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/36589 info:doi/10.1172/JCI36589 American Society for Clinical Investigation Karen Honey http://www.jci.org/articles/view/36588 info:doi/10.1172/JCI36588 American Society for Clinical Investigation Harry Ostrer http://www.jci.org/articles/view/36572 info:doi/10.1172/JCI36572 American Society for Clinical Investigation Joshua Tate Dudman http://www.jci.org/articles/view/36571 info:doi/10.1172/JCI36571 American Society for Clinical Investigation Donald B. Bloch, Thomas J. Wang, Robert E. Gerszten http://www.jci.org/articles/view/36270 JCI, Cleutjens et al. describe the application of a peptide array technique toward the development of antibody biomarkers of ruptured atherosclerotic lesions (see the related article beginning on page 2979). A phage-display library was prepared from mRNA derived from ruptured peripheral human atherosclerotic plaques, and the phages containing immunoreactive peptides were screened with serum from patients with ruptured atherosclerotic lesions. Antibodies reacting with 2 peptides, E1 and E12, were particularly sensitive for the early diagnosis of acute myocardial infarction. Further studies that include an adequate number of patients presenting very early after the onset of symptoms and additional control patient populations are warranted to compare the utility of these biomarkers to those in clinical use. ]]> info:doi/10.1172/JCI36270 American Society for Clinical Investigation Bethan Psaila, James B. Bussel http://www.jci.org/articles/view/36451 JCI, two highly novel studies of Fc–FcR interactions provide new insights into the role of FcRs in immune thrombocytopenia. Asahi et al. utilized a comprehensive platform of immunological assays to examine the mechanism underlying Helicobacter pylori–associated immune thrombocytopenic purpura, and Ghevaert et al. describe a specially designed antibody that saturates binding sites on fetal platelets without initiating FcγR-mediated platelet phagocytosis, preventing the binding of pathological maternal anti-HLA antibodies that cause fetomaternal alloimmune thrombocytopenia (see the related articles beginning on pages 2939 and 2929, respectively). These reports illustrate how a remarkably detailed molecular understanding of the FcR network may translate into new therapeutic strategies with high clinical impact. ]]> info:doi/10.1172/JCI36451 American Society for Clinical Investigation Mark E. Kleinman, Jayakrishna Ambati http://www.jci.org/articles/view/36515 JCI, Yang et al. present a functional genetics study that identifies a role for prominin 1 (PROM1), best known as a stem cell and/or progenitor cell marker, in the biogenesis of retinal photoreceptor disk arrays (see the related article beginning on page 2908). This study supports an established model in which disk morphogenesis occurs through membrane evagination and extends other recent studies assigning PROM1 important functions outside of the stem cell niche. ]]> info:doi/10.1172/JCI36515 American Society for Clinical Investigation Vicki Seyfert-Margolis, Laurence A. Turka http://www.jci.org/articles/view/36552 JCI, Martínez-Llordella et al. identify a profile of biomarkers that predict tolerance in liver transplant recipients (see the related article beginning on page 2845). These findings translate into a new means for prospectively selecting liver transplant patients who would benefit from immunosuppression withdrawal and ultimately may guide development of tolerogenic therapies that allow for allograft acceptance without the use of long-term immunosuppression. ]]> info:doi/10.1172/JCI36552 American Society for Clinical Investigation Katherine P. Ponder http://www.jci.org/articles/view/36521 JCI, Dickson et al. demonstrate that anti-enzyme antibodies inhibit enzyme uptake