jci.org/impactAugust 2014

Also in this issue:

Modified gut bacteria block obesity 7

Salivary gland recovery after radiation 9

Kisspeptin promotes egg maturation 10

Autophagy protects pancreatic β cells 12

A summary of this month’s Journal of Clinical investigation

Incorporating red blood cells in clots p. 6

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Alejandro Aballay

Abul K. Abbas

Domenico Accili

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Journal of Clinical Investigation Consulting Editors

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Weiping Zou

t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t A u g u s t 2 0 1 4 1

editorHoward A. Rockman

Deputy editor Garnett Kelsoe, Bryan L. Roth

Associate editorsSoman N. Abraham, Vann Bennett,Gerard Blobe, Kathleen M. Caron,Marc G. Caron, John P. Chute,Thomas M. Coffman, Anna Mae Diehl,Ronald J. Falk, Michael B. Kastan, Daniel P. Kelly, Mary E. Klotman, Rodger A. Liddle, Nigel Mackman, Larry G. Moss, Deborah M. Muoio, Christopher B. Newgard,Paul W. Noble, Cam Patterson, Geoffrey S. Pitt, Jeffrey C. Rathmell, W. Kimryn Rathmell, Bryan Roth, Jonathan S. Serody, Norman Sharpless, Yiping Yang

Clinical Medicine Associate editorsMichael A. Morse, Andrew J. Muir,Scott M. Palmer, Mark A. Stacy

Asia editorsDavid M. Virshup

Chair, executive CouncilRobert J. Lefkowitz

BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen

BioethicistArthur L. Caplan

senior science editorSarah C. Jackson

Assistant science editorsJillian Hurst, Corinne Williams

editor at largeUshma S. Neill

issn 2324-7703 (print)issn 2325-4556 (online)

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

ImpactAugust 2014

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The JCI’s Editorial Board is composed of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. Editorial Board members review and oversee peer review of each manuscript that is submitted to the JCI, and the board meets weekly to discuss the manuscripts undergoing review.

Featured Editor

Mary E. Klotman, M.D., Associate Editor, is Professor of Medicine (Infectious Diseases) and Medical Genet-ics and Microbiology and Chair of the Department of Medicine, Duke University School of Medicine. She trained in molecular virology in the Laboratory of Tumor Cell Biology at the NIH prior to establishing a research program at Mount Sinai School of Medicine in the molecular pathogenesis of HIV. At Mount Sinai, she also served as Chief of the Division of Infectious Diseases and Co-Director of Mount Sinai’s Global Health and Emerging Pathogens Institute.

Klotman and her collaborators have focused on the role of HIV in renal disease, demonstrating that HIV resides in and evolves separately in kidney cells, which is a critical step in HIV-associated kidney disease. These studies have established the kidney as a unique compartment for HIV. More recently, they have shown that direct cell contact between renal epithelial cells and T cells leads to efficient bidirectional spread of the virus. Her research group also has determined the role of soluble host factors involved in an innate immune response to HIV in an effort to improve prevention strategies.

Publication highlights

Chen P, Chen BK, Mosoian A, Hays T, Ross MJ, Klotman PE, Klotman ME. Virological synapses allow HIV-1 uptake and gene expression in renal tubular epithelial cells. J Am Soc Nephrol. 2011;22(3):496–507.

Mosoian A, Teixeira A, Burns CS, Sander LE, Gusella GL, He C, Blander JM, Klot-man P, Klotman ME. Prothymosin-α inhibits HIV-1 via Toll-like receptor 4-mediat-ed type I interferon induction. Proc Natl Acad Sci U S A. 2010;107(22):10178–10183.

Chang TL, Vargas J, DelPortillo A, Klotman ME. Dual role of α-defensin-1 in anti–HIV-1 innate immunity. J Clin Invest. 2005;115(3):765–773.

Winston JA, Bruggeman LA, Ross MD, Jacobson J, Ross L, D’Agati VD, Klotman PE, Klotman ME. Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N Engl J Med. 2001;344(26):1979–1984.

t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t A u g u s t 2 0 1 42

CardiologyRNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processingHenrike Maatz, Marvin Jens, Martin Liss, Sebastian Schafer, Matthias Heinig, Marieluise Kirchner, Eleonora Adami, Carola Rintisch, Vita Dauksaite, Michael H. Radke, Matthias Selbach, Paul J.R. Barton, Stuart A. Cook, Nikolaus Rajewsky, Michael Gotthardt, Markus Landthaler, and Norbert Hubner http://jci.me/74523

the vestigial enzyme D-dopachrome tautomerase protects the heart against ischemic injuryDake Qi, Kwame Atsina, Lintao Qu, Xiaoyue Hu, Xiaohong Wu, Bin Xu, Marta Piecychna, Lin Leng, Günter Fingerle-Rowson, Jiasheng Zhang, Richard Bucala, and Lawrence H. Young http://jci.me/73061

EndocrinologyAmyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetesJinyoung Kim, Hwanju Cheon, Yeon Taek Jeong, Wenying Quan, Kook Hwan Kim, Jae Min Cho, Yu-Mi Lim, Seung Hoon Oh, Sang-Man Jin, Jae Hyeon Kim, Moon-Kyu Lee, Sunshin Kim, Masaaki Komatsu, Sang-Wook Kang, and Myung-Shik Lee http://jci.me/69625

