jci.org/this-month

Neuroprotective effects of bone marrow in CNS injury 3

Stemming metastasis in stem-like breast cancer cells 3

Gene therapies see progress in retinitis pigmentosa 3

Astrocytes improve neural progenitor transplantation 4

Review Series: Fibrosis edited by Dean Sheppard 6

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

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January 2018

Mitochondrial ADHFE1 reprograms tumor metabolism p. 2

This Month

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j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 8 1

For the JCI EditorGordon F. Tomaselli

Deputy EditorsRexford S. Ahima, Arturo Casadevall

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

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

Featured Editor

Arturo Casadevall, MD, PhD, Deputy Editor, is Chair and Professor in the Department of Microbiology and Immunology at Johns Hopkins University and Bloomberg Distinguished Professor at Johns Hopkins Bloomberg School of Public Health. Dr. Casadevall completed both his medical degree and research training at New York University. Prior to joining Johns Hopkins in 2015, he served as the director of the Center for Immunological Sciences at the Albert Einstein College of Medicine.

Dr. Casadevall is a globally recognized expert in humoral immunity, molecular biology, and virulence. His current research focuses on microbial pathogenesis, with the goal of identifying antibody-based approaches to prevent the spread of new and resistant infectious diseases. He is currently studying the human patho-genic fungus Cryptococcus neoformans, a frequent cause of disease in immuno-compromised individuals, as well as Bacillus anthracis and Mycobacterium tuberculosis. Dr. Casadevall is a member of the American Society for Clinical Investigation, the Association of American Physicians, the National Academy of Medicine, and the American Academy of Arts and Sciences.

Publication highlights

Prados-Rosales R, Carreño L, Cheng T, Blanc C, Weinrick B, Malek A, Lowary TL, Baena A, Joe M, Bai Y, Kalscheuer R, Batista-Gonzalez A, Saavedra NA, Sampedro L, Tomás J, Anguita J, Hung SC, Tripathi A, Xu J, Glatman-Freedman A, Jacobs WR Jr, Chan J, Porcelli SA, Achkar JM, Casadevall A. Enhanced control of Mycobacterium tuberculosis extrapulmonary dissemination in mice by an arabinomannan-protein conjugate vaccine. PLoS Pathog. 2017;13(3):e1006250.

Bowen A, Wear MP, Cordero RJ, Oscarson S, Casadevall A. A monoclonal antibody to Cryptococcus neoformans glucuronoxylomannan manifests hydrolytic activity for both peptides and polysaccharides. J Biol Chem. 2017;292(2):417–434.

McClelland EE, Ramagopal UA, Rivera J, Cox J, Nakouzi A, Prabu MM, Almo SC, Casadevall A. A small protein associated with fungal energy metabolism affects the viru-lence of Cryptococcus neoformans in mammals. PLoS Pathog. 2016;12(9):e1005849.

This MonthJanuary 2018

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j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 82

research

Editor’s picks

oncology

During malignant transformation, cellular metabolism is modified to support the energetic demands of cancer cells. Studies characterizing these metabolic alterations have identified biomarkers to aid in cancer diagnosis as well as metabolic pathways that may be sensitive to therapeutic targeting. Prior work by Stefan Ambs’s group demonstrated that elevations in the oncogenic metabolite 2-hydroxyglutarate (2HG) distinguish a subtype of breast cancer associated with poor prognosis. Although in glioma and leukemia, isocitrate dehydrogenase (IDH) mutations cause 2HG elevations, corresponding mutations were not associated with increased 2HG in breast cancer. Instead, 2HG accumulation in breast tumors was linked to

aberrant MYC activation. In this month’s issue of the JCI, Prachi Mishra et al. determined that the mitochondrial enzyme ADHFE1 is responsible for metabolic reprogramming associated with 2HG accumulation, oxidative stress, and growth of human breast tumors. They show that MYC upregulates ADHFE1 by altering iron metabolism. In turn, ADHFE1 induces changes in the epigenetic landscape and cellular redox status that promote epithelial-to-mesenchymal transition and other oncogenic processes. The cover image depicts the role of mitochondrial ADHFE1 in 2HG production, highlighting the contribu-tions of the enzyme and oncogenic 2HG to breast cancer progression.

Mitochondrial enzyme ADHFE1 reprograms metabolism and differentiation in breast tumors

on the jci cover

ADHFE1 is a breast cancer oncogene and induces metabolic reprogrammingPrachi Mishra, Wei Tang, Vasanta Putluri, Tiffany H. Dorsey, Feng Jin, Fang Wang, Donewei Zhu, Lauren Amable, Tao Deng, Shaofei Zhang, J. Keith Killian, Yonghong Wang, Tsion Z. Minas, Harry G. Yfantis, Dong H. Lee, Arun Sreekumar, Michael Bustin, Wei Liu, Nagireddy Putluri, and Stefan Ambs http://jci.me/93815

Mcl-1–targeted therapy sensitizes cancer cells to DNA replication stressDNA damage that occurs as a result of normal cellular activity, aging, or environmental factors generates double-strand breaks (DSBs) that are repaired via one of two mechanisms. Nonhomolo-gous end joining (NHEJ) can introduce mutations because it uses damaged templates to repair DNA. In contrast, homologous recombination (HR) repairs from an undamaged template, resulting in higher genomic fidelity. Guo Chen and coworkers demonstrate that expression of the antiapoptotic protein Mcl-1 controls the selection of DSB repair mechanisms. They observed that increases in Mcl-1

expression interfered with effectors of the NHEJ pathway, enhancing HR-mediated repair. The researchers then identified a small molecule, MI-223, that targets the key binding domain of Mcl-1 to inhibit HR-mediated DNA repair. MI-223 treatment sensitized human lung cancer cells to DNA replication stress and synergized with PARP inhibitor and hydroxyurea treatments to suppress tumor growth in a xenograft model. These findings introduce a potential strategy for increasing the efficacy of cancer therapies targeting the DNA damage response.

Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapyGuo Chen, Andrew T. Magis, Ke Xu, Dongkyoo Park, David S. Yu, Taofeek K. Owonikoko, Gabriel L. Sica, Sarah W. Satola, Suresh S. Ramalingam, Walter J. Curran, Paul W. Doetsch, and Xingming Deng http://jci.me/92742

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 8 3

JCI | Research: Editor’s picks

ophthalmology

oncology

Suppressing proapoptotic PUMA boosts metastasis of stem-like breast cancer cells

A positive outlook on gene augmentation therapies for retinitis pigmentosaThe ongoing development of gene therapies for CNGβ1-deficient retinitis pigmentosa (RP), an inherited cause of blindness, is beginning to yield promising results. As CNGB1-targeting therapies progress toward the clinic, their refinement and ultimate success will depend on accurate assessments in ongoing preclinical trials. Simon Petersen-Jones and colleagues evaluated the phenotypes of canine and murine RP models relative to the clinical characteristics observed in a cohort of patients with RP. They describe the suitability of the canine model for assessing clinically relevant RP progression and reversal based on advanced retinal imaging and a successful preclinical trial of CNGB1-based gene therapy. These findings support the outlook that gene augmentation strategies may achieve both preservation and rescue of retinal function in patients with RP. The accompanying images show the progressive retinal thinning observed in the Cngb1-deficient canine model.

