http://www.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://www.jci.org/articles/view/35705 info:doi/10.1172/JCI35705 American Society for Clinical Investigation Karen Honey http://www.jci.org/articles/view/35821 info:doi/10.1172/JCI35821 American Society for Clinical Investigation Ira B. Wilson http://www.jci.org/articles/view/35627 info:doi/10.1172/JCI35627 American Society for Clinical Investigation Anne E. Kwitek http://www.jci.org/articles/view/35743 info:doi/10.1172/JCI35743 American Society for Clinical Investigation Teri A. Manolio, Lisa D. Brooks, Francis S. Collins http://www.jci.org/articles/view/34772 info:doi/10.1172/JCI34772 American Society for Clinical Investigation Barbara R. Pober, Mark Johnson, Zsolt Urban http://www.jci.org/articles/view/35309 elastin gene, leading to elastin haploinsufficiency, underlie the arteriopathy. In this review we describe potential links between elastin expression and arteriopathy, possible explanations for disease variability, and current treatment options and their limitations, and we propose several new directions for the development of nonsurgical preventative therapies based on insights from elastin biology. ]]> info:doi/10.1172/JCI35309 American Society for Clinical Investigation Ashley A. Manzoor, Thies Schroeder, Mark W. Dewhirst http://www.jci.org/articles/view/35543 JCI, Matsumoto and colleagues reveal their development and use of a novel imaging approach, combining pulsed electron paramagnetic resonance imaging (EPRI) with conventional MRI to image squamous cell carcinoma tumor–bearing mice (see the related article beginning on page 1965). This method provides coregistered images of oxygenation and blood volume/flow with the underlying anatomy and concentrations of metabolites such as lactate and choline. This technique, combining functional and anatomic imaging, shows immediate preclinical applicability in monitoring factors that control tumor hypoxia and metabolism and may have future clinical potential for monitoring tumor response to treatment. ]]> info:doi/10.1172/JCI35543 American Society for Clinical Investigation Rexford S. Ahima http://www.jci.org/articles/view/35655 JCI, Sharma and colleagues assessed the role of adiponectin, an adipose-derived hormone, in the pathogenesis of albuminuria (see the related article beginning on page 1645). Obese African Americans had reduced adiponectin levels associated with albuminuria. Adiponectin deficiency in mice induced oxidative stress, fusion of podocyte foot processes in the kidney glomerulus, and urinary albumin excretion. Adiponectin treatment reversed these abnormalities, likely through activation of AMPK. The benefits of adiponectin were observed in diabetic and nondiabetic mice. These findings suggest that adiponectin is a biomarker for kidney disease and may be targeted for prevention and treatment. ]]> info:doi/10.1172/JCI35655 American Society for Clinical Investigation Frank Kirchhoff, Guido Silvestri http://www.jci.org/articles/view/35487 JCI, Prost and colleagues show that the viral accessory protein Negative factor (Nef) plays a potentially critical role in the pathogenesis of HIV/SIV-associated hematopoietic dysfunction by affecting the clonogenic potential of HSCs (see the related article beginning on page 1765). Soluble Nef induces PPARγ in uninfected HSCs, thereby suppressing the expression of STAT5A and STAT5B, two factors necessary for proper HSC function. The identification of this novel activity of extracellular Nef defines a new mechanism of HIV/SIV pathogenesis and suggests that approaches aimed at increasing STAT5A and STAT5B expression may be considered in HIV-infected individuals with prominent hematological abnormalities. The results also raise the question of whether dysregulation of hematopoiesis by extracellular Nef plays a role in the development of T cell immunodeficiency and the high levels of chronic immune activation associated with AIDS. ]]> info:doi/10.1172/JCI35487 American Society for Clinical