and substantially limit the therapeutic efficacy of ERT in canines with MPS I (see the related article beginning on page 2868). Furthermore, the induction of immune tolerance — via oral delivery of cyclosporine A and azathioprine for two months at the time of initiation of ERT with recombinant human α-l-iduronidase — improved enzyme uptake in organs. Therefore, transient immunosuppression may enhance ERT for lysosomal storage diseases. ]]> info:doi/10.1172/JCI36521 American Society for Clinical Investigation Rubin M. Tuder, Jeong H. Yun http://www.jci.org/articles/view/36536 JCI, Kang et al. show that exposure to cigarette smoke induces alterations in the innate immune response to viral infection and that these changes hasten alveolar destruction characteristic of emphysema in mice (see the related beginning on page 2771). This study builds on evidence that patients with chronic obstructive pulmonary disease have clinical exacerbations associated with viral or bacterial infections, which lead to worsened lung function and increased mortality. This novel paradigm may aid related genetic, biomarker, and therapeutic developments and provides important insights into the pathogenesis of emphysematous lung destruction. ]]> info:doi/10.1172/JCI36536 American Society for Clinical Investigation Vishwajeet Puri, Michael P. Czech http://www.jci.org/articles/view/36554 JCI, Nishino et al. show that FSP27 also helps to maintain the characteristically large unilocular lipid droplet structure within each white adipocyte (see the related article beginning on page 2808). Fragmentation of lipid droplets in white adipocytes from FSP27-KO mice caused both increased lipolysis and upregulation of genes enhancing mitochondrial oxidative metabolism. This increased energy expenditure in turn protected the mice from diet-induced obesity and insulin resistance. These new results highlight powerful mechanisms that tightly coordinate rates of triglyceride storage in lipid droplets with mitochondrial fatty acid oxidation in white adipocytes. ]]> info:doi/10.1172/JCI36554 American Society for Clinical Investigation Zhi Gang Li, Paul Mathew, Jun Yang, Michael W. Starbuck, Amado J. Zurita, Jie Liu, Charles Sikes, Asha S. Multani, Eleni Efstathiou, Adriana Lopez, Jing Wang, Tina V. Fanning, Victor G. Prieto, Vikas Kundra, Elba S. Vazquez, Patricia Troncoso, Austin K. Raymond, Christopher J. Logothetis, Sue-Hwa Lin, Sankar Maity, Nora M. Navone http://www.jci.org/articles/view/33093 info:doi/10.1172/JCI33093 American Society for Clinical Investigation Goutham Narla, Analisa DiFeo, Yolanda Fernandez, Saravana Dhanasekaran, Fei Huang, Jaya Sangodkar, Eldad Hod, Devin Leake, Scott L. Friedman, Simon J. Hall, Arul M. Chinnaiyan, William L. Gerald, Mark A. Rubin, John A. Martignetti http://www.jci.org/articles/view/34780 KLF6) tumor suppressor gene, known as KLF6-SV1, in tumors from men after prostatectomy predicted markedly poorer survival and disease recurrence profiles. Analysis of tumor samples revealed that KLF6-SV1 levels were specifically upregulated in hormone-refractory metastatic PCa. In 2 complementary mouse models of metastatic PCa, KLF6-SV1–overexpressing PCa cells were shown by in vivo and ex vivo bioluminescent imaging to metastasize more rapidly and to disseminate to lymph nodes, bone, and brain more often. Interestingly, while KLF6-SV1 overexpression increased metastasis, it did not affect localized tumor growth. KLF6-SV1 inhibition using RNAi induced spontaneous apoptosis in cultured PCa cell lines and suppressed tumor growth in mice. Together, these findings demonstrate that KLF6-SV1 expression levels in PCa tumors at the time of diagnosis can predict the metastatic behavior of the tumor; thus, KLF-SV1 may represent a novel therapeutic target. ]]> info:doi/10.1172/JCI34780 