kelly R. Bijanki, Joseph R. Manns, Cory S. Inman, Ki Sueng Choi, Sahar Harati, Nigel P. Pedersen, Daniel L. Drane, Allison C. Waters, Rebecca E. Fasano, Helen S. Mayberg, and Jon T. Willie http://jci.me/120110

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophyDevesh C. Pant, Imen Dorboz, Agatha Schluter, Stéphane Fourcade, Nathalie Launay, Javier Joya, Sergio Aguilera-Albesa, Maria Eugenia Yoldi, Carlos Casasnovas, Mary J. Willis, Montserrat Ruiz, Dorothée Ville, Gaetan Lesca, Karine Siquier-Pernet, Isabelle Desguerre, Huifang Yan, Jinming Wang, Margit Burmeister, Lauren Brady, Mark Tarnopolsky, Carles Cornet, Davide Rubbini, Javier Terriente, Kiely N. James, Damir Musaev, Maha S. Zaki, Marc C. Patterson, Brendan C. Lanpher, Eric W. Klee, Filippo Pinto e Vairo, Elizabeth Wohler, Nara Lygia de M. Sobreira, Julie S. Cohen, Reza Maroofian, Hamid Galehdari, Neda Mazaheri, Gholamreza Shariati, Laurence Colleaux, Diana Rodriguez, Joseph G. Gleeson, Cristina Pujades, Ali Fatemi, Odile Boespflug-Tanguy, and Aurora Pujol http://jci.me/123959

APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1 p. 3Masaya Tachibana, Marie-Louise Holm, Chia-Chen Liu, Mitsuru Shinohara, Tomonori Aikawa, Hiroshi Oue, Yu Yamazaki, Yuka A. Martens, Melissa E. Murray, Patrick M. Sullivan, Kathrin Weyer, Simon Glerup, Dennis W. Dickson, Guojun Bu, and Takahisa Kanekiyo http://jci.me/124853

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DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humansGergely Karsai, Florian Kraft, Natja Haag, G. Christoph Korenke, Benjamin Hänisch, Alaa Othman, Saranya Suriyanarayanan, Regula Steiner, Cordula Knopp, Michael Mull, Markus Bergmann, J. Michael Schröder, Joachim Weis, Miriam Elbracht, Matthias Begemann, Thorsten Hornemann, and Ingo Kurth http://jci.me/124159

oncologyStress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cellsBai Cui, Yuanyuan Luo, Pengfei Tian, Fei Peng, Jinxin Lu, Yongliang Yang, Qitong Su, Bing Liu, Jiachuan Yu, Xi Luo, Liu Yin, Wei Cheng, Fan An, Bin He, Dapeng Liang, Sijin Wu, Peng Chu, Luyao Song, Xinyu Liu, Huandong Luo, Jie Xu, Yujia Pan, Yang Wang, Dangsheng Li, Peng Huang, Qingkai Yang, Lingqiang Zhang, Binhua P. Zhou, Suling Liu, Guowang Xu, Eric W.-F. Lam, Keith W. Kelley, and Quentin Liu http://jci.me/121685

Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasisAmirali B. Bukhari, Cody W. Lewis, Joanna J. Pearce, Deandra Luong, Gordon K. Chan, and Armin M. Gamper http://jci.me/122622

Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1Gaoxiang Zhao, Liyan Gong, Dan Su, Yujuan Jin, Chenchen Guo, Meiting Yue, Shun Yao, Zhen Qin, Yi Ye, Ying Tang, Qibiao Wu, Jian Zhang, Binghai Cui, Qiurong Ding, Hsinyi Huang, Liang Hu, Yuting Chen, Peiyuan Zhang, Guohong Hu, Luonan Chen, Kwok-Kin Wong, Daming Gao, and Hongbin Ji http://jci.me/122779

PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancerRoman M. Chabanon, Gareth Muirhead, Dragomir B. Krastev, Julien Adam, Daphné Morel, Marlène Garrido, Andrew Lamb, Clémence Hénon, Nicolas Dorvault, Mathieu Rouanne, Rebecca Marlow, Ilirjana Bajrami, Marta Llorca Cardeñosa, Asha Konde, Benjamin Besse, Alan Ashworth, Stephen J. Pettitt, Syed Haider, Aurélien Marabelle, Andrew N.J. Tutt, Jean-Charles Soria, Christopher J. Lord, and Sophie Postel-Vinay http://jci.me/123319

Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers p. 2Parisa Malekzadeh, Anna Pasetto, Paul F. Robbins, Maria R. Parkhurst, Biman C. Paria, Li Jia, Jared J. Gartner, Victoria Hill, Zhiya Yu, Nicholas P. Restifo, Abraham Sachs, Eric Tran, Winifred Lo, Robert P.T. Somerville, Steven A. Rosenberg, and Drew C. Deniger http://jci.me/123791

MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signalingWei Wang, Tao Shen, Bingning Dong, Chad J. Creighton, Yanling Meng, Wolong Zhou, Qing Shi, Hao Zhou, Yinjie Zhang, David D. Moore, and Feng Yang http://jci.me/97712

vascular biologyc-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flowBochuan Li, Jinlong He, Huizhen Lv, Yajin Liu, Xue Lv, Chenghu Zhang, Yi Zhu, and Ding Ai http://jci.me/122440

Platelet-derived miR-223 promotes a phenotypic switch in arterial injury repair p. 5Zhi Zeng, Luoxing Xia, Xuejiao Fan, Allison C. Ostriker, Timur Yarovinsky, Meiling Su, Yuan Zhang, Xiangwen Peng, Yi Xie, Lei Pi, Xiaoqiong Gu, Sookja Kim Chung, Kathleen A. Martin, Renjing Liu, John Hwa, and Wai Ho Tang http://jci.me/124508

Long noncoding RNA NEXN-AS1 mitigates atherosclerosis by regulating the actin-binding protein NEXNYan-Wei Hu, Feng-Xia Guo, Yuan-Jun Xu, Pan Li, Zhi-Feng Lu, David G. McVey, Lei Zheng, Qian Wang, John H. Ye, Chun-Min Kang, Shao-Guo Wu, Jing-Jing Zhao, Xin Ma, Zhen Yang, Fu-Chun Fang, Yu-Rong Qiu, Bang-Ming Xu, Lei Xiao, Qian Wu, Li-Mei Wu, Li Ding, Tom R. Webb, Nilesh J. Samani, and Shu Ye http://jci.me/98230

jci.org/this-month

Omega-3 fatty acids limit pathogen-induced placental inflammation 11

Ciliary gene loss linked to obesity impairs neurodevelopment 11

Isoquercetin improves hypercoagulability in thrombosis-prone patients 12

Heart failure–induced metabolic shift protects against damage 13

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

March 2019

PXR signaling underlies quetiapine-induced hyperlipidemia p. 10

This Month

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Christopher M. Adams

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Laura M. Bohn

Nunzio Bottini

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G.R. Scott Budinger

George A. Calin

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Yuan Chang

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Quetiapine activates intestinal PXR signaling to increase hyperlipidemia in mice

Quetiapine is an atypical antipsychotic that is com-monly prescribed to treat several psychiatric conditions, including bipolar disorders, schizophrenia, major depres-sive disorder, and general anxiety disorder. Quetiapine is efficacious as a long-term treatment for these disorders and has a reduced risk of drug-induced movement disorders

compared with other antipsychotic drugs. Unfortunately, long-term users of que-tiapine are at increased risk of cardiovascular disease (CVD) as a consequence of hyperlipidemia; however, it is not clear how this drug promotes lipid dysfunc-tion. In this issue, Zhaojie Meng and colleagues investigate the role of pregnane X receptor (PXR), which is an important regulator of lipid homeostasis, in que-tiapine-induced dyslipidemia. The authors show that quetiapine activates PXP in the intestine, as mice lacking intestinal PXR were protected from quetiapine-induced dyslipidemia. Quetiapine-induced PXR activation was shown to stimu-late the intestinal expression of cholesterol transporter NPC1L1 and microsomal triglyceride transfer protein (MTP), leading to increased intestinal lipid absorp-tion. Moreover, treatment of murine enteroids and human intestinal cells with quetiapine promoted PXR-associated gene expression and cholesterol uptake. Together, the results reveal that adverse effects of quetiapine are mediated by PXR activation. The cover image shows the accumulation of lipid droplets in an H&E-stained intestine section from a quetiapine-treated mouse.