Human IAPP–induced pancreatic β cell toxicity and its regulation by autophagyNayumi Shigihara, Ayako Fukunaka, Akemi Hara, Koji Komiya, Akira Honda, Toyoyoshi Uchida, Hiroko Abe, Yukiko Toyofuku, Motoyuki Tamaki, Takeshi Ogihara, Takeshi Miyatsuka, Henry J. Hiddinga, Setsuya Sakagashira, Masato Koike, Yasuo Uchiyama, Tamotsu Yoshimori, Norman L. Eberhardt, Yoshio Fujitani, and Hirotaka Watada http://jci.me/69866

Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity

Jacqueline F. Rivera, Safia Costes, Tatyana Gurlo, Charles G. Glabe, and Peter C. Butler http://jci.me/71981

Related Commentary for all Endocrinology articles by Dhananjay gupta and Jack L. Leahy More on these articles , p. 12

GastroenterologyPediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature

Yael Haberman, Timothy L. Tickle, Phillip J. Dexheimer, Mi-Ok Kim, Dora Tang, Rebekah Karns, Robert N. Baldassano, Joshua D. Noe, Joel Rosh, James Markowitz, Melvin B. Heyman, Anne M. Griffiths, Wallace V. Crandall, David R. Mack, Susan S. Baker, Curtis Huttenhower, David J. Keljo, Jeffrey S. Hyams, Subra Kugathasan, Thomas D. Walters, Bruce Aronow, Ramnik J. Xavier, Dirk Gevers, and Lee A. Denson http://jci.me/75436

More, p. 10

Research articles in the current issue of the JCI

Amyloid accumulation

Altered microbiota in Crohn disease

Autophagy in β cells

t h e j o u r n a l o f c l i n i c a l i n v e s t i g a t i o n j c i . o r g / i m p a c t A u g u s t 2 0 1 4 3

Research articles in the current issue of the JCI

Hematologythe Rothmund-thomson syndrome helicase RECQL4 is essential for hematopoiesisMonique F. Smeets, Elisabetta DeLuca, Meaghan Wall, Julie M. Quach, Alistair M. Chalk, Andrew J. Deans, Jörg Heierhorst, Louise E. Purton, David J. Izon, and Carl R. Walkley http://jci.me/75334

Factor XIII activity mediates red blood cell retention in venous thrombiMaria M. Aleman, James R. Byrnes, Jian-Guo Wang, Reginald Tran, Wilbur A. Lam, Jorge Di Paola, Nigel Mackman, Jay L. Degen, Matthew J. Flick, and Alisa S. Wolberg http://jci.me/75386 More, p. 6

HepatologytAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesisSayaka Inokuchi-Shimizu, Eek Joong Park, Yoon Seok Roh, Ling Yang, Bi Zhang, Jingyi Song, Shuang Liang, Michael Pimienta, Koji Taniguchi, Xuefeng Wu, Kinji Asahina, William Lagakos, Mason R. Mackey, Shizuo Akira, Mark H. Ellisman, Dorothy D. Sears, Jerrold M. Olefsky, Michael Karin, David A. Brenner, and Ekihiro Seki http://jci.me/74068

Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARαYan Lu, Xing Liu, Yang Jiao, Xuelian Xiong, E Wang, Xiaolin Wang, Zhijian Zhang, Huijie Zhang, Lingling Pan, Youfei Guan, Dongsheng Cai, Guang Ning, and Xiaoying Li http://jci.me/74438

More, p. 11

ImmunologyChronic viral infection promotes sustained th1-derived immunoregulatory IL-10 via BLIMP-1Ian A. Parish, Heather D. Marshall, Matthew M. Staron, Philipp A. Lang, Anne Brüstle, Jonathan H. Chen, Weiguo Cui, Yao-Chen Tsui, Curtis Perry, Brian J. Laidlaw, Pamela S. Ohashi, Casey T. Weaver, and Susan M. Kaech http://jci.me/66108

Fragile tIM-4–expressing tissue resident macrophages are migratory and immunoregulatoryThomas B. Thornley, Zemin Fang, Savithri Balasubramanian, Rafael A. Larocca, Weihua Gong, Shipra Gupta, Eva Csizmadia, Nicolas Degauque, Beom Seok Kim, Maria Koulmanda, Vijay K. Kuchroo, and Terry B. Strom http://jci.me/73527 More, p. 10

HtLV-1 induces a th1-like state in CD4+CCR4+ t cellsNatsumi Araya, Tomoo Sato, Hitoshi Ando, Utano Tomaru, Mari Yoshida, Ariella Coler-Reilly, Naoko Yagishita, Junji Yamauchi, Atsuhiko Hasegawa, Mari Kannagi, Yasuhiro Hasegawa, Katsunori Takahashi, Yasuo Kunitomo, Yuetsu Tanaka, Toshihiro Nakajima, Kusuki Nishioka, Atae Utsunomiya, Steven Jacobson, and Yoshihisa Yamano http://jci.me/75250

MetabolismIncorporation of therapeutically modified bacteria into gut microbiota inhibits obesityZhongyi Chen, Lilu Guo, Yongqin Zhang, Rosemary L. Walzem, Julie S. Pendergast, Richard L. Printz, Lindsey C. Morris, Elena Matafonova, Xavier Stein, Li Kang, Denis Coulon, Owen P. McGuinness, Kevin D. Niswender, and Sean S. Davies http://jci.me/72517 More, p. 7

Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophyMarcelo A. Mori, Thomas Thomou, Jeremie Boucher, Kevin Y. Lee, Susanna Lallukka, Jason K. Kim, Martin Torriani, Hannele Yki-Järvinen, Steven K. Grinspoon, Aaron M. Cypess, and C. Ronald Kahn http://jci.me/73468

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Research articles in the current issue of the JCI

Muscle biologyKLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathyAnkit Garg, Jason O’Rourke, Chengzu Long, Jonathan Doering, Gianina Ravenscroft, Svetlana Bezprozvannaya, Benjamin R. Nelson, Nadine Beetz, Lin Li, She Chen, Nigel G. Laing, Robert W. Grange, Rhonda Bassel-Duby, and Eric N. Olson http://jci.me/74994 More, p. 11

NephrologyIntegrin-mediated type II tgF-β receptor tyrosine dephosphorylation controls sMAD-dependent profibrotic signalingXiwu Chen, Hongtao Wang, Hong-Jun Liao, Wen Hu, Leslie Gewin, Glenda Mernaugh, Sheng Zhang, Zhong-Yin Zhang, Lorenzo Vega-Montoto, Roberto M. Vanacore, Reinhard Fässler, Roy Zent, and Ambra Pozzi http://jci.me/71668

NeuroscienceExtrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damageFederico N. Soria, Alberto Pérez-Samartín, Abraham Martin, Kiran Babu Gona, Jordi Llop, Boguslaw Szczupak, Juan Carlos Chara, Carlos Matute, and María Domercq http://jci.me/71886

With related Commentary by Kathryn J. Reissner More, p. 7

Network modulation following sham surgery in Parkinson’s diseaseJi Hyun Ko, Andrew Feigin, Paul J. Mattis, Chris C. Tang, Yilong Ma, Vijay Dhawan, Matthew J. During, Michael G. Kaplitt, and David Eidelberg http://jci.me/75073

With related Commentary by Mariya V. Cherkasova and A. Jon stoessl More, p. 7

transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itchJoao M. Braz, Dina Juarez-Salinas, Sarah E. Ross, and Allan I. Basbaum http://jci.me/75214

Oncologythe deubiquitinase usP28 controls intestinal homeostasis and promotes colorectal cancerMarkus E. Diefenbacher, Nikita Popov, Sophia M. Blake, Christina Schülein-Völk, Emma Nye, Bradley Spencer-Dene, Laura A. Jaenicke, Martin Eilers, and Axel Behrens http://jci.me/73733

More, p. 9

Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endotheliumEverett J. Moding, Chang-Lung Lee, Katherine D. Castle, Patrick Oh, Lan Mao, Shan Zha, Hooney D. Min, Yan Ma, Shiva Das, and David G. Kirsch http://jci.me/73932

With related Commentary by Ester M. Hammond and Ruth J. Muschel More, p. 8

A phosphotyrosine switch determines the antitumor activity of ERβBin Yuan, Long Cheng, Huai-Chin Chiang, Xiaojie Xu, Yongjian Han, Hang Su, Lingxue Wang, Bo Zhang, Jing Lin, Xiaobing Li, Xiangyang Xie, Tao Wang, Rajeshwar R. Tekmal, Tyler J. Curiel, Zhi-Min Yuan, Richard Elledge, Yanfen Hu, Qinong Ye, and Rong Li http://jci.me/74085

More, p. 9

Liver fibrosis

USP28 in colon

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Research articles in the current issue of the JCI

Neurotrophic factor gDNF promotes survival of salivary stem cellsNan Xiao, Yuan Lin, Hongbin Cao, Davud Sirjani, Amato J. Giaccia, Albert C. Koong, Christina S. Kong, Maximilian Diehn, and Quynh-Thu Le http://jci.me/74096

With related Commentary by Adam swick and Randall J. Kimple More, p. 9

RAs interaction with PI3K p110α is required for tumor-induced angiogenesisMiguel Manuel Murillo, Santiago Zelenay, Emma Nye, Esther Castellano, Francois Lassailly, Gordon Stamp, and Julian Downward http://jci.me/74134

Pulmonologysystems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertensionThomas Bertero, Yu Lu, Sofia Annis, Andrew Hale, Balkrishen Bhat, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Sara O. Vargas, Brian B. Graham, Rahul Kumar, Stephen M. Black, Sohrab Fratz, Jeffrey R. Fineman, James D. West, Kathleen J. Haley, Aaron B. Waxman, B. Nelson Chau, Katherine A. Cottrill, and Stephen Y. Chan http://jci.me/74773

Reproductive biologyKisspeptin-54 triggers egg maturation in women undergoing in vitro fertilizationChanna N. Jayasena, Ali Abbara, Alexander N. Comninos, Gurjinder M.K. Nijher, Georgios Christopoulos, Shakunthala Narayanaswamy, Chioma Izzi-Engbeaya, Mathini Sridharan, Alexina J. Mason, Jane Warwick, Deborah Ashby, Mohammad A. Ghatei, Stephen R. Bloom, Anna Carby, Geoffrey H. Trew, and Waljit S. Dhillo http://jci.me/75730

