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Estrogen’s role in binge eating 7

The immune system in hypertension 7

Mesothelial cells promote metastasis 9

Review series: Gut microbiome edited by Martin J. Blaser 10

A summary of this month’s Journal of Clinical investigation

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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 o c t o b e r 2 0 1 4 1

editorHoward A. Rockman

Deputy editorsGarnett Kelsoe, Bryan L. Roth

Associate editorsSoman N. Abraham, Vann Bennett,Gerard C. 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, Jonathan S. Serody, Norman Sharpless, Yiping Yang

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

Asia editorDavid M. Virshup

Chair, executive CouncilRobert J. Lefkowitz

BiostatisticiansCynthia Coffman, Barry Moser, Maren Olsen

BioethicistArthur L. Caplan

senior science editorSarah C. Jackson

science editorJillian Hurst

Assistant science editorCorinne 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.

Impactoctober 2014

Contact the JCiThe Journal of Clinical Investigation2015 Manchester RoadAnn Arbor, Michigan 48104, USAPhone: 734.222.6050E-mail: staff@the-jci.org

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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

Paul Noble, M.D., Associate editor, is Professor and Chair of the Department of Medicine and Director of the Women’s Guild Lung Institute at Cedars-Sinai Medical Center. He was previously a Professor and Chief of the Division of Pul-monary, Allergy, and Critical Care Medicine at Duke University. His clinical areas of expertise are interstitial lung disease, connective tissue disease–related pulmonary disease, and bron-chiolitis, and his group conducts clinical trials in idiopathic pulmonary fibrosis. The Noble lab’s research centers on cellular and molecular mechanisms of lung inflammation and fibrosis,

with a focus on the extracellular matrix glycosaminoglycan hyaluronan, the role of lung stem cells in pulmonary fibrosis, and the role of host defense in non-infectious lung inflammation and fibrosis. Some of his recent work on the development of lung fibrosis demonstrated that β-arrestin, CD44, and hyaluro-nan signaling is necessary for fibroblasts to invade tissue, suggesting a possible therapeutic target to combat fibrosis. Dr. Noble is a member of the American Society for Clinical Investigation and the Association of American Physicians.

Publication highlights

Lovgren A, Kovacs J, Xie T, Liang C, Meltzer E, Jiang D, Lefkowitz R, Noble PW. β-Arrestin deficiency protects against pulmonary fibrosis and prevents fibroblast invasion of extracellular matrix. Sci Transl Med. 2011;3(74):74ra23.

King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 tiral of pirfenidone in patients with idiopathoic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083–2092.

Jiang D, Liang C, Tager A, Camanella G, Luster AD, Noble PW. Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4. J Clin Invest. 2010;120(6):2049–2057.

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Research articles in the current issue of the JCI

AIDS/HIVHeme oxygenase-1 deficiency accompanies neuropathogenesis of HIV-associated neurocognitive disordersAlexander J. Gill, Colleen E. Kovacsics, Stephanie A. Cross, Patricia J. Vance, Lorraine L. Kolson, Kelly L. Jordan-Sciutto, Benjamin B. Gelman, and Dennis L. Kolson http://jci.me/72279

EndocrinologySorcS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cellsMelkam A. Kebede, Angie T. Oler, Trillian Gregg, Allison J. Balloon, Adam Johnson, Kelly Mitok, Mary Rabaglia, Kathryn Schueler, Donald Stapleton, Candice Thorstenson, Lindsay Wrighton, Brendan J. Floyd, Oliver Richards, Summer Raines, Kevin Eliceiri, Nabil G. Seidah, Christopher Rhodes, Mark P. Keller, Joshua L. Coon, Anjon Audhya, and Alan D. Attie http://jci.me/74072

Maternal diet–induced microrNAs and mtor underlie β cell dysfunction in offspringEmilyn U. Alejandro, Brigid Gregg, Taylor Wallen, Doga Kumusoglu, Daniel Meister, Angela Chen, Matthew J. Merrins, Leslie S. Satin, Ming Liu, Peter Arvan, and Ernesto Bernal-Mizrachi http://jci.me/74237

the arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight lossAnna Secher, Jacob Jelsing, Arian F. Baquero, Jacob Hecksher-Sørensen, Michael A. Cowley, Louise S. Dalbøge, Gitte Hansen, Kevin L. Grove, Charles Pyke, Kirsten Raun, Lauge Schäffer, Mads Tang-Christensen, Saurabh Verma, Brent M. Witgen, Niels Vrang, and Lotte Bjerre Knudsen http://jci.me/75276

With related commentary by Laurie L. baggio and Daniel J. Drucker More, p. 9

HematologySyntaxin-binding protein StXbP5 inhibits endothelial exocytosis and promotes platelet secretionQiuyu Zhu, Munekazu Yamakuchi, Sara Ture, Maria de la Luz Garcia-Hernandez, Kyung Ae Ko, Kristina L. Modjeski, Michael B. LoMonaco, Andrew D. Johnson, Christopher J. O’Donnell, Yoshimi Takai, Craig N. Morrell, and Charles J. Lowenstein http://jci.me/71245