The atypical antipsychotic quetiapine induces hyperlipidemia by activating intestinal PXR signalingZhaojie Meng, Taesik Gwag, Yipeng Sui, Se-Hyung Park, Xiangping Zhou, and Changcheng Zhou http://jci.me/125657

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Editor’s picks

Obesity-associated mutation linked to aberrant neurodevelopment

Omega-3 fatty acids ameliorate Fusobacterium nucleatum–induced placental inflammation

metabolism

microbiology

Intronic polymorphisms in α-ketoglutarate–dependent dioxygenase (FTO) are linked to obesity and alter regulation of the nearby ciliary gene RPGRIP1L. In mice, global Rpgrip1l deletion is embryonic lethal; however, POMC neuron–specific Rpgrip1l deletion increases food intake, leading to obesity. Liheng Wang and colleagues have now shown that RPGRIP1L depletion–associated obesity and hyperphagia phenotypes are due to neurode-velopmental defects, including a reduced ratio of POMC to NPY neurons and increased arcuate nucleus (ARH) axonal projections to the paraven-

tricular nucleus. Moreover, neurons derived from human induced pluripotent stem cells (iPSCs) with reduced RPGRIP1L had reduced ciliogenesis (see the accompanying image) and decreased responsive-ness to neurospecification signals. ARH-like neurons derived from FTO obesity risk allele–harboring embryonic stem cells had decreased RPGRIP1L expression and reduced numbers of POMC neurons. In contrast, RPGRIP1L overexpression increased POMC neuron number. These results demonstrate that RPGRIP1L is required for appropriate development of ARH neurons.

Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron developmentLiheng Wang, Alain J. De Solis, Yossef Goffer, Kathryn E. Birkenbach, Staci E. Engle, Ross Tanis, Jacob M. Levenson, Xueting Li, Richard Rausch, Manika Purohit, Jen-Yi Lee, Jerica Tan, Maria Caterina De Rosa, Claudia A. Doege, Holly L. Aaron, Gabriela J. Martins, Jens C. Brüning, Dieter Egli, Rui Costa, Nicolas Berbari, Rudolph L. Leibel, and George Stratigopoulos http://jci.me/123337

Intrauterine infection, particularly with the oral anaerobe Fusobacterium nucleatum, during pregnancy is a prevalent cause of adverse outcomes, including preterm birth and neonatal sepsis. Jeewon Garcia-So and colleagues determined that F. nucleatum activates TLR4 on maternal endothelial cells, thereby triggering placental inflammation. Placental inflammation led to a coordinated inflammatory response, characterized by initiation of NF-κB signaling in maternal endothelial cells, followed by NF-κB signaling in the surrounding cells, leading to proinflammatory effector expression. Administration of omega-3 fatty acids to pregnant mice prior to F. nucleatum infection markedly reduced placental inflammation, decreased

bacterial burden, and improved fetal outcomes. This study suggests that omega-3 fatty acid supplementation should be further explored for improving adverse pregnancy outcomes.

Omega-3 fatty acids suppress Fusobacterium nucleatum–induced placental inflammation originating from maternal endothelial cellsJeewon Garcia-So, Xinwen Zhang, Xiaohua Yang, Mara Roxana Rubinstein, De Yu Mao, Jan Kitajewski, Kang Liu, and Yiping W. Han http://jci.me/125436

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JCI Insight | Editor’s picks

12

autoimmunity

clinical trials

Isoquercetin reduces coagulation markers in patients at risk of thrombosisThe release of protein disulfide isomerase (PDI) from cells during disease or in response to injury has been shown to exacerbate pathological processes, including thromboembolism and, as such, is currently being explored as a therapeutic target. Jeffrey Zwicker and colleagues report on the results of a multicenter phase II trial of the PDI-targeting flavonoid isoquercetin in cancer patients at high risk of thrombosis. One cohort received 500 mg isoquercetin per day, while a second cohort was given a daily 1000-mg dose. Thromboem-bolism and major hemorrhagic events did not occur in either cohort. Isoquercetin inhibited PDI activity in plasma and decreased platelet-dependent thrombin generation in a dose-dependent manner. At the higher dose, isoquercetin reduced levels of D-dimer and P selectin in circulation. The noted reduction in coagulation markers supports further evaluation of isoquercetin in patients at risk of thrombosis.

Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancerJeffrey I. Zwicker, Benjamin L. Schlechter, Jack D. Stopa, Howard A. Liebman, Anita Aggarwal, Maneka Puligandla, Thomas Caughey, Kenneth A. Bauer, Nancy Kuemmerle, Ellice Wong, Ted Wun, Marilyn McLaughlin, Manuel Hidalgo, Donna Neuberg, Bruce Furie, and Robert Flaumenhaft on behalf of CATIQ Investigators http://jci.me/125851

Baseline immunotypes predict type 1 diabetes progression and treatment responseβ Cell function declines at variable rates among individuals newly diagnosed with type 1 diabetes (T1D), though factors that determine this heterogeneity are poorly defined. Matthew Dufort and colleagues analyzed β cell function and performed RNA-Seq on individuals with new-onset T1D and identified age-depen-dent immunotypes associated with disease progression. Young patients with high B cell and low neutrophil levels at diagnosis lost insulin secretion at a rapid rate, while those with high neutrophil levels at diagnosis exhibited slow progression. In a second study, Peter Linsley and colleagues identified the same immunotypes in an evaluation of the response of patients newly diagnosed with T1D to abatacept. At baseline, both abatacept- and placebo-treated groups exhibited similar immunotypes as those identified by Dufort and colleagues, and exhibited an age-related link between baseline immunotype and disease progression. Moreover, patients who were resistant to abatacept expressed a unique

immunology

Identification of intratumor heterogeneity of immune response pathway expressionHeterogeneity within tumors has been linked to the variable responses of a variety of cancers to immunotherapy. A better understanding of the effects of this heterogeneity on outcome and treatment response will be essential to improve cancer treatment. Ke-Yue Ma and colleagues used single-cell RNA-Seq data from lung adenocarcinoma patients and cell lines to evaluate the intratumoral heterogeneity of the immune response. IFN-γ pathway genes in particular were expressed variably in single cancer cells, and downregulation of IFN-γ–mediated genes in cell lines was associated with acquisition of resistance. Moreover, expression of tumor-restricted antigens was variable between cells. Together, these results reveal a high level of intratumor heterogeneity and indicate that multifactorial approaches will be essential to prevent tumor escape and treatment resistance.

Single-cell RNA sequencing of lung adenocarcinoma reveals heterogeneity of immune response– related genesKe-Yue Ma, Alexandra A. Schonnesen, Amy Brock, Carla Van Den Berg, S. Gail Eckhardt, Zhihua Liu, and Ning Jiang http://jci.me/121387

immunotype with a transient increase in activated B cells. These two studies reveal age-related heterogeneity of baseline immunotypes in T1D that are predictive of T1D progression in young patients and may affect treatment response.

Related ResearchCell type–specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetesMatthew J. Dufort, Carla J. Greenbaum, Cate Speake, and Peter S. Linsley http://jci.me/125556

B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetesPeter S. Linsley, Carla J. Greenbaum, Cate Speake, S. Alice Long, and Matthew J. Dufort http://jci.me/126136

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JCI Insight | Editor’s picks

Metabolic switch to ketone body utilization is protective in heart failure

Adrenergic stimulation after Kawasaki disease vasculitis induces myocardial fibrosis

cardiology

Kawasaki disease (KD) is an acute illness that primarily affects children, and is characterized by systemic vascular inflammation and fever; it can progress to coronary artery abnormalities, aneurysms, myocarditis, and myocardial dysfunction. KD is also known to lead to long-term cardiac remodeling that can persist into adulthood, increasing the risk of cardiovascular complica-tions, including myocardial fibrosis. Using a murine model of KD, Harry Matundan, Jon Sin, and colleagues determined that adrenergic stimulation after establishment of KD vasculitis increases cardiac hypertrophy and myocardial fibrosis (see the accompanying image) and reduces ejection fraction. These findings were linked to IL-1β signaling and reduced endothelial CD31 expression, a marker of capillary rarefication. This study identifies a link between adrenergic stimulation after KD and the development of myocardial fibrosis. Additional longitudinal studies are needed to study the relevance of these experimental observations to KD patients.