With related Attending Physician by steven L. Young More, p. 10

TransplantationNon-self recognition by monocytes initiates allograft rejectionMartin H. Oberbarnscheidt, Qiang Zeng, Qi Li, Hehua Dai, Amanda L. Williams, Warren D. Shlomchik, David M. Rothstein, and Fadi G. Lakkis http://jci.me/74370

Virologytrace amounts of sporadically reappearing HCV RNA can cause infectionNaga Suresh Veerapu, Su-Hyung Park, Damien C. Tully, Todd M. Allen, and Barbara Rehermann http://jci.me/73104

More, p. 13

CDK9 inhibitor FIt-039 prevents replication of multiple DNA virusesMakoto Yamamoto, Hiroshi Onogi, Isao Kii, Suguru Yoshida, Kei Iida, Hiroyuki Sakai, Minako Abe, Toshiaki Tsubota, Nobutoshi Ito, Takamitsu Hosoya, and Masatoshi Hagiwara http://jci.me/73805

Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcomeEric G. Meissner, David Wu, Anu Osinusi, Dimitra Bon, Kimmo Virtaneva, Dan Sturdevant, Steve Porcella, Honghui Wang, Eva Herrmann, John McHutchison, Anthony F. Suffredini, Michael Polis, Stephen Hewitt, Ludmila Prokunina-Olsson, Henry Masur, Anthony S. Fauci, and Shyamasundaran Kottili http://jci.me/75938

Interferon-stimulated genes

miRs in pulmonary hypertension

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Venous thrombosis is characterized by clots with a high red blood cell (rbc) content. How rbc are incorporated has not been clear; how-ever, some models suggested that rbc are passively trapped during fibrin deposition. Alisa Wolberg and colleagues now provide evidence that coagulation factor XIII (FXIII) plays an active role in retaining rbc in clots and, consequently, clot size. Plasma FXIII is a heterotetramer consisting of two catalytic subunits (FXIII-A2) and two noncatalytic subunits (FXIII-B2). Following the initiation of clotting, thrombin promotes cleavage of FXIII-A2, which in turn acts to promote cross-linking among fibrin molecules in the clot. Using mice with a mutation in fibrinogen near the FXIII crosslinking site (Fibγ390–396A), the Wolberg team determined that these residues are critical for factor XIII activation and the rbc content of clots. Clots triggered in vivo and ex vivo had reduced retention of rbc, suggesting that rbc incorporation is an active rather than passive process. Blood from mice lacking FXIII-A as well as blood from a human patient deficient in FXIII similarly formed clots with decreased rbc content. Moreover, in vitro treatment of normal human blood with an inhibitor of the active FXIII enzyme resulted in smaller clots containing fewer rbc. Cumulatively, the authors’ work indicates that FXIII actively incorporates rbc in clots and suggests that targeting this enzyme may provide an effec-tive strategy for modulating clot formation. The accompanying artwork depicts fibrinogen and rbc in a clot. Image credit: Ash Conrad.

Caught in the act: factor XIII traps red blood cells in clots

Editor’s picksResearch

Factor XIII activity mediates red blood cell retention in venous thrombiMaria M. Aleman, James R. Byrnes, Jian-Guo Wang, Reginald Tran, Wilbur A. Lam, Jorge Di Paola, Nigel Mackman, Jay L. Degen, Matthew J. Flick, and Alisa S. Wolberg http://jci.me/75386

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Research | Editor’s picks

metabolism

neuroscience

A cystine/glutamate antiporter mediates ischemia-induced glutamate release

Glutamate is an excitatory neurotransmitter that has been linked to damage resulting from ischemic CNS injury. Ischemia causes energy failure and oxygen deprivation, which induce a loss of membrane potential in neurons and glia that is associated with a large glutamate-evoked inward current mediated by N-methyl-d-aspartate receptors (NMDARs). To identify mechanisms underlying altered glutamate homeostasis during ischemic episodes,

Federico Soria and colleagues monitored ischemia-induced currents after oxygen and glucose deprivation in cortical slices from rodents. They found that treatment with pharmacological inhibitors of a cystine/glutamate antiporter, SLC7A11, attenuated ischemia-induced glutamate currents. Additionally, Soria and colleagues demonstrated that glutamate release mediated by the cystine/glutamate antiporter activated extrasynaptic NMDARs, which mediated ischemic neuronal death. The image shows greater ischemic damage in the brains of WT mice (left) than in those of Slc7a11-deficient mice (right) subjected to oxygen and glucose deprivation (OGD).

Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damageFederico N. Soria, Alberto Pérez-Samartín, Abraham Martin, Kiran Babu Gona, Jordi Llop, Boguslaw Szczupak, Juan Carlos Chara, Carlos Matute, and María Domercq http://jci.me/71886

Related Commentarythe cystine/glutamate antiporter: when too much of a good thing goes badKathryn J. Reissner http://jci.me/76627

Sham-responsive brain networks in Parkinson’s diseasethe sham/placebo effect is a response to an inert intervention that the patient believes is therapeutic. Such effects can confound the evaluation of different therapies and are a particular problem in Parkinson’s disease (PD). Ji Hyun Ko and colleagues used 18F-fluorodeoxyglucose (FDG) and PET to identify a pattern of metabolic alterations, referred to as a network, in the brains of patients undergoing sham surgery as part of a gene therapy trial for PD. Expression of this network correlated with the sham subjects’ clinical outcomes under blinded conditions. The network changes reversed when the procedure was revealed to the subjects (and the investigators) to be a sham. Importantly, reported outcomes also correlated with baseline network expression levels, suggesting that this could be used as an objective measure to identify individuals who are more susceptible to the placebo effect under blinded conditions. In the accompanying Commentary, Mariya Cherkasova and Jon Stoessl discuss the significance of sham/placebo-responsive brain networks, particularly with regard to the design of clinical trials.