Patients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approachSimon M. Petersen-Jones, Laurence M. Occelli, Paige A. Winkler, Winston Lee, Janet R. Sparrow, Mai Tsukikawa, Sanford L. Boye, Vince Chiodo, Jenina E. Capasso, Elvir Becirovic, Christian Schön, Mathias W. Seeliger, Alex V. Levin, Stylianos Michalakis, William W. Hauswirth, and Stephen H. Tsang http://jci.me/95161

Bone marrow–derived cells contribute to CNS recovery from radiation injuryCranial irradiation therapies induce injury to the CNS that can lead to progressive loss of brain volume as well as delayed-onset neurologic and neuropsychiatric complications. There are currently no therapies to mitigate this neurotoxicity and CNS injury in long-term cancer survivors. Jorg Dietrich, Ninib Baryawno, and colleagues observed that administer-ing the cytokine G-CSF rescued radiation-induced deficits in cell proliferation, accelerated neuronal repair, and improved neurocognitive function in mice exposed to sublethal doses of radiation. In the aftermath of radiation-induced CNS injury, G-CSF receptor–expressing bone marrow–derived monocytes and microglia mediated these neuroprotective effects of G-CSF administration. These findings indicate that the hematopoietic system contributes to neuroregenerative processes, supporting further evaluation of clinically available cytokine-targeting strategies as interventions in CNS injury.

Bone marrow drives central nervous system regeneration after radiation injuryJorg Dietrich, Ninib Baryawno, Naema Nayyar, Yannis K. Valtis, Betty Yang, Ina Ly, Antoine Besnard, Nicolas Severe, Karin U. Gustafsson, Ovidiu C. Andronesi, Tracy T. Batchelor, Amar Sahay, and David T. Scadden http://jci.me/90647

neuroscience

Breast cancer subtypes can predict the response to therapy in some patients but do not adequately identify the metastatic potential of a tumor. Metastases originate from tumor- initiating cells that often possess stem-like characteristics. The markers and mechanisms that regulate mammary stem cells may therefore hint at vulnerable pathways in these metastasis-prone cells. Qi Sun and coworkers examined a population of mammary stem-like cells found in aggressive breast tumors that are

distinguished by low expression of the proapoptotic molecule PUMA. They identified a signaling axis involving integrin αvβ3, the transcription factor Slug, and Src kinase that limits PUMA expression to promote stemness in these cells. In a xenograft model, interrupting the αvβ3/Slug/Src signaling axis increased PUMA expression and suppressed metastasis, suggesting that PUMA-targeted therapies may be a strategy to hinder metastasis and tumor progression in multiple breast cancer subtypes.

Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasisQi Sun, Jacqueline Lesperance, Hiromi Wettersten, Elaine Luterstein, Yoko S. DeRose, Alana Welm, David A. Cheresh,and Jay S. Desgrosellier http://jci.me/93707

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 84

JCI | Research: Editor’s picks

neuroscience

Astrocyte cotransplantation improves neural progenitor cell engraftment in Parkinsonian ratsTransplantation of neural progenitor cells (NPCs) represents a promising potential approach to countering the degeneration of midbrain-type dopaminergic (mDA) neurons in patients with Parkinson’s disease. However, immunological and inflammatory responses to transplantation-induced injury hinder the survival and function of engrafted NPCs. Jae-Jin Song and coworkers demonstrate that cografting astrocytes with NPCs improves the success of NPC transplantation. Astrocytes derived from the rodent midbrain were most effective in enhancing NPC and mDA neuron engraftment and long-term therapeutic outcomes in Parkinsonian rats (see the associated image). The neurotrophic effects of cografted astrocytes were enhanced when they were engineered to express the neuropro-tective transcription factors Nurr1 and Foxa2. In the accompanying Commentary, Robert Tsai indicates that further research into cografting strategies may eventually enable successful NPC transplantation in patients.

Antisense oligonucleotides ameliorate neuropathy in models of Charcot-Marie-Tooth diseaseCharcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary neuropathy characterized by progressive demyelination of peripheral sensory and motor nerves. CMT1A is caused by duplications of a 1.4-Mb fragment in chromosome 17 that lead to overexpression of peripheral myelin protein 22 (PMP22). Hien Zhao and colleagues developed antisense oligonucleotides (ASO) to target PMP22 mRNA in two well-characterized rodent models of CMT1A. In C22 mice, which express multiple copies of the human PMP22 gene, weekly ASO treatment reduced the expression of human PMP22 and murine Pmp22 genes in a dose-dependent manner and reversed multiple measures of neuropathy, including motor function and electrophysiological properties. ASO treatment also reduced Pmp22 expression and restored myelination in a rat model of CMT1A (see the associated image). Michael Shy’s accompanying Commentary weighs the evidence that clinical ASO-based strategies have potential to treat CMT1A and other neurodegenerative diseases.

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent modelsHien Tran Zhao, Sagar Damle, Karli Ikeda-Lee, Steven Kuntz, Jian Li, Apoorva Mohan, Aneeza Kim, Gene Hung, Mark A. Scheideler, Steven S. Scherer, John Svaren, Eric E. Swayze, and Holly B. Kordasiewicz http://jci.me/96499

Related CommentaryAntisense oligonucleotides offer hope to patients with Charcot-Marie-Tooth disease type 1AMichael E. Shy http://jci.me/98617

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease modelJae-Jin Song, Sang-Min Oh, Oh-Chan Kwon, Noviana Wulnansari, Hyun-Seob Lee, Mi-Yoon Chang, Eunsoo Lee, Woong Sun, Sang-Eun Lee, Sunghoe Chang, Heeyoung An, C. Justin Lee, and Sang-Hun Lee http://jci.me/93924

Related CommentaryCreating a graft-friendly environment for stem cells in diseased brainsRobert Y.L. Tsai http://jci.me/98490

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 8 5

JCI | Research: Editor’s picks

hematologyreproductive biology

STAT5BN642H mutation induces an Aurora kinase inhibitor–sensitive T cell malignancyHyperactivating mutations in STAT5A and STAT5B are common in hematopoietic cancers. These proteins are downstream targets of cytokines and growth factors and are highly expressed in most hematopoietic cell types, suggesting a role for STAT5 proteins in normal and pathogenic hematopoietic transformation. Ha Pham and colleagues induced the expression of STAT5BN642H, a common mutation in hematopoietic malignan-cies, in hematopoietic cells of mice. This activating mutation initiated an aggressive, transplantable CD8+ T cell lymphoma as well as alterations in gene expression and DNA methylation. STAT5BN642H-expressing T cells were sensitive to FDA-approved inhibitors of JAK and Aurora kinase (see the associated image). Lisa Heppler and David Frank discuss the potential therapeutic implications for these inhibitors in STAT5BN642H lymphomas and leukemias in the accompanying Commentary.