With related commentary by David Lillicrap More, p. 8

Platelet secretion and hemostasis require syntaxin-binding protein StXbP5Shaojing Ye, Yunjie Huang, Smita Joshi, Jinchao Zhang, Fanmuyi Yang, Guoying Zhang, Susan S. Smyth, Zhenyu Li, Yoshimi Takai, and Sidney W. Whiteheart http://jci.me/75572

With related commentary by David Lillicrap More, p. 8STXBP5 in platelets

SORCS1-deficient islets

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Research articles in the current issue of the JCI

Plasma fibronectin supports hemostasis and regulates thrombosisYiming Wang, Adili Reheman, Christopher M. Spring, Jalil Kalantari, Alexandra H. Marshall, Alisa S. Wolberg, Peter L. Gross, Jeffrey I. Weitz, Margaret L. Rand, Deane F. Mosher, John Freedman, and Heyu Ni http://jci.me/74630

Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria

Wenyi Shen, Michael J. Clemente, Naoko Hosono, Kenichi Yoshida, Bartlomiej Przychodzen, Tetsuichi Yoshizato, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa, Jaroslaw P. Maciejewski, and Hideki Makishima http://jci.me/74747

With related commentary by Stanley chun-Wei Lee and omar Abdel-Wahab More, p. 8

Disposable platform provides visual and color-based point-of-care anemia self-testingErika A. Tyburski, Scott E. Gillespie, William A. Stoy, Robert G. Mannino, Alexander J. Weiss, Alexa F. Siu, Rayford H. Bulloch, Karthik Thota, Anyela Cardenas, Wilena Session, Hanna J. Khoury, Siobhán O’Connor, Silvia T. Bunting, Jeanne Boudreaux, Craig R. Forest, Manila Gaddh, Traci Leong, L. Andrew Lyon, and Wilbur A. Lam http://jci.me/76666

tMeM14c is required for erythroid mitochondrial heme metabolismYvette Y. Yien, Raymond F. Robledo, Iman J. Schultz, Naoko Takahashi-Makise, Babette Gwynn, Daniel E. Bauer, Abhishek Dass, Gloria Yi, Liangtao Li, Gordon J. Hildick-Smith, Jeffrey D. Cooney, Eric L. Pierce, Kyla Mohler, Tamara A. Dailey, Non Miyata, Paul D. Kingsley, Caterina Garone, Shilpa M. Hattangadi, Hui Huang, Wen Chen, Ellen M. Keenan, Dhvanit I. Shah, Thorsten M. Schlaeger, Salvatore DiMauro, Stuart H. Orkin, Alan B. Cantor, James Palis, Carla M. Koehler, Harvey F. Lodish, Jerry Kaplan, Diane M. Ward, Harry A. Dailey, John D. Phillips, Luanne L. Peters, and Bary H. Paw http://jci.me/76979

ImmunologyMast cells aggravate sepsis by inhibiting peritoneal macrophage phagocytosisAlbert Dahdah, Gregory Gautier, Tarik Attout, Frédéric Fiore, Emeline Lebourdais, Rasha Msallam, Marc Daëron, Renato C. Monteiro, Marc Benhamou, Nicolas Charles, Jean Davoust, Ulrich Blank, Bernard Malissen, and Pierre Launay http://jci.me/75212

cD45 ligation expands tregs by promoting interactions with DcsGeoffrey Camirand, Ying Wang, Yuning Lu, Yisong Y. Wan, Yan Lin, Songyan Deng, Galip Guz, David L. Perkins, Patricia W. Finn, Donna L. Farber, Richard A. Flavell, Warren D. Shlomchik, Fadi G. Lakkis, Christopher E. Rudd, and David M. Rothstein http://jci.me/74087

tGF-β prevents t follicular helper cell accumulation and b cell autoreactivityMark J. McCarron and Julien C. Marie http://jci.me/76179

cSF-1–dependant donor-derived macrophages mediate chronic graft-versus-host diseaseKylie A. Alexander, Ryan Flynn, Katie E. Lineburg, Rachel D. Kuns, Bianca E. Teal, Stuart D. Olver, Mary Lor, Neil C. Raffelt, Motoko Koyama, Lucie Leveque, Laetitia Le Texier, Michelle Melino, Kate A. Markey, Antiopi Varelias, Christian Engwerda, Jonathan S. Serody, Baptiste Janela, Florent Ginhoux, Andrew D. Clouston, Bruce R. Blazar, Geoffrey R. Hill, and Kellie P.A. MacDonald http://jci.me/75935

Proteinase 3–dependent caspase-3 cleavage modulates neutrophil death and inflammationFabien Loison, Haiyan Zhu, Kutay Karatepe, Anongnard Kasorn, Peng Liu, Keqiang Ye, Jiaxi Zhou, Shannan Cao, Haiyan Gong, Dieter E. Jenne, Eileen Remold-O’Donnell, Yuanfu Xu, and Hongbo R. Luo http://jci.me/76246

cD4+ and cD8+ t cell–dependent antiviral immunity requires StIM1 and StIM2Patrick J. Shaw, Carl Weidinger, Martin Vaeth, Kevin Luethy, Susan M. Kaech, and Stefan Feske http://jci.me/76602