Investigation Tom Van Belle, Matthias von Herrath http://www.jci.org/articles/view/35639 JCI, Monti et al. report that immune conditioning via use of the Edmonton protocol — a treatment approach in which T1DM patients infused with pancreatic islets from multiple cadaveric donors simultaneously receive immunosuppressive drugs — results in lymphopenia that is associated with elevated serum levels of the homeostatic cytokines IL-7 and IL-15, which causes in vivo expansion of the autoreactive CD8⁺ T cell population (see the related article beginning on page 1806). Reemergence of autoreactivity is likely the main culprit underlying long-term islet graft failure, and new strategies will need to be tested to circumvent this homeostatic expansion and recurrent autoreactivity. ]]> info:doi/10.1172/JCI35639 American Society for Clinical Investigation Juanita L. Merchant http://www.jci.org/articles/view/35344 JCI, a study in mice by Ernst et al. provides new insight into the role of IL-11 and its glycoprotein 130 (gp130) receptor in inflammation-associated gastric epithelial cell oncogenic transformation, which they show is mediated by and dependent on increased activation of Stat3 and, to a lesser extent, Stat1 (see the related article beginning on page 1727). Prior studies from this group have shown that Stat3 hyperactivity stimulates the TGF-β inhibitor Smad7. Collectively, the studies suggest that an important pathway of oncogenic transformation in the stomach is through suppression of growth inhibitory signals, such as members of the TGF-β family, that originate from the stroma. ]]> info:doi/10.1172/JCI35344 American Society for Clinical Investigation Kensuke Noma, Yoshiyuki Rikitake, Naotsugu Oyama, Guijun Yan, Pilar Alcaide, Ping-Yen Liu, Hongwei Wang, Daniela Ahl, Naoki Sawada, Ryuji Okamoto, Yukio Hiroi, Koichi Shimizu, Francis W. Luscinskas, Jianxin Sun, James K. Liao http://www.jci.org/articles/view/29226 Rock1 (Rock1^+/–) and Rock2 (Rock2^+/–) mice and performed carotid artery ligations. Following this intervention, we found reduced neointima formation in Rock1^+/– mice compared with that of WT or Rock2^+/– mice. This correlated with decreased vascular smooth muscle cell proliferation and survival, decreased levels proinflammatory adhesion molecule expression, and reduced leukocyte infiltration. In addition, thioglycollate-induced peritoneal leukocyte recruitment and accumulation were substantially reduced in Rock1^+/– mice compared with those of WT and Rock2^+/– mice. To determine the role of leukocyte-derived ROCK1 in neointima formation, we performed reciprocal bone marrow transplantation (BMT) in WT and Rock1^+/– mice. Rock1^+/– to WT BMT led to reduced neointima formation and leukocyte infiltration following carotid ligation compared with those of WT to WT BMT. In contrast, WT to Rock1^+/– BMT resulted in increased neointima formation. These findings indicate that ROCK1 in BM-derived cells mediates neointima formation following vascular injury and suggest that ROCK1 may represent a promising therapeutic target in vascular inflammatory diseases. ]]> info:doi/10.1172/JCI29226 American Society for Clinical Investigation Kumar Sharma, Satish RamachandraRao, Gang Qiu, Hitomi Kataoka Usui, Yanqing Zhu, Stephen R. Dunn, Raogo Ouedraogo, Kelly Hough, Peter McCue, Lawrence Chan, Bonita Falkner, Barry J. Goldstein http://www.jci.org/articles/view/32691 Ad^–/–) mice. Albuminuria had a negative correlation with plasma adiponectin in obese patients, and Ad^–/– mice exhibited increased albuminuria and fusion of podocyte foot processes. In cultured podocytes, adiponectin administration was associated with increased activity of AMPK, and both adiponectin and AMPK activation reduced podocyte permeability to albumin and podocyte dysfunction, as evidenced by zona occludens–1 translocation to the membrane. These effects seemed to be caused by reduction of oxidative stress, as adiponectin and AMPK activation both reduced protein levels of the NADPH