http://content.jci.org/current en-us 2008 The American Society for Clinical Investigation http://www.jci.org/icons/banner/rss_title.gif http://content.jci.org http://content.jci.org/articles/view/37288 info:doi/10.1172/JCI37288 American Society for Clinical Investigation Reed E. Pyeritz http://content.jci.org/articles/view/37204 info:doi/10.1172/JCI37204 American Society for Clinical Investigation Karen Honey http://content.jci.org/articles/view/37389 info:doi/10.1172/JCI37389 American Society for Clinical Investigation Laura J. Niedernhofer http://content.jci.org/articles/view/36963 info:doi/10.1172/JCI36963 American Society for Clinical Investigation Jack Hoadley http://content.jci.org/articles/view/36964 info:doi/10.1172/JCI36964 American Society for Clinical Investigation Kevin Jon Williams http://content.jci.org/articles/view/35206 info:doi/10.1172/JCI35206 American Society for Clinical Investigation Tomohiro Kurosaki http://content.jci.org/articles/view/37099 JCI, Matsushita et al. report that the timing of this therapy is critical for the management of EAE, a mouse model of human MS (see the related article beginning on page 3420). The results suggest the existence of two opposite actions executed by B cells during the course of autoimmune pathology; CD1d^hiCD5⁺ regulatory B cells suppress EAE induction, whereas B cells are required for the expansion of autoantigen-specific T cells during disease progression. Given the existence of such regulatory B cells in humans, these findings not only resolve previously unexplained contradictions with respect to the outcome of B cell–depleting therapy but also provide insight into the best regimen for this treatment approach. ]]> info:doi/10.1172/JCI37099 American Society for Clinical Investigation Linda E. Greenbaum http://content.jci.org/articles/view/37189 JCI, using a myofibroblast-cholangiocyte coculture system and genetically modified mice, Omenetti and colleagues present evidence supporting the importance of paracrine hedgehog signaling between the two cell types and increased expression of mesenchymal markers in cholangiocytes (see the related article beginning on page 3331). These findings set the stage for future studies to further investigate the contribution of hedgehog signaling in both cholangiocyte repair and fibrogenesis in biliary diseases. ]]> info:doi/10.1172/JCI37189 American Society for Clinical Investigation Rachel L. Miller http://content.jci.org/articles/view/37171 JCI, Hollingsworth and colleagues report on the effect of prenatal maternal dietary intake of methyl donors on the risk of allergic airway disease in offspring in mice and show that these effects involve epigenetic regulation (see the related article beginning on page 3462). Supplementation of the maternal diet with methyl donors was associated with greater airway allergic inflammation and IgE production in F1 and, to some extent, F2 progeny. Site-specific differences in DNA methylation and reduced transcriptional activity were detected. If these findings are confirmed, a new paradigm for asthma pathogenesis may be emerging. ]]> info:doi/10.1172/JCI37171 American Society for Clinical Investigation Jeffrey A. Frelinger http://content.jci.org/articles/view/37125 + T cells are critical to diabetogenesis in NOD mice, evidence of their involvement in human type 1 diabetes (T1D) has been circumstantial. The existence of CD8⁺ T cells specific for β cell peptides has been demonstrated, but functional data regarding the role of these cells in T1D have been lacking. In this issue of the JCI, Skowera et al. describe an unusual self-peptide epitope derived from the leader sequence of preproinsulin (PPI) and show that 50% of HLA-A2⁺ patients with new-onset T1D possessed circulating CD8⁺ T cells specific for this epitope, suggesting that PPI plays a critical role in the development of T1D (see the related article beginning on page 3390). They also report that β cells upregulate PPI expression in the presence of high glucose levels, rendering these cells more susceptible to lysis and potentially accelerating disease. This suggests that interventions aimed at decreasing the PPI-specific CD8⁺ T cell response early after T1D diagnosis may be efficacious in ameliorating the disease process. ]]> info:doi/10.1172/JCI37125 