Cutaneous fibrosis

Plasma fibronectin-fibrin network

Macrophage phagocytosis

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Research articles in the current issue of the JCI

ImmunologyDc isoketal-modified proteins activate t cells and promote hypertensionAnnet Kirabo, Vanessa Fontana, Ana P.C. de Faria, Roxana Loperena, Cristi L. Galindo, Jing Wu, Alfiya T. Bikineyeva, Sergey Dikalov, Liang Xiao, Wei Chen, Mohamed A. Saleh, Daniel W. Trott, Hana A. Itani, Antony Vinh, Venkataraman Amarnath, Kalyani Amarnath, Tomasz J. Guzik, Kenneth E. Bernstein, Xiao Z. Shen, Yu Shyr, Sheau-chiann Chen, Raymond L. Mernaugh, Cheryl L. Laffer, Fernando Elijovich, Sean S. Davies, L. Heitor Moreno, Meena S. Madhur, Jackson Roberts II, and David G. Harrison http://jci.me/74084

With related commentary by Jordan S. Pober More, p. 7

Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defensesOle E. Sørensen, Stine N. Clemmensen, Sara L. Dahl, Ole Østergaard, Niels H. Heegaard, Andreas Glenthøj, Finn Cilius Nielsen, and Niels Borregaard http://jci.me/76009

With related commentary by William M. Nauseef More, p. 7

Infectious diseaseLongistatin in tick saliva blocks advanced glycation end-product receptor activationAnisuzzaman, Takeshi Hatta, Takeharu Miyoshi, Makoto Matsubayashi, M. Khyrul Islam, M. Abdul Alim, M. Abu Anas, M. Mehedi Hasan, Yasunobu Matsumoto, Yasuhiko Yamamoto, Hiroshi Yamamoto, Kozo Fujisaki, and Naotoshi Tsuji http://jci.me/74917

More, p. 9

InflammationPeptide-sirNA nanocomplexes targeting NF-κb subunit p65 suppress nascent experimental arthritisHui-fang Zhou, Huimin Yan, Hua Pan, Kirk K. Hou, Antonina Akk, Luke E. Springer, Ying Hu, J. Stacy Allen, Samuel A. Wickline, Christine T.N. Pham http://jci.me/75673

Muscle biologyHuman satellite cells have regenerative capacity and are genetically manipulableAndreas Marg, Helena Escobar, Sina Gloy, Markus Kufeld, Joseph Zacher, Andreas Spuler, Carmen Birchmeier, Zsuzsanna Izsvák, and Simone Spuler http://jci.me/63992

Neuroscienceestrogens stimulate serotonin neurons to inhibit binge-like eating in miceXuehong Cao, Pingwen Xu, Mario G. Oyola, Yan Xia, Xiaofeng Yan, Kenji Saito, Fang Zou, Chunmei Wang, Yongjie Yang, Antentor Hinton Jr., Chunling Yan, Hongfang Ding, Liangru Zhu, Likai Yu, Bin Yang, Yuxin Feng, Deborah J. Clegg, Sohaib Khan, Richard DiMarchi, Shaila K. Mani, Qingchun Tong, and Yong Xu http://jci.me/74726

More, p. 7

Neurotrophin receptor p75Ntr mediates Huntington’s disease–associated synaptic and memory dysfunctionVerónica Brito, Albert Giralt, Lilian Enriquez-Barreto, Mar Puigdellívol, Nuria Suelves, Alfonsa Zamora-Moratalla, Jesús J. Ballesteros, Eduardo D. Martín, Nuria Dominguez-Iturza, Miguel Morales, Jordi Alberch, and Sílvia Ginés http://jci.me/74809

Neutrophil extracellular traps

Muscle satellite cells

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Research articles in the current issue of the JCI

Deranged NMDAergic cortico-subthalamic transmission underlies parkinsonian motor deficitsMing-Kai Pan, Chun Hwei Tai, Wen-Chuan Liu, Ju-Chun Pei, Wen-Sung Lai, and Chung-Chin Kuo http://jci.me/75587

OncologyMesothelial cells promote early ovarian cancer metastasis through fibronectin secretionHilary A. Kenny, Chun-Yi Chiang, Erin A. White, Elizabeth M. Schryver, Mohammed Habis, Iris L. Romero, Andras Ladanyi, Carla V. Penicka, Joshy George, Karl Matlin, Anthony Montag, Kristen Wroblewski, S. Diane Yamada, Andrew P. Mazar, David Bowtell, and Ernst Lengyel http://jci.me/74778

More, p. 9

endothelial deficiency of L1 reduces tumor angiogenesis and promotes vessel normalizationElena Magrini, Alessandra Villa, Francesca Angiolini, Andrea Doni, Giovanni Mazzarol, Noemi Rudini, Luigi Maddaluno, Mina Komuta, Baki Topal, Hans Prenen, Melitta Schachner, Stefano Confalonieri, Elisabetta Dejana, Fabrizio Bianchi, Massimiliano Mazzone, and Ugo Cavallaro http://jci.me/70683

b7-H1–expressing antigen-presenting cells mediate polarization of protumorigenic th22 subsetsDong-Ming Kuang, Xiao Xiao, Qiyi Zhao, Min-Min Chen, Xue-Feng Li, Rui-Xian Liu, Yuan Wei, Fang-Zhu Ouyang, Dong-Ping Chen, Yan Wu, Xiang-Ming Lao, Hong Deng, and Limin Zheng http://jci.me/74381

