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ALSO IN THIS ISSUE:

EMC3 organizes pulmonary surfactant synthesis 4

Astrocyte-derived neuroprotection against retinal injury 5

Neuropeptide Y regulates hematopoietic stem cell trafficking 6

Histamine-releasing factor amplifies food allergy 7

JCI Insight 11

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December 2017

Hepatic NRG4 signaling delays steatohepatitis p. 1

This Month

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This MonthDecember 2017

Hepatic NRG4 signals a switch from benign to pathologic steatosis

On the JCI cover

The rising prevalence of obesity corresponds with increased incidence of fatty liver, or hepatic steatosis, char-acterized by the accumulation of excess lipids in hepatocytes. Though initially reversible, hepatic steatosis can advance to nonalcoholic steatohepatitis (NASH), a chronic inflammatory condition in which unresolved liver injury, inflammation, and ensuing fibrosis progress toward end-stage liver disease. Multiple pathogenic processes are ascribed to NASH initiation and pro-gression, but identifying mechanisms that stave off NASH onset may provide valuable insight into its treatment and prevention.

Recent studies implicate deficiencies in the growth factor NRG4 or its recep-tor, the tyrosine kinase ERBB4, as putative risk factors in patients with obesity and fatty liver disease. Predominantly a product of metabolically active brown adipose tissue, NRG4 has been shown to inhibit lipogenic responses in hepa-tocytes. In this issue of the JCI, Liang Guo et al. demonstrate that NRG4 has protective effects against diet-induced NASH. Mice fed a high-fat, high-fructose diet recapitulated key aspects of NASH pathology, displaying increased hepa-tocyte death as well as liver injury, inflammation, and fibrosis. Loss of NRG4 exacerbated NASH-like symptoms in these mice, whereas NRG4 overexpres-sion had a protective effect. Mechanistically, the researchers determined that NRG4 curbs liver injury by preventing the ubiquitination and degradation of c-FLIPL, a prosurvival factor, in hepatocytes. These findings define a beneficial physiological pathway with the potential to influence NASH initiation and pro-gression. The featured image depicts adipose tissue, the source of NRG4, with lipid droplets indicated in green and cell membranes in red. Image credit: Guo-Xiao Wang and Stephanie King.

Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progressionLiang Guo, Peng Zhang, Zhimin Chen, Houjun Xia, Siming Li, Yanqiao Zhang, Sune Kobberup, Weiping Zou, and Jiandie D. Lin http://jci.me/96324

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

j c i . o r g / t h i s - m o n t h d e c e m b e r 2 0 1 72

research

Editor’s picks

immunology

TNF contributes to pathogenesis of NLRP3-associated autoinflammatory disordersCryopyrin-associated periodic syndromes (CAPS) encompasses a spectrum of autoinflamma-tory diseases that are mediated by IL-1β and linked to mutations in NLRP3, which encodes a component of the inflammasome. In mouse models of CAPS, IL-1β and IL-18 deficiency does not completely resolve the disease phenotype, suggesting the involvement of additional pathogenic mechanisms. Matthew McGeough, Alexander Wree, and colleagues observed that IL-1β/IL-18–deficient CAPS mice displayed striking increases in serum TNF in response to LPS injection. They noted similar elevations in TNF in human CAPS patients receiving IL-1–blocking therapy. Treatment with the TNF inhibitor etanercept or TNF deficiency rescued disease phenotypes in CAPS mice (see the associated image). In the accompanying Commentary, Balaji Banoth and Fayyaz Sutterwala consider the need for additional research targeting TNF as a potential therapeutic approach for CAPS patients who respond inadequately to IL-1 inhibitors.

TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathiesMatthew D. McGeough, Alexander Wree, Maria E. Inzaugarat, Ariela Haimovich, Casey D. Johnson, Carla A. Peña, Raphaela Goldbach-Mansky, Lori Broderick, Ariel E. Feldstein, and Hal M. Hoffman http://jci.me/90699

Related CommentaryConfounding role of tumor necrosis factor in cryopyrin-associated periodic syndromesBalaji Banoth and Fayyaz S. Sutterwala http://jci.me/98322

Dual defects in IFN pathways underlie a human primary immunodeficiencyPrimary immunodeficiencies are rare diseases typically linked to single-gene defects that increase an individual’s vulnerability to specific pathogens. Single-gene mutations that affect IFN pathways, however, often affect host immune responses to categories of pathogens, such as viruses (type I IFNs) or intracellular bacterial parasites (type II IFNs). Rodrigo Hoyos-Bachiloglu, Janet Chou, Catherine Sodroski, and colleagues performed whole-genome sequencing in an infant who tested positive for Streptococcus viridans, severe CMV viremia, and Mycobacterium abscessus. The patient’s consanguineous parentage indicated the likelihood of a recessive immunodeficiency disorder, which was confirmed by the identifica-tion of mutations in two IFN pathway genes: a homozygous frameshift deletion in IFNGR2 that abolished downstream signaling of the IFN-γ receptor, and a homozygous mutation in the signaling subunit of the IFN-γ receptor. The combined defects in both type I and type II IFN pathways underlie the patient’s increased susceptibility to both viral and bacterial infection.

A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutationsRodrigo Hoyos-Bachiloglu, Janet Chou, Catherine N. Sodroski, Abdallah Beano, Wayne Bainter, Magdalena Angelova, Eman Al Idrissi, Murad K. Habazi, Hamza Ali Alghamdi, Fahd Almanjomi, Mohamed Al Shehri, Nagi Elsidig, Morsi Alaa Eldin, David M. Knipe, Mofareh AlZahrani, and Raif S. Geha http://jci.me/93486

j c i . o r g / t h i s - m o n t h d e c e m b e r 2 0 1 7 3

JCI | Research: Editor’s picks

nephrology

Mutations in actin-binding advillin disrupt glomerular formation and function

Investigating a non-dopaminergic pathway that mediates inattentive and hyperactive-impulsive behaviorCommon treatments for attention-deficit/hyperactivity disorder (ADHD), including methylphenidate, evolved from observations of deficient dopamine signaling in ADHD patients. However, recent studies have connected a genetic locus containing the cell stress–response gene NDRG2 with ADHD susceptibility, suggesting that multiple pathologies may underlie this heterogeneous disorder. Work led by Lize Xiong and Yan Li evaluated the mechanisms contributing to ADHD-like behavior observed in Ndrg2-deficient mice. The authors determined that impaired glutamate clearance in Ndrg2-deficient mice led to increased excitatory signaling that linked to ADHD-like attention deficit, hyperactivity, impulsivity, and memory impairments in these mice. Although methylphenidate did not ameliorate ADHD-like behaviors in Ndrg2-deficient mice, treatment with the NDRG2 peptide rescued their behavioral phenotype. These findings support a dopamine- independent mechanism underlying ADHD pathogenesis, providing important insight into its pathogenesis and treatment.

Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behaviorYan Li, Anqi Yin, Xin Sun, Ming Zhang, Jianfang Zhang, Ping Wang, Rougang Xie, Wen Li, Ze Fan, Yuanyuan Zhu, Han Wang, Hailong Dong, Shengxi Wu, and Lize Xiong http://jci.me/94455

neuroscience

Over 50 single-gene mutations are known to cause steroid-resistant nephrotic system (SRNS), a progressive kidney disorder culminating in end-stage renal disease. Many of the proteins that these mutations encode form pathogenic complexes that interfere in critical functions of glomerular podocytes. Ji Rao, Shazia Ashraf, and coworkers identified mutations in the gene encoding the actin-binding protein advillin (AVIL) in SRNS patients from three unrelated families. Each AVIL mutation impaired actin bundling in human podocytes (see the accompanying image) and facilitated the interaction of AVIL with the actin-modulating complex ARP2/3 and the phospholipase PLCE1, which were both previously implicated in SRNS pathogenesis. These interactions abrogated lamellipodia formation and thereby podocyte migration, demonstrating a pathogenic mechanism by which AVIL mutations impair podocyte function in the glomerular filtration barrier.

Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndromeJia Rao, Shazia Ashraf, Weizhen Tan, Amelie T. van der Ven, Heon Yung Gee, Daniela A. Braun, Krisztina Fehér, Sudeep P. George, Amin Esmaeilniakooshkghazi, Won-Il Choi, Tilman Jobst-Schwan, Ronen Schneider, Johanna Magdalena Schmidt, Eugen Widmeier, Jillian K. Warejko, Tobias Hermle, David Schapiro, Svjetlana Lovric, Shirlee Shril, Ankana Daga, Ahmet Nayir, Mohan Shenoy, Yincent Tse, Martin Bald, Udo Helmchen, Sevgi Mir, Afig Berdeli, Jameela A. Kari, Sherif El Desoky, Neveen A. Soliman, Arvind Bagga, Shrikant Mane, Mohamad A. Jairajpuri, Richard P. Lifton, Seema Khurana, Jose C. Martins, and Friedhelm Hildebrandt http://jci.me/94138

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JCI | Research: Editor’s picks

pulmonology

endocrinology

ER complex subunit EMC3 organizes the synthesis of pulmonary surfactant

mTORC1 maintains mature α cell mass and glucagon secretionFalling insulin levels trigger pancreatic α cells to secrete glucagon, stimulating gluconeogenesis. This nutrient-dependent endocrine axis underpins glucose homeostasis. Nadejda Bozadjieva and coworkers describe a critical role for mTOR complex 1 (mTORC1) in supporting mature α cells to maintain glucagon secretion. Mice lacking the mTORC1 component Raptor in α cells developed normally, but adult mice exhibited low glucagon levels in fed, fasting, and hypoglycemic states (see the accompanying image). Decreases in α cell mass were observed starting at weaning age and persisted into adulthood in the Raptor-deficient mice. Chronic rapamycin treatment also impaired glucagon secretion. Further investigation revealed that mTORC1 supports normal secretory responses in α cells and regulates the expression of key genes involved in α cell development, maintenance, and secretory function. Identifying this essential role for mTORC1 in α cells provides important insights into the impact of rapamycin-based pharmacotherapies on glucagon-mediated glucose homeostasis.

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretionNadejda Bozadjieva, Manuel Blandino-Rosano, Jennifer Chase, Xiao-Qing Dai, Kelsey Cummings, Jennifer Gimeno, Danielle Dean, Alvin C. Powers, George K. Gittes, Markus A. Rüegg, Michael N. Hall, Patrick E. MacDonald, and Ernesto Bernal-Mizrachi http://jci.me/90004

Lung epithelial cells produce surfactant, a complex mixture of lipids and proteins that reduces surface tension at alveoli to facilitate lung inflation. Mutations in genes encoding surfactant proteins SP-B and SP-C or in the phospholipid transport protein ABCA3 cause respiratory failure in infants, but the mecha-nisms supporting normal surfactant production

are not well understood. Xiaofang Tang and coworkers show an essential role for the ER complex subunit EMC3 in the synthesis of surfactant in murine lung epithelial cells. EMC3 was required for normal synthesis and trafficking of surfactant components. Loss of EMC3 in lung epithelial cells induced the unfolded protein response (UPR) and impaired

processing of SP-B, SP-C, and ABCA3, leading to surfactant deficiency and respiratory failure in neonatal mice (see the accompanying image). EMC3’s actions in multiple aspects of pulmonary surfactant synthesis provide insight into the mechanisms that coordinate the assembly of this lipoprotein complex that is critical for respiration.

EMC3 coordinates surfactant protein and lipid homeostasis required for respirationXiaofang Tang, John M. Snowball, Yan Xu, Cheng-Lun Na, Timothy E. Weaver, Geremy Clair, Jennifer E. Kyle, Erika M. Zink, Charles Ansong, Wei Wei, Meina Huang, Xinhua Lin, and Jeffrey A. Whitsett http://jci.me/94152

j c i . o r g / t h i s - m o n t h d e c e m b e r 2 0 1 7 5

JCI | Research: Editor’s picks

ophthalmology

Neuroprotective effects of astrocyte-derived lipoxin B4 mitigate retinal degenerationToxic astrocyte activity is implicated in driving progressive damage to retinal ganglion cells (RGCs) in glaucoma. However, loss of protective glial signals may also contribute to neuronal injury in retinal and other neurodegenerative diseases. Izhar Livne-Bar, Jessica Wei, and colleagues sought to identify neuroprotective glial factors in an in vitro astrocyte model. Unexpect-edly, they determined that two lipid mediators, the lipoxins LXA4 and LXB4, have direct neuroprotective effects on retinal neurons. LXA4 and LXB4 application was associated with enhanced RGC survival in models of retinal injury (see the accompanying image). The more potent neuroprotective effects of LXB4 were mediated through a distinct neuroprotective signaling mechanism that influenced mitochondrial activity in primary RGCs or cortical neurons. Furthermore, therapeutic LXB4 treatment rescued RGC function and survival in a chronic model of glaucoma, indicating that manipulation of lipoxin signaling may be efficacious in neurodegenerative disease.

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injuryIzhar Livne-Bar, Jessica Wei, Hsin-Hua Liu, Samih Alqawlaq, Gah-Jone Won, Alessandra Tuccitto, Karsten Gronert, John G. Flanagan, and Jeremy M. Sivak http://jci.me/77398

GTPase targeting interrupts pathogenic VEGFR2 trafficking in diabetic retinopathyDiabetic retinopathy is a common complication of diabetes and a major cause of blindness. It is linked to increases in vascular permeability that result from retinal overexpression of the vascular growth factor VEGF. Many patients with diabetic retinopathy develop resistance to anti-VEGF therapies, necessitating more effective therapeutic approaches. Researchers in Dean Li’s laboratory turned their attention to VEGFR2, a key mediator of VEGF-driven pathogenesis. They hypothesized that interrupting VEGFR2 trafficking by targeting the small GTPase ARF6 would ameliorate disease. They determined that two GEFs, ARNO and GEP100, regulate ARF6 activation via distinct pathways. Blocking ARF6 interac-tions with either ARNO or GEP100 attenuated VEFR2 signaling. Finally, intraocular injection of a small-molecule inhibitor of ARF6 (developed by

their corporate collaborator, A6) decreased vascular permeability in multiple models of diabetic retinopathy, indicating that ARF6 is a prospective therapeutic target for ocular vascular disease.

Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathyWeiquan Zhu, Dallas S. Shi, Jacob M. Winter, Bianca E. Rich, Zongzhong Tong, Lise K. Sorensen, Helong Zhao, Yi Huang, Zhengfu Tai, Tara M. Mleynek, Jae Hyuk Yoo, Christine Dunn, Jing Ling, Jake A. Bergquist, Jackson R. Richards, Amanda Jiang, Lisa A. Lesniewski, M. Elizabeth Hartnett, Diane M. Ward, Alan L. Mueller, Kirill Ostanin, Kirk R. Thomas, Shannon J. Odelberg, and Dean Y. Li http://jci.me/91770

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JCI | Research: Editor’s picks

metabolism

Integrative metabolite profiling validates biomarker for liver fat and diabetesNonalcoholic fatty liver disease (NAFLD) is a progressive condition that has been identified as an independent risk factor for cardiovascular disease. Blood biomarkers may be a way to identify individuals at risk for NAFLD and comorbid conditions at earlier disease stages. John O’Sullivan, Jordan Morningstar, and collaborators evaluated metabolite peaks, genetic information, and liver fat in 470 Framingham Heart Study participants and singled out dimethylguanidino valeric acid (DMGV) as a potential biomarker for NAFLD. They validated the diagnostic value of DMGV for biopsy-proven nonalcoholic steatohepatitis (NASH) in a separate cohort of individuals undergoing gastric bypass surgery. In three additional human cohorts, DMGV was an independent indicator of diabetes up to 12 years before diagnosis. The data sets used in these investigations will be made available to facilitate further analyses integrating metabolite profiling, GWAS, and human phenotypes to identify additional biomarkers that correlate with hepatic fat and disease.

Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetesJohn F. O’Sullivan, Jordan E. Morningstar, Qiong Yang, Baohui Zheng, Yan Gao, Sarah Jeanfavre, Justin Scott, Celine Fernandez, Hui Zheng, Sean O’Connor, Paul Cohen, Ramachandran S. Vasan, Michelle T. Long, James G. Wilson, Olle Melander, Thomas J. Wang, Caroline Fox, Randall T. Peterson, Clary B. Clish, Kathleen E. Corey, and Robert E. Gerszten http://jci.me/95995

Neuropeptide Y signaling in bone marrow facilitates HSPC mobilizationBone marrow endothelium (BME) provides a supportive niche for hematopoietic stem and progenitor cells (HSPCs). Some HSPCs egress to peripheral blood to participate in innate immune responses and are able to re-home in the bone marrow, a process that helps maintain hematopoietic homeostasis. Pratibha Singh and colleagues investigated the mechanisms that regulate cytokine-stimulated HSPC trafficking in mice and discovered an unexpected role for dipeptidyl peptidase 4 (DPP4, also known as CD26). They observed that granulocyte-CSF (G-CSF) treatment increased DPP4 expression in BME cells and discovered that DPP4 targets and truncates neuropeptide Y (NPY) within the bone marrow. The truncated peptide activates NPY2 and NPY5 receptors at BME cell junctions, leading to an increase in vascular permeability that facilitates HSPC migration and mobilization. In the accompanying Commentary, Tomer Itkin, Jesús María Gómez-Salinero, and Shahin Rafii indicate the urgent need for further research into the active role for BME in gating cytokine-driven HSPC trafficking.

Neuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cellsPratibha Singh, Jonathan Hoggatt, Malgorzata M. Kamocka, Khalid S. Mohammad, Mary R. Saunders, Hongge Li, Jennifer Speth, Nadia Carlesso, Theresa A. Guise, and Louis M. Pelus http://jci.me/94687

Related CommentaryOpen the gates: vascular neurocrine signaling mobilizes hematopoietic stem and progenitor cellsTomer Itkin, Jesús María Gómez-Salinero, and Shahin Rafii http://jci.me/98323

stem cellsoncology

UBC silencing causes synthetic lethal ubiquitin depletion in UBB-repressed cancersCancer subtypes associated with gain-of- function oncogenes can often be targeted by selective inhibitors. In contrast, loss-of-function mutations require the identification of a secondary gene that, when targeted, can induce synthetic lethality. Alexia Kedves and colleagues identified transcriptional repression of the polyubiquitin gene UBB in a subset of patients with gynecological cancers, including high-grade serous ovarian cancer (HGSOC). In HGSOC patients, UBB silencing was associated with poor patient survival. The researchers discovered that silencing a second polyubiquitin gene, UBC, led to ubiquitin deficiency and cell death in UBB-repressed cells. UBC silencing also reduced tumor burden and increased survival in animals bearing UBB-deficient tumors, establishing a synthetic lethal relationship between these genes. In the accompanying Commentary, Diane Haakonson and Michael Rape discuss this work in the context of recent interest in ubiquitin pathways as therapeutic targets for difficult-to-treat pathologies.

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin CAlexia T. Kedves, Scott Gleim, Xiaoyou Liang, Dennis M. Bonal, Frederic Sigoillot, Fred Harbinski, Sneha Sanghavi, Christina Benander, Elizabeth George, Prafulla C. Gokhale, Quang-De Nguyen, Paul T. Kirschmeier, Robert J. Distel, Jeremy Jenkins, Michael S. Goldberg, and William C. Forrester http://jci.me/92914

Related CommentaryUbiquitin levels: the next target against gynecological cancers?Diane L. Haakonsen and Michael Rape http://jci.me/98262

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JCI | Research: Editor’s picks

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inflammation

Histamine-releasing factor potentiates IgE-dependent inflammation in food allergyFood allergy–evoked inflammation is mediated mainly through IgE- and mast cell–dependent responses. A recent observation that histamine-releasing factor (HRF) can promote IgE-dependent inflammation led Tomoaki Ando, Jun-ichi Kashiwakura, and colleagues to investigate its role in food allergy. OVA-sensitized mice displayed increases in proinflammatory cytokines, HRF-reactive IgE, and HRF dimers during the elicitation phase of inflammatory responses. Pretreating these mice with an HRF inhibitor reduced allergic sensitivity. The researchers determined that mechanistically, HRF potentiates IgE’s proinflammatory effects by interacting with the high-affinity IgE receptor FcεRI on mucosal mast cells. Further, they demonstrated that patients with egg allergy have elevated levels of HRF-reactive IgE relative to nonallergic subjects. Successful immunotherapy in this patient group was coupled to a decrease in HRF-reactive IgE. In the

accompanying Commentary, Marsha Wills-Karp details the evidence that HRF may be an important biomarker as well as a potential therapeutic target in food allergy.