oxidase Nox4 in podocytes. Ad^–/– mice treated with adiponectin exhibited normalization of albuminuria, improvement of podocyte foot process effacement, increased glomerular AMPK activation, and reduced urinary and glomerular markers of oxidant stress. These results suggest that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes. ]]> info:doi/10.1172/JCI32691 American Society for Clinical Investigation Takaharu Ichimura, Edwin J.P.v. Asseldonk, Benjamin D. Humphreys, Lakshman Gunaratnam, Jeremy S. Duffield, Joseph V. Bonventre http://www.jci.org/articles/view/34487 info:doi/10.1172/JCI34487 American Society for Clinical Investigation Anja Fritsch, Stefan Loeckermann, Johannes S. Kern, Attila Braun, Michael R. Bösl, Thorsten A. Bley, Hauke Schumann, Dominik von Elverfeldt, Dominik Paul, Miriam Erlacher, Dirk Berens von Rautenfeld, Ingrid Hausser, Reinhard Fässler, Leena Bruckner-Tuderman http://www.jci.org/articles/view/34292 info:doi/10.1172/JCI34292 American Society for Clinical Investigation Beichu Guo, Elmer Y. Chang, Genhong Cheng http://www.jci.org/articles/view/33342 info:doi/10.1172/JCI33342 American Society for Clinical Investigation Juliana Hamzah, Delia Nelson, Gerd Moldenhauer, Bernd Arnold, Günter J. Hämmerling, Ruth Ganss http://www.jci.org/articles/view/33201 info:doi/10.1172/JCI33201 American Society for Clinical Investigation Peter S. Kim, Todd D. Armstrong, Hong Song, Matthew E. Wolpoe, Vivian Weiss, Elizabeth A. Manning, Lan Qing Huang, Satoshi Murata, George Sgouros, Leisha A. Emens, R. Todd Reilly, Elizabeth M. Jaffee http://www.jci.org/articles/view/34333 neu transgenic mice can be achieved by administration of neu-specific mAb concurrently with a HER-2/neu–expressing, GM-CSF–secreting whole cell vaccine. In this report, we show that one mechanism of improved antitumor activity induced by the combination of these 2 neu-targeted interventions was enhanced Fc-mediated activation of APCs. Specifically, in vivo studies demonstrated localization of radiolabeled neu-specific mAb at the vaccine site. Subsequently, increased accumulation of neu-specific mAb at the vaccine-draining lymph node correlated with increased vaccine cell uptake by DCs in vivo. This led to enhancement of CD8⁺ neu-specific T cell function in terms of proliferation, cytokine production, and central memory development. Thus, the administration of a neu-specific mAb with a neu-targeted GM-CSF–secreting tumor vaccine enhanced induction of neu-specific CD8⁺ T cells through Fc-mediated activation of DCs. This multimodality attack on the same tumor antigen may have the potential to overcome tolerance to self antigens and weaken the immunosuppressive networks within the tumor microenvironment. ]]> info:doi/10.1172/JCI34333 American Society for Clinical Investigation Maureen A. Su, Karen Giang, Kristina Žumer, Huimin Jiang, Irena Oven, John L. Rinn, Jason J. DeVoss, Kellsey P.A. Johannes, Wen Lu, James Gardner, Angela Chang, Paula Bubulya, Howard Y. Chang, B. Matija Peterlin, Mark S. Anderson http://www.jci.org/articles/view/34523 AIRE cause autoimmune polyglandular syndrome type 1 (APS 1), which manifests in a classic triad of hypoparathyroidism, adrenal insufficiency, and candidiasis. Interestingly, a kindred with a specific G228W AIRE variant presented with an autosomal dominant autoimmune phenotype distinct from APS 1. We utilized a novel G228W-knockin mouse model to show that this variant acted in a dominant-negative manner to cause a unique autoimmunity syndrome. In addition, the expression of a large number of Aire-regulated thymic antigens was partially inhibited in these animals, demonstrating the importance of quantitative changes in thymic antigen expression in determining organ-specific autoimmunity. Furthermore, the dominant-negative effect of the G228W variant was exerted through recruitment of WT Aire away from active sites of transcription in the nucleus of medullary thymic epithelial cells in vivo. Together, these results may demonstrate a mechanism