Myocardial fibrosis after adrenergic stimulation as a long-term sequela in a mouse model of Kawasaki disease vasculitisHarry H. Matundan, Jon Sin, Magali Noval Rivas, Michael C. Fishbein, Thomas J. Lehman, Shuang Chen, Roberta A. Gottlieb, Timothy R. Crother, Masanori Abe, and Moshe Arditi http://jci.me/126279

Energy utilization in the heart is optimized for specific developmental time points and is flexible to accommodate variability in fuel source. Recent metabolic profiling of hypertrophied and failing hearts indicates a shift toward ketone body oxidation in response to a reduced capacity for fatty acid oxidation; however, it is not clear whether this metabolic shift is adaptive or destructive. Julie Horton and colleagues generated mice that are unable to oxidize the ketone body 3-hydroxybutyrate (3OHB) in the heart and determined that these mice develop exacerbated heart failure compared with WT animals. Moreover, delivery of exogenous 3OHB reduced cardiac dysfunction and ameliorated pathological remodeling in a canine model of progressive heart failure. Lastly, 3OHB induced enhance-

ment of mitochondrial thermodynamics under fatty acid–limiting conditions. Together, these results indicate that the 3OHB utilization is a protective metabolic response that should be further explored for limiting damage in heart failure.

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defenseJulie L. Horton, Michael T. Davidson, Clara Kurishima, Rick B. Vega, Jeffery C. Powers, Timothy R. Matsuura, Christopher Petucci, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Fabio A. Recchia, and Daniel P. Kelly (ASCI) http://jci.me/124079

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Current articles

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in miceJonathan S. Fletcher, Jianqiang Wu, Walter J. Jessen, Jay Pundavela, Jacob A. Miller, Eva Dombi, Mi-Ok Kim, Tilat A. Rizvi, Kashish Chetal, Nathan Salomonis, and Nancy Ratner http://jci.me/98601

Ciliary gene RPGRIP1L is required for hypothalamic arcuate neuron development p. 11Liheng Wang, Alain J. De Solis, Yossef Goffer, Kathryn E. Birkenbach, Staci E. Engle, Ross Tanis, Jacob M. Levenson, Xueting Li, Richard Rausch, Manika Purohit, Jen-Yi Lee, Jerica Tan, Maria Caterina De Rosa, Claudia A. Doege, Holly L. Aaron, Gabriela J. Martins, Jens C. Brüning, Dieter Egli, Rui Costa, Nicolas Berbari, Rudolph L. Leibel, and George Stratigopoulos http://jci.me/123337

Elevated PTEN expression maintains anergy in human B cells and reveals unexpectedly high repertoire autoreactivityMia J. Smith, B. Rhodes Ford, Marynette Rihanek, Brianne M. Coleman, Andrew Getahun, Virginia D. Sarapura, Peter A. Gottlieb, and John C. Cambier http://jci.me/123384

Inhibition of B cell–dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantationNatalia F. Smirnova, Thomas M. Conlon, Carmela Morrone, Peter Dorfmuller, Marc Humbert, Georgios T. Stathopoulos, Stephan Umkehrer, Franz Pfeiffer, Ali Ö. Yildirim, and Oliver Eickelberg (ASCI) http://jci.me/123971

IFN regulatory factor–8 expression in macrophages governs an antimetastatic programDanielle Y.F. Twum, Sean H. Colligan, Nicholas C. Hoffend, Eriko Katsuta, Eduardo Cortes Gomez, Mary Lynn Hensen, Mukund Seshadri, Michael J. Nemeth, and Scott I. Abrams http://jci.me/124267

Endothelial mitochondria determine rapid barrier failure in chemical lung injuryRebecca F. Hough, Mohammad N. Islam, Galina A. Gusarova, Guangchun Jin, Shonit Das, and Jahar Bhattacharya http://jci.me/124329

TIGIT signaling restores suppressor function of Th1 TregsLiliana E. Lucca, Pierre-Paul Axisa, Emily R. Singer, Neal M. Nolan, Margarita Dominguez-Villar, and David A. Hafler http://jci.me/124427