American Society for Clinical Investigation Kristina E. Hoot, Jessyka Lighthall, Gangwen Han, Shi-Long Lu, Allen Li, Wenjun Ju, Molly Kulesz-Martin, Erwin Bottinger, Xiao-Jing Wang http://www.jci.org/articles/view/33713 Smad4^–/– mouse epidermis develops spontaneous skin squamous cell carcinomas (SCCs), and Smad3^–/– mice are resistant to carcinogen-induced skin cancer; however, the role of Smad2 in skin carcinogenesis has not been explored. In the present study, we found that Smad2 and Smad4, but not Smad3, were frequently lost in human SCCs. Mice with keratinocyte-specific Smad2 deletion exhibited accelerated formation and malignant progression of chemically induced skin tumors compared with WT mice. Consistent with the loss of Smad2 in poorly differentiated human SCCs, Smad2^–/– tumors were poorly differentiated and underwent epithelial-mesenchymal transition (EMT) prior to spontaneous Smad4 loss. Reduced E-cadherin and activation of its transcriptional repressor Snail were also found in Smad2^–/– mouse epidermis and occurred more frequently in Smad2-negative human SCCs than in Smad2-positive SCCs. Knocking down Snail abrogated Smad2 loss–associated EMT, suggesting that Snail upregulation is a major mediator of Smad2 loss–associated EMT. Furthermore, Smad2 loss led to a significant increase in Smad4 binding to the Snail promoter, and knocking down either Smad3 or Smad4 in keratinocytes abrogated Smad2 loss–associated Snail overexpression. Our data suggest that enhanced Smad3/Smad4-mediated Snail transcription contributed to Smad2 loss–associated EMT during skin carcinogenesis. ]]> info:doi/10.1172/JCI33713 American Society for Clinical Investigation Meizi Jiang, Hideaki Bujo, Kenji Ohwaki, Hiroyuki Unoki, Hiroyuki Yamazaki, Tatsuro Kanaki, Manabu Shibasaki, Kazuhiko Azuma, Kenichi Harigaya, Wolfgang J. Schneider, Yasushi Saito http://www.jci.org/articles/view/32381 LR11 gene greatly reduces intimal thickening of arteries through attenuation of Ang II–induced migration of SMCs. Serum concentrations of sLR11 were positively correlated with IMT in dyslipidemic subjects, and multivariable regression analysis suggested sLR11 levels as an index of IMT, independent of classical atherosclerosis risk factors. In Lr11^–/– mice, femoral artery intimal thickness after cuff placement was decreased, and Ang II–stimulated migration and attachment of SMCs from these mice were largely abolished. In isolated murine SMCs, sLR11 caused membrane ruffle formation via activation of focal adhesion kinase/ERK/Rac1 accompanied by complex formation between uPAR and integrin αvβ3, a process accelerated by Ang II. Overproduction of sLR11 decreased the sensitivity of Ang II–induced activation pathways to inhibition by an Ang II type 1 receptor blocker in mice. Thus, we demonstrate a requirement for sLR11 in Ang II–induced SMC migration and propose what we believe is a novel role for sLR11 as a biomarker of carotid IMT. ]]> info:doi/10.1172/JCI32381 American Society for Clinical Investigation Yassine Sassi, Larissa Lipskaia, Grégoire Vandecasteele, Viacheslav O. Nikolaev, Stéphane N. Hatem, Fleur Cohen Aubart, Frans G. Russel, Nathalie Mougenot, Cédric Vrignaud, Philippe Lechat, Anne-Marie Lompré, Jean-Sébastien Hulot http://www.jci.org/articles/view/35067 info:doi/10.1172/JCI35067 American Society for Clinical Investigation Byung-Kwan Lim, Dingding Xiong, Andrea Dorner, Tae-Jin Youn, Aaron Yung, Taylor I. Liu, Yusu Gu, Nancy D. Dalton, Adam T. Wright, Sylvia M. Evans, Ju Chen, Kirk L. Peterson, Andrew D. McCulloch, Toshitaka Yajima, Kirk U. Knowlton http://www.jci.org/articles/view/34777 info:doi/10.1172/JCI34777 American Society for Clinical Investigation Min-Jong Kang, Chun Geun Lee, Jae-Young Lee, Charles S. Dela Cruz, Zhijian J. Chen, Richard Enelow, Jack A. Elias