by which autoimmune predisposition to phenotypes distinct from APS 1 can be mediated in a dominant-negative fashion by Aire. ]]> info:doi/10.1172/JCI34523 American Society for Clinical Investigation Matthias Ernst, Meri Najdovska, Dianne Grail, Therese Lundgren-May, Michael Buchert, Hazel Tye, Vance B. Matthews, Jane Armes, Prithi S. Bhathal, Norman R. Hughes, Eric G. Marcusson, James G. Karras, Songqing Na, Jonathon D. Sedgwick, Paul J. Hertzog, Brendan J. Jenkins http://www.jci.org/articles/view/34944 gp130^Y757F/Y757F mouse model of gastric cancer, which carries a mutated gp130 cytokine receptor signaling subunit that cannot bind the negative regulator of cytokine signaling SOCS3 and is characterized by hyperactivation of the signaling molecules STAT1 and STAT3, we have provided genetic evidence that IL-11 promotes chronic gastric inflammation and associated tumorigenesis. Expression of IL-11 was increased in gastric tumors in gp130^Y757F/Y757F mice, when compared with unaffected gastric tissue in wild-type mice, while gp130^Y757F/Y757F mice lacking the IL-11 ligand–binding receptor subunit (IL-11Rα) showed normal gastric STAT3 activation and IL-11 expression and failed to develop gastric tumors. Furthermore, reducing STAT3 activity in gp130^Y757F/Y757F mice, either genetically or by therapeutic administration of STAT3 antisense oligonucleotides, normalized gastric IL-11 expression and alleviated gastric tumor burden. Surprisingly, the genetic reduction of STAT1 expression also reduced gastric tumorigenesis in gp130^Y757F/Y757F mice and coincided with reduced gastric inflammation and IL-11 expression. Collectively, our data have identified IL-11 as a crucial cytokine promoting chronic gastric inflammation and associated tumorigenesis mediated by excessive activation of STAT3 and STAT1. ]]> info:doi/10.1172/JCI34944 American Society for Clinical Investigation Stefan Pfister, Wibke G. Janzarik, Marc Remke, Aurélie Ernst, Wiebke Werft, Natalia Becker, Grischa Toedt, Andrea Wittmann, Christian Kratz, Heike Olbrich, Rezvan Ahmadi, Barbara Thieme, Stefan Joos, Bernhard Radlwimmer, Andreas Kulozik, Torsten Pietsch, Christel Herold-Mende, Astrid Gnekow, Guido Reifenberger, Andrey Korshunov, Wolfram Scheurlen, Heymut Omran, Peter Lichter http://www.jci.org/articles/view/33656 BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment. ]]> info:doi/10.1172/JCI33656 American Society for Clinical Investigation Rodger E. Tiedemann, Xinliang Mao, Chang-Xin Shi, Yuan Xiao Zhu, Stephen E. Palmer, Michael Sebag, Ron Marler, Marta Chesi, Rafael Fonseca, P. Leif Bergsagel, Aaron D. Schimmer, A. Keith Stewart http://www.jci.org/articles/view/34149 CCND1 and CCND2, respectively) inhibits proliferation and is progressively cytotoxic in human myeloma cells. By screening a chemical library using a cell-based assay for inhibition of CCND2 trans-activation, we identified the plant cytokinin kinetin riboside as an inhibitor of CCND2 trans-activation. Kinetin riboside induced marked suppression of CCND2 transcription and rapidly suppressed cyclin D1 and D2 protein expression in primary myeloma cells and tumor lines, causing cell-cycle arrest, tumor cell–selective apoptosis, and inhibition of myeloma growth in xenografted mice. Mechanistically, kinetin riboside upregulated expression of transcription repressor isoforms of cAMP-response element modulator (CREM) and blocked both trans-activation of CCND2 by various myeloma oncogenes and cis-activation of translocated CCND1, suggesting induction of an overriding repressor activity that blocks multiple oncogenic pathways targeting cyclin D genes. These data support targeted repression of cyclin D genes as a therapeutic strategy for human malignancies. ]]> info:doi/10.1172/JCI34149 American Society for Clinical Investigation Stéphane Prost, Mikael Le Dantec, Sylvie Augé, Roger Le Grand, Sonia Derdouch, Gwenaelle Auregan, Nicole Déglon, Francis Relouzat, Anne-Marie Aubertin, Bernard Maillere, Isabelle Dusanter-Fourt, Marek