Hypomorphic mutations of TRIP11 cause odontochondrodysplasiaAnika Wehrle, Tomasz M. Witkos, Sheila Unger, Judith Schneider, John A. Follit, Johannes Hermann, Tim Welting, Virginia Fano, Marja Hietala, Nithiwat Vatanavicharn, Katharina Schoner, Jürgen Spranger, Miriam Schmidts, Bernhard Zabel, Gregory J. Pazour, Agnes Bloch-Zupan, Gen Nishimura, Andrea Superti-Furga, Martin Lowe, and Ekkehart Lausch http://jci.me/124701

Multimodal imaging guides surgical management in a preclinical spinal implant infection modelStephen D. Zoller, Howard Y. Park, Tove Olafsen, Charles Zamilpa, Zachary D.C. Burke, Gideon Blumstein, William L. Sheppard, Christopher D. Hamad, Kellyn R. Hori, Jen-Chieh Tseng, Julie Czupryna, Craig McMannus, Jason T. Lee, Mafalda Bispo, Francisco Romero Pastrana, Elisa J.M. Raineri, Jeffery F. Miller, Lloyd S. Miller, Jan Maarten van Dijl, Kevin P. Francis, and Nicholas M. Bernthal http://jci.me/124813

Omega-3 fatty acids suppress Fusobacterium nucleatum–induced placental inflammation originating from maternal endothelial cells p. 11Jeewon Garcia-So, Xinwen Zhang, Xiaohua Yang, Mara Roxana Rubinstein, De Yu Mao, Jan Kitajewski, Kang Liu, and Yiping W. Han http://jci.me/125436

Mass cytometry identifies distinct CD4+ T cell clusters distinguishing HIV-1–infected patients according to antiretroviral therapy initiationYonas Bekele, Tadepally Lakshmikanth, Yang Chen, Jaromir Mikes, Aikaterini Nasi, Stefan Petkov, Bo Hejdeman, Petter Brodin, and Francesca Chiodi http://jci.me/125442

The atypical antipsychotic quetiapine induces hyperlipidemia by activating intestinal PXR signaling p. 10Zhaojie Meng, Taesik Gwag, Yipeng Sui, Se-Hyung Park, Xiangping Zhou, and Changcheng Zhou http://jci.me/125657

Excess growth hormone suppresses DNA damage repair in epithelial cellsVera Chesnokova, Svetlana Zonis, Robert Barrett, Hiraku Kameda, Kolja Wawrowsky, Anat Ben-Shlomo, Masaaki Yamamoto, John Gleeson, Catherine Bresee, Vera Gorbunova, and Shlomo Melmed (ASCI) http://jci.me/125762

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

Current articles

Comprehensive transcriptome analysis of cerebral cavernous malformation across multiple species and genotypesJanne Koskimäki, Romuald Girard, Yan Li, Laleh Saadat, Hussein A. Zeineddine, Rhonda Lightle, Thomas Moore, Seán Lyne, Kenneth Avner, Robert Shenkar, Ying Cao, Changbin Shi, Sean P. Polster, Dongdong Zhang, Julián Carrión-Penagos, Sharbel Romanos, Gregory Fonseca, Miguel A. Lopez-Ramirez, Eric M. Chapman, Evelyn Popiel, Alan T. Tang, Amy Akers, Pieter Faber, Jorge Andrade, Mark Ginsberg, W. Brent Derry, Mark L. Kahn, Douglas A. Marchuk, and Issam A. Awad http://jci.me/126167

Myocardial fibrosis after adrenergic stimulation as a long-term sequela in a mouse model of Kawasaki disease vasculitis p. 13Harry H. Matundan, Jon Sin, Magali Noval Rivas, Michael C. Fishbein, Thomas J. Lehman, Shuang Chen, Roberta A. Gottlieb, Timothy R. Crother, Masanori Abe, and Moshe Arditi http://jci.me/126279

Single-cell RNA sequencing of lung adenocarcinoma reveals heterogeneity of immune response–related genes p. 12Ke-Yue Ma, Alexandra A. Schonnesen, Amy Brock, Carla Van Den Berg, S. Gail Eckhardt, Zhihua Liu, and Ning Jiang http://jci.me/121387