MicrorNA-182 drives metastasis of primary sarcomas by targeting multiple genes

Mohit Sachdeva, Jeffrey K. Mito, Chang-Lung Lee, Minsi Zhang, Zhizhong Li, Rebecca D. Dodd, David Cason, Lixia Luo, Yan Ma, David Van Mater, Rebecca Gladdy, Dina C. Lev, Diana M. Cardona, and David G. Kirsch http://jci.me/77116

mir-33a promotes glioma-initiating cell self-renewal via PKA and NotcH pathwaysHui Wang, Tao Sun, Jing Hu, Rui Zhang, Yanhua Rao, Shuai Wang, Rui Chen, Roger E. McLendon, Allan H. Friedman, Stephen T. Keir, Darell D. Bigner, Qi-Jing Li, Huibo Wang, and Xiao-Fan Wang http://jci.me/75284

Stem cellstransient vascularization of transplanted human adult–derived progenitors promotes self-organizing cartilageTakanori Takebe, Shinji Kobayashi, Hiromu Suzuki, Mitsuru Mizuno, Yu-Min Chang, Emi Yoshizawa, Masaki Kimura, Ayaka Hori, Jun Asano, Jiro Maegawa, and Hideki Taniguchi http://jci.me/76443

Vascular biologytargeting Ve-PtP activates tIe2 and stabilizes the ocular vasculatureJikui Shen, Maike Frye, Bonnie L. Lee, Jessica L. Reinardy, Joseph M. McClung, Kun Ding, Masashi Kojima, Huiming Xia, Christopher Seidel, Raquel Lima e Silva, Aling Dong, Sean F. Hackett, Jiangxia Wang, Brian W. Howard, Dietmar Vestweber, Christopher D. Kontos, Kevin G. Peters, and Peter A. Campochiaro http://jci.me/74527

Protein kinase LKb1 promotes rAb7-mediated neuropilin-1 degradation to inhibit angiogenesisImoh S. Okon, Kathleen A. Coughlan, Cheng Zhang, Cate Moriasi, Ye Ding, Ping Song, Wencheng Zhang, Guangpu Li, and Ming-Hui Zou http://jci.me/75371

A lymphatic defect causes ocular hypertension and glaucoma in miceBenjamin R. Thomson, Stefan Heinen, Marie Jeansson, Asish K. Ghosh, Anees Fatima, Hoon-Ki Sung, Tuncer Onay, Hui Chen, Shinji Yamaguchi, Aris N. Economides, Ann Flenniken, Nicholas W. Gale, Young-Kwon Hong, Amani Fawzi, Xiaorong Liu, Tsutomu Kume, and Susan E. Quaggin http://jci.me/77162

Mesothelial matrix secretion

CD34-stained hepatoma

Human cartilage progenitors

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While many changes have taken place in the Journal since its launch 90 years ago, a common thread has remained as to its core mission: to serve as a platform to communicate discoveries that provide insight into the mechanisms of disease. In 1924, the Journal published 32 papers, accepting the vast majority of submissions. In the last 12 months, we received ~4,500 manuscripts, published 389, with an acceptance rate of 8%. While medical research and scientific publishing have been remarkably trans-formed in the intervening years, I’d like to focus on key aspects of the Journal: the science we publish and the peer review process. To determine causa-tion in mechanistic studies, many papers published in the JCI take advantage of the power of mouse genetic models. However, true to our early roots of publishing clinical studies, we recently launched the Clinical Medicine category to publish human clinical trials that have the potential to change the practice of medicine. The peer review process has also evolved at the Journal through the years. Since 1942, peer review has been a staple of our editorial adjudicative process. In recent years, though, the revisions re-quested by reviewers have vastly increased. To coun-teract this trend, we’ve made changes to our policies to limit requests by reviewers for experimentation that does not appreciably affect the paper’s conclu-sion. With these changes and others implemented, we hope that the JCI remains at the forefront of bio-medical publishing while staying true to the mission set forth by our pioneering founders and maintained over the last 90 years by our 23 Editors and 18 Edito-rial Boards in thousands of papers.

Howard A. Rockman,Editor in Chief

To read Dr. Rockman’s full editorial, see http://jci.me/78708

Happy Birthday JCI

Editor’s picksresearch

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Research | Editor’s picks

Papillon-Lefèvre syndrome patient provides insight into neutrophil-mediated defensePapillon-lefèvre syndrome (Pls) is a rare autosomal recessive genetic disorder caused by mutations in the cathepsin C–encoding gene CTSC and is characterized by periodontitis and abnormal thickening of the palms and soles. In this issue, Ole Sørensen and colleagues describe a PLS patient suffering from severe periodontal disease. Exomic sequencing revealed a homozygous mutation in CTSC, and granules isolated from the patient’s neutrophils were deficient in several serine proteases, including neutrophil elastase (NE), which is believed to play a critical role in immunity due to its role in the formation of neutrophil extracellular traps (NETs). Despite the lack of NE and NET formation, the immunodeficiency exhibited by the patient was very mild, particularly compared with that of NE-deficient mice, which exhibit a much more severe phenotype. These results indicate that NET formation is not a major antimicrobial defense mechanism. In the accompanying Commentary, William Nauseef discusses how these findings shed light on the function of serine proteases in neutrophils, particularly with regard to antimicrobial activity and host defense.