Kirszenbaum http://www.jci.org/articles/view/33037 info:doi/10.1172/JCI33037 American Society for Clinical Investigation Christofer Samuelsson, Jürgen Hausmann, Henning Lauterbach, Michaela Schmidt, Shizuo Akira, Hermann Wagner, Paul Chaplin, Mark Suter, Meredith O’Keeffe, Hubertus Hochrein http://www.jci.org/articles/view/33940 info:doi/10.1172/JCI33940 American Society for Clinical Investigation Hiroshi Takayama, Yoshitaka Hosaka, Kazuyuki Nakayama, Kamon Shirakawa, Katsuki Naitoh, Tomokazu Matsusue, Mikihiko Shinozaki, Motoyasu Honda, Yukiko Yatagai, Tetsushi Kawahara, Jiro Hirose, Tooru Yokoyama, Michiru Kurihara, Shoji Furusako http://www.jci.org/articles/view/32513 info:doi/10.1172/JCI32513 American Society for Clinical Investigation Jennifer W. Hill, Kevin W. Williams, Chianping Ye, Ji Luo, Nina Balthasar, Roberto Coppari, Michael A. Cowley, Lewis C. Cantley, Bradford B. Lowell, Joel K. Elmquist http://www.jci.org/articles/view/32964 info:doi/10.1172/JCI32964 American Society for Clinical Investigation Paolo Monti, Miriam Scirpoli, Paola Maffi, Nadia Ghidoli, Francesca De Taddeo, Federico Bertuzzi, Lorenzo Piemonti, Marika Falcone, Antonio Secchi, Ezio Bonifacio http://www.jci.org/articles/view/35197 + T cells, highly enriched in autoreactive glutamic acid decarboxylase 65–specific T cell clones. Immunosuppression with FK506 and rapamycin after transplantation resulted in a chronic homeostatic expansion of T cells, which acquired effector function after immunosuppression was removed. In contrast, the cytostatic drug mycophenolate mofetil efficiently blocked homeostatic T cell expansion. We propose that the increased production of cytokines that induce homeostatic expansion could contribute to recurrent autoimmunity in transplanted patients with autoimmune disease and that therapy that prevents the expansion of autoreactive T cells will improve the outcome of islet transplantation. ]]> info:doi/10.1172/JCI35197 American Society for Clinical Investigation Yiling Mi, Dorothy Fiete, Jacques U. Baenziger http://www.jci.org/articles/view/32467 N-acetylgalactosamine structure (GalNAc-4-SO₄) that mediates its clearance from the blood. To determine the significance of this terminal structure, we ablated the gene encoding the sulfotransferase responsible for sulfate addition to GalNAc on LH, GalNAc-4-sulfotransferase-1 (GalNAc-4-ST1) in mice. Mice lacking GalNAc-4-ST1 exhibited increased levels of circulating LH. In male mice, this resulted in elevated levels of testosterone and precocious maturation of testis and seminal vesicles. Female mice lacking GalNAc-4-ST1 demonstrated elevated estrogen levels and exhibited precocious sexual maturation and increased fecundity. Female mice remained in estrus for prolonged periods and produced almost 50% more litters per mouse than wild-type mice over the same period of time. Thus, sulfate modification of the terminal glycosylation of LH plays a central role in regulating the hypothalamic-pituitary-gonad axis in vivo. ]]> info:doi/10.1172/JCI32467 American Society for Clinical Investigation Majed N. Aljamali, Paris Margaritis, Alexander Schlachterman, Shing Jen Tai, Elise Roy, Ralph Bunte, Rodney M. Camire, Katherine A. High http://www.jci.org/articles/view/32878 info:doi/10.1172/JCI32878 American Society for Clinical Investigation A. Ross Lopes, Paul Kellam, Abhishek Das, Claire Dunn, Antonia Kwan, Joanna Turner, Dimitra Peppa, Richard J. Gilson, Adam Gehring, Antonio Bertoletti, Mala K. Maini http://www.jci.org/articles/view/33402 + T cells are critical for a successful immune response to HBV infection. They are markedly diminished in number in patients who fail to control the virus, but the mechanisms resulting in their depletion remain ill defined. Here, we dissected the defective HBV-specific CD8⁺ T cell response associated with chronic HBV infection by gene expression profiling. We found that HBV-specific CD8⁺ T cells from patients with different clinical outcomes could be distinguished by