American Society for Clinical Investigation Brad E. Hoffman, Roland W. Herzog http://content.jci.org/articles/view/37079 JCI, Lüth and colleagues demonstrate that hepatic expression of a brain protein is protective against neuroinflammatory disease in a mouse model of human MS (see the related article beginning on page 3403). Suppression of autoimmunity was dependent on transgene expression in the liver and was mediated by induction of antigen-specific CD4⁺CD25⁺Foxp3⁺ Tregs. These findings suggest that the introduction of antigens to the liver may have potential as a preventative or therapeutic intervention for autoimmune disease. ]]> info:doi/10.1172/JCI37079 American Society for Clinical Investigation Peter C. Doherty, Anne Kelso http://content.jci.org/articles/view/37232 + T cell memory diminish the danger posed by these variant viruses? Pre-existing CD8⁺ T cell–mediated immunity directed at peptides from conserved internal proteins of the influenza A virus does not prevent infection, but it can promote early virus clearance and decrease morbidity in mice. In this issue of the JCI, Lee et al. show that people who have not been exposed to avian influenza A (H5N1) viruses have cross-reactive CD8⁺ T cell memory to a wide range of H5N1 peptides (see the related article beginning on page 3478). These peptides could be used to add a CD8⁺ T cell component to current antibody-focused vaccine strategies with a view to reducing the impact of infection with novel influenza A viruses. ]]> info:doi/10.1172/JCI37232 American Society for Clinical Investigation Hartmut Weiler http://content.jci.org/articles/view/37243 JCI, the study by Redecha et al. clarifies that in mice, the contribution of TF to this pathogenic mechanism is independent of its role in coagulation and thrombosis, but involves inflammatory signaling through the receptor PAR2 (see the related article beginning on page 3453). The study not only sheds light on a critical effector mechanism of aPL-induced fetal loss, but also suggests that treatment with statins, which decrease TF and PAR2 expression, may hold promise as a therapeutic approach to antiphospholipid syndrome–associated pregnancy complications. ]]> info:doi/10.1172/JCI37243 American Society for Clinical Investigation Mohit Kapoor, Shangxi Liu, Xu Shi-wen, Kun Huh, Matthew McCann, Christopher P. Denton, James R. Woodgett, David J. Abraham, Andrew Leask http://content.jci.org/articles/view/35381 GSK3A and GSK3B. GSK-3 is thought to be involved in tissue repair and fibrogenesis, but its role in these processes is currently unknown. To investigate the function of GSK-3β in fibroblasts, we generated mice harboring a fibroblast-specific deletion of Gsk3b and evaluated their wound-healing and fibrogenic responses. We have shown that Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhibited accelerated wound closure, increased fibrogenesis, and excessive scarring compared with control mice. In addition, Gsk3b-CKO mice showed elevated collagen production, decreased cell apoptosis, elevated levels of profibrotic α-SMA, and increased myofibroblast formation during wound healing. In cultured Gsk3b-CKO fibroblasts, adhesion, spreading, migration, and contraction were enhanced. Both Gsk3b-CKO mice and fibroblasts showed elevated expression and production of endothelin-1 (ET-1) compared with control mice and cells. Antagonizing ET-1 reversed the phenotype of Gsk3b-CKO fibroblasts and mice. Thus, GSK-3β appears to control the progression of wound healing and fibrosis by modulating ET-1 levels. These results suggest that targeting the GSK-3β pathway or ET-1 may be of benefit in controlling tissue repair and fibrogenic responses in vivo. ]]> info:doi/10.1172/JCI35381 American Society for Clinical Investigation Shao H. Yang, Douglas A. Andres, H. Peter Spielmann, Stephen G. Young, Loren G. Fong http://content.jci.org/articles/view/35876 Lmna^HG/+). The amelioration of disease, however, is incomplete, leading us to hypothesize that nonfarnesylated progerin also might be capable of eliciting disease. To test this hypothesis, we created knockin mice expressing nonfarnesylated progerin (Lmna^nHG/+). Lmna^nHG/+ mice developed the same disease phenotypes observed in Lmna^HG/+ mice, although the phenotypes were milder, and