Papillon-Lefèvre syndrome patient reveals species-dependent requirements for neutrophil defensesOle E. Sørensen, Stine N. Clemmensen, Sara L. Dahl, Ole Østergaard, Niels H. Heegaard, Andreas Glenthøj, Finn Cilius Nielsen, and Niels Borregaard http://jci.me/76009

related commentaryProteases, neutrophils, and periodontitis: the Net effectWilliam M. Nauseef http://jci.me/77985

immunology

Researchers localize estrogen’s effects on binge eatingneuroscience

The autoimmune response in hypertensiont cells contribute to hypertension, inflammation, and end-organ damage. As DCs process and present antigens to activate T cells, Annet Kirabo and colleagues examined how DCs contribute to T cell activation in hypertension. Hypertensive stimuli increased ROS production in DCs, leading to isoketals, oxidized products of arachidonic acid that adduct proteins. These modified self-proteins are presented as self-antigens, activating T cells to generate an autoimmune response. Administration of isoketal-activated DCs in WT mice increased blood pressure in a T cell–dependent manner, while administration of isoketal scavengers lowered blood pressure. Moreover, plasma F2-isoprostanes, which are formed in concert with isoketals, were elevated in hypertensive patients. In the accompanying Commentary, Jordan Pober discusses how these findings support a role for autoimmunity in hypertension.

DC isoketal-modified proteins activate T cells and promote hypertensionAnnet Kirabo, Vanessa Fontana, Ana P.C. de Faria, Roxana Loperena, Cristi L. Galindo, Jing Wu, Alfiya T. Bikineyeva, Sergey Dikalov, Liang Xiao, Wei Chen, Mohamed A. Saleh, Daniel W. Trott, Hana A. Itani, Antony Vinh, Venkataraman Amarnath, Kalyani Amarnath, Tomasz J. Guzik, Kenneth E. Bernstein, Xiao Z. Shen, Yu Shyr, Sheau-chiann Chen, Raymond L. Mernaugh, Cheryl L. Laffer, Fernando Elijovich, Sean S. Davies, L. Heitor Moreno, Meena S. Madhur, Jackson Roberts II, and David G. Harrison http://jci.me/74084

related commentaryIs hypertension an autoimmune disease?Jordan S. Pober http://jci.me/77766

Binge eating, which is strongly associated with eating disorders, is more prevalent in women, inversely correlated with circulating levels of 17β-estradiol, and is a phenotype in ovariectomized mice. Yong Xu and colleagues found that estrogen replacement therapy attenuated binge eating in ovariectomized mice and that this effect was mediated by the estrogen receptor-α (ERα) in serotonergic neurons of the dorsal raphe nuclei (DRN). Moreover, Cao and colleagues demonstrated that systemic administration of a glucagon-like peptide-1–estrogen (GLP-1–estrogen) conjugate, a new compound that has been shown to avoid side effects commonly associated with estrogen therapy (e.g., breast cancer), substantially suppresses binge eating. These data identify the mechanism by which estrogen suppresses

binge eating in mice and indicate that DRN ERα is a potential therapeutic target for the treatment of binge eating–associated disorders.

estrogens stimulate serotonin neurons to inhibit binge-like eating in miceXuehong Cao, Pingwen Xu, Mario G. Oyola, Yan Xia, Xiaofeng Yan, Kenji Saito, Fang Zou, Chunmei Wang, Yongjie Yang, Antentor Hinton Jr., Chunling Yan, Hongfang Ding, Liangru Zhu, Likai Yu, Bin Yang, Yuxin Feng, Deborah J. Clegg, Sohaib Khan, Richard DiMarchi, Shaila K. Mani, Qingchun Tong, and Yong Xu http://jci.me/74726

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Research | Editor’s picks

STXBP5 modulates platelet and endothelial cell exocytosis

Abnormalities of vWF, which regulates coagulation and influences blood flow and vessel wall characteristics, have been linked to venous thrombosis and defective hemostasis. Syntaxin-binding protein 5 (STXBP5), which participates in the docking and fusion of exocytic vesicles, has recently been identified as a factor affecting vWF plasma levels. In this issue, two independent groups of researchers led by Charles Lowenstein and Sidney Whiteheart demonstrate that STXBP5 plays a critical role in the function of endothelial cells and platelets. The Lowenstein group demonstrated that STXBP5 inhibits exocytosis in human endothelial cells,

reducing secretion of vWF and the adhesion factor P-selectin; additionally, mice lacking Stxbp5 had higher plasma levels of vWF, greater platelet–endothelial cell interaction (see accompanying image), and hemostasis defects. The Whiteheart group found that Stxbp5-deficient murine platelets exhibited decreased granule secretion and granule cargo levels, which are required for clotting; moreover, Stxbp5 KO mice exhibited defective hemostasis. In the accompanying Commentary, David Lillicrap discusses how these studies reveal a differential role for STXBP5 in endothelial cells and platelets and how it influences vascular disease.