their patterns of gene expression. Microarray analysis revealed that overlapping clusters of functionally related apoptotic genes were upregulated in HBV-specific CD8⁺ T cells from patients with chronic compared with resolved infection. Further analysis confirmed that levels of the proapoptotic protein Bcl2-interacting mediator (Bim) were upregulated in HBV-specific CD8⁺ T cells from patients with chronic HBV infection. Blocking Bim-mediated apoptosis enhanced recovery of HBV-specific CD8⁺ T cells both in culture and directly ex vivo. Consistent with evidence that Bim mediates apoptosis of CD8⁺ T cells expressing low levels of CD127 (IL-7R), the few surviving HBV-specific CD8⁺ T cells were CD127^hi and had elevated levels of the antiapoptotic protein Mcl1, suggesting they were amenable to IL-7–mediated rescue from apoptosis. We therefore postulate that Bim-mediated attrition of HBV-specific CD8⁺ T cells contributes to the inability of these cell populations to persist and control viral replication. ]]> info:doi/10.1172/JCI33402 American Society for Clinical Investigation Georg Hansmann, Vinicio A. de Jesus Perez, Tero-Pekka Alastalo, Cristina M. Alvira, Christophe Guignabert, Janine M. Bekker, Stefan Schellong, Takashi Urashima, Lingli Wang, Nicholas W. Morrell, Marlene Rabinovitch http://www.jci.org/articles/view/32503 info:doi/10.1172/JCI32503 American Society for Clinical Investigation Wei Jin, Mikyoung Chang, Emmanuel M. Paul, Geetha Babu, Andrew J. Lee, William Reiley, Ato Wright, Minying Zhang, Jun You, Shao-Cong Sun http://www.jci.org/articles/view/34257 info:doi/10.1172/JCI34257 American Society for Clinical Investigation Xin-Ming Shen, Taku Fukuda, Kinji Ohno, Steven M. Sine, Andrew G. Engel http://www.jci.org/articles/view/34527 info:doi/10.1172/JCI34527 American Society for Clinical Investigation Jormay Lim, Martin Balastik, Tae Ho Lee, Kazuhiro Nakamura, Yih-Cherng Liou, Anyang Sun, Greg Finn, Lucia Pastorino, Virginia M.-Y. Lee, Kun Ping Lu http://www.jci.org/articles/view/34308 info:doi/10.1172/JCI34308 American Society for Clinical Investigation Toshihiro Uesaka, Mayumi Nagashimada, Shigenobu Yonemura, Hideki Enomoto http://www.jci.org/articles/view/34425 RET gene are the primary cause of Hirschsprung disease (HSCR), or congenital intestinal aganglionosis. However, how RET malfunction leads to HSCR is not known. It has recently been shown that glial cell line–derived neurotrophic factor (GDNF) family receptor α1 (GFRα1), which binds to GDNF and activates RET, is essential for the survival of enteric neurons. In this study, we investigated Ret regulation of enteric neuron survival and its potential involvement in HSCR. Conditional ablation of Ret in postmigratory enteric neurons caused widespread neuronal death in the colon, which led to colonic aganglionosis. To further examine this finding, we generated a mouse model for HSCR by reducing Ret expression levels. These mice recapitulated the genetic and phenotypic features of HSCR and developed colonic aganglionosis due to impaired migration and successive death of enteric neural crest–derived cells. Death of enteric neurons was also induced in the colon, where reduction of Ret expression was induced after the period of enteric neural crest cell migration, indicating that diminished Ret expression directly affected the survival of colonic neurons. Thus, enteric neuron survival is sensitive to RET dosage, and cell death is potentially involved in the etiology of HSCR. ]]> info:doi/10.1172/JCI34425 American Society for Clinical Investigation Bret F. Bessac, Michael Sivula, Christian A. von Hehn, Jasmine Escalera, Lauren Cohn, Sven-Eric Jordt http://www.jci.org/articles/view/34192 2+ influx and membrane currents in an oxidant-sensitive subpopulation of chemosensory neurons. These responses were absent in neurons from mice lacking TRPA1, an ion channel of the transient receptor potential (TRP) gene family. TRPA1 channels were strongly activated by hypochlorite and hydrogen peroxide in