http://www.jci.org/articles/view/32709 info:doi/10.1172/JCI32709 American Society for Clinical Investigation Guoqing Sheng, Xingshun Xu, Yung-Feng Lin, Chuan-En Wang, Juan Rong, Dongmei Cheng, Junmin Peng, Xiaoyan Jiang, Shi-Hua Li, Xiao-Jiang Li http://www.jci.org/articles/view/35339 Hap1-knockout mice showed significantly reduced Ahi1 levels, defective cerebellar development, and abnormal axonal decussation. Suppression of Ahi1 also decreased the level of Hap1; and truncated Ahi1, which corresponds to the mutations in Joubert syndrome, inhibited neurite outgrowth in neuronal culture. Reducing Hap1 expression suppressed the level and internalization of TrkB, a neurotrophic factor receptor that mediates neurogenesis and neuronal differentiation, which led to decreased TrkB signaling. These findings provide insight into the pathogenesis of Joubert syndrome and demonstrate the critical role of the Ahi1-Hap1 complex in early brain development. ]]> info:doi/10.1172/JCI35339 American Society for Clinical Investigation Fabrizio Trinchese, Mauro Fa’, Shumin Liu, Hong Zhang, Ariel Hidalgo, Stephen D. Schmidt, Hisako Yamaguchi, Narihiko Yoshii, Paul M. Mathews, Ralph A. Nixon, Ottavio Arancio http://www.jci.org/articles/view/34254 info:doi/10.1172/JCI34254 American Society for Clinical Investigation Naonobu Nishino, Yoshikazu Tamori, Sanshiro Tateya, Takayuki Kawaguchi, Tetsuro Shibakusa, Wataru Mizunoya, Kazuo Inoue, Riko Kitazawa, Sohei Kitazawa, Yasushi Matsuki, Ryuji Hiramatsu, Satoru Masubuchi, Asako Omachi, Kazuhiro Kimura, Masayuki Saito, Taku Amo, Shigeo Ohta, Tomohiro Yamaguchi, Takashi Osumi, Jinglei Cheng, Toyoshi Fujimoto, Harumi Nakao, Kazuki Nakao, Atsu Aiba, Hitoshi Okamura, Tohru Fushiki, Masato Kasuga http://www.jci.org/articles/view/34090 FSP27-deficient mice were protected from diet-induced obesity and insulin resistance and displayed an increased metabolic rate due to increased mitochondrial biogenesis in white adipose tissue (WAT). Depletion of FSP27 by siRNA in murine cultured white adipocytes resulted in the formation of numerous small lipid droplets, increased lipolysis, and decreased triacylglycerol storage, while expression of FSP27 in COS cells promoted the formation of large lipid droplets. Our results suggest that FSP27 contributes to efficient energy storage in WAT by promoting the formation of unilocular lipid droplets, thereby restricting lipolysis. In addition, we found that the nature of lipid accumulation in WAT appears to be associated with maintenance of energy balance and insulin sensitivity. ]]> info:doi/10.1172/JCI34090 American Society for Clinical Investigation John Falardeau, Wilson C.J. Chung, Andrew Beenken, Taneli Raivio, Lacey Plummer, Yisrael Sidis, Elka E. Jacobson-Dickman, Anna V. Eliseenkova, Jinghong Ma, Andrew Dwyer, Richard Quinton, Sandra Na, Janet E. Hall, Celine Huot, Natalie Alois, Simon H.S. Pearce, Lindsay W. Cole, Virginia Hughes, Moosa Mohammadi, Pei Tsai, Nelly Pitteloud http://www.jci.org/articles/view/34538 FGFR1) cause human GnRH deficiency, to date no specific ligand for FGFR1 has been identified in GnRH neuron ontogeny. Using a candidate gene approach, we identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes. These patients exhibited varied degrees of GnRH deficiency, including the rare adult-onset form of hypogonadotropic hypogonadism. Four mutations affected all 4 FGF8 splice isoforms (FGF8a, FGF8b, FGF8e, and FGF8f), while 2 mutations affected FGF8e and FGF8f isoforms only. The mutant FGF8b and FGF8f ligands exhibited decreased biological activity in vitro. Furthermore, mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. In conclusion, we identified FGF8 as a gene implicated in GnRH deficiency in both humans and mice and demonstrated an exquisite sensitivity of GnRH neuron development to