related researchSyntaxin-binding protein StXbP5 inhibits endothelial exocytosis and promotes platelet secretionQiuyu Zhu, Munekazu Yamakuchi, Sara Ture, Maria de la Luz Garcia-Hernandez, Kyung Ae Ko, Kristina L. Modjeski, Michael B. LoMonaco, Andrew D. Johnson, Christopher J. O’Donnell, Yoshimi Takai, Craig N. Morrell, and Charles J. Lowenstein http://jci.me/71245

Platelet secretion and hemostasis require syntaxin-binding protein StXbP5Shaojing Ye, Yunjie Huang, Smita Joshi, Jinchao Zhang, Fanmuyi Yang, Guoying Zhang, Susan S. Smyth, Zhenyu Li, Yoshimi Takai, and Sidney W. Whiteheart http://jci.me/75572

related commentarySyntaxin-binding protein 5 exocytosis regulation: differential role in endothelial cells and plateletsDavid Lillicrap http://jci.me/77511

Paroxysmal nocturnal hemoglobinuria (Pnh) is a rare form of hemolytic anemia. PNH is thought to be driven by acquired phosphatidylinositol glycan A (PIGA) mutations in hematopoietic stem cells (HSCs), which may confer a growth advantage. In order to delineate the HSC mutations that underlie PNH pathogenesis, Wenyi Shen and colleagues performed whole-exome sequencing in paired PNH+ and PNH– bone marrow fractions from PNH patients. They identified multiple somatic mutations, including genes such as TET2, SUZ12, JAK2, and U2AF1, which are frequently found in my-eloid neoplasms. Importantly, many of these mutations arose in subclones of PIGA mutant populations or prior to the acquisition of PIGA mutations. In the accompanying Commentary, Omar Abdel-Wahab and Stanley Chun-Wei Lee discuss how these findings demonstrate that PNH has a complex hierarchical clonal architecture.

Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuriaWenyi Shen, Michael J. Clemente, Naoko Hosono, Kenichi Yoshida, Bartlomiej Przychodzen, Tetsuichi Yoshizato, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa, Jaroslaw P. Maciejewski, and Hideki Makishima http://jci.me/74747

related commentarythe mutational landscape of paroxysmal nocturnal hemoglobinuria revealed: new insights into clonal dominanceStanley Chun-Wei Lee and Omar Abdel-Wahab http://jci.me/77984

Stepwise acquisition of mutations underlies paroxysmal nocturnal hemoglobinuria

hematology

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Research | Editor’s picks

Diabetes drug liraglutide induces weight loss via the arcuate nucleusliraglutide, a glucagon-like peptide-1 receptor (GlP-1R) agonist, is a type 2 diabetes drug that lowers blood glucose and reduces body weight. Liraglutide is being investigated for the treatment of obesity; however, the mechanism of action underlying weight loss is not clear. In this issue, Anna Secher, Jacob Jelsing, and colleagues found that fluorescently labeled liraglutide bound neurons in the arcuate nucleus as well as other discrete regions of the hypothalamus in rats. Uptake was abolished in the absence of GLP-1R expression. Within the arcuate nucleus, GLP-1R signaling activated centrally projecting neurons that express proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which regulate appetite and are activated by leptin and insulin. Further-more, liraglutide inhibited neuropeptide Y–expressing neurons, which enhance appetite. In the accompanying Commentary, Daniel Drucker and Laurie Baggio discuss how these findings suggest that liraglutide action in POMC/CART neurons mediates weight loss.

the arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight lossAnna Secher, Jacob Jelsing, Arian F. Baquero, Jacob Hecksher-Sørensen, Michael A. Cowley, Louise S. Dalbøge, Gitte Hansen, Kevin L. Grove, Charles Pyke, Kirsten Raun, Lauge Schäffer, Mads Tang-Christensen, Saurabh Verma, Brent M. Witgen, Niels Vrang, and Lotte Bjerre Knudsen http://jci.me/75276

related commentaryGlucagon-like peptide-1 receptors in the brain: controlling food intake and body weightLaurie L. Baggio and Daniel J. Drucker http://jci.me/78371

A tick salivary gland protein attenuates host inflammatory responsesticks can serve as vectors for a variety of diseases, including Lyme disease, Rocky Mountain spotted fever, and tick-born encephalitis, among others. When a tick bites into human skin, its mouth lacerates tissues and blood vessels to establish a blood pool that allows the tick to feed on its host’s blood while passing on pathogens. In order for the pathogen to successfully invade the host, it is necessary to reduce the host inflammatory response. Naotoshi Tsuji and colleagues demonstrated that longistatin, a protein expressed in the tick salivary gland, interacts with a host inflammatory mediator, receptor for advanced glycation end products (RAGE), to reduce the host inflammatory response. Binding of longistatin to RAGE attenuated oxidative stress and NF-κB translocation to prevent production of adhesion molecules and cytokines. These results suggest that tick-produced longistatin attenuates the host inflammatory response to promote tick feeding.