Histamine-releasing factor enhances food allergyTomoaki Ando, Jun-ichi Kashiwakura, Naoka Itoh-Nagato, Hirotaka Yamashita, Minato Baba, Yu Kawakami, Shih Han Tsai, Naoki Inagaki, Kiyoshi Takeda, Tsutomu Iwata, Naoki Shimojo, Takao Fujisawa, Mizuho Nagao, Kenji Matsumoto, Yuko Kawakami, and Toshiaki Kawakami http://jci.me/96525

Related CommentaryHistamine-releasing factor: a promising therapeutic target for food allergyMarsha Wills-Karp http://jci.me/98297

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Current research articles

aids/hivHIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cellsRebecca T. Veenhuis, Zachary T. Freeman, Jack Korleski, Laura K. Cohen, Guido Massaccesi, Alessandra Tomasi, Austin W. Boesch, Margaret E. Ackerman, Joseph B. Margolick, Joel N. Blankson, Michael A. Chattergoon, and Andrea L. Cox http://jci.me/95375

cardiologyCardiomyocyte proliferation prevents failure in pressure overload but not volume overloadKarl Toischer, Wuqiang Zhu, Mark Hünlich, Belal A. Mohamed, Sara Khadjeh, Sean P. Reuter, Katrin Schäfer, Deepak Ramanujam, Stefan Engelhardt, Loren J. Field, and Gerd Hasenfuss http://jci.me/81870

endocrinologyLoss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion p. 4Nadejda Bozadjieva, Manuel Blandino-Rosano, Jennifer Chase, Xiao-Qing Dai, Kelsey Cummings, Jennifer Gimeno, Danielle Dean, Alvin C. Powers, George K. Gittes, Markus A. Rüegg, Michael N. Hall, Patrick E. MacDonald, and Ernesto Bernal-Mizrachi http://jci.me/90004

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferationHong Soon Kang, Dhirendra Kumar, Grace Liao, Kristin Lichti-Kaiser, Kevin Gerrish, Xiao-Hui Liao, Samuel Refetoff, Raja Jothi, and Anton M. Jetten http://jci.me/94417

hematologyEndothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppressionPeipei Guo, Michael G. Poulos, Brisa Palikuqi, Chaitanya R. Badwe, Raphael Lis, Balvir Kunar, Bi-Sen Ding, Sina Y. Rabbany, Koji Shido, Jason M. Butler, and Shahin Rafii http://jci.me/92309

Pharmacological inhibition of the transcription factor PU.1 in leukemiaIléana Antony-Debré, Ananya Paul, Joana Leite, Kelly Mitchell, Hye Mi Kim, Luis A. Carvajal, Tihomira I. Todorova, Kenneth Huang, Arvind Kumar, Abdelbasset A. Farahat, Boris Bartholdy, Swathi-Rao Narayanagari, Jiahao Chen, Alberto Ambesi-Impiombato, Adolfo A. Ferrando, Ioannis Mantzaris, Evripidis Gavathiotis, Amit Verma, Britta Will, David W. Boykin, W. David Wilson, Gregory M.K. Poon, and Ulrich Steidl http://jci.me/92504

Protein kinase A determines platelet life span and survival by regulating apoptosisLili Zhao, Jun Liu, Chunyan He, Rong Yan, Kangxi Zhou, Qingya Cui, Xingjun Meng, Xiaodong Li, Yang Zhang, Yumei Nie, Yang Zhang, Renping Hu, Yancai Liu, Lian Zhao, Mengxing Chen, Weiling Xiao, Jingluan Tian, Yunxiao Zhao, Lijuan Cao, Ling Zhou, Anning Lin, Changgeng Ruan, and Kesheng Dai http://jci.me/95109

hepatologyHepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression p. 1Liang Guo, Peng Zhang, Zhimin Chen, Houjun Xia, Siming Li, Yanqiao Zhang, Sune Kobberup, Weiping Zou, and Jiandie D. Lin http://jci.me/96324

immunologyTNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies p. 2Matthew D. McGeough, Alexander Wree, Maria E. Inzaugarat, Ariela Haimovich, Casey D. Johnson, Carla A. Peña, Raphaela Goldbach-Mansky, Lori Broderick, Ariel E. Feldstein, and Hal M. Hoffman http://jci.me/90699

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A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations p. 2Rodrigo Hoyos-Bachiloglu, Janet Chou, Catherine N. Sodroski, Abdallah Beano, Wayne Bainter, Magdalena Angelova, Eman Al Idrissi, Murad K. Habazi, Hamza Ali Alghamdi, Fahd Almanjomi, Mohamed Al Shehri, Nagi Elsidig, Morsi Alaa Eldin, David M. Knipe, Mofareh AlZahrani, and Raif S. Geha http://jci.me/93486

infectious diseasesiRNA rescues nonhuman primates from advanced Marburg and Ravn virus diseaseEmily P. Thi, Chad E. Mire, Amy C.H. Lee, Joan B. Geisbert, Raul Ursic-Bedoya, Krystle N. Agans, Marjorie Robbins, Daniel J. Deer, Robert W. Cross, Andrew S. Kondratowicz, Karla A. Fenton, Ian MacLachlan, and Thomas W. Geisbert http://jci.me/96185

inflammationHistamine-releasing factor enhances food allergy p. 7Tomoaki Ando, Jun-ichi Kashiwakura, Naoka Itoh-Nagato, Hirotaka Yamashita, Minato Baba, Yu Kawakami, Shih Han Tsai, Naoki Inagaki, Kiyoshi Takeda, Tsutomu Iwata, Naoki Shimojo, Takao Fujisawa, Mizuho Nagao, Kenji Matsumoto, Yuko Kawakami, and Toshiaki Kawakami http://jci.me/96525

metabolismDimethylguanidino valeric acid is a marker of liver fat and predicts diabetes p. 6John F. O’Sullivan, Jordan E. Morningstar, Qiong Yang, Baohui Zheng, Yan Gao, Sarah Jeanfavre, Justin Scott, Celine Fernandez, Hui Zheng, Sean O’Connor, Paul Cohen, Ramachandran S. Vasan, Michelle T. Long, James G. Wilson, Olle Melander, Thomas J. Wang, Caroline Fox, Randall T. Peterson, Clary B. Clish, Kathleen E. Corey, and Robert E. Gerszten http://jci.me/95995

muscle biologyAmphiphysin (BIN1) negatively regulates dynamin 2 for normal muscle maturationBelinda S. Cowling, Ivana Prokic, Hichem Tasfaout, Aymen Rabai, Frédéric Humbert, Bruno Rinaldi, Anne-Sophie Nicot, Christine Kretz, Sylvie Friant, Aurélien Roux, and Jocelyn Laporte http://jci.me/90542

nephrologyAdvillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome p. 3Jia Rao, Shazia Ashraf, Weizhen Tan, Amelie T. van der Ven, Heon Yung Gee, Daniela A. Braun, Krisztina Fehér, Sudeep P. George, Amin Esmaeilniakooshkghazi, Won-Il Choi, Tilman Jobst-Schwan, Ronen Schneider, Johanna Magdalena Schmidt, Eugen Widmeier, Jillian K. Warejko, Tobias Hermle, David Schapiro, Svjetlana Lovric, Shirlee Shril, Ankana Daga, Ahmet Nayir, Mohan Shenoy, Yincent Tse, Martin Bald, Udo Helmchen, Sevgi Mir, Afig Berdeli, Jameela A. Kari, Sherif El Desoky, Neveen A. Soliman, Arvind Bagga, Shrikant Mane, Mohamad A. Jairajpuri, Richard P. Lifton, Seema Khurana, Jose C. Martins, and Friedhelm Hildebrandt http://jci.me/94138

neuroscienceS-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiencyAvadh Kumar, Borislav Dejanovic, Florian Hetsch, Marcus Semtner, Debora Fusca, Sita Arjune, Jose Angel Santamaria-Araujo, Aline Winkelmann, Scott Ayton, Ashley I. Bush, Peter Kloppenburg, Jochen C. Meier, Guenter Schwarz, and Abdel Ali Belaidi http://jci.me/89885

5 suppressor NDRG2 leads to attention deficit and hyperactive behavior p. 3Yan Li, Anqi Yin, Xin Sun, Ming Zhang, Jianfang Zhang, Ping Wang, Rougang Xie, Wen Li, Ze Fan, Yuanyuan Zhu, Han Wang, Hailong Dong, Shengxi Wu, and Lize Xiong http://jci.me/94455

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JCI | Current research articles

oncologyp120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasiaSarah P. Short, Jumpei Kondo, Whitney G. Smalley-Freed, Haruna Takeda, Michael R. Dohn, Anne E. Powell, Robert H. Carnahan, Mary K. Washington, Manish Tripathi, D. Michael Payne, Nancy A. Jenkins, Neal G. Copeland, Robert J. Coffey, and Albert B. Reynolds http://jci.me/77217

JAK2-binding long noncoding RNA promotes breast cancer brain metastasisShouyu Wang, Ke Liang, Qingsong Hu, Ping Li, Jian Song, Yuedong Yang, Jun Yao, Lingegowda Selanere Mangala, Chunlai Li, Wenhao Yang, Peter K. Park, David H. Hawke, Jianwei Zhou, Yan Zhou, Weiya Xia, Mien-Chie Hung, Jeffrey R. Marks, Gary E. Gallick, Gabriel Lopez-Berestein, Elsa R. Flores, Anil K. Sood, Suyun Huang, Dihua Yu, Liuqing Yang, and Chunru Lin http://jci.me/91553

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C p. 6Alexia T. Kedves, Scott Gleim, Xiaoyou Liang, Dennis M. Bonal, Frederic Sigoillot, Fred Harbinski, Sneha Sanghavi, Christina Benander, Elizabeth George, Prafulla C. Gokhale, Quang-De Nguyen, Paul T. Kirschmeier, Robert J. Distel, Jeremy Jenkins, Michael S. Goldberg, and William C. Forrester http://jci.me/92914

ophthalmologyAstrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury p. 5Izhar Livne-Bar, Jessica Wei, Hsin-Hua Liu, Samih Alqawlaq, Gah-Jone Won, Alessandra Tuccitto, Karsten Gronert, John G. Flanagan, and Jeremy M. Sivak http://jci.me/77398

Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy p. 5Weiquan Zhu, Dallas S. Shi, Jacob M. Winter, Bianca E. Rich, Zongzhong Tong, Lise K. Sorensen, Helong Zhao, Yi Huang, Zhengfu Tai, Tara M. Mleynek, Jae Hyuk Yoo, Christine Dunn, Jing Ling, Jake A. Bergquist, Jackson R. Richards, Amanda Jiang, Lisa A. Lesniewski, M. Elizabeth Hartnett, Diane M. Ward, Alan L. Mueller, Kirill Ostanin, Kirk R. Thomas, Shannon J. Odelberg, and Dean Y. Li http://jci.me/91770

Angiopoietin-1 is required for Schlemm’s canal development in mice and humansBenjamin R. Thomson, Tomokazu Souma, Stuart W. Tompson, Tuncer Onay, Krishnakumar Kizhatil, Owen M. Siggs, Liang Feng, Kristina N. Whisenhunt, Tammy L. Yanovitch, Luba Kalaydjieva, Dimitar N. Azmanov, Simone Finzi, Christine E. Tanna, Alex W. Hewitt, David A. Mackey, Yasmin S. Bradfield, Emmanuelle Souzeau, Shari Javadiyan, Janey L. Wiggs, Francesca Pasutto, Xiaorong Liu, Simon W.M. John, Jamie E. Craig, Jing Jin, Terri L. Young, and Susan E. Quaggin http://jci.me/95545

pulmonologyEMC3 coordinates surfactant protein and lipid homeostasis required for respiration p. 4Xiaofang Tang, John M. Snowball, Yan Xu, Cheng-Lun Na, Timothy E. Weaver, Geremy Clair, Jennifer E. Kyle, Erika M. Zink, Charles Ansong, Wei Wei, Meina Huang, Xinhua Lin, and Jeffrey A. Whitsett http://jci.me/94152

stem cellsNeuropeptide Y regulates a vascular gateway for hematopoietic stem and progenitor cells p. 6Pratibha Singh, Jonathan Hoggatt, Malgorzata M. Kamocka, Khalid S. Mohammad, Mary R. Saunders, Hongge Li, Jennifer Speth, Nadia Carlesso, Theresa A. Guise, and Louis M. Pelus http://jci.me/94687

vascular biologyLeukocyte RhoA exchange factor Arhgef1 mediates vascular inflammation and atherosclerosisMaria Luigia Carbone, Gilliane Chadeuf, Sandrine Heurtebise-Chrétien, Xavier Prieur, Thibault Quillard, Yann Goueffic, Nathalie Vaillant, Marc Rio, Laure Castan, Maxim Durand, Céline Baron-Menguy, Julien Aureille, Juliette Desfrançois, Angela Tesse, Raul M. Torres, and Gervaise Loirand http://jci.me/92702

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Editor’s picks

pulmonology

metabolism

Muscle wasting in hemodialysis patients linked to systemic inflammation

Disparate outcomes of ACE-mediated degradation of acetylated PGPThe chemoattractant PGP promotes recruitment of neutrophils to sites of collagen breakdown. Neutrophilia is limited by PGP degradation, which is mediated by the neutrophil-generated leukotriene hydrolase LTA4H; however, acetylation of PGP prevents LTA4H-mediated breakdown. Bronchoalveolar lavage fluid (BALF) from influenza-infected mice was recently shown to degrade acetylated PGP (AcPGP); therefore, Philip O’Reilly, Qiang Ding, and colleagues sought to characterize the AcPGP-degrading enzyme. The authors identified angiotensin-1-converting enzyme (ACE) as the AcPGP-targeting enzyme. ACE was elevated in the lungs of patients with idiopathic pulmonary fibrosis (IPF) but not in the lungs of patients with chronic obstructive pulmonary disorder (COPD), which is characterized by high levels of PGP and AcPGP and neutrophilic infiltration. In a murine model of pulmonary fibrosis, in which ACE levels were elevated, administration of AcPGP or inhibition of ACE was protective against fibrosis (see the accompanying image). Together, these results support further exploration of the disparate roles of ACE and AcPGP in lung diseases.

Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosisPhilip J. O’Reilly, Qiang Ding, Samia Akthar, Guoqiang Cai, Kristopher R. Genschmer, Dhiren F. Patel, Patricia L. Jackson, Liliana Viera, Mojtaba Roda, Morgan L. Locy, Ellen A. Bernstein, Clare M. Lloyd, Kenneth E. Bernstein, Robert J. Snelgrove, and J. Edwin Blalock http://jci.me/91923

Patients with end-stage renal disease on maintenance hemodialysis often exhibit systemic inflammation and muscle wasting. It is thought that systemic inflammation directly underlies the loss of muscle in these patients; however, this link has not been thoroughly explored in humans. Serpil Deger and colleagues used stable isotope kinetics to assess whole body and skeletal muscle protein turnover in patients on maintenance hemodialysis. Regardless of the comorbid conditions that may influence protein metabolism, high levels of C-reactive protein, indicative of systemic inflammation, were directly correlated with a loss of skeletal muscle mass characterized by increased protein degradation and decreased protein synthesis. Moreover, muscle wasting observed in a mouse model of chronic

kidney disease was associated with increased proteasome subunit expression, ubiquitin conjugates, and p-Akt. Together, these results indicate that reducing systemic inflammation in patients undergoing maintenance hemodialysis may potentially prevent muscle wasting.

Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patientsSerpil M. Deger, Adriana M. Hung, Jorge L. Gamboa, Edward D. Siew, Charles D. Ellis, Cindy Booker, Feng Sha, Haiming Li, Aihua Bian, Thomas G. Stewart, Roy Zent, William E. Mitch, Naji N. Abumrad, and T. Alp Ikizler http://jci.me/95185

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vaccines

JCI Insight | Editor’s picks

neuroscience

Screen identifies neuroleptics for potential amyotrophic lateral sclerosis treatment strategy

Plasmodium falciparum RH5-based vaccine shows promise in early clinical trialPlasmodium falciparum is responsible for the majority of malaria-related deaths worldwide, with young children especially vulnerable to severe disease. Currently, the most effective strategies for limiting disease are mosquito control and prophylactic treatment in susceptible populations; however, as drug resistance is becoming more prevalent in malaria-endemic regions, effective vaccines will be essential for disease eradica-tion. Ruth Payne, Simon Draper, and colleagues evaluated the immune response in healthy volunteers following vaccination with the simian adenovirus ChAd63 and modified vaccinia virus Ankara (MVA) expressing the P. falciparum blood-stage antigen RH5 in a heterologous prime-boost regimen. The vaccines were well tolerated, and vaccinated subjects developed RH5-specific antibodies that were able to inhibit growth of multiple strains of P. falciparum in vitro and inhibit interactions within the RH5 invasion complex. The results of this study support moving RH5 vaccines into the efficacy testing phase.

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactionsRuth O. Payne, Sarah E. Silk, Sean C. Elias, Kazutoyo Miura, Ababacar Diouf, Francis Galaway, Hans de Graaf, Nathan J. Brendish, Ian D. Poulton, Oliver J. Griffiths, Nick J. Edwards, Jing Jin, Geneviève M. Labbé, Daniel G.W. Alanine, Loredana Siani, Stefania Di Marco, Rachel Roberts, Nicky Green, Eleanor Berrie, Andrew S. Ishizuka, Carolyn M. Nielsen, Martino Bardelli, Frederica D. Partey, Michael F. Ofori, Lea Barfod, Juliana Wambua, Linda M. Murungi, Faith H. Osier, Sumi Biswas, James S. McCarthy, Angela M. Minassian, Rebecca Ashfield, Nicola K. Viebig, Fay L. Nugent, Alexander D. Douglas, Johan Vekemans, Gavin J. Wright, Saul N. Faust, Adrian V.S. Hill, Carole A. Long, Alison M. Lawrie, and Simon J. Draper http://jci.me/96381

Amyotrophic lateral sclerosis (ALS) is character-ized by motor neuron degeneration and progressive muscle function loss. There are no cures for ALS, and therapies to limit progression are only modestly effective. Shunmoogum Patten, Dina Aggad, and colleagues used multiple preclinical ALS models to screen clinically approved compounds to identify those that improved motor function. A class of neuroleptics, in particular pimozide, stabilized motility in C. elegans and zebrafish. Moreover, pimozide stabilized neuromuscular junctions and reduced axonal abnormalities in zebrafish (see the accompanying image) and mice. As pimozide is approved for human use, the authors conducted a small, pilot randomized trial in a cohort of patients with sporadic ALS. Pimozide was tolerable and engaged at neuromuscular junctions. Compared with placebo, pimozide-treated subjects had less of a change in decremental response of right hand abductor pollicis brevis. Finally, the MRC sum score, which reflects motility, was stabilized in pimozide-treated patients. These results warrant further clinical assessment of pimozide in ALS, and a larger multicenter clinical trial has recently launched.

Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosisShunmoogum A. Patten, Dina Aggad, Jose Martinez, Elsa Tremblay, Janet Petrillo, Gary A.B. Armstrong, Alexandre La Fontaine, Claudia Maios, Meijiang Liao, Sorana Ciura, Xiao-Yan Wen, Victor Rafuse, Justin Ichida, Lorne Zinman, Jean-Pierre Julien, Edor Kabashi, Richard Robitaille, Lawrence Korngut, J. Alexander Parker, and Pierre Drapeau http://jci.me/97152

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JCI Insight | Editor’s picks

genetics

autoimmunity

Identification of genes associated with incretin levels

Microbiome disruption alters efficacy of immunosuppression

Glucose homeostasis is achieved through precise control of insulin and glucagon release from the pancreas along with secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) from the gastrointestinal tract. As glucose homeostasis is disrupted in type 2 diabetes, strategies that promote incretin secretion have the potential to treat disease. Peter Almgren and colleagues performed a genome-wide association study to identify loci

associated with circulating insulin, glucagon, GIP, and GLP-1 concentrations during an oral glucose tolerance test in over 7,000 individuals. The authors identified six loci, SLC5A1, GIPR, ABO, GLP2R, F13A1, and HOXD1, that were linked to plasma incretin concentrations. Moreover, the products of ABO, HOXD1 (see the accompanying image), and GIPR were present in human incretin-producing enteroendocrine cells, further supporting these genes as regulators of incretin secretion and potential therapeutic targets.