reductions in FGF8 signaling. ]]> info:doi/10.1172/JCI34538 American Society for Clinical Investigation Alexey Bersenev, Chao Wu, Joanna Balcerek, Wei Tong http://www.jci.org/articles/view/35808 Lnk^–/– mice have an increased quiescent fraction, decelerated cell cycle kinetics, and enhanced resistance to repeat treatments with cytoablative 5-fluorouracil in vivo compared with WT HSCs. We further provide genetic evidence demonstrating that Lnk controls HSC quiescence and self-renewal, predominantly through Mpl. Consistent with this observation, Lnk^–/– HSCs displayed potentiated activation of JAK2 specifically in response to TPO. Biochemical experiments revealed that Lnk directly binds to phosphorylated tyrosine residues in JAK2 following TPO stimulation. Of note, the JAK2 V617F mutant, found at high frequencies in myeloproliferative diseases, retains the ability to bind Lnk. Therefore, we identified Lnk as a physiological negative regulator of JAK2 in stem cells and TPO/Mpl/JAK2/Lnk as a major regulatory pathway in controlling stem cell self-renewal and quiescence. ]]> info:doi/10.1172/JCI35808 American Society for Clinical Investigation Marc Martínez-Llordella, Juan José Lozano, Isabel Puig-Pey, Giuseppe Orlando, Giuseppe Tisone, Jan Lerut, Carlos Benítez, Jose Antonio Pons, Pascual Parrilla, Pablo Ramírez, Miquel Bruguera, Antoni Rimola, Alberto Sánchez-Fueyo http://www.jci.org/articles/view/35342 + T cells exerted the predominant influence. These data suggest that transcriptional profiling of peripheral blood can be employed to identify liver transplant recipients who can discontinue immunosuppressive therapy and that innate immune cells are likely to play a major role in the maintenance of operational tolerance in liver transplantation. ]]> info:doi/10.1172/JCI35342 American Society for Clinical Investigation Angel L. Pey, Ming Ying, Nunilo Cremades, Adrian Velazquez-Campoy, Tanja Scherer, Beat Thöny, Javier Sancho, Aurora Martinez http://www.jci.org/articles/view/34355 PAH). Over 500 disease-causing mutations have been identified in humans, most of which result in PAH protein misfolding and increased turnover in vivo. The use of pharmacological chaperones to stabilize or promote correct folding of mutant proteins represents a promising new direction in the treatment of misfolding diseases. We performed a high-throughput ligand screen of over 1,000 pharmacological agents and identified 4 compounds (I–IV) that enhanced the thermal stability of PAH and did not show substantial inhibition of PAH activity. In further studies, compounds III (3-amino-2-benzyl-7-nitro-4-(2-quinolyl)-1,2-dihydroisoquinolin-1-one) and IV (5,6-dimethyl-3-(4-methyl-2-pyridinyl)-2-thioxo-2,3-dihydrothieno[2,3- d]pyrimidin-4(1H)-one) stabilized the functional tetrameric conformation of recombinant WT-PAH and PKU mutants. These compounds also significantly increased activity and steady-state PAH protein levels in cells transiently transfected with either WT-PAH or PKU mutants. Furthermore, PAH activity in mouse liver increased after a 12-day oral administration of low doses of compounds III and IV. Thus, we have identified 2 small molecules that may represent promising alternatives in the treatment of PKU. ]]> info:doi/10.1172/JCI34355 American Society for Clinical Investigation Patricia Dickson, Maryn Peinovich, Michael McEntee, Thomas Lester, Steven Le, Aimee Krieger, Hayden Manuel, Catherine Jabagat, Merry Passage, Emil D. Kakkis http://www.jci.org/articles/view/34676 l-iduronidase successfully reduces lysosomal storage in canines and humans with iduronidase-deficient MPS I, but therapy usually also induces antibodies specific for the recombinant enzyme that could reduce its efficacy. To understand the potential impact of α-l-iduronidase–specific antibodies, we studied whether