mouse embryonic fibroblasts (MEFs) derived from these mice contained fewer misshapen nuclei. The steady-state levels of progerin in Lmna^nHG/+ MEFs and tissues were lower, suggesting a possible explanation for the milder phenotypes. These data support the concept that inhibition of protein farnesylation in progeria could be therapeutically useful but also suggest that this approach may be limited, as progerin elicits disease phenotypes whether or not it is farnesylated. ]]> info:doi/10.1172/JCI35876 American Society for Clinical Investigation Tobias Eckle, Almut Grenz, Stefanie Laucher, Holger K. Eltzschig http://content.jci.org/articles/view/34203 A2BAR gene was specifically associated with reduced survival time and increased pulmonary albumin leakage after injury. In WT mice, treatment with an A2BAR-selective antagonist resulted in enhanced pulmonary inflammation, edema, and attenuated gas exchange, while an A2BAR agonist attenuated VILI. In bone marrow–chimeric A2BAR mice, although the pulmonary inflammatory response involved A2BAR signaling from bone marrow–derived cells, A2BARs located on the lung tissue attenuated VILI-induced albumin leakage and pulmonary edema. Furthermore, measurement of alveolar fluid clearance (AFC) demonstrated that A2BAR signaling enhanced amiloride-sensitive fluid transport and elevation of pulmonary cAMP levels following VILI, suggesting that A2BAR agonist treatment protects by drying out the lungs. Similar enhancement of pulmonary cAMP and AFC were also observed after β-adrenergic stimulation, a pathway known to promote AFC. Taken together, these studies reveal a role for A2BAR signaling in attenuating VILI and implicate this receptor as a potential therapeutic target during acute lung injury. ]]> info:doi/10.1172/JCI34203 American Society for Clinical Investigation Stefania Corti, Monica Nizzardo, Martina Nardini, Chiara Donadoni, Sabrina Salani, Dario Ronchi, Francesca Saladino, Andreina Bordoni, Francesco Fortunato, Roberto Del Bo, Dimitra Papadimitriou, Federica Locatelli, Giorgia Menozzi, Sandra Strazzer, Nereo Bresolin, Giacomo P. Comi http://content.jci.org/articles/view/35432 info:doi/10.1172/JCI35432 American Society for Clinical Investigation Alessia Omenetti, Alessandro Porrello, Youngmi Jung, Liu Yang, Yury Popov, Steve S. Choi, Rafal P. Witek, Gianfranco Alpini, Juliet Venter, Hendrika M. Vandongen, Wing-Kin Syn, Gianluca Svegliati Baroni, Antonio Benedetti, Detlef Schuppan, Anna Mae Diehl http://content.jci.org/articles/view/35875 info:doi/10.1172/JCI35875 American Society for Clinical Investigation Hyung J. Chun, Ziad A. Ali, Yoko Kojima, Ramendra K. Kundu, Ahmad Y. Sheikh, Rani Agrawal, Lixin Zheng, Nicholas J. Leeper, Nathan E. Pearl, Andrew J. Patterson, Joshua P. Anderson, Philip S. Tsao, Michael J. Lenardo, Euan A. Ashley, Thomas Quertermous http://content.jci.org/articles/view/34871 ApoE-KO mice, exogenous Ang II induced atherosclerosis and abdominal aortic aneurysm formation; we found that coinfusion of apelin abrogated these effects. Similarly, apelin treatment rescued Ang II–mediated increases in neointimal formation and vascular remodeling in a vein graft model. NO has previously been implicated in the vasodepressor function of apelin; we found that apelin treatment increased NO bioavailability in ApoE-KO mice. Furthermore, infusion of an NO synthase inhibitor blocked the apelin-mediated decrease in atherosclerosis and aneurysm formation. In rat primary aortic smooth muscle cells, apelin inhibited Ang II–mediated transcriptional regulation of multiple targets as measured by reporter assays. In addition, we demonstrated by coimmunoprecipitation and fluorescence resonance energy transfer analysis that the Ang II and apelin receptors interacted physically. Taken together, these findings indicate that apelin signaling can block Ang II actions in vascular disease by increasing NO production and inhibiting Ang II cellular signaling. ]]> info:doi/10.1172/JCI34871 American Society for Clinical Investigation Masahiro Murakami, Loc T. Nguyen, Zhen W. Zhang, Karen L. Moodie, Peter Carmeliet, Radu V. Stan, Michael Simons http://content.jci.org/articles/view/35298 info:doi/10.1172/JCI35298 American Society for Clinical Investigation Maciej Kujawski, Marcin Kortylewski, Heehyoung