Network modulation following sham surgery in Parkinson’s diseaseJi Hyun Ko, Andrew Feigin, Paul J. Mattis, Chris C. Tang, Yilong Ma, Vijay Dhawan, Matthew J. During, Michael G. Kaplitt, and David Eidelberg http://jci.me/75073

Related CommentaryA brain network response to sham surgeryMariya V. Cherkasova and A. Jon Stoessl http://jci.me/77193

Designer bugs prevent obesity in micethe composition of the gut microbiota has been shown to directly influence metabolism and susceptibility to obesity. Bacteria in the gut synthesize a variety of molecules that influence host physiology. Zhongyi Chen, Lilu Guo, and colleagues hypothesized that introducing bacteria that synthesized anorexigenic lipids could reduce obesity in mice fed a high-fat diet. N-acylphosphatidylethanolamines (NAPEs) are precursors to highly anorexigenic N-acyl-ethanolamides (NAEs) that are normally

synthesized in the small intestine in response to feeding, but their synthesis is impaired by a high-fat diet. Chen, Guo, and colleagues found that mice provided with water containing NAPE-producing E. coli (E. coli Nissle 1917) had dramatically lower food intake, adiposity, insulin resistance, and hepatosteatosis compared with mice that received plain water or bacteria that did not produce NAPEs. Further, NAPE-expressing E. coli impaired weight gain in a polygenic mouse model of obesity. This study suggests that the

introduction of therapeutic bacteria could potentially treat metabolic disorders.

Incorporation of therapeutically modified bacteria into gut microbiota inhibits obesityZhongyi Chen, Lilu Guo, Yongqin Zhang, Rosemary L. Walzem, Julie S. Pendergast, Richard L. Printz, Lindsey C. Morris, Elena Matafonova, Xavier Stein, Li Kang, Denis Coulon, Owen P. McGuinness, Kevin D. Niswender, and Sean S. Davies http://jci.me/72517

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Research | Editor’s picks

Loss of ATM preferentially sensitizes tumor-associated endothelium to radiationRoughly 50% of cancer patients are treated with radiation therapy; however, toxicity can prevent delivery of sufficient radiation to eradicate some tumors. Endothelial cell–specific deletion of ataxia telangiectasia mutated (ATM), a kinase that participates in the DNA damage response, has previously been reported to impair the development of tumor vasculature and slow the growth of tumor xenografts. To determine how endothelial ATM contributes to primary tumor development and radiation response, Everett Moding and colleagues used a novel dual recombinase technology to generate a murine model of primary sarcoma with endothelial cell–specific deletion of Atm. In contrast to the study of

xenograft tumors, they found that Atm deletion in endothelial cells did not affect the development of tumor vasculature or growth of primary sarcomas. However, Atm deletion specifically radiosensitized proliferating endothelial cells in tumor vasculature, but not quiescent endothelial cells in the heart. The accompanying fluorescence molecular tomography image shows accumulation of a fluorescent blood pool imaging agent in sarcomas after radiation in a control mouse (left) and a mouse lacking endothelial ATM (right). In the accompanying Commentary, Ester Hammond and Ruth Muschel discuss how these findings could affect the development of radiosensitizing drugs.

Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endotheliumEverett J. Moding, Chang-Lung Lee, Katherine D. Castle, Patrick Oh, Lan Mao, Shan Zha, Hooney D. Min, Yan Ma, Shiva Das, and David G. Kirsch http://jci.me/73932

Related CommentaryRadiation and AtM inhibition: the heart of the matterEster M. Hammond and Ruth J. Muschel http://jci.me/77195

oncology

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Research | Editor’s picks

The deubiquitinase USP28 stabilizes c-MYC to promote colorectal tumorigenesis

Stem cell–derived GDNF promotes salivary gland recovery after radiationXerostomia, or severe dry mouth syndrome, results from damage to the salivary glands and can be caused by radiation for the treatment of head and neck cancers, iatrogenic effects of medications, or systemic diseases such as Sjögren syndrome. Nan Xiao and colleagues identified submandibular gland stem cells in adult mice that formed salispheres in vitro and restored salivation when transplanted into irradiated animals. The accompanying image shows incorporation of these stem cells into the secretory ducts of the submandibular gland. Gene expression analysis revealed that these cells express high levels of glial cell line–derived neurotrophic factor (GDNF). Importantly, GDNF rescued saliva production in irradiated mice, but did not protect differentiated submandibular gland cells against radiation-mediated damage. In the accompanying Commentary, Adam Swick and Randall Kimple discuss how GDNF could potentially be used to improve xerostomia treatment.

estrogen signaling in breast cancer cells is mediated by two receptors, ERα and ERβ, which have opposing effects on tumor cell proliferation. Because these receptors share considerable sequence homology, the mechanisms underlying their different activities are unclear. In this issue, Bin Yuan, Long Cheng, and colleagues demonstrate that in ERβ, phosphorylation of Y36, which is not conserved in ERα, is required for ERβ-dependent growth inhibition in tumor cells and murine breast cancer xenografts. ERβ Y36 phosphorylation was mediated by the c-ABL tyrosine kinase, while dephosphorylation was mediated by the tyrosine phosphatase EYA2. Importantly, elevated ERβ Y36 phosphorylation in patient breast cancer samples

was positively correlated with disease-free and overall survival. These findings indicate that ERβ Y36 phosphorylation could serve as a prognostic marker and therapeutic target in breast cancer.