Human antigen R as a therapeutic target in pathological cardiac hypertrophyLisa C. Green, Sarah R. Anthony, Samuel Slone, Lindsey Lanzillotta, Michelle L. Nieman, Xiaoqing Wu, Nathan Robbins, Shannon M. Jones, Sudeshna Roy, A. Phillip Owens III, Jeffrey Aube, Liang Xu, John N. Lorenz, Burns C. Blaxall, Jack Rubinstein, Joshua B. Benoit, and Michael Tranter http://jci.me/121541

Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cellsQiyin Zhou, Hua Li, Yuanyuan Li, Mingjia Tan, Shaohua Fan, Cong Cao, Feilong Meng, Ling Zhu, Lili Zhao, Min-Xin Guan, Hongchuan Jin, and Yi Sun http://jci.me/121582

A collagen IV–derived peptide disrupts α5β1 integrin and potentiates Ang2/Tie2 signalingAdam C. Mirando, Jikui Shen, Raquel Lima e Silva, Zenny Chu, Nicholas C. Sass, Valeria E. Lorenc, Jordan J. Green, Peter A. Campochiaro, Aleksander S. Popel, and Niranjan B. Pandey http://jci.me/122043

Glomerular filtrate proteins in acute cardiorenal syndromeRumie Wakasaki, Katsuyuki Matsushita, Kirsti Golgotiu, Sharon Anderson, Mahaba B. Eiwaz, Daniel J. Orton, Sang Jun Han, H. Thomas Lee, Richard D. Smith, Karin D. Rodland, Paul D. Piehowski, and Michael P. Hutchens http://jci.me/122130

GPR55 controls functional differentiation of self-renewing epithelial progenitors for salivationSolomiia Korchynska, Mirjam I. Lutz, Erzsébet Borók, Johannes Pammer, Valentina Cinquina, Nataliya Fedirko, Andrew J. Irving, Ken Mackie, Tibor Harkany, and Erik Keimpema http://jci.me/122947

Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infectionLi Liu, Qiang Wei, Qingqing Lin, Jun Fang, Haibo Wang, Hauyee Kwok, Hangying Tang, Kenji Nishiura, Jie Peng, Zhiwu Tan, Tongjin Wu, Ka-Wai Cheung, Kwok-Hung Chan, Xavier Alvarez, Chuan Qin, Andrew Lackner, Stanley Perlman, Kwok-Yung Yuen, and Zhiwei Chen http://jci.me/123158

Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKDErica L. Clinkenbeard, Megan L. Noonan, Joseph C. Thomas, Pu Ni, Julia M. Hum, Mohammad Aref, Elizabeth A. Swallow, Sharon M. Moe, Matthew R. Allen, and Kenneth E. White http://jci.me/123817

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense p. 13Julie L. Horton, Michael T. Davidson, Clara Kurishima, Rick B. Vega, Jeffery C. Powers, Timothy R. Matsuura, Christopher Petucci, E. Douglas Lewandowski, Peter A. Crawford, Deborah M. Muoio, Fabio A. Recchia, and Daniel P. Kelly (ASCI) http://jci.me/124079

PARP1 inhibition alleviates injury in ARH3-deficient mice and human cellsMasato Mashimo, Xiangning Bu, Kazumasa Aoyama, Jiro Kato, Hiroko Ishiwata-Endo, Linda A. Stevens, Atsushi Kasamatsu, Lynne A. Wolfe, Camilo Toro, David Adams, Thomas Markello, William A. Gahl, and Joel Moss (ASCI) http://jci.me/124519

Long non-coding RNA Malat1 regulates differential activation of macrophages and response to lung injuryHuachun Cui, Sami Banerjee, Sijia Guo, Na Xie, Jing Ge, Dingyuan Jiang, Martin Zörnig, Victor J. Thannickal, and Gang Liu http://jci.me/124522

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Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regressionJian-Da Lin, Hitoo Nishi, Jordan Poles, Xiang Niu, Caroline Mccauley, Karishma Rahman, Emily J. Brown, Stephen T. Yeung, Nikollaq Vozhilla, Ada Weinstock, Stephen A. Ramsey, Edward A. Fisher, and P’ng Loke http://jci.me/124574