Lee, Andreas Herrmann, Heidi Kay, Hua Yu http://content.jci.org/articles/view/35213 info:doi/10.1172/JCI35213 American Society for Clinical Investigation Benbo Song, Donalyn Scheuner, David Ron, Subramaniam Pennathur, Randal J. Kaufman http://content.jci.org/articles/view/34587 Chop deletion in multiple mouse models of type 2 diabetes and found that Chop^–/– mice had improved glycemic control and expanded β cell mass in all conditions analyzed. In both genetic and diet-induced models of insulin resistance, CHOP deficiency improved β cell ultrastructure and promoted cell survival. In addition, we found that isolated islets from Chop^–/– mice displayed increased expression of UPR and oxidative stress response genes and reduced levels of oxidative damage. These findings suggest that CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in β cells under conditions of increased insulin demand. ]]> info:doi/10.1172/JCI34587 American Society for Clinical Investigation Ania Skowera, Richard J. Ellis, Ruben Varela-Calviño, Sefina Arif, Guo Cai Huang, Cassie Van-Krinks, Anna Zaremba, Chloe Rackham, Jennifer S. Allen, Timothy I.M. Tree, Min Zhao, Colin M. Dayan, Andrew K. Sewell, Wendy Unger, Jan W. Drijfhout, Ferry Ossendorp, Bart O. Roep, Mark Peakman http://content.jci.org/articles/view/35449 A*0201 allele) molecules. Processing of these was unconventional, requiring neither the proteasome nor transporter associated with processing (TAP). However, both epitopes were major targets for circulating effector CD8⁺ T cells from HLA-A2⁺ patients with type 1 diabetes. Moreover, cloned preproinsulin signal peptide–specific CD8⁺ T cells killed human β cells in vitro. Critically, at high glucose concentration, β cell presentation of preproinsulin signal epitope increased, as did CTL killing. This study provides direct evidence that autoreactive CTLs are present in the circulation of patients with type 1 diabetes and that they can kill human β cells. These results also identify a mechanism of self-antigen presentation that is under pathophysiological regulation and could expose insulin-producing β cells to increasing cytotoxicity at the later stages of the development of clinical diabetes. Our findings suggest that autoreactive CTLs are important targets for immune-based interventions in type 1 diabetes and argue for early, aggressive insulin therapy to preserve remaining β cells. ]]> info:doi/10.1172/JCI35449 American Society for Clinical Investigation Stefan Lüth, Samuel Huber, Christoph Schramm, Thorsten Buch, Stefan Zander, Christine Stadelmann, Wolfgang Brück, David C. Wraith, Johannes Herkel, Ansgar W. Lohse http://content.jci.org/articles/view/32132 +CD25⁺Foxp3⁺ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4⁺CD25^– T cell proliferation after antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4⁺CD25⁺Foxp3⁺ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by TGF-β–dependent peripheral conversion from conventional non-Tregs. Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases. ]]> info:doi/10.1172/JCI32132 American Society for Clinical Investigation Laure Michel, Laureline Berthelot, Ségolène Pettré, Sandrine Wiertlewski, Fabienne Lefrère, Cécile Braudeau, Sophie Brouard, Jean-Paul Soulillou, David-Axel Laplaud http://content.jci.org/articles/view/35365 +CD25^high T cells has been implicated in the pathogenesis of the disease. Here, we reanalyzed the function of this T cell subset in patients with MS, but we depleted cells expressing IL-7 receptor α-chain (CD127), a marker recently described as present on activated T cells but not Tregs. Similar to other studies, we observed a marked defect in the suppressive function of unseparated CD4⁺CD25^high T cells isolated from MS patients. However, when CD127^high cells were removed from the CD4⁺CD25^high population, patient and control cells inhibited T cell proliferation and cytokine production equally. Likewise, when the CD25 gate used to sort the cells was stringent enough to eliminate CD127^high cells, CD4⁺CD25^high T cells from patients with MS and healthy individuals had similar regulatory function. Additional analysis indicated that the CD127^high cells within the CD4⁺CD25^high T cell population from patients with MS appeared more proliferative and secreted