primary sensory neurons and heterologous cells. In tests of respiratory function, Trpa1^–/– mice displayed profound deficiencies in hypochlorite- and hydrogen peroxide–induced respiratory depression as well as decreased oxidant-induced pain behavior. Our results indicate that TRPA1 is an oxidant sensor in sensory neurons, initiating neuronal excitation and subsequent physiological responses in vitro and in vivo. ]]> info:doi/10.1172/JCI34192 American Society for Clinical Investigation Salvatore Papa, Francesca Zazzeroni, Yang-Xin Fu, Concetta Bubici, Kellean Alvarez, Kathryn Dean, Peter A. Christiansen, Robert A. Anders, Guido Franzoso http://www.jci.org/articles/view/33913 Gadd45b in the regulation of hepatocyte fate during liver regeneration after partial hepatectomy. We generated Gadd45b^–/– mice and found that they exhibited decreased hepatocyte proliferation and increased PCD during liver regeneration. Notably, JNK activity was markedly increased and sustained in livers of Gadd45b^–/– mice compared with control animals after partial hepatectomy. Furthermore, imposition of a Jnk2-null mutation, attenuating JNK activity, completely rescued the regenerative response in Gadd45b^–/– mice. Interestingly, Gadd45β ablation did not affect hepatotoxic JNK signaling after a TNFR-mediated immune challenge, suggesting specificity in the inducible hepatic program for JNK restraint activated during distinct TNFR-mediated challenges. These data provide a basis for JNK suppression during liver regeneration and identify Gadd45β as a potential therapeutic target in liver diseases. ]]> info:doi/10.1172/JCI33913 American Society for Clinical Investigation Nathalie Sabaa, Lucia de Franceschi, Philippe Bonnin, Yves Castier, Giorgio Malpeli, Haythem Debbabi, Ariane Galaup, Micheline Maier-Redelsperger, Sophie Vandermeersch, Aldo Scarpa, Anne Janin, Bernard Levy, Robert Girot, Yves Beuzard, Christophe Leboeuf, Annie Henri, Stéphane Germain, Jean-Claude Dussaule, Pierre-Louis Tharaux http://www.jci.org/articles/view/33308 info:doi/10.1172/JCI33308 American Society for Clinical Investigation Arunima Ghosh, Wei Li, Maria Febbraio, Ricardo G. Espinola, Keith R. McCrae, Erin Cockrell, Roy L. Silverstein http://www.jci.org/articles/view/34904 – mice do not have a bleeding diathesis, we show here that they do have significantly prolonged thrombotic occlusion times in response to FeCl₃-induced vascular injury. Because cell-derived microparticles (MPs) are generated in response to vascular injury and circulate in patients with prothrombotic diseases, we hypothesized that PS exposed on their surfaces could be an endogenous CD36 ligand that transmits an activating signal to platelets. We found that MPs prepared from human ECs, monocytes, or platelets or isolated from blood of normal subjects bound to platelets. Binding was not observed with platelets from CD36^– donors and was inhibited by an anti-CD36 antibody or by blockade of exposed PS by annexin V or anti-PS IgM. Preincubation of platelets with MPs led to CD36-dependent augmentation of platelet activation in response to low doses of ADP, as assessed by measuring α_2bβ₃ activation, P-selectin expression, and aggregation. Immunofluorescence confocal microscopy of murine carotid thrombi from CD36^– mice showed a significant decrement in endothelial antigen accumulation, which suggests that CD36 plays a role in MP recruitment into thrombi. These results provide what we believe to be a novel role for CD36 in thrombosis. ]]> info:doi/10.1172/JCI34904 American Society for Clinical Investigation Motoyuki Otsuka, Min Zheng, Masaaki Hayashi, Jing-Dwan Lee, Osamu Yoshino, Shengcai Lin, Jiahuai Han http://www.jci.org/articles/view/33680 Dicer1 null alleles in mice has limited our ability to address the role of Dicer1 in normal mouse growth and development. To address this question, we used a mouse mutant with a hypomorphic Dicer1 allele (Dicer^d/d) and found that Dicer1 deficiency resulted in female infertility. This defect in