STAT5BN642H is a driver mutation for T cell neoplasiaHa Thi Thanh Pham, Barbara Maurer, Michaela Prchal-Murphy, Reinhard Grausenburger, Eva Grundschober, Tahereh Javaheri, Harini Nivarthi, Auke Boersma, Thomas Kolbe, Mohamed Elabd, Florian Halbritter, Jan Pencik, Zahra Kazemi, Florian Grebien, Markus Hengstschläger, Lukas Kenner, Stefan Kubicek, Matthias Farlik, Christoph Bock, Peter Valent, Mathias Müller, Thomas Rülicke, Veronika Sexl, and Richard Moriggl http://jci.me/94509

Related CommentaryRare mutations provide unique insight into oncogenic potential of STAT transcription factorsLisa N. Heppler and David A. Frank http://jci.me/98619

Polycomb complex subunit BMI1 modulates progesterone sensitivity in early pregnancyWomen with a history of pregnancy loss are commonly prescribed progesterone analogs to enhance the success of blastocyst implantation, but the underlying drivers of impaired implantation are unknown. Research led by Haibin Wang investigated the role of BMI1, a component of the polycomb repressive complex, in mediating progesterone sensitivity and implantation success in mice. Ablating BMI1 in uterine cells impaired embryo implantation and progesterone receptor (PR) sensitivity in spite of normal circulating progesterone levels in these mice. Mechanistically, the researchers determined that BMI1 acts independently of the polycomb repressive complex to regulate PR ubiquitination, a step required for normal progesterone responses. Decreased BMI1 expression in women who had experienced spontaneous miscarriage or recurrent implantation failure supports BMI1’s role in successful implantation and implicates its involvement in spontaneous pregnancy loss. The accompanying image shows the effect of Bmi1 deletion (bottom panel) on epithelial membrane transformation.

Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantationQiliang Xin, Shuangbo Kong, Junhao Yan, Jingtao Qiu, Bo He, Chan Zhou, Zhangli Ni, Haili Bao, Lin Huang, Jinhua Lu, Guoliang Xia, Xicheng Liu, Zi-Jiang Chen, Chao Wang, and Haibin Wang http://jci.me/92862

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 866

JCI | Research: Features

viewpoint

JCI Review Series FIBROSISSeries Editor: Dean Sheppard

Repair gone wrong: mechanisms underlying fibrosis progression and resolutionFibrosis develops in response to injury and is characterized by pathologic production of extracellular matrix, leading to accumulation of collagen that forms stiff scar tissue and ultimately compromises organ function. Chronic liver conditions and lung diseases are well-known outcomes of fibrosis progression, but the condition can affect any organ. Few therapeutic options exist to intercede in fibrotic disease. This Review Series, developed by series editor Dean Sheppard, MD, at UCSF’s Comprehensive Cancer Center, reveals progress in understanding fibrosis, from its transcriptional processes to recent therapeutic developments. The reviews in this series identify molecular pathways that initiate, sustain, and interrupt fibrotic remodeling, discuss the origins of fibroblasts, provide insights into genetic predisposition, detail the links between fibrosis and cancer, and highlight relevant observations in the field of organ regeneration.

The fibrotic tumor stromaMitsuo Yamauchi, Thomas H. Barker, Don L. Gibbons, and Jonathan M. Kurie http://jci.me/93554

Fibroblast heterogeneity: implications for human diseaseMagnus D. Lynch and Fiona M. Watt http://jci.me/93555

Insights from human genetic studies of lung and organ fibrosisChristine Kim Garcia http://jci.me/93556

Extracellular matrix as a driver of progressive fibrosisJeremy Herrera, Craig A. Henke, and Peter B. Bitterman http://jci.me/93557

The 2017 Nobel Prize in Medicine: a sign of the time

While your genes are probably unaware of your New Year’s resolutions, they may have influenced your bedtime on New Year’s Eve. Jeffrey Hall, Michael Rosbash, and Michael Young were awarded the 2017 Nobel Prize in Physiology or Medicine for their work uncovering the mechanisms that entrain this biological clock. These discoveries laid the groundwork for understanding how circadian rhythms — and their

disruption — contribute to human health and disease. In a Viewpoint, Amita Sehgal describes the fruit fly experimentation that led to the identification of PER and TIM, proteins that regulate 24-hour periodicity and behavioral rhythms in flies and humans alike.

Flies come through again, periodAmita Sehgal http://jci.me/97839

The perivascular origin of pathological fibroblastsSelene E. Di Carlo and Lucie Peduto http://jci.me/93558

Endoplasmic reticulum stress in the pathogenesis of fibrotic diseaseJonathan A. Kropski and Timothy S. Blackwell http://jci.me/93560

Mechanosensing and fibrosisDaniel J. Tschumperlin, Giovanni Ligresti, Moira B. Hilscher, and Vijay H. Shah http://jci.me/93561

The balancing act of the liver: tissue regeneration versus fibrosisLucía Cordero-Espinoza and Meritxell Huch http://jci.me/93562

Resolution of organ fibrosisJoon-Il Jun and Lester F. Lau http://jci.me/93563

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 8 7

Current research articles

bone biologyPolycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesisZhousheng Xiao, Jerome Baudry, Li Cao, Jinsong Huang, Hao Chen, Charles R. Yates, Wei Li, Brittany Dong, Christopher M. Waters, Jeremy C. Smith, and L. Darryl Quarles http://jci.me/93725

Paracrine osteoprotegerin and β-catenin stabilization support synovial sarcomagenesis in periosteal cellsJared J. Barrott, Benjamin E. Illum, Huifeng Jin, Matthew L. Hedberg, Yanliang Wang, Allie Grossman, Malay Haldar, Mario R. Capecchi, and Kevin B. Jones http://jci.me/94955

gastroenterologyFODMAP diet modulates visceral nociception by lipopolysaccharide-mediated intestinal inflammation and barrier dysfunctionShi-Yi Zhou, Merritt Gilliland III, Xiaoyin Wu, Pornchai Leelasinjaroen, Guanpo Zhang, Hui Zhou, Bo Ye, Yuanxu Lu, and Chung Owyang http://jci.me/92390

Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathwaySaara Ollila, Eva Domènech-Moreno, Kaisa Laajanen, Iris P.L. Wong, Sushil Tripathi, Nalle Pentinmikko, Yajing Gao, Yan Yan, Elina H. Niemelä, Timothy C. Wang, Benoit Viollet, Gustavo Leone, Pekka Katajisto, Kari Vaahtomeri, and Tomi P. Mäkelä http://jci.me/93597

hematologyHypoxia-induced upregulation of BMX kinase mediates therapeutic resistance in acute myeloid leukemiaJolieke G. van Oosterwijk, Daelynn R. Buelow, Christina D. Drenberg, Aksana Vasilyeva, Lie Li, Lei Shi, Yong-Dong Wang, David Finkelstein, Sheila A. Shurtleff, Laura J. Janke, Stanley Pounds, Jeffrey E. Rubnitz, Hiroto Inaba, Navjotsingh Pabla, and Sharyn D. Baker http://jci.me/91893