Sirtuin 2 enhances allergic asthmatic inflammationYong Gyu Lee, Brenda F. Reader, Derrick Herman, Adam Streicher, Joshua A. Englert, Mathias Ziegler, Sangwoon Chung, Manjula Karpurapu, Gye Young Park, John W. Christman, and Megan N. Ballinger http://jci.me/124710

Hyperglycemia induces skeletal muscle atrophy via a WWP1/KLF15 axisYu Hirata, Kazuhiro Nomura, Yoko Senga, Yuko Okada, Kenta Kobayashi, Shiki Okamoto, Yasuhiko Minokoshi, Michihiro Imamura, Shin’ichi Takeda, Tetsuya Hosooka, and Wataru Ogawa http://jci.me/124952

Prevention of cancer dormancy by Fbxw7 ablation eradicates disseminated tumor cellsHideyuki Shimizu, Shoichiro Takeishi, Hirokazu Nakatsumi, and Keiichi I. Nakayama http://jci.me/125138

Cell type–specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes p. 12Matthew J. Dufort, Carla J. Greenbaum, Cate Speake, and Peter S. Linsley http://jci.me/125556

Direct activation of PP2A for the treatment of tyrosine kinase inhibitor–resistant lung adenocarcinomaRita Tohmé, Sudeh Izadmehr, Sai Gandhe, Giancarlo Tabaro, Sanjay Vallabhaneni, Ava Thomas, Neal Vasireddi, Neil S. Dhawan, Avi Ma’ayan, Neelesh Sharma, Matthew D. Galsky, Michael Ohlmeyer, Jaya Sangodkar, and Goutham Narla (ASCI) http://jci.me/125693

Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer p. 12Jeffrey I. Zwicker, Benjamin L. Schlechter, Jack D. Stopa, Howard A. Liebman, Anita Aggarwal, Maneka Puligandla, Thomas Caughey, Kenneth A. Bauer, Nancy Kuemmerle, Ellice Wong, Ted Wun, Marilyn McLaughlin, Manuel Hidalgo, Donna Neuberg, Bruce Furie, and Robert Flaumenhaft on behalf of CATIQ Investigators http://jci.me/125851

Skin sympathetic nerve activity and the temporal clustering of cardiac arrhythmiasTakashi Kusayama, Juyi Wan, Anisiia Doytchinova, Johnson Wong, Ryan A. Kabir, Gloria Mitscher, Susan Straka, Changyu Shen, Thomas H. Everett IV, and Peng-Sheng Chen (ASCI) http://jci.me/125853

Vaccine induction of antibodies and tissue-resident CD8+ T cells enhances protection against mucosal SHIV-infection in young macaquesCaroline Petitdemange, Sudhir Pai Kasturi, Pamela A. Kozlowski, Rafiq Nabi, Clare Quarnstrom, Pradeep Babu Jagadeesh Reddy, Cynthia A. Derdeyn, Lori M. Spicer, Parin Patel, Traci Legere, Yevgeniy O. Kovalenkov, Celia C. Labranche, François Villinger, Mark Tomai, John Vasilakos, Barton Haynes, C. Yong Kang, James S. Gibbs, Jonathan W. Yewdell, Dan Barouch, Jens Wrammert, David Montefiori, Eric Hunter, Rama R. Amara, David Masopust, and Bali Pulendran http://jci.me/126047

B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes p. 12Peter S. Linsley, Carla J. Greenbaum, Cate Speake, S. Alice Long, and Matthew J. Dufort http://jci.me/126136

Intestinal epithelial potassium channels and CFTR chloride channels activated in ErbB tyrosine kinase inhibitor diarrheaTianying Duan, Onur Cil, Jay R. Thiagarajah, and Alan S. Verkman (ASCI) http://jci.me/126444

Minimally invasive method for the point-of-care quantification of lymphatic vessel functionAnna K. Polomska, Steven T. Proulx, Davide Brambilla, Daniel Fehr, Mathias Bonmarin, Simon Brändli, Mirko Meboldt, Christian Steuer, Tsvetina Vasileva, Nils Reinke, Jean-Christophe Leroux, and Michael Detmar http://jci.me/126515

ReviewThe BAG3-dependent and -independent roles of cardiac small heat shock proteinsXi Fang, Julius Bogomolovas, Christa Trexler, and Ju Chen http://jci.me/126464

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