Genetic determinants of circulating GIP and GLP-1 concentrationsPeter Almgren, Andreas Lindqvist, Ulrika Krus, Liisa Hakaste, Emilia Ottosson-Laakso, Olof Asplund, Emily Sonestedt, Rashmi B. Prasad, Esa Laurila, Marju Orho-Melander, Olle Melander, Tiinamaija Tuomi, Jens Juul Holst, Peter M. Nilsson, Nils Wierup, Leif Groop, and Emma Ahlqvist http://jci.me/93306

The microbiome has been shown to influence immune system activity and function. Dysbiosis is thought to contribute to several inflammatory diseases and has potential to influence immune tolerance. Elke Gülden, Nalini Vudattu, and colleagues used humanized mice to evaluate the effect of microbiome alterations on human immune cell function. Compared with controls, humanized mice treated with antibiotics had increased effector T cell frequency, elevated IFN-γ, and developed anti-nuclear antibodies, suggesting a breach in immune tolerance. The anti-CD3 mAb teplizumab prolonged skin xenograft survival in humanized mice; however, teplizumab was unable to induce tolerance in antibiotic-treated animals. The reduced efficacy of teplizumab following microbiome disruption was linked to decreased IL-10 production and alterations in

CD11b+CD11c+ cell populations that resulted in increased T cell activation in the presence of teplizumab. Taken together, the results of this study demonstrate that alterations in the microbiome influence the response to immunosuppressive therapies.

Microbiota control immune regulation in humanized miceElke Gülden, Nalini K. Vudattu, Songyan Deng, Paula Preston-Hurlburt, Mark Mamula, James C. Reed, Sindhu Mohandas, Betsy C. Herold, Richard Torres, Silvio M. Vieira, Bentley Lim, Jose D. Herazo-Maya, Martin Kriegel, Andrew L. Goodman, Chris Cotsapas, and Kevan C. Herold http://jci.me/91709

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Current articles

B cell–derived IL-4 acts on podocytes to induce proteinuria and foot process effacementAlfred H.J. Kim, Jun-Jae Chung, Shreeram Akilesh, Ania Koziell, Sanjay Jain, Jeffrey B. Hodgin, Mark J. Miller, Thaddeus S. Stappenbeck, Jeffrey H. Miner, and Andrey S. Shaw http://jci.me/81836

Notch1 haploinsufficiency causes ascending aortic aneurysms in miceSara N. Koenig, Stephanie LaHaye, James D. Feller, Patrick Rowland, Kan N. Hor, Aaron J. Trask, Paul M.L. Janssen, Freddy Radtke, Brenda Lilly, and Vidu Garg http://jci.me/91353

Human regulatory T cells undergo self-inflicted damage via granzyme pathways upon activationEsilida Sula Karreci, Siawosh K. Eskandari, Farokh Dotiwala, Sujit K. Routray, Ahmed T. Kurdi, Jean Pierre Assaker,

Pavlo Luckyanchykov, Albana B. Mihali, Omar Maarouf, Thiago J. Borges, Abdullah Alkhudhayri, Kruti R. Patel, Amr Radwan, Irene Ghobriel, Martina McGrath, Anil Chandraker, Leonardo V. Riella, Wassim Elyaman, Reza Abdi, Judy Lieberman, and Jamil Azzi http://jci.me/91599

Microbiota control immune regulation in humanized mice p. 13Elke Gülden, Nalini K. Vudattu, Songyan Deng, Paula Preston-Hurlburt, Mark Mamula, James C. Reed, Sindhu Monhandas, Betsy C. Herold, Richard Torres, Silvio M. Vieira, Bentley Lim, Jose D. Herazo-Maya, Martin Kriegel, Andrew L. Goodman, Chris Cotsapas, and Kevan C. Herold http://jci.me/91709

Genetic determinants of circulating GIP and GLP-1 concentrations p. 13Peter Almgren, Andreas Lindqvist, Ulrika Krus, Liisa Hakaste, Emilia Ottosson-Laakso, Olof Asplund, Emily Sonestedt, Rashmi B. Prasad, Esa Laurila, Marju Orho-Melander, Olle Melander, Tiinamaija Tuomi, Jens Juul Holst, Peter M. Nilsson, Nils Wierup, Leif Groop, and Emma Ahlqvist http://jci.me/93306

NOTCH3 regulates stem-to–mural cell differentiation in infantile hemangiomaAndrew K. Edwards, Kyle Glithero, Peter Grzesik, Alison A. Kitajewski, Naikhoba C.O. Munabi, Krista Hardy, Qian Kun Tan, Michael Schonning, Thaned Kangsamaksin, Jan K. Kitajewski, Carrie J. Shawber, and June K. Wu http://jci.me/93764

Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolismPeter R. Baker II, Zachary Patinkin, Allison L.B. Shapiro, Becky A. De La Houssaye, Michael Woontner, Kristen E. Boyle, Lauren Vanderlinden, Danna Dabelea, and Jacob E. Friedman http://jci.me/94200

Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossificationsFrédéric Torossian, Bernadette Guerton, Adrienne Anginot, Kylie A. Alexander, Christophe Desterke, Sabrina Soave, Hsu-Wen Tseng, Nassim Arouche, Laetitia Boutin, Irina Kulina, Marjorie Salga, Beulah Jose, Allison R. Pettit, Denis Clay, Nathalie Rochet, Erica Vlachos, Guillaume Genet, Charlotte Debaud, Philippe Denormandie, François Genet, Natalie A. Sims, Sébastien Banzet, Jean-Pierre Levesque, Jean-Jacques Lataillade, and Marie-Caroline Le Bousse-Kerdilès http://jci.me/96034

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancerCharli Dominguez, Kristen K. McCampbell, Justin M. David, and Claudia Palena http://jci.me/94296

Thinning of the aortic wall

Hemangioma stem cells

CXCR2 expression in breast cancer cells

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Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergenJames D. Nolin, Ying Lai, Herbert Luke Ogden, Anne M. Manicone, Ryan C. Murphy, Dowon An, Charles W. Frevert, Farideh Ghomashchi, Gajendra S. Naika, Michael H. Gelb, Gail M. Gauvreau, Adrian M. Piliponsky, William A. Altemeier, and Teal S. Hallstrand http://jci.me/94929

T cells presenting viral antigens or autoantigens induce cytotoxic T cell anergyNathalie E. Blachère, Dana E. Orange, Emily C. Gantman, Bianca D. Santomasso, Graeme C. Couture, Teresa Ramirez-Montagut, John Fak, Kevin J. O’Donovan, Zhong Ru, Salina Parveen, Mayu O. Frank, Michael J. Moore, and Robert B. Darnell http://jci.me/96173

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions p. 12Ruth O. Payne, Sarah E. Silk, Sean C. Elias, Kazutoyo Miura, Ababacar Diouf, Francis Galaway, Hans de Graaf, Nathan J. Brendish, Ian D. Poulton, Oliver J. Griffiths, Nick J. Edwards, Jing Jin, Geneviève M. Labbé, Daniel G.W. Alanine, Loredana Siani, Stefania Di Marco, Rachel Roberts, Nicky Green, Eleanor Berrie, Andrew S. Ishizuka, Carolyn M. Nielsen, Martino Bardelli, Frederica D. Partey, Michael F. Ofori, Lea Barfod, Juliana Wambua, Linda M. Murungi, Faith H. Osier, Sumi Biswas, James S. McCarthy, Angela M. Minassian, Rebecca Ashfield, Nicola K. Viebig, Fay L. Nugent, Alexander D. Douglas, Johan Vekemans, Gavin J. Wright, Saul N. Faust, Adrian V.S. Hill, Carole A. Long, Alison M. Lawrie, and Simon J. Draper http://jci.me/96381

Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatmentAmar N. Mirza, Micah A. Fry, Nicole M. Urman, Scott X. Atwood, Jon Roffey, Gregory R. Ott, Bin Chen, Alex Lee, Alexander S. Brown, Sumaira Z. Aasi, Tyler Hollmig, Mark A. Ator, Bruce D. Dorsey, Bruce R. Ruggeri, Craig A. Zificsak, Marina Sirota, Jean Y. Tang, Atul Butte, Ervin Epstein, Kavita Y. Sarin, and Anthony E. Oro http://jci.me/97071

Loss of miR-141/200c ameliorates hepatic steatosis and inflammation by reprogramming multiple signaling pathways in NASHMelanie Tran, Sang-Min Lee, Dong-Ju Shin, and Li Wang http://jci.me/96094

Angiotensin-converting enzyme defines matrikine-regulated inflammation and fibrosis p. 11

Philip J. O’Reilly, Qiang Ding, Samia Akthar, Guoqiang Cai, Kristopher R. Genschmer, Dhiren F. Patel, Patricia L. Jackson, Liliana Viera, Mojtaba Roda, Morgan L. Locy, Ellen A. Bernstein, Clare M. Lloyd, Kenneth E. Bernstein, Robert J. Snelgrove, and J. Edwin Blalock http://jci.me/91923

A simple, clinically relevant therapeutic vaccine shows long-term protection in an aggressive, delayed-treatment B lymphoma modelPallab Pradhan, Jardin Leleux, Jiaying Liu, and Krishnendu Roy http://jci.me/92522

Clonal relationships of CSF B cells in treatment-naive multiple sclerosis patientsErica L. Eggers, Brady A. Michel, Hao Wu, Sheng-zhi Wang, Carolyn J. Bevan, Aya Abounasr, Natalie S. Pierson, Antje Bischof, Max Kazer, Elizabeth Leitner, Ariele L. Greenfield, Stanislas Demuth, Michael R. Wilson, Roland G. Henry, Bruce A.C. Cree, Stephen L. Hauser, and H.-Christian von Büdingen http://jci.me/92724

Hepatic macrophage activation

Mucus-producing airway passages

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JCI Insight | Current articles

CD11c+ resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitisMichiko Itoh, Takayoshi Suganami, Hideaki Kato, Sayaka Kanai, Ibuki Shirakawa, Takeru Sakai, Toshihiro Goto, Masahiro Asakawa, Isao Hidaka, Hiroshi Sakugawa, Koji Ohnishi, Yoshihiro Komohara, Kenichi Asano, Isao Sakaida, Masato Tanaka, and Yoshihiro Ogawa http://jci.me/92902

Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients p. 11Serpil M. Deger, Adriana M. Hung, Jorge L. Gamboa, Edward D. Siew, Charles D. Ellis, Cindy Booker, Feng Sha, Haiming Li, Aihua Bian, Thomas G. Stewart, Roy Zent, William E. Mitch, Naji N. Abumrad, and T. Alp Ikizler http://jci.me/95185

Increased Ca2+ signaling through CaV1.2 channel promotes bone formation and prevents estrogen deficiency–induced bone lossChike Cao, Yinshi Ren, Adam S. Barnett, Anthony J. Mirando, Douglas Rouse, Se Hwan Mun, Kyung-Hyun Park-Min, Amy L. McNulty, Farshid Guilak, Courtney M. Karner, Matthew J. Hilton, and Geoffrey S. Pitt http://jci.me/95512

Akt3 inhibits adipogenesis and protects from diet-induced obesity via signaling pathwayLiang Ding, Lifang Zhang, Sudipta Biswas, Rebecca C. Schugar, J. Mark Brown, Tatiana Byzova, and Eugene Podrez http://jci.me/95687

Nasospheroids permit measurements of CFTR-dependent fluid transportJennifer S. Guimbellot, Justin M. Leach, Imron G. Chaudhry, Nancy L. Quinney, Susan E. Boyles, Michael Chua, Inmaculada Aban, Ilona Jaspers, and Martina Gentzsch http://jci.me/95734

Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicityShih-Yu Chang, Elijah J. Weber, Viktoriya S. Sidorenko, Alenka Chapron, Catherine K. Yeung, Chunying Gao, Qingcheng Mao, Danny Shen, Joanne Wang, Thomas A. Rosenquist, Kathleen G. Dickman, Thomas Neumann, Arthur P. Grollman, Edward J. Kelly, Jonathan Himmelfarb, and David L. Eaton http://jci.me/95978

IL-7–dependent STAT1 activation limits homeostatic CD4 T cell expansionCecile Le Saout, Megan A. Luckey, Alejandro V. Villarino, Mindy Smith, Rebecca B. Hasley, Timothy G. Myers, Hiromi Imamichi, Jung-Hyun Park, John J. O’Shea, H. Clifford Lane, and Marta Catalfamo http://jci.me/96228

Recapitulation of developmental mechanisms to revascularize the ischemic heartKarina N. Dubé, Tonia M. Thomas, Sonali Munshaw, Mala Rohling, Paul R. Riley, and Nicola Smart http://jci.me/96800

Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis p. 12

Shunmoogum A. Patten, Dina Aggad, Jose Martinez, Elsa Tremblay, Janet Petrillo, Gary A.B. Armstrong, Alexandre La Fontaine, Claudia Maios, Meijiang Liao, Sorana Ciura, Xiao-Yan Wen, Victor Rafuse, Justin Ichida, Lorne Zinman, Jean-Pierre Julien, Edor Kabashi, Richard Robitaille, Lawrence Korngut, J. Alexander Parker, and Pierre Drapeau http://jci.me/97152

Integrating light-sheet imaging with virtual reality to recapitulate developmental cardiac mechanicsYichen Ding, Arash Abiri, Parinaz Abiri, Shuoran Li, Chih-Chiang Chang, Kyung In Baek, Jeffrey J. Hsu, Elias Sideris, Yilei Li, Juhyun Lee, Tatiana Segura, Thao P. Nguyen, Alexander Bui, René R. Sevag Packard, Peng Fei, and Tzung K. Hsiai http://jci.me/97180

Fentanyl-related designer drugs W-18 and W-15 lack appreciable opioid activity in vitro and in vivoXi-Ping Huang, Tao Che, Thomas J. Mangano, Valerie Le Rouzic, Ying-Xian Pan, Susruta Majumdar, Michael D. Cameron, Michael H. Baumann, Gavril W. Pasternak, and Bryan L. Roth http://jci.me/97222

Active osteogenesis in mouse femur

Vascular sprouting from epicardial cells

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