Drug-perturbation-based stratification of blood cancerSascha Dietrich, Małgorzata Oleś, Junyan Lu, Leopold Sellner, Simon Anders, Britta Velten, Bian Wu, Jennifer Hüllein, Michelle da Silva Liberio, Tatjana Walther, Lena Wagner, Sophie Rabe, Sonja Ghidelli-Disse, Marcus Bantscheff, Andrzej K. Oleś, Mikołaj Słabicki, Andreas Mock, Christopher C. Oakes, Shihui Wang, Sina Oppermann, Marina Lukas, Vladislav Kim, Martin Sill, Axel Benner, Anna Jauch, Lesley Ann Sutton, Emma Young, Richard Rosenquist, Xiyang Liu, Alexander Jethwa, Kwang Seok Lee, Joe Lewis, Kerstin Putzker, Christoph Lutz, Davide Rossi, Andriy Mokhir, Thomas Oellerich, Katja Zirlik, Marco Herling, Florence Nguyen-Khac, Christoph Plass, Emma Andersson, Satu Mustjoki, Christof von Kalle, Anthony D. Ho, Manfred Hensel, Jan Dürig, Ingo Ringshausen, Marc Zapatka, Wolfgang Huber, and Thorsten Zenz http://jci.me/93801

STAT5BN642H is a driver mutation for T cell neoplasia p. 5Ha Thi Thanh Pham, Barbara Maurer, Michaela Prchal-Murphy, Reinhard Grausenburger, Eva Grundschober, Tahereh Javaheri, Harini Nivarthi, Auke Boersma, Thomas Kolbe, Mohamed Elabd, Florian Halbritter, Jan Pencik, Zahra Kazemi, Florian Grebien, Markus Hengstschläger, Lukas Kenner, Stefan Kubicek, Matthias Farlik, Christoph Bock, Peter Valent, Mathias Müller, Thomas Rülicke, Veronika Sexl, and Richard Moriggl http://jci.me/94509

Loss of pleckstrin-2 reverts lethality and vascular occlusions in JAK2V617F-positive myeloproliferative neoplasmsBaobing Zhao, Yang Mei, Lan Cao, Jingxin Zhang, Ronen Sumagin, Jing Yang, Juehua Gao, Matthew J. Shipma, Yanfeng Wang, Chelsea Thorsheim, Liang Zhao, Timothy Stalker, Brady Stein, Qiang Jeremy Wen, John D. Crispino, Charles S. Abrams, and Peng Ji http://jci.me/94518

immunologyEndothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejectionChien-Chia Chen, Eric Pouliquen, Alexis Broisat, Francesco Andreata, Maud Racapé, Patrick Bruneval, Laurence Kessler, Mitra Ahmadi, Sandrine Bacot, Carole Saison-Delaplace, Marina Marcaud, Jean-Paul Duong Van Huyen, Alexandre Loupy, Jean Villard, Sandrine Demuylder-Mischler, Thierry Berney, Emmanuel Morelon, Meng-Kun Tsai, Marie-Nathalie Kolopp-Sarda, Alice Koenig, Virginie Mathias, Stéphanie Ducreux, Catherine Ghezzi, Valerie Dubois, Antonino Nicoletti, Thierry Defrance, and Olivier Thaunat http://jci.me/93542

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Current research articles

immunology γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation programRyunosuke Muro, Takeshi Nitta, Kenta Nakano, Tadashi Okamura, Hiroshi Takayanagi, and Harumi Suzuki http://jci.me/95837

metabolismHyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistanceKeiji Tanigaki, Anastasia Sacharidou, Jun Peng, Ken L. Chambliss, Ivan S. Yuhanna, Debabrata Ghosh, Mohamed Ahmed, Alexander J. Szalai, Wanpen Vongpatanasin, Robert F. Mattrey, Qiushi Chen, Parastoo Azadi, Ildiko Lingvay, Marina Botto, William L. Holland, Jennifer J. Kohler, Shashank R. Sirsi, Kenneth Hoyt, Philip W. Shaul, and Chieko Mineo http://jci.me/89333

Thioesterase-mediated control of cellular calcium homeostasis enables hepatic ER stressBaran A. Ersoy, Kristal M. Maner-Smith, Yingxia Li, Ipek Alpertunga, and David E. Cohen http://jci.me/93123

nephrologyShifts in podocyte histone H3K27me3 regulate mouse and human glomerular diseaseSyamantak Majumder, Karina Thieme, Sri N. Batchu, Tamadher A. Alghamdi, Bridgit B. Bowskill, M. Golam Kabir, Youan Liu, Suzanne L. Advani, Kathryn E. White, Laurette Geldenhuys, Karthik K. Tennankore, Penelope Poyah, Ferhan S. Siddiqi, and Andrew Advani http://jci.me/95946

neuroscienceBone marrow drives central nervous system regeneration after radiation injury p. 3Jorg Dietrich, Ninib Baryawno, Naema Nayyar, Yannis K. Valtis, Betty Yang, Ina Ly, Antoine Besnard, Nicolas Severe, Karin U. Gustafsson, Ovidiu C. Andronesi, Tracy T. Batchelor, Amar Sahay, and David T. Scadden http://jci.me/90647

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model p. 4Jae-Jin Song, Sang-Min Oh, Oh-Chan Kwon, Noviana Wulansari, Hyun-Seob Lee, Mi-Yoon Chang, Eunsoo Lee, Woong Sun, Sang-Eun Lee, Sunghoe Chang, Heeyoung An, C. Justin Lee, and Sang-Hun Lee http://jci.me/93924

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models p. 4Hien Tran Zhao, Sagar Damle, Karli Ikeda-Lee, Steven Kuntz, Jian Li, Apoorva Mohan, Aneeza Kim, Gene Hung, Mark A. Scheideler, Steven S. Scherer, John Svaren, Eric E. Swayze, and Holly B. Kordasiewicz http://jci.me/96499

oncologyCRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2Liying Chen, Gabriela Alexe, Neekesh V. Dharia, Linda Ross, Amanda Balboni Iniguez, Amy Saur Conway, Emily Jue Wang, Veronica Veschi, Norris Lam, Jun Qi, W. Clay Gustafson, Nicole Nasholm, Francisca Vazquez, Barbara A. Weir, Glenn S. Cowley, Levi D. Ali, Sasha Pantel, Guozhi Jiang, William F. Harrington, Yenarae Lee, Amy Goodale, Rakela Lubonja, John M. Krill-Burger, Robin M. Meyers, Aviad Tsherniak, David E. Root, James E. Bradner, Todd R. Golub, Charles W.M. Roberts, William C. Hahn, William A. Weiss, Carol J. Thiele, and Kimberly Stegmaier http://jci.me/90793

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in boneHernan Roca, Jacqueline D. Jones, Marta C. Purica, Savannah Weidner, Amy J. Koh, Robert Kuo, John E. Wilkinson, Yugang Wang, Stephanie Daignault-Newton, Kenneth J. Pienta, Todd M. Morgan, Evan T. Keller, Jacques E. Nör, Lonnie D. Shea, and Laurie K. McCauley http://jci.me/92466

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Rotate to read JCI Insight content.