female Dicer^d/d mice was caused by corpus luteum (CL) insufficiency and resulted, at least in part, from the impaired growth of new capillary vessels in the ovary. We found that the impaired CL angiogenesis in Dicer^d/d mice was associated with a lack of miR17-5p and let7b, 2 miRNAs that participate in angiogenesis by regulating the expression of the antiangiogenic factor tissue inhibitor of metalloproteinase 1. Furthermore, injection of miR17-5p and let7b into the ovaries of Dicer^d/d mice partially normalized tissue inhibitor of metalloproteinase 1 expression and CL angiogenesis. Our data indicate that the development and function of the ovarian CL is a physiological process that appears to be regulated by miRNAs and requires Dicer1 function. ]]> info:doi/10.1172/JCI33680 American Society for Clinical Investigation Mariacarmela Allocca, Monica Doria, Marco Petrillo, Pasqualina Colella, Maria Garcia-Hoyos, Daniel Gibbs, So Ra Kim, Albert Maguire, Tonia S. Rex, Umberto Di Vicino, Luisa Cutillo, Janet R. Sparrow, David S. Williams, Jean Bennett, Alberto Auricchio http://www.jci.org/articles/view/34316 Abca4 and human MYO7A and CEP290 genes, which are mutated in common blinding diseases, was obtained, suggesting that this packaging efficiency is independent of the specific sequence packaged. Expression of proteins of the appropriate size and function was observed following transduction with rAAV2/5 carrying large genes. Intraocular administration of rAAV2/5 encoding ABCA4 resulted in protein localization to rod outer segments and significant and stable morphological and functional improvement of the retina in Abca4^–/– mice. This use of rAAV2/5 may be a promising therapeutic strategy for recessive Stargardt disease, the most common form of inherited macular degeneration. The possibility of packaging large genes in AAV greatly expands the therapeutic potential of this vector system. ]]> info:doi/10.1172/JCI34316 American Society for Clinical Investigation Shingo Matsumoto, Fuminori Hyodo, Sankaran Subramanian, Nallathamby Devasahayam, Jeeva Munasinghe, Emi Hyodo, Chandramouli Gadisetti, John A. Cook, James B. Mitchell, Murali C. Krishna http://www.jci.org/articles/view/34928 2) in solid tumors, a key prognostic factor in cancer treatment outcome, could greatly improve treatment planning in radiotherapy and chemotherapy. Pulsed electron paramagnetic resonance imaging (EPRI) provides quantitative 3D maps of tissue pO₂ in living objects. In this study, we implemented an EPRI set-up that could acquire pO₂ maps in almost real time for 2D and in minutes for 3D. We also designed a combined EPRI and MRI system that enabled generation of pO₂ maps with anatomic guidance. Using EPRI and an air/carbogen (95% O₂ plus 5% CO₂) breathing cycle, we visualized perfusion-limited hypoxia in murine tumors. The relationship between tumor blood perfusion and pO₂ status was examined, and it was found that significant hypoxia existed even in regions that exhibited blood flow. In addition, high levels of lactate were identified even in normoxic tumor regions, suggesting the predominance of aerobic glycolysis in murine tumors. This report presents a rapid, noninvasive method to obtain quantitative maps of pO₂ in tumors, reported with anatomy, with precision. In addition, this method may also be useful for studying the relationship between pO₂ status and tumor-specific phenotypes such as aerobic glycolysis. ]]> info:doi/10.1172/JCI34928 American Society for Clinical Investigation Olga V. Nikolskaia, Ana Paula C. de A. Lima, Yuri V. Kim, John D. Lonsdale-Eccles, Toshihide Fukuma, Julio Scharfstein, Dennis J. Grab http://www.jci.org/articles/view/27798C1 info:doi/10.1172/JCI27798C1 American Society for Clinical Investigation Scott J. Brodie, Bruce K. Patterson, Deborah A. Lewinsohn, Kurt Diem, David Spach, Phillip D. Greenberg, Stanley R. Riddell, Lawrence Corey http://www.jci.org/articles/view/8707EX1 info:doi/10.1172/JCI8707EX1 American Society for Clinical Investigation