jci impact celebrating 90 years of publishing scientific ... · alejandro aballay abul k. abbas...
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jci.org/impactoctober 2014
Also in this issue:
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
Celebrating 90 years of publishing scientific discoveries in medicinep. 6
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Alejandro Aballay
Abul K. Abbas
Domenico Accili
Rexford S. Ahima
Qais Al-Awqati
Kari Alitalo
James Allison
Dario C. Altieri
Masayuki Amagai
Mark E. Anderson
Brian H. Annex
Alan Attie
Jane E. Aubin
Steven P. Balk
Michael F. Beers
John A. Belperio
Nina Bhardwaj
Morris J. Birnbaum
Joyce Bischoff
Mina J. Bissell
Craig Blackstone
Bruce R. Blazar
Nancy Bonini
Brendan Boyce
Jonathan Bromberg
Frank C. Brosius
Hal E. Broxmeyer
Andrew Butler
Michael J. Caplan
Ruben D. Carrasco
Diego H. Castrillon
Harold Chapman
Ajay Chawla
Benjamin K. Chen
Benny J. Chen
Ju Chen
Marie-Françoise Chesselet
Vivian G. Cheung
Yongwon Choi
Thomas Clemens
Ronald G. Collman
Marco Colonna
George Cotsarelis
Shaun R. Coughlin
Christopher M. Counter
Peter D. Crompton
Tyler J. Curiel
David D’alessio
Richard T. D’Aquila
Riccardo Dalla-Favera
Alan Daugherty
Ted Dawson
Sudhansu Dey
Harry C. Dietz III
Michael Dustin
Connie J. Eaves
Jack A. Elias
Joel K. Elmquist
Stephen G. Emerson
Jeffrey A. Engelman
Jonathan A. Epstein
Adrian Erlebacher
Joel D. Ernst
James M. Ervasti
Robert V. Farese Jr.
Eric R. Fearon
Edward A. Fisher
Susan Fisher
Richard A. Flavell
Tatiana Foroud
Velia M. Fowler
Martin Friedlander
Stephen J. Galli
J. Victor Garcia-Martinez
Alfred L. George Jr.
Stanton L. Gerson
Robert E. Gerszten
Todd Golde
Stanley Goldfarb
Larry B. Goldstein
Fred Sanford Gorelick
Kathleen J. Green
J. Timothy Greenamyre
Theresa A. Guise
David Hafler
Jonathan J. Hansen
Raymond C. Harris
Stanley L. Hazen
Peter Heeringa
Brian A. Hemmings
Meenhard Herlyn
Joachim Herz
Katherine A. High
Helen H. Hobbs
Ronald Hoffman
V. Michael Holers
Steven M. Holland
Michael J. Holtzman
Lawrence B. Holzman
Tamas L. Horvath
Gokhan S. Hotamisligil
Steven R. Houser
Scott J. Hultgren
Christopher A. Hunter
Ciro Indolfi
David E. James
William G. Kaelin Jr.
Klaus Kaestner
Mark L. Kahn
Raghu Kalluri
S. Ananth Karumanchi
Robert S. Kass
Masato Kasuga
Dontscho Kerjaschki
Sundeep Khosla
Richard N. Kitsis
Peter S. Klein
Steven Kliewer
Björn C. Knollmann
Walter J. Koch
Jay K. Kolls
Issei Komuro
Christopher D. Kontos
Murray Korc
Gary Koretzky
Calvin Kuo
Antonio La Cava
Fadi G. Lakkis
Terri Laufer
Mitchell A. Lazar
Brendan Lee
William M.F. Lee
Rudolph L. Leibel
Stanley M. Lemon
Jon D. Levine
Ross L. Levine
Klaus Ley
Richard M. Locksley
Gary Lopaschuk
Richard B. Mailman
Andrew R. Marks
Jack Martin
Steven O. Marx
Rodger P. McEver
Elizabeth McNally
Cornelius J. Melief
Shlomo Melmed
George Michalopoulos
Jeffrey H. Miner
Beverly Mitchell
Peter J. Mohler
Kelle Harbert Moley
Jeffrey Molkentin
David D. Moore
Edward E. Morrisey
James H. Morrissey
Deborah M. Muoio
Anthony J. Muslin
Martin G. Myers Jr.
Benjamin G. Neel
Eric N. Olson
Harry T. Orr
William C. Parks
Warren S. Pear
Richard M. Peek Jr.
Sallie R. Permar
David J. Pinsky
Edward Plow
Jeffrey Pollard
Kornelia Polyak
Catherine Postic
Josef Prchal
Alice S. Prince
Louis J. Ptáček
Luigi Puglielli
Pere Puigserver
Bali Pulendran
Ellen Puré
Susan E. Quaggin
Marlene Rabinovitch
Daniel J. Rader
Shahin Rafii
Gwendalyn J. Randolph
Barbara Rehermann
Steven L. Reiner
Sarah A. Robertson
Paul B. Rosenberg
Theodora S. Ross
Marc E. Rothenberg
Anil Rustgi
J. Evan Sadler
Junichi Sadoshima
Jose-Alain Sahel
Jean E. Schaffer
Philipp E. Scherer
Michael D. Schneider
Detlef Schuppan
Michael W. Schwartz
William K. Scott
Randy Seeley
Amita Sehgal
Clay Semenkovich
Gregg L. Semenza
John Seykora
Steven D. Shapiro
Mari Shinohara
Steven E. Shoelson
Gerald I. Shulman
Roy L. Silverstein
M. Celeste Simon
Journal of Clinical Investigation Consulting Editors
Mihaela Skobe
Lois Smith
Steven R. Smith
Susan S. Smyth
Weihong Song
Ashley L. St. John
Herman F. Staats
Jonathan S. Stamler
John R. Stanley
Colin L. Stewart
Doris Stoffers
Warren Strober
Maureen A. Su
Katalin Susztak
Catharina Svanborg
Ira Tabas
Alan R. Tall
Sakae Tanaka
Victor J. Thannickal
Andrei Thomas-Tikhonenko
Georgia D. Tomaras
Peter Tontonoz
Laurence A. Turka
Raphael H. Valdivia
Marcel R.M. van den Brink
Luc Van Kaer
Matthias von Herrath
Yisong Y. Wan
Hong Wang
David Weinstock
Jeffrey Weiser
Stephen J. Weiss
Bart O. Williams
Joseph C. Wu
Thomas A. Wynn
Rudolf Zechner
Kang Zhang
Len Zon
Ming-Hui Zou
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 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: [email protected]
For the full JcI online, go to jci.me/124/10 or scan the code at left with your mobile device.
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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