Longistatin in tick saliva blocks advanced glycation end-product receptor activationAnisuzzaman, Takeshi Hatta, Takeharu Miyoshi, Makoto Matsubayashi, M. Khyrul Islam, M. Abdul Alim, M. Abu Anas, M. Mehedi Hasan, Yasunobu Matsumoto, Yasuhiko Yamamoto, Hiroshi Yamamoto, Kozo Fujisaki, and Naotoshi Tsuji http://jci.me/74917

oncology

Ovarian cancer and mesothelial cells work together to promote metastasis

infectious diseaseendocrinology

ovarian cancer metastasizes to abdominal organs, which are covered by mesothelial cells. Mesothelial cells have long been considered bystanders in the metastatic process, as the metastasizing ovarian cancer cells slip through the mesothelial layer to invade the organs beneath. In this issue, Hilary Kenny and colleagues demonstrate that mesothelial

cells actively promote metastasis. Using organotypic 3D cultures, Kenny and colleagues demonstrated that mesothelial cells secrete fibronectin to promote tumor cell adhesion and invasion. Human samples of tumor stroma from omental metastases also exhibited increased fibronectin expression (see accompanying image). Moreover, ovarian cancer cells displayed decreased adhesion, invasion, and metastasis in mice with fibronectin-deficient mesothelial cells compared with WT mice. Mechanistic studies revealed that ovarian cancer cells secrete TGF-β1, which activates a fibronectin secretion pathway in mesothelial cells; antibody-mediated inhibition of this pathway also reduced metastasis in a murine model of ovarian cancer.

Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretionHilary A. Kenny, Chun-Yi Chiang, Erin A. White, Elizabeth M. Schryver, Mohammed Habis, Iris L. Romero, Andras Ladanyi, Carla V. Penicka, Joshy George, Karl Matlin, Anthony Montag, Kristen Wroblewski, S. Diane Yamada, Andrew P. Mazar, David Bowtell, and Ernst Lengyel http://jci.me/74778

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the microbial basis of inflammatory bowel diseasesSushila R. Dalal and Eugene B. Chang

the contributory role of gut microbiota in cardiovascular diseaseW.H. Wilson Tang and Stanley L. Hazen

Deciphering the tête-à-tête between the microbiota and the immune systemNeeraj K. Surana and Dennis L. Kasper

Series Editor: Martin J. Blaser

Our gut microbiomes, ourselves

review Series

the human gastrointestinal tract harbors approximately 1013 microbial cells, collectively known as the gut microbiome. We have been aware of these friendly bacteria for around a century, but we are only now beginning to appreciate their influence in multiple aspects of human physiology and disease. Reviews in this series explore how perturbation of the microbiome not only contributes to disease but also helps to reveal its function; the impact of the microbiome on the metabolism of therapeutics and dietary nutrients; the contributions of commensal bacteria to disease, includ-ing cancer and cardiovascular disease; and the role of the microbiome in the development and maintenance of the immune system. Series editor Martin Blaser discusses how our understanding of the gut microbiome has evolved and is currently being aided by new technologies and approach-es that combine ecological principles with biomedical tech-niques and takes into account both the pathological and commensal aspects of the microbes that inhabit our bodies.

the microbiome revolutionMartin J. Blaser http://jci.me/78366

Antibiotics and the gut microbiotaSheetal R. Modi, James J. Collins, and David A. Relman

Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesisCynthia L. Sears, Abby L. Geis, and Franck Housseau

Gut microbiome

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobioticsRachel N. Carmody and Peter J. Turnbaugh

Clostridium difficile and the microbiotaAnna M. Seekatz and Vincent B. Young

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The effect of antibiotics on the gut microbiota

Review Series | Gut microbiome

A complex relationship: the gut microbiota and the immune systemCommensal organisms in the gut have a complex role in the host immune system. Unlike pathological microbes, which are attacked by the immune system, commensal microbes and the host exist under a carefully negotiated truce. The host provides an ecological niche and nutrient source, while the microbiota aid in a variety of processes, including digestion, protection against pathogens, and the development and maintenance of the immune system. Neeraj Surana and Dennis Kasper explore the relationship between the microbiota and the immune system, including an overview of microbe-induced immune maturation, the mechanisms by which the microbiota can modulate the immune system, and the contribution of this immunomodulation to human health and disease.

Deciphering the tête-à-tête between the microbiota and the immune systemNeeraj K. Surana and Dennis L. Kasper http://jci.me/72332

Inflammatory bowel disease and the microbial communityinflammatory bowel diseases (iBD), including ulcerative colitis and Crohn’s disease, are caused by a confluence of environmental and genetic triggers. Importantly, many IBD susceptibility genes are involved in the host’s relationship with gut microbes, and imbalances in the gut microbiota (intestinal dysbiosis) are now recognized as an integral part of disease pathogenesis. Sushila Dalal and Eugene Chang discuss the role of intestinal dysbiosis in IBD and how dietary, environmental, and host factors influence microbial assemblage. Additionally, they propose combining the techniques of microbial ecology and clinical pathology to understand the etiology of IBD and guide the development of therapeutic approaches.