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanomaArvind M. Venkatesan, Rajesh Vyas, Alec K. Gramann, Karen Dresser, Sharvari Gujja, Sanchita Bhatnagar, Sagar Chhangawala, Camilla Borges Ferreira Gomes, Hualin Simon Xi, Christine G. Lian, Yariv Houvras, Yvonne J. K. Edwards, April Deng, Michael Green, and Craig J. Ceol http://jci.me/92513

Hedgehog signaling drives medulloblastoma growth via CDK6David R. Raleigh, Pervinder K. Choksi, Alexis Leigh Krup, Wasima Mayer, Nicole Santos, and Jeremy F. Reiter http://jci.me/92710

Targeting Mcl-1 enhances DNA replication stress sensitivity to cancer therapy p. 2Guo Chen, Andrew T. Magis, Ke Xu, Dongkyoo Park, David S. Yu, Taofeek K. Owonikoko, Gabriel L. Sica, Sarah W. Satola, Suresh S. Ramalingam, Walter J. Curran, Paul W. Doetsch, and Xingming Deng http://jci.me/92742

Differential impact of RB status on E2F1 reprogramming in human cancerChristopher McNair, Kexin Xu, Amy C. Mandigo, Matteo Benelli, Benjamin Leiby, Daniel Rodrigues, Johan Lindberg, Henrik Gronberg, Mateus Crespo, Bram De Laere, Luc Dirix, Tapio Visakorpi, Fugen Li, Felix Y. Feng, Johann de Bono, Francesca Demichelis, Mark A. Rubin, Myles Brown, and Karen E. Knudsen http://jci.me/93566

Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis p. 3Qi Sun, Jacqueline Lesperance, Hiromi Wettersten, Elaine Luterstein, Yoko S. DeRose, Alana Welm, David A. Cheresh, and Jay S. Desgrosellier http://jci.me/93707

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming p. 2Prachi Mishra, Wei Tang, Vasanta Putluri, Tiffany H. Dorsey, Feng Jin, Fang Wang, Donewei Zhu, Lauren Amable, Tao Deng, Shaofei Zhang, J. Keith Killian, Yonghong Wang, Tsion Z. Minas, Harry G. Yfantis, Dong H. Lee, Arun Sreekumar, Michael Bustin, Wei Liu, Nagireddy Putluri, and Stefan Ambs http://jci.me/93815

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growthHironari Tamiya, Hyungsoo Kim, Oleksiy Klymenko, Heejung Kim, Yongmei Feng, Tongwu Zhang, Ji Yun Han, Ayako Murao, Scott J. Snipas, Lucia Jilaveanu, Kevin Brown, Harriet Kluger, Hao Zhang, Kazuhiro Iwai, and Ze’ev A. Ronai http://jci.me/95410

SPOP mutation drives prostate neoplasia without stabilizing oncogenic transcription factor ERGJonathan Shoag, Deli Liu, Mirjam Blattner, Andrea Sboner, Kyung Park, Lesa Deonarine, Brian D. Robinson, Juan Miguel Mosquera, Yu Chen, Mark A. Rubin, and Christopher E. Barbieri http://jci.me/96551

ophthalmologyPatients and animal models of CNGβ1-deficient retinitis pigmentosa support gene augmentation approach p. 3Simon M. Petersen-Jones, Laurence M. Occelli, Paige A. Winkler, Winston Lee, Janet R. Sparrow, Mai Tsukikawa, Sanford L. Boye, Vince Chiodo, Jenina E. Capasso, Elvir Becirovic, Christian Schön, Mathias W. Seeliger, Alex V. Levin, Stylianos Michalakis, William W. Hauswirth, and Stephen H. Tsang http://jci.me/95161

reproductive biologyPolycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation p. 5Qiliang Xin, Shuangbo Kong, Junhao Yan, Jingtao Qiu, Bo He, Chan Zhou, Zhangli Ni, Haili Bao, Lin Huang, Jinhua Lu, Guoliang Xia, Xicheng Liu, Zi-Jiang Chen, Chao Wang, and Haibin Wang http://jci.me/92862

H3K27me3 dynamics dictate evolving uterine states in pregnancy and parturitionPatrice Nancy, Johan Siewiera, Gabrielle Rizzuto, Elisa Tagliani, Ivan Osokine, Priyanka Manandhar, Igor Dolgalev, Caterina Clementi, Aristotelis Tsirigos, and Adrian Erlebacher http://jci.me/95937

jci.org/this-month

Ion channel modulators prevent antibiotic-induced hair cell death 13

Pridopidine improves symptoms in Huntington disease mouse model 13

2-Chlorofatty acids linked to sepsis-induced ARDS 14

Antibody dynamics predict HIV-1 incidence 14

NK cells require glucose metabolism to control viral infection 15

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

January 2018

ICAM1+ neutrophils in autoimmune demyelination p. 16

This Month

Christopher M. Adams

Maria-Luisa Alegre

Ravi K. Amaravadi

John K. Amory

Jennifer H. Anolik

Cristian Apetrei

Rajendra S. Apte

Zoltan Arany

Hossein Ardehali

Kenneth I. Ataga

Joseph Bass

Alexander G. Bassuk

Antonio C. Bianco

Jonathan S. Bogan

Laura M. Bohn

Nunzio Bottini

Sebastien G. Bouret

Jason Brenchley

Renier J. Brentjens

G.R. Scott Budinger

George A. Calin

Stephen Chan

Yuan Chang

Zhou-Feng Chen

Keith A. Choate

Wendy Chung

Craig M. Coopersmith

George Cotsarelis

Peter Crawford

Lisa L. Cunningham

Ronald P. DeMatteo

Elia J. Duh

Sarah K. England

Mark W. Feinberg

John H. Fingert

Robert Flaumenhaft

Edward A. Fon

Lawrence Fong

Nikolaos G. Frangogiannis

Anthony R. French

Terrence L. Geiger

Noyan Gokce

Raphaela Goldbach-Mansky

Daniel R. Goldstein

Douglas K. Graham

Khalid A. Hanafy

Eric B. Haura

John Cijiang He

Robert O. Heuckeroth

Cory M. Hogaboam

Young-Kwon Hong

Benjamin D. Humphreys

Ken Inoki

Shingo Kajimura

Pawel Kalinski

John Y. Kao

Mariana J. Kaplan

Michael G. Kaplitt

Barbara I. Kazmierczak

Hans-Peter Kiem

William Y. Kim

David G. Kirsch

Mathias Lichterfeld

André Lieber

Michail S. Lionakis

Carey N. Lumeng

Leo Luznik

Ivan Maillard

Ziad Mallat

Peter Mannon

Franck Mauvais-Jarvis

Dermot P.B. McGovern

Borna Mehrad

Ingo K. Mellinghoff

Jason C. Mills

Joshua D. Milner

Satdarshan (Paul) Singh Monga

Hidayatullah G. Munshi

Matthias Nahrendorf

Mary Nakamura

Lisa F.P. Ng

Mark Nicolls

Laura J. Niedernhofer

Deborah V. Novack

S. Tiong Ong

Puneet Opal

Daniel Ory

Sophie Paczesny

Stephanie T. Page

Mary-Elizabeth Patti

Janos Peti-Peterdi

Fernando P. Polack

Matthew D. Ringel

Steven M. Rowe

Svati H. Shah

Vijay H. Shah

Alice T. Shaw

Rhonda F. Souza

Fayyaz S. Sutterwala

Shu Takeda

Natalie J. Torok

Stephen H. Tsang

Ellie Tzima

Fumihiko Urano

Charles P. Venditti

Joseph M. Vinetz

Sing Sing Way

Bernd Wollnik

Minna Woo

Prescott G. Woodruff

Lori M. Zeltser

Yutong Zhao

Binhua P. Zhou

JCI Insight Consulting Editors

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 8 16

For JCI InsightEditorHoward A. Rockman

Associate EditorsRodger A. Liddle, Yiping Yang

Executive EditorSarah C. Jackson

Science EditorCorinne Williams

ASCI StaffExecutive DirectorJohn B. HawleyManaging DirectorKaren D. GuthAssociate DirectorMaya HoptmanProduction EditorsCatherine Ahmann, Ken Beauchamp, Lara L. McCarronAssociate Production EditorMolly JeanScientific IllustratorBruce WordenCopy EditorsClare Cross, Meredith Dimick, Barbara Fabyan, Rachel Nelson, Chet ProvodaAssociate Copy EditorRachel BullenPublications CoordinatorMegan JenkinsSystems Analyst and DeveloperShawn PyleSystem Administrator and DeveloperBryan EnglishWeb DeveloperAustin BrewerScience Communications SpecialistNeha AggarwalAccounts ManagerPaula KremidasAdministrative AssistantTheresa KaiserFigures CoordinatorKeith Kalinowski