more IFN-γ and IL-2 than the same cells from healthy individuals. Taken together, we conclude that CD4⁺CD25^highCD127^low Tregs from MS patients and healthy individuals exhibit similar suppressive functions. The decreased inhibitory function of unfractioned CD4⁺CD25^high cells previously observed might be due to abnormal activation of CD127^high T cells in patients with MS. ]]> info:doi/10.1172/JCI35365 American Society for Clinical Investigation Takashi Matsushita, Koichi Yanaba, Jean-David Bouaziz, Manabu Fujimoto, Thomas F. Tedder http://content.jci.org/articles/view/36030 hiCD5⁺ regulatory B cell subset (B10 cells), since the adoptive transfer of splenic B10 cells before EAE induction normalized EAE in B cell–depleted mice. While transfer of regulatory B10 cells was maximally effective during early EAE initiation, they had no obvious role during disease progression. Rather, B cell depletion during EAE disease progression dramatically suppressed symptoms. Specifically, B cells were required for the generation of CD4⁺ T cells specific for CNS autoantigen and the entry of encephalitogenic T cells into the CNS during disease progression. These results demonstrate reciprocal regulatory roles for B cells during EAE immunopathogenesis. The therapeutic effect of B cell depletion for the treatment of autoimmunity may therefore depend on the relative contributions and the timing of these opposing B cell activities during the course of disease initiation and pathogenesis. ]]> info:doi/10.1172/JCI36030 American Society for Clinical Investigation Olivier Manches, David Munn, Anahita Fallahi, Jeffrey Lifson, Laurence Chaperot, Joel Plumas, Nina Bhardwaj http://content.jci.org/articles/view/34823 + T cells into Tregs with suppressive function. This differentiation was independent of pDC production of IFN-α and primarily dependent on pDC expression of indoleamine 2,3-dioxygenase, which was induced through the TLR/MyD88 pathway, following binding of HIV to CD4 and triggering of TLR7 by HIV genomic RNA. Functionally, the Tregs induced by pDCs were shown to inhibit the maturation of bystander conventional DCs. This study therefore reveals what we believe to be a novel mechanism by which pDC may regulate and potentially limit anti-HIV immune responses. ]]> info:doi/10.1172/JCI34823 American Society for Clinical Investigation Marein A.W.P. de Jong, Lot de Witte, Menno J. Oudhoff, Sonja I. Gringhuis, Philippe Gallay, Teunis B.H. Geijtenbeek http://content.jci.org/articles/view/34721 trans-infection of T cells. Genital infections such as Candida albicans and Neisseria gonorrhea not only triggered TLRs but also induced TNF-α production in vaginal and skin explants. Thus, during coinfection, LCs could be directly activated by pathogenic structures and indirectly activated by inflammatory factors, thereby increasing the risk of acquiring HIV-1. Our data demonstrate a decisive role for LCs in HIV-1 transmission during genital coinfections and suggest antiinflammatory therapies as potential strategies to prevent HIV-1 transmission. ]]> info:doi/10.1172/JCI34721 American Society for Clinical Investigation Patricia Redecha, Claus-Werner Franzke, Wolfram Ruf, Nigel Mackman, Guillermina Girardi http://content.jci.org/articles/view/36089 Par2^–/– mice treated with aPL exhibited reduced neutrophil activation and normal pregnancies, which indicates that PAR2 plays an important role in the pathogenesis of aPL-induced fetal injury. We also demonstrated that simvastatin and pravastatin decreased TF and PAR2 expression on neutrophils and prevented pregnancy loss. Our results suggest that TF/FVIIa/PAR2 signaling mediates neutrophil activation and fetal death in APS and that statins may be a good treatment for women with aPL-induced pregnancy complications. ]]> info:doi/10.1172/JCI36089 American Society for Clinical Investigation John W. Hollingsworth, Shuichiro Maruoka, Kathy Boon, Stavros Garantziotis, Zhuowei Li, John Tomfohr, Nathaniel Bailey, Erin N. Potts, Gregory Whitehead, David M. Brass, David A. Schwartz http://content.jci.org/articles/view/34378 Runx3), a gene known to negatively regulate allergic airway disease, was found to be excessively methylated, and Runx3 mRNA and protein levels were suppressed in progeny exposed in utero to a high-methylation