A phosphotyrosine switch determines the antitumor activity of ERβBin Yuan, Long Cheng, Huai-Chin Chiang, Xiaojie Xu, Yongjian Han, Hang Su, Lingxue Wang, Bo Zhang, Jing Lin, Xiaobing Li, Xiangyang Xie, Tao Wang, Rajeshwar R. Tekmal, Tyler J. Curiel, Zhi-Min Yuan, Richard Elledge, Yanfen Hu, Qinong Ye, and Rong Li http://jci.me/74085

oncology

the majority of colorectal cancers are characterized by misregulation and overexpression of the tumorigenic protein c-MYC. Levels of c-MYC are controlled by the ubiquitin-proteasome system, which mediates the degradation of target proteins. Ubiquitination of c-MYC is mediated by the E3 ubiquitin ligase FBW7; however, ubiquitination is antagonized by the deubiquitinase USP28, which stabilizes c-MYC protein. In this issue, Markus Diefenbacher and colleagues examined the role of USP28 in a murine model of

colorectal cancer. They found that USP28 is expressed in intestinal crypt cells, where it promotes proliferation and stabilizes c-MYC, c-JUN, and NOTCH1. Usp28-deficient mice had fewer intestinal tumors, decreased tumor size, and longer lifespans compared with WT animals. Additionally, Usp28-deficient tumors exhibited decreased proliferation and greater differentiation. Importantly, USP28 was highly expressed in both human and murine colorectal tumors, which indicates that USP28 may be a potential therapeutic target in colorectal cancer.

the deubiquitinase usP28 controls intestinal homeostasis and promotes colorectal cancerMarkus E. Diefenbacher, Nikita Popov, Sophia M. Blake, Christina Schülein-Völk, Emma Nye, Bradley Spencer-Dene, Laura A. Jaenicke, Martin Eilers, and Axel Behrens http://jci.me/73733

Neurotrophic factor gDNF promotes survival of salivary stem cellsNan Xiao, Yuan Lin, Hongbin Cao, Davud Sirjani, Amato J. Giaccia, Albert C. Koong, Christina S. Kong, Maximilian Diehn, and Quynh-Thu Le http://jci.me/74096

Related CommentaryWetting the whistle: neurotropic factor improves salivary functionAdam Swick and Randall J. Kimple http://jci.me/77194

Turning on antitumor estrogen signaling in breast cancer

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Research | Editor’s picks

immunology gastroenterology

Macrophage subset promotes immunoregulation to prolong allograft survivalthe activity of tissue-resident macrophages plays a critical role in allograft survival by shaping the T cell repertoire that can mediate either tolerance or rejection. Thomas Thornley, Zemin Fang, and colleagues identified a subset of tissue-resident M2 macrophages that express high levels of the phosphatidylserine receptor TIM-4. These cells represented a significant portion of tissue-resident macrophages and exhibited immunoregulatory functions. Upon oxidative stress, TIM-4hi macrophages homed to lymph nodes, where they exhibited a hypostimulatory phenotype and preferentially induced antigen-stimulated Tregs that promoted allograft survival. Importantly, these cells were highly susceptible to apoptosis induced by oxidative stress, but were rendered resistant upon loss of Tim4. Using a murine cardiac transplant model, Thornley, Fang, and colleagues found that genetic ablation of Tim4 enhanced survival of this macrophage subset and prolonged allograft survival.

Fragile tIM-4–expressing tissue resident macrophages are migratory and immunoregulatoryThomas B. Thornley, Zemin Fang, Savithri Balasubramanian, Rafael A. Larocca, Weihua Gong, Shipra Gupta, Eva Csizmadia, Nicolas Degauque, Beom Seok Kim, Maria Koulmanda, Vijay K. Kuchroo, and Terry B. Strom http://jci.me/73527

Researchers define host-microbe interactions in pediatric inflammatory bowel diseasesthe inflammatory bowel diseases Crohn disease (CD) and ulcerative colitis (UC) are caused by a confluence of factors that alter the host mucosal immune system, including the host genetic background, environmental factors, and the microbiota. To help define the relationship between the host genetic background and the microbiota, Yael Haberman and colleagues characterized ileal gene expression and ileal microbial communities in 359 treatment-naive pediatric patients with UC and CD. Haberman and colleagues identified specific expression patterns for DUOX2 and APOA1 that were associated with increased oxidative stress and immune response polarization, which were positively correlated with the severity of mucosal injury. Additionally, abnormal DUOX2 expression was associated with expansion of Proteobacteria in UC and CD, while abnormal APOA1 expression in CD was associated with alterations in Firmicutes. Regression modeling using baseline APOA1 expression and microbial abundance was able to predict the 6-month clinical outcomes in CD.

Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signatureYael Haberman, Timothy L. Tickle, Phillip J. Dexheimer, Mi-Ok Kim, Dora Tang, Rebekah Karns, Robert N. Baldassano, Joshua D. Noe, Joel Rosh, James Markowitz, Melvin B. Heyman, Anne M. Griffiths, Wallace V. Crandall, David R. Mack, Susan S. Baker, Curtis Huttenhower, David J. Keljo, Jeffrey S. Hyams, Subra Kugathasan, Thomas D. Walters, Bruce Aronow, Ramnik J. Xavier, Dirk Gevers, and Lee A. Denson http://jci.me/75436

Administration of the fertility hormone kisspeptin-54 promotes egg maturation

reproductive biology

Kisspeptins are small peptide hormones that act via the hypothalamus to stimulate the release of luteinizing hormone, which is required for ovulation, thereby modulating fertility. Patients with mutations in the kisspeptin signaling pathway fail to undergo puberty and are infertile. In this issue, Channa Jayasena, Ali Abbara, and colleagues report on a human clinical trial in which kisspeptin-54 was used to trigger egg maturation in women undergoing in vitro fertilization therapy. After undergoing a procedure to induce ovulation, 53 women were treated with a single subcutaneous injection of kisspeptin-54 using a range of doses. Eggs were retrieved 36 hours after treatment, assessed for maturation, and fertilized in vitro, followed by transfer of 1 to 2 of the resulting embryos. Egg maturation was observed with each dose of kisspeptin-54, and pregnancy occurred in 23% of patients, indicating that pregnancy can occur following kisspeptin-54 administration. In the accompanying Attending Physician, Steven Young discusses how kisspeptin

and other peptide hormones could potentially be used to improve in vitro fertilization protocols.

Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilizationChanna N. Jayasena, Ali Abbara, Alexander N. Comninos, Gurjinder M.K. Nijher, Georgios Christopoulos, Shakunthala Narayanaswamy, Chioma Izzi-Engbeaya, Mathini Sridharan, Alexina J. Mason, Jane Warwick, Deborah Ashby, Mohammad A. Ghatei, Stephen R. Bloom, Anna Carby, Geoffrey Trew, and Waljit S. Dhillo http://jci.me/75730

Related Attending PhysicianA “kiss” before conception: triggering ovulation with kisspeptin-54 may improve IVFSteven L. Young http://jci.me/77196

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Research | Editor’s picks

Loss of sarcomere protein stability in nemaline myopathynemaline myopathy (nM) is a congenital neuromuscular disorder that is characterized by delayed motor development and muscle weakness in the limbs, face, throat, and trunk. The disorder has been linked to mutations in components of the sarcomere thin filament, the structure that mediates muscle contraction. NM is also associated with mutations in the BTB-BACK-kelch family proteins, including KLHL40, which has not been associated previously with the thin filament. In this issue, Ankit Garg and colleagues found that muscle-specific Klhl40 deficiency in mice results in an NM-like disorder, with muscle abnormalities that are highly similar to those seen in patients with KLHL40 mutations (see the accompanying image). Subsequent mechanistic investigations revealed that KLHL40 localizes

to the I and A bands of the sarcomere, in which it binds to the thin filament protein nebulin and a protein of unknown function, leiomodin 3 (LMOD3). KLHL40 stabilized both nebulin and LMOD3 and prevented ubiquitination of LMOD3. These results elucidate the pathogenic mechanisms of KLHL40 mutations in NM and suggest a role for LMOD3 in sarcomere function.

KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathyAnkit Garg, Jason O’Rourke, Chengzu Long, Jonathan Doering, Gianina Ravenscroft, Svetlana Bezprozvannaya, Benjamin R. Nelson, Nadine Beetz, Lin Li, She Chen, Nigel G. Laing, Robert W. Grange, Rhonda Bassel-Duby, and Eric N. Olson http://jci.me/74994

Periostin mediates triglyceride accumulation in fatty liver diseasenonalcoholic fatty liver disease (nAFlD), a condition strongly associated with obesity, is characterized by the accumulation of increased lipogenesis and fatty acid uptake in liver cells; however, the cellular mechanisms that drive this process are unclear. Yan Lu, Xing Liu, Yang Jiao, and colleagues found that the secreted cellular adhesion protein periostin is substantially upregulated in the livers of obese humans and rodents (see the accompanying image). Virus-mediated overexpression of periostin in mice promoted triglyceride accumulation in the liver and serum. Conversely, administration of periostin-targeted shRNA or a neutralizing antibody improved hepatosteatosis in obese mice. Lu and colleagues demonstrated that continuous glucose infusion stimulated periostin expression in liver, where it bound α6β4 integrin to stimulate JNK-mediated downregulation of PPARα expression. Decreased PPARα expression resulted in impaired fatty acid oxidation and triglyceride accumulation. These studies identify a previously unappreciated role for periostin in lipid metabolism and fatty liver disease, suggesting that it could serve as a therapeutic target in diseases characterized by dyslipidemia.

Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARαYan Lu, Xing Liu, Yang Jiao, Xuelian Xiong, E Wang, Xiaolin Wang, Zhijian Zhang, Huijie Zhang, Lingling Pan, Youfei Guan, Dongsheng Cai, Guang Ning, and Xiaoying Li http://jci.me/74438

Hepatology

muscle biology

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Research | Editor’s picks

Autophagy deficiency promotes amyloid accumulation and dysfunction in pancreatic β cellsone of the hallmarks of type 2 diabetes (t2D) is the accumulation of human islet amyloid polypeptide (hIAPP) in pancreatic β cells. This feature is not replicated in murine models of T2D, as mouse islet amyloid polypeptide does not form aggregates. Importantly, dysregulated autophagy, a cellular process that normally mediates clearance of dysfunctional organelles and damaged or aggregated proteins, has been linked to T2D pathogenesis. In this issue, three independent research groups examined the connection among T2D, dysregulated autophagy, and hIAPP accumulation. The research groups, which were led by Peter Butler, Yoshio Fujitani, and Myung-Shik Lee, developed murine models with

β cell–specific autophagy deficits that expressed hIAPP. In each model, the mutant mice developed an overt diabetic phenotype, and loss of autophagy, in combination with the expression of hIAPP, resulted in increased accumulation of hIAPP oligomers and increased β cell death. The accompanying image from the Butler lab shows oxidative damage in pancreatic β cells from WT (left) and autophagy-deficient, hIAPP-expressing (right) animals. In the accompanying Commentary, Dhananjay Gupta and Jack Leahy discuss how these three studies demonstrate that autophagy prevents the accumulation of hIAPP oligomers, which promote β cell dysfunction and death, thereby contributing to T2D pathogenesis.

endocrinology

A D V E R t I s E M E N t

Related ResearchAutophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicityJacqueline F. Rivera, Safia Costes, Tatyana Gurlo, Charles G. Glabe, and Peter C. Butler http://jci.me/71981

Human IAPP–induced pancreatic β cell toxicity and its regulation by autophagyNayumi Shigihara, Ayako Fukunaka, Akemi Hara, Koji Komiya, Akira Honda, Toyoyoshi Uchida, Hiroko Abe, Yukiko Toyofuku, Motoyuki Tamaki, Takeshi Ogihara, Takeshi Miyatsuka, Henry J. Hiddinga, Setsuya Sakagashira, Masato Koike, Yasuo Uchiyama, Tamotsu Yoshimori, Norman L. Eberhardt, Yoshio Fujitani, and Hirotaka Watada http://jci.me/69866

Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetesJinyoung Kim, Hwanju Cheon, Yeon Taek Jeong, Wenying Quan, Kook Hwan Kim, Jae Min Cho, Yu-Mi Lim, Seung Hoon Oh, Sang-Man Jin, Jae Hyeon Kim, Moon-Kyu Lee, Sunshin Kim, Masaaki Komatsu, Sang-Wook Kang, and Myung-Shik Lee http://jci.me/69625

Related CommentaryIslet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification?Dhananjay Gupta and Jack L. Leahy http://jci.me/77506

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Research | Features

Napoleone Ferrara

conversations with giants in medicine

Angiogenesis plays a critical role in both normal development and disease, including various forms of cancer and neovascular eye disease. In 1989, Napoleone Ferrara and his colleagues at Genentech purified VEGF, a potent

regulator of angiogenesis and vasculogenesis. Ferrara went on to demonstrate that VEGF is necessary and sufficient to stimulate vascular endothelial cell proliferation and blood vessel growth in rodents. He then developed an antibody that blocked the activity of VEGF and inhibited the growth of tumor xenografts in mice, opening the door to the clinical use of anti-VEGF compounds. VEGF-targeting antibodies are now approved for the treatment of metastatic colorectal cancer

and wet age-related macular edema. In this issue, Ferrara discusses his childhood and early medical training in Italy, his early neuroendocrinology research in Richard Weiner’s lab at UCSF, and his groundbreaking work on VEGF.

http://jci.me/77540

virology

Chronic infection with hepatitis C virus (hCV) is the leading cause of liver inflammation, cirrhosis, and cancer. Successful treatment with pegylated IFN-α/ribavirin is defined by the absence of detectable virus 6 months after the cessation of treatment. Although a later virological relapse is exceedingly rare, there are documented cases in which viral RNA, detectable only by sensitive PCR and below the detection limit of quantitative assays, reappears in treatment responders. In this issue, Naga

Suresh Veerapu, Su-Hyung Park, and colleagues assessed the ability of trace levels of viral RNA to transmit HCV infection. The authors infused three chimpanzees with cryopreserved plasma or peripheral blood mononuclear cells from treatment responders who tested positive for trace amounts of HCV RNA. All three animals generated HCV-specific T cells. One of the three chimpanzees developed decreased HCV-specific T cell counts followed by high-level systemic viremia after 27 weeks. These results

demonstrate that HCV RNA from successfully treated patients can be infectious and that transmission can be masked for several months in the recipient by an extended eclipse phase prior to establishing high-level viremia.

trace amounts of sporadically reappearing HCV RNA can cause infectionNaga Suresh Veerapu, Su-Hyung Park, Damien C. Tully, Todd M. Allen, and Barbara Rehermann http://jci.me/73104

Hepatitis C virus infection from trace amounts of viral RNA

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