For JCI Insight online: jci.me/insight/2/23jci.me/insight/2/24

Macrophage-like neutrophil population mediates experimental autoimmune encephalomyelitis development

On the JCI insight cover

The progressive loss of myelin in demyelinating autoimmune diseases results in dysfunctional conduction and neuronal cell death. Neutrophils are linked to demyelination, as depletion of these cells is protective in murine experi-mental autoimmune encephalomyelitis (EAE) models; however, the function and phenotype of disease-mediating neutro-phils have not been characterized. In this month’s JCI Insight, Ryder Whittaker

Hawkins, Alexandre Patenaude, and colleagues identify a population of extrava-sated, ICAM1-expressing neutrophils in the mouse CNS during EAE that have macrophage-like properties and are capable of antigen presentation and for-mation of immune synapses with both T cells and B cells. Aspartic peptidase retroviral-like 1 (ASPRV1) was highly expressed in ICAM1+ neutrophils and increased in the CNS during EAE. Additionally, ASPRV1 was elevated in brain lesions of patients with severe multiple sclerosis (MS). Compared with WT animals, ASPRV1-deficient mice developed a less severe form of chronic inflam-mation following immunization with a B cell–dependent myelin antigen; however, ICAM1+ neutrophils were still present in the CNS, indicating that ASPRV1 does not influence neutrophil mobilization. Together, these findings identify ICAM1+ mac-rophage–like neutrophils as important mediators of autoimmune demyelination. The accompanying image was captured by super-resolution STED microscopy and shows an ICAM1+ neutrophil (ICAM1, pink; neutrophil reporter, green) making a synapse with a T lymphocyte (CD3, white) in the spinal cord of a mouse with EAE. Nuclei are stained with DAPI.

ICAM1+ neutrophils promote chronic inflammation via ASPRV1 in B cell–dependent autoimmune encephalomyelitisRyder F. Whittaker Hawkins, Alexandre Patenaude, Aline Dumas, Rajiv Jain, Yodit Tesfagiorgis, Steven Kerfoot, Takeshi Matsui, Matthias Gunzer, Patrice E. Poubelle, Catherine Larochelle, Martin Pelletier, and Luc Vallières http://jci.me/96882

This MonthJanuary 2018

Make your 18-hour days count.

Submit your work to JCI Insight today.

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 815

Editor’s picks

Influence of maternal vaccination on offspring response to dengue virusDengue virus (DENV) causes a debilitating disease and infects over 200 million people annually. As DENV serotypes are quite divergent, infection by one DENV strain may not be protective against another. Additionally, waning immunity has been linked to severe symptoms, and there is concern that babies born to vaccinated or previously infected mothers may be at risk of developing exacerbated disease due to antibody-dependent enhancement (ADE) of infection. Jian Hang Lam and colleagues immunized female mice with DENV2 PDK53, the core component of a live attenuated tetravalent DENV candidate vaccine, prior to pregnancy and then infected pups with different DENV strains. While pups were protected from the parental DENV strain, infection with heterologous strain resulted in ADE. Additionally, pups from PDK53-vaccinated dams were unable to seroconvert in response to PDK53 vaccination due to maternal antibody interference but did develop a multifunctional CD8+ T cell response that was protective against a heterologous DENV strain. This work indicates that elicitation of a strong DENV-specific CD8+ T cell response can confer protection in the context of enhancing, interfering maternal antibodies.

Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodiesJian Hang Lam, Yen Leong Chua, Pei Xuan Lee, Julia María Martínez Gómez, Eng Eong Ooi, and Sylvie Alonso http://jci.me/94500

Glucose fuels NK cells for viral attackNK cells are innate lymphoid cells poised to eliminate tumor and virus-infected cells. Glycolytic and oxidative metabolism have been linked to NK cell activation in vitro; however, the contribution of glycolysis to NK cell function during infection has not been fully explored. Annelise Mah and colleagues determined that glycolytic metabolism is essential for both murine and human NK cell proliferation, cytotoxicity, and target cell killing in response to IL-15 stimulation. In a murine model of cytomegalovirus (CMV) infection, animals treated with the glucose metabolism inhibitor 2DG had increased viral loads and mortality. Treatment of murine CMV–infected, 2DG-treated mice with an IL-15 superagonist (ALT-803) restored NK cell activity and prolonged survival. Importantly, administration of ALT-803 to a hematopoi-etic cell transplant recipient with recurrent, treatment-resistant CMV reduced viremia to undetectable levels for 7 weeks and was associated with an increase in NK cell responsive-ness. The results of this study identify glucose metabolism as a critical factor for antiviral activity of NK cells. The accompanying image shows decreased actin accumulation in 2DG-treated cells, suggesting abnormal target cell anchoring.

Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus controlAnnelise Y. Mah, Armin Rashidi, Molly P. Keppel, Nermina Saucier, Emily K. Moore, Joshua B. Alinger, Sandeep K. Tripathy, Sandeep K. Agarwal, Emily K. Jeng, Hing C. Wong, Jeffrey S. Miller, Todd A. Fehniger, Emily M. Mace, Anthony R. French, and Megan A. Cooper http://jci.me/95128

immunologyinfectious disease

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 8 14

JCI Insight | Editor’s picks

Bioactive lipid associates with sepsis-induced acute respiratory distress syndromeAcute respiratory distress syndrome (ARDS) is a dangerous sepsis-associated complication. Neutrophil infiltration into the lungs of ARDS patients has been associated with high mortality. The extent of neutrophil influx is not readily discernible; therefore, markers to evaluate neutrophilic damage are of great interest. A team of investigators led by David Ford and Nuala Meyer evaluated plasma levels of 2-chlorofatty acid (2-ClFA) in patients with sepsis, as neutrophil-generated myeloperoxidase (MPO) generates this bioactive lipid. High levels of 2-CIFA in plasma associated with both ARDS and mortality and correlated with plasma markers of endothelial injury. Combining 2-CIFA levels with subjects’ Acute Physiology and Chronic Health Evaluation (APACHE) III scores improved ARDS prediction. Finally, pulmonary endothelium treated with 2-CIFA elaborated injury markers and exhibited increased permeability. These results support 2-CIFA as a predictive marker for ARDS and implicate 2-CIFA in endothelial injury.

Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndromeNuala J. Meyer, John P. Reilly, Rui Feng, Jason D. Christie, Stanley L. Hazen, Carolyn J. Albert, Jacob D. Franke, Celine L. Hartman, Jane McHowat, and David A. Ford http://jci.me/96432

oncology

aids/hivinfectious disease

Antibody biomarkers for predicting HIV-1 incidenceThe ability to accurately predict the incidence of HIV-1 in a given population is essential for devising and implementing prevention strategies. Current incidence assays have limited utility, and approaches that better distinguish recent from long-term infections are needed. HIV-1–targeting antibodies are dynamic during the course of infection and have potential to discriminate duration of infection. Georgia Tomaras, Kelly Seaton, and colleagues performed a retrospective analysis of circulating antibodies from patients with recent and longstanding HIV-1 infections and evaluated antibody subclass and binding avidity to HIV-1 antigens. Four antibody biomarkers were identified that classified recent and longstanding infections, with a low overall misclassification rate. Moreover, these antibodies were validated in a blinded panel of specimens and were more accurate than a commercially available incidence assay, particularly for ART-treated patients. Together, these results support further development of assays that include these biomarkers for determining HIV-1 incidence.

Computational analysis of antibody dynamics identifies recent HIV-1 infectionKelly E. Seaton, Nathan A. Vandergrift, Aaron W. Deal, Wes Rountree, John Bainbridge, Eduard Grebe, David Anderson, Sheetal Sawant, Xiaoying Shen, Nicole L. Yates, Thomas N. Denny, Hua-Xin Liao, Barton F. Haynes, Merlin L. Robb, Neil Parkin, Breno R. Santos, Nigel Garrett, Matthew A. Price, Denise Naniche, Ann C. Duerr, The CEPHIA group, Sheila Keating, Dylan Hampton, Shelley Facente, Kara Marson, Alex Welte, Christopher D. Pilcher, Myron S. Cohen, and Georgia D. Tomaras http://jci.me/94355

Mutational profiles of breast cancer metastases from a rapid autopsy series reveal multiple evolutionary trajectoriesBracha Erlanger Avigdor, Ashley Cimino-Mathews, Angelo M. DeMarzo, Jessica L. Hicks, James Shin, Saraswati Sukumar, John Fetting, Pedram Argani, Ben H. Park, and Sarah J. Wheelan http://jci.me/96896

Profiling breast cancer metastases identifies sources of heterogeneityFor patients with breast cancer, metastatic disease is the leading cause of mortality. Marked heterogeneity between tumors can impede diagnosis and make treatment challenging. Bracha Avigdor and colleagues used a rapid biopsy and sequencing approach to survey tumors in 5 patients with metastatic breast cancer to determine origin and identify metastasis-associated clones. In three cases, metastatic tumors arose from a single clone within the primary tumor, while in two cases, tumors arose from at least two distinct subclones in the primary tumor. Histological analysis of the primary tumor from the patients with multiple metastatic clones revealed mixed pathologic and histologic features that manifested in variable expression of markers, such as estrogen receptor (ER) and progester-one receptor (PR), in metastases (see the accompanying image). In total, these results demonstrate that multiple metastatic clones can arise in a primary tumor, resulting in genetic heterogeneity and complicating tumor-targeting strategies.

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 813

JCI Insight | Editor’s picks

Early pridopidine administration improves phenotypes in Huntington disease modelHuntington disease (HD) is an inherited neurodegenerative disorder that has been linked to the disruption of a variety of cellular and molecular processes. Pridopidine, a compound that acts primarily through the sigma-1 receptor, is currently being investigated as a treatment for HD. Marta Garcia-Miralles and colleagues treated YAC128 mice, a model of HD, with various doses of pridopidine at early and late stages of disease. Animals that received pridopidine at early stages of disease had improved motor coordination and reduced depression-like symptoms but still exhibited notable neuropathology. Initiation of treatment at a later stage of disease only improved depression-like phenotypes. Early treatment was also shown to upregulate some genes that are downregulated in HD. Together, these results support continued development of pridopidine for treating HD.

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease miceMarta Garcia-Miralles, Michal Geva, Jing Ying Tan, Nur Amirah Binte Mohammad Yusof, Yoonjeong Cha, Rebecca Kusko, Liang Juin Tan, Xiaohong Xu, Iris Grossman, Aric Orbach, Michael R. Hayden, and Mahmoud A. Pouladi http://jci.me/95665

Targeting ion channels prevents cochlear hair cell death

PI3K signaling in leptin-responsive cells mediates metabolic and reproductive phenotypesPI3K signaling coordinates a variety of cellular functions. Class IA isoforms PI3Kα and PI3Kβ respond to metabolic cues, and mice harboring mutations that globally reduce PI3Kα activity have decreased body weight and a beneficial metabolic profile. However, increasing PI3K activity specifically in leptin receptor–expressing cells results in a similar phenotype, and it is not clear how leptin- and PI3K-mediated responses are coordinated. David Garcia-Galiano and colleagues evaluated the effects of disrupting PI3Kα and PI3Kβ signaling in leptin receptor–expressing cells and found that loss of both increased leptin sensitivity, producing a lean phenotype with increased energy expenditure, movement, and thermogenesis. Additionally, leptin receptor cell-specific loss of PI3Kα impeded growth and delayed puberty. These phenotypes were not the result of alterations in insulin receptor signaling, as deletion of the insulin receptor in leptin receptor–expressing cells did not recapitulate the metabolic or reproductive alterations associated with reduced PI3K signaling. Together, these results identify insulin-independent actions of PI3Ks in leptin-responsive cells that regulate energy expenditure, growth, and reproductive development.

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproductionDavid Garcia-Galiano, Beatriz C. Borges, Jose Donato Jr., Susan J. Allen, Nicole Bellefontaine, Mengjie Wang, Jean J. Zhao, Kenneth M. Kozloff, Jennifer W. Hill, and Carol F. Elias http://jci.me/96728

neurosciencereproductive biology

Aminoglycoside antibiotics are important agents for the treatment of severe bacterial infections. Unfortunately, these drugs can damage cochlear hair cells, resulting in long-term hearing loss. Several compounds have been shown to protect hair cells from aminoglycoside-induced damage in zebrafish; however, many of these compounds have not been effective in the mammalian cochlea. As aminoglycosides enter hair cells through ion

channels, Emma Kenyon and colleagues screened ion-channel modifiers for those that protected zebrafish lateral line hair cells from antibiotic-induced death. Of the compounds that were effective in the zebrafish model, 13 prevented aminoglycoside-induced hair cell death in mouse cochlear cultures (see the accompanying image). Importantly, none of the tested compounds interfered with aminoglycoside antibacterial action, supporting further exploration of these compounds for clinical development.