inducing antigen-specific immune tolerance to iduronidase could improve the effectiveness of recombinant iduronidase treatment in canines. A total of 24 canines with MPS I were either tolerized to iduronidase or left nontolerant. All canines received i.v. recombinant iduronidase at the FDA-approved human dose or a higher dose for 9–44 weeks. Nontolerized canines developed iduronidase-specific antibodies that proportionally reduced in vitro iduronidase uptake. Immune-tolerized canines achieved increased tissue enzyme levels at either dose in most nonreticular tissues and a greater reduction in tissue GAG levels, lysosomal pathology, and urinary GAG excretion. Tolerized MPS I dogs treated with the higher dose received some further benefit in the reduction of GAGs in tissues, urine, and the heart valve. Therefore, immune tolerance to iduronidase improved the efficacy of enzyme replacement therapy with recombinant iduronidase in canine MPS I and could potentially improve outcomes in patients with MPS I and other lysosomal storage diseases. ]]> info:doi/10.1172/JCI34676 American Society for Clinical Investigation Sara E. Pinney, Courtney MacMullen, Susan Becker, Yu-Wen Lin, Cheryl Hanna, Paul Thornton, Arupa Ganguly, Show-Ling Shyng, Charles A. Stanley http://www.jci.org/articles/view/35414 + (K_ATP) channel in the pancreatic β cell. Though most disease-causing mutations of the 2 genes encoding K_ATP subunits, ABCC8 (SUR1) and KCNJ11 (Kir6.2), are recessively inherited, some cases of dominantly inherited inactivating mutations have been reported. To better understand the differences between dominantly and recessively inherited inactivating K_ATP mutations, we have identified and characterized 16 families with 14 different dominantly inherited K_ATP mutations, including a total of 33 affected individuals. The 16 probands presented with hypoglycemia at ages from birth to 3.3 years, and 15 of 16 were well controlled on diazoxide, a K_ATP channel agonist. Of 29 adults with mutations, 14 were asymptomatic. In contrast to a previous report of increased diabetes risk in dominant K_ATP hyperinsulinism, only 4 of 29 adults had diabetes. Unlike recessive mutations, dominantly inherited K_ATP mutant subunits trafficked normally to the plasma membrane when expressed in COSm6 cells. Dominant mutations also resulted in different channel-gating defects, as dominant ABCC8 mutations diminished channel responses to magnesium adenosine diphosphate or diazoxide, while dominant KCNJ11 mutations impaired channel opening, even in the absence of nucleotides. These data highlight distinctive features of dominant K_ATP hyperinsulinism relative to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy, without the need for surgical pancreatectomy. ]]> info:doi/10.1172/JCI35414 American Society for Clinical Investigation Bertrand Huard, Thomas McKee, Carine Bosshard, Stéphane Durual, Thomas Matthes, Samir Myit, Olivier Donze, Christophe Frossard, Carlo Chizzolini, Christiane Favre, Rudolf Zubler, Jean Philippe Guyot, Pascal Schneider, Eddy Roosnek http://www.jci.org/articles/view/33760 L, and mcl-1. The in situ localization of APRIL was consistent with such a prosurvival role in MALT. In upper MALT, tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils recruited from the blood infiltrated the crypt epithelium. Heparan sulfate proteoglycans (HSPGs) retained secreted APRIL in the subepithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL, giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. Furthermore, we found that mucosal humoral immunity in APRIL-deficient mice is less persistent than in WT mice. Hence, production of APRIL by inflammation-recruited neutrophils may create plasma cell niches in MALT to sustain a local antibody production. ]]> info:doi/10.1172/JCI33760 American