the microbial basis of inflammatory bowel diseasesSushila R. Dalal and Eugene B. Chang http://jci.me/72330

Antibiotics play a pivotal role in modern medicine; however, their use can also alter the taxonomic, genomic, and functional capacity of the gut microbiota. David Relman and colleagues discuss the effect of antibiotic use on bacterial diversity and genetic alterations, which can enable the intrusion of pathogenic organisms. Commensal bacteria prevent pathogen invasion by outcompeting virulent

microbes for space and nutrients and by inducing host defenses. As shown in the accompanying image, antibiotic exposure disrupts the microbial community, which opens up new niches and reduces host defense responses. Additionally, antibiotic exposure increases the mobility of antibiotic resistance genes, which could potentially be acquired by pathogenic species. An improved

understanding of these alterations could aid in the development of new therapies that treat infections while preserving the microbiota.

Antibiotics and the gut microbiotaSheetal R. Modi, James J. Collins, and David A. Relman http://jci.me/72333

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Review Series | Gut microbiome

Leveraging the microbiota to combat Clostridium difficileClostridium difficile is a Gram-positive, spore-forming bacteria that causes inflammatory diarrhea. It is the leading cause of hospital-acquired infections and kills up to 14,000 people in the US each year. A major risk factor for the disease is antibiotic use, which disrupts the gut microbiota, leading to loss of colonization resistance. Anna Seekatz and Vincent Young review the pathogenesis of C. difficile infection (CDI) and the role of the gut microbiota in preventing colonization. They also discuss current therapeutic strategies for the treatment of CDI, including fecal microbiota transplantation, and treatment methods that are currently under investigation.

Clostridium difficile and the microbiotaAnna M. Seekatz and Vincent B. Young http://jci.me/72336

the gut microbiota play an important role in digestion, both in generating and responding to metabolites that are derived from what we eat. Researchers led by Stanley Hazen and W. H. Wilson Tang recently demonstrated that the gut microbiota process dietary nutrients into a metabolite that is linked to cardiovascular disease. Choline, phosphatidylcholine, and L-carnitine, which are found in high-cholesterol/high-fat foods such as red meat and eggs, are converted by the gut microbiota into trimethylamine (TMA), which is oxidized by hepatic flavin monooxygenase 3 (FMO3) to form trimethylamine-N-oxide (TMAO), a metabolite that contributes to the development of atherosclerotic

heart disease (see accompanying image). In this Review, Tang and Hazen discuss their recent findings and consider the role of the gut microbiota as a large endocrine organ that substantially influences multiple metabolic and physiological processes that could potentially serve as therapeutic targets.

the contributory role of gut microbiota in cardiovascular diseaseW.H. Wilson Tang and Stanley L. Hazen http://jci.me/72331

Microbial influence in cardiovascular disease

Bacteroides fragilis is an anaerobic species that colonizes most humans and can act as both a symbiont and a pathogen. The factor determining the relationship of B. fragilis to its human host is the ability to secrete B. fragilis toxin (BFT), a zinc-dependent metalloprotease. Enterotoxigenic B. fragilis (ETBF) strains can induce intestinal inflammation and diarrhea, although some hosts remain asymptomatic. Several recent studies have demonstrated that ETBF colonization promotes colon tumorigenesis in mice (see accompanying image) and

suggested that these bacteria may also play a role in human colon cancer. Cynthia Sears and colleagues review the epidemiology of ETBF in humans and discuss the molecular links between BFT and colon carcinogenesis.

Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesisCynthia L. Sears, Abby L. Geis, and Franck Housseau http://jci.me/72334

The two faces of Bacteroides fragilis

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Review Series | Gut microbiome

Editing the genome: recent advances in engineered nucleases

the past decade has seen substantial innovation in the development of genome-editing tools. In this issue, Rajat Gupta and Kiran Musunuru review three

different engineered nucleases: zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered regularly interspaced short repeats–Cas9 (CRISPR-Cas9) system. Each of these nucleases can be used to insert, replace, or remove DNA from the genome at specific sites that are targeted via sequence-specific DNA-binding domains. All three technologies are currently being used to generate mammalian models of disease and are under investigation for potential use in therapeutic applications. The accompanying image depicts binding specificity of ZFNs and TALENs.

expanding the genetic editing tool kit: ZFNS, tALeNs, and crISPr-cas9Rajat M. Gupta and Kiran Musunuru http://jci.me/72992

Xenobiotics, including dietary nutrients and therapeutic drugs, undergo a variety of metabolic processes, many of which are mediated by the gut microbiota. Rachel Carmody and Peter Turnbaugh examine the microbial influence on host responses to xenobiotics, providing evidence that the enzymatic activities of the gut microbiota have a profound effect on the activity

of pharmaceutical and nutritional compounds. They identify eight primary routes by which the gut microbiota modifies xenobiotic metabolism. Additionally, they highlight key studies providing evidence that interindividual differences in the gut microbiota contribute to variations in drug response and discuss how these findings can be used to improve medicine.

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobioticsRachel N. Carmody and Peter J. Turnbaugh http://jci.me/72335

review: genomic engineeringA D V e r t I S e M e N t

Microbial impact on xenobiotic metabolism

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