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell deathEmma J. Kenyon, Nerissa K. Kirkwood, Siân R. Kitcher, Molly O’Reilly, Marco Derudas, Daire M. Cantillon, Richard J. Goodyear, Abigail Secker, Sarah Baxendale, James C. Bull, Simon J. Waddell, Tanya T. Whitfield, Simon E. Ward, Corné J. Kros, and Guy P. Richardson http://jci.me/96773

j c i . o r g / t h i s - m o n t h j a n u a r y 2 0 1 8 12

Current articles

Elevated urinary CRELD2 is associated with endoplasmic reticulum stress–mediated kidney diseaseYeawon Kim, Sun-Ji Park, Scott R. Manson, Carlos A.F. Molina, Kendrah Kidd, Heather Thiessen-Philbrook, Rebecca J. Perry, Helen Liapis, Stanislav Kmoch, Chirag R. Parikh, Anthony J. Bleyer, and Ying Maggie Chen http://jci.me/92896

Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivoNathaniel H. Boyd, Kiera Walker, Joshua Fried, James R. Hackney, Paul C. McDonald, Gloria A. Benavides, Raffaella Spina,

Alessandra Audia, Sarah E. Scott, Catherine J. Libby, Anh Nhat Tran, Mark O. Bevensee, Corinne Griguer, Susan Nozell, G. Yancey Gillespie, Burt Nabors, Krishna P. Bhat, Eli E. Bar, Victor Darley-Usmar, Bo Xu, Emily Gordon, Sara J. Cooper, Shoukat Dedhar, and Anita B. Hjelmeland http://jci.me/92928

Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapyChristopher A. Klebanoff, Joseph G. Crompton, Anthony J. Leonardi, Tori N. Yamamoto, Smita S. Chandran, Robert L. Eil, Madhusudhanan Sukumar, Suman K. Vodnala, Jinhui Hu, Yun Ji, David Clever, Mary A. Black, Devikala Gurusamy, Michael J. Kruhlak, Ping Jin, David F. Stroncek, Luca Gattinoni, Steven A. Feldman, and Nicholas P. Restifo http://jci.me/95103

Human pericytes adopt myofibroblast properties in the microenvironment of the IPF lungParid Sava, Anand Ramanathan, Amelia Dobronyi, Xueyan Peng, Huanxing Sun, Adrian Ledesma-Mendoza, Erica L. Herzog, and Anjelica L. Gonzalez http://jci.me/96352

Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control p. 15Annelise Y. Mah, Armin Rashidi, Molly P. Keppel, Nermina Saucier, Emily K. Moore, Joshua B. Alinger, Sandeep K. Tripathy,

Sandeep K. Agarwal, Emily K. Jeng, Hing C. Wong, Jeffrey S. Miller, Todd A. Fehniger, Emily M. Mace, Anthony R. French, and Megan A. Cooper http://jci.me/95128

Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice p. 13Marta Garcia-Miralles, Michal Geva, Jing Ying Tan, Nur Amirah Binte Mohammad Yusof, Yoonjeong Cha, Rebecca Kusko, Liang Juin Tan, Xiaohong Xu, Iris Grossman, Aric Orbach, Michael R. Hayden, and Mahmoud A. Pouladi http://jci.me/95665

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction p. 13David Garcia-Galiano, Beatriz C. Borges, Jose Donato Jr., Susan J. Allen, Nicole Bellefontaine, Mengjie Wang, Jean J. Zhao, Kenneth M. Kozloff, Jennifer W. Hill, and Carol F. Elias http://jci.me/96728

Requirement of Treg-intrinsic CTLA4/PKCη signaling pathway for suppressing tumor immunityChristophe Pedros, Ann J. Canonigo-Balancio, Kok-Fai Kong, and Amnon Altman http://jci.me/95692

Dysregulated aldosterone secretion in persons of African descent with endothelin-1 gene variantsJia W. Tan, Tina Gupta, Worapaka Manosroi, Tham M. Yao, Paul N. Hopkins, Jonathan S. Williams, Gail K. Adler, Jose R. Romero, and Gordon H. Williams http://jci.me/95992

Myeloperoxidase-derived 2-chlorofatty acids contribute to human sepsis mortality via acute respiratory distress syndrome p. 14Nuala J. Meyer, John P. Reilly, Rui Feng, Jason D. Christie, Stanley L. Hazen, Carolyn J. Albert, Jacob D. Franke, Celine L. Hartman, Jane McHowat, and David A. Ford http://jci.me/96432

Renal proximal tubules

Pericyte-produced fibrotic lesion

Leptin-sensitive hypothalamic cells

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Nrf2/antioxidant pathway mediates β cell self-repair after damage by high-fat diet–induced oxidative stressTsehay Abebe, Jana Mahadevan, Lindsey Bogachus, Stephanie Hahn, Michele Black, Elizabeth Oseid, Fumihiko Urano, Vincenzo Cirulli, and R. Paul Robertson http://jci.me/92854

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A neutrophil interacts with T cells

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Alveolar injury and regeneration following deletion of ABCA3Tara N. Rindler, Courtney A. Stockman, Alyssa L. Filuta, Kari M. Brown, John M. Snowball, Wenjia Zhou, Ruud Veldhuizen, Erika M. Zink, Sydney E. Dautel, Geremy Clair, Charles Ansong, Yan Xu, James P. Bridges, and Jeffrey A. Whitsett http://jci.me/97381

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Domenico Ventrella, Cathal Wilson, Carlo Gesualdo, Settimio Rossi, Francesca Simonelli, and Enrico Maria Surace http://jci.me/96560

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effectsMohammed Z. Ferdaus, Lauren N. Miller, Larry N. Agbor, Turgay Saritas, Jeffrey D. Singer, Curt D. Sigmund, and James A. McCormic http://jci.me/96700

Intestinal, but not hepatic, ChREBP is required for fructose toleranceMiSung Kim, Inna I. Astapova, Sarah N. Flier, Sarah Hannou, Ludivine Doridot, Ashot Sargsyan, Henry H. Kou, Alan J. Fowler, Guosheng Liang, and Mark A. Herman http://jci.me/96703

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death p. 13Emma J. Kenyon, Nerissa K. Kirkwood, Siân R. Kitcher, Molly O’Reilly, Marco Derudas, Daire M. Cantillon, Richard J. Goodyear, Abigail Secker, Sarah Baxendale, James C. Bull, Simon J. Waddell, Tanya T. Whitfield, Simon E. Ward, Corné J. Kros, and Guy P. Richardson http://jci.me/96773

Mutational profiles of breast cancer metastases from a rapid autopsy series reveal multiple evolutionary trajectories p. 14Bracha Erlanger Avigdor, Ashley Cimino-Mathews, Angelo M. DeMarzo, Jessica L. Hicks, James Shin, Saraswati Sukumar, John Fetting, Pedram Argani, Ben H. Park, and Sarah J. Wheelan http://jci.me/96896

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Fully automated, deep learning segmentation of oxygen-induced retinopathy imagesSa Xiao, Felicitas Bucher, Yue Wu, Ariel Rokem, Cecilia S. Lee, Kyle V. Marra, Regis Fallon, Sophia Diaz-Aguilar,

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C5aR1 promotes acute pyelonephritis induced by uropathogenic E. coliKe Li, Kun-Yi Wu, Weiju Wu, Na Wang, Ting Zhang, Naheed Choudhry, Yun Song, Conrad A. Farrar, Liang Ma, Lin-lin Wei, Zhao-Yang Duan, Xia Dong, En-Qi Liu, Zong-Fang Li, Steven H. Sacks, and Wuding Zhou http://jci.me/97626

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Inflamed alveoli