diet. Moreover, treatment with a demethylating agent increased Runx3 gene transcription, further supporting our claim that a methyl-rich diet can affect methylation status and consequent transcriptional regulation. Our findings indicate that dietary factors can modify the heritable risk of allergic airway disease through epigenetic mechanisms during a vulnerable period of fetal development in mice. ]]> info:doi/10.1172/JCI34378 American Society for Clinical Investigation Shih-Heng Chen, Hui-Wen Yao, I-Te Chen, Biehuoy Shieh, Ching Li, Shun-Hua Chen http://content.jci.org/articles/view/35114 Egr-1 by a DNA-based enzyme greatly reduced the mortality of HSV-1–infected mice by decreasing viral loads in tissues. This study provides what we believe is the first evidence that Egr-1 increases the mortality of HSV-1 encephalitis by enhancing viral replication. Moreover, blocking this cellular machinery exploited by the virus could prevent host mortality. ]]> info:doi/10.1172/JCI35114 American Society for Clinical Investigation Laurel Yong-Hwa Lee, Do Lien Anh Ha, Cameron Simmons, Menno D. de Jong, Nguyen Van Vinh Chau, Reto Schumacher, Yan Chun Peng, Andrew J. McMichael, Jeremy J. Farrar, Geoffrey L. Smith, Alain R.M. Townsend, Brigitte A. Askonas, Sarah Rowland-Jones, Tao Dong http://content.jci.org/articles/view/32460 + and CD8⁺ memory T cell responses to overlapping peptides spanning the full proteome of influenza A/Viet Nam/CL26/2005 (H5N1) and influenza A/New York/232/2004 (H3N2) in healthy individuals from the United Kingdom and Viet Nam. Memory CD4⁺ and CD8⁺ T cells isolated from the majority of participants exhibited human influenza–specific responses and showed cross-recognition of at least one H5N1 internal protein. Participant CD4⁺ and CD8⁺ T cells recognized multiple synthesized influenza peptides, including peptides from the H5N1 strain. Matrix protein 1 (M1) and nucleoprotein (NP) were the immunodominant targets of cross-recognition. In addition, cross-reactive CD4⁺ and CD8⁺ T cells recognized target cells infected with recombinant vaccinia viruses expressing either H5N1 M1 or NP. Thus, vaccine formulas inducing heterosubtypic T cell–mediated immunity may confer broad protection against avian and human influenza A viruses. ]]> info:doi/10.1172/JCI32460 American Society for Clinical Investigation Oliver Soehnlein, Ylva Kai-Larsen, Robert Frithiof, Ole E. Sorensen, Ellinor Kenne, Karin Scharffetter-Kochanek, Einar E. Eriksson, Heiko Herwald, Birgitta Agerberth, Lennart Lindbom http://content.jci.org/articles/view/35740 Staphylococcus aureus both in vitro and in murine models in vivo. PMN secretion activated macrophages, resulting in upregulation of the Fcγ receptors CD32 and CD64, which then mediated the enhanced phagocytosis of IgG-opsonized bacteria. The phagocytosis-stimulating activity within the PMN secretion was found to be due to proteins released from PMN primary granules; thorough investigation revealed heparin-binding protein (HBP) and human neutrophil peptides 1–3 (HNP1–3) as the mediators of the macrophage response to PMN secretion. The use of blocking antibodies and knockout mice revealed that HBP acts via β₂ integrins, but the receptor for HNP1–3 remained unclear. Mechanistically, HBP and HNP1–3 triggered macrophage release of TNF-α and IFN-γ, which acted in an autocrine loop to enhance expression of CD32 and CD64 and thereby enhance phagocytosis. Thus, we attribute what may be a novel role for PMN granule proteins in regulating the immune response to bacterial infections. ]]> info:doi/10.1172/JCI35740 American Society for Clinical Investigation Gregory D. Lewis, Ru Wei, Emerson Liu, Elaine Yang, Xu Shi, Maryann Martinovic, Laurie Farrell, Aarti Asnani, Marcoli Cyrille, Arvind Ramanathan, Oded Shaham, Gabriel Berriz, Patricia A. Lowry, Igor F. Palacios, Murat Taşan, Frederick P. Roth, Jiangyong Min, Christian Baumgartner, Hasmik Keshishian, Terri Addona, Vamsi K. Mootha, Anthony Rosenzweig, Steven A. Carr, Michael A. Fifer, Marc S. Sabatine, Robert E. Gerszten http://content.jci.org/articles/view/35111 info:doi/10.1172/JCI35111 American Society for Clinical Investigation Steven Grant http://content.jci.org/articles/view/36898E1 info:doi/10.1172/JCI36898E1 American Society for Clinical Investigation