Society for Clinical Investigation Ying-Hua Wang, Betty Diamond http://www.jci.org/articles/view/35618 info:doi/10.1172/JCI35618 American Society for Clinical Investigation Zhenglin Yang, Yali Chen, Concepcion Lillo, Jeremy Chien, Zhengya Yu, Michel Michaelides, Martin Klein, Kim A. Howes, Yang Li, Yuuki Kaminoh, Haoyu Chen, Chao Zhao, Yuhong Chen, Youssef Tawfik Al-Sheikh, Goutam Karan, Denis Corbeil, Pascal Escher, Shin Kamaya, Chunmei Li, Samantha Johnson, Jeanne M. Frederick, Yu Zhao, Changguan Wang, D. Joshua Cameron, Wieland B. Huttner, Daniel F. Schorderet, Frances L. Munier, Anthony T. Moore, David G. Birch, Wolfgang Baehr, David M. Hunt, David S. Williams, Kang Zhang http://www.jci.org/articles/view/35891 PROM1) causes 3 forms of autosomal-dominant macular degeneration. In transgenic mice expressing R373C mutant human PROM1, both mutant and endogenous PROM1 were found throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments, where PROM1 is normally localized. Moreover, the outer segment disk membranes were greatly overgrown and misoriented, indicating defective disk morphogenesis. Immunoprecipitation studies showed that PROM1 interacted with protocadherin 21 (PCDH21), a photoreceptor-specific cadherin, and with actin filaments, both of which play critical roles in disk membrane morphogenesis. Collectively, our results identify what we believe to be a novel complex involved in photoreceptor disk morphogenesis and indicate a possible role for PROM1 and PCDH21 in macular degeneration. ]]> info:doi/10.1172/JCI35891 American Society for Clinical Investigation Daniel Cruz, Andrew D. Watson, Christopher S. Miller, Dennis Montoya, Maria-Teresa Ochoa, Peter A. Sieling, Miguel A. Gutierrez, Mohamad Navab, Srinivasa T. Reddy, Joseph L. Witztum, Alan M. Fogelman, Thomas H. Rea, David Eisenberg, Judith Berliner, Robert L. Modlin http://www.jci.org/articles/view/34189 Mycobacterium leprae, the causative agent of leprosy, is thought to be the mycobacterium most dependent on host metabolic pathways, including host-derived lipids. Although fatty acids and phospholipids accumulate in the lesions of individuals with the lepromatous (also known as disseminated) form of human leprosy (L-lep), the origin and significance of these lipids remains unclear. Here we show that in human L-lep lesions, there was preferential expression of host lipid metabolism genes, including a group of phospholipases, and that these genes were virtually absent from the mycobacterial genome. Host-derived oxidized phospholipids were detected in macrophages within L-lep lesions, and 1 specific oxidized phospholipid, 1-palmitoyl-2-(5,6-epoxyisoprostane E₂)-sn-glycero-3-phosphorylcholine (PEIPC), accumulated in macrophages infected with live mycobacteria. Mycobacterial infection and host-derived oxidized phospholipids both inhibited innate immune responses, and this inhibition was reversed by the addition of normal HDL, a scavenger of oxidized phospholipids, but not by HDL from patients with L-lep. The accumulation of host-derived oxidized phospholipids in L-lep lesions is strikingly similar to observations in atherosclerosis, which suggests that the link between host lipid metabolism and innate immunity contributes to the pathogenesis of both microbial infection and metabolic disease. ]]> info:doi/10.1172/JCI34189 American Society for Clinical Investigation Cedric Ghevaert, David A. Wilcox, Juan Fang, Kathryn L. Armour, Mike R. Clark, Willem H. Ouwehand, Lorna M. Williamson http://www.jci.org/articles/view/34708 + platelets and substantially inhibited binding of clinical HPA-1a–specific sera to HPA-1a⁺ platelets. The response of monocytes to B2G1Δnab-sensitized platelets was substantially less than their response to unmodified B2G1, as measured by chemiluminescence. In addition, B2G1Δnab inhibited chemiluminescence induced by B2G1 and HPA-1a–specific sera. In a chimeric mouse model, B2G1 and polyclonal Ig preparations from clinical HPA-1a–specific sera reduced circulating HPA-1a⁺ platelets, concomitant with transient thrombocytopenia. As the Δnab constant region is uninformative in mice, F(ab′)₂ B2G1 was used as a proof of principle blocking antibody and prevented the in vivo platelet destruction seen with B2G1 and polyclonal HPA-1a–specific antibodies. These results provide rationale for human clinical studies. ]]> info:doi/10.1172/JCI34708 American Society for Clinical Investigation Atsuko Asahi, Tetsuya Nishimoto, Yuka Okazaki, Hidekazu Suzuki, Tatsuhiro Masaoka, Yutaka Kawakami, Yasuo Ikeda, Masataka Kuwana http://www.jci.org/articles/view/34496 Helicobacter pylori, the number of platelets recovers after eradication of H. pylori. To examine the role of H. pylori infection in the pathogenesis of ITP, the response of 34 ITP patients to treatment with a standard H. pylori eradication regimen, irrespective of whether they were infected with H. pylori, was evaluated. Eradication of H. pylori was achieved in all H. pylori–positive patients, and a significant increase in platelets was observed in 61% of these patients. By contrast, none of the H. pylori–negative patients showed increased platelets. At baseline, monocytes from the H. pylori–positive patients exhibited an enhanced phagocytic capacity and low levels of the inhibitory Fcγ receptor IIB (FcγRIIB). One week after starting the H. pylori eradication regimen, this activated monocyte phenotype was suppressed and improvements in autoimmune and platelet kinetic parameters followed. Modulation of monocyte FcγR balance was also found in association with H. pylori infection in individuals who did not have ITP and in mice. Our findings strongly suggest that the recovery in platelet numbers observed in ITP patients after H. pylori eradication is mediated through a change in FcγR balance toward the inhibitory FcγRIIB. ]]> info:doi/10.1172/JCI34496 American Society for Clinical Investigation Jaemin Lee, Bruno Di Jeso, Peter Arvan http://www.jci.org/articles/view/35164 info:doi/10.1172/JCI35164 American Society for Clinical Investigation Hiraku Ono, Alessandro Pocai, Yuhua Wang, Hideyuki Sakoda, Tomoichiro Asano, Jonathan M. Backer, Gary J. Schwartz, Luciano Rossetti http://www.jci.org/articles/view/34277 info:doi/10.1172/JCI34277 American Society for Clinical Investigation Joshua H. Wong, Jonathan Dukes, Robert E. Levy, Brandon Sos, Sara E. Mason, Tina S. Fong, Ethan J. Weiss http://www.jci.org/articles/view/34957 little (lit) mice were protected from thrombosis, and pulsatile GH given to lit mice restored the male clotting phenotype. Moreover, pulsatile GH administration resulted in a male clotting phenotype in control female mice, while continuous GH caused a female clotting phenotype in control male mice. Expression of the coagulation inhibitors Proc, Serpinc1, Serpind1, and Serpina5 were strongly modulated by sex-specific GH patterns, and GH modulated resistance to activated protein C. These results reveal what we believe to be a novel mechanism whereby sex-specific GH patterns mediate sex differences in thrombosis through coordinated changes in the expression of coagulation inhibitor genes in the liver. ]]> info:doi/10.1172/JCI34957 American Society for Clinical Investigation Kitty B.J.M. Cleutjens, Birgit C.G. Faber, Mat Rousch, Ruben van Doorn, Tilman M. Hackeng, Cornelis Vink, Piet Geusens, Hugo ten Cate, Johannes Waltenberger, Vadim Tchaikovski, Marc Lobbes, Veerle Somers, Anneke Sijbers, Darcey Black, Peter J.E.H.M. Kitslaar, Mat J.A.P. Daemen http://www.jci.org/articles/view/32767 info:doi/10.1172/JCI32767 American Society for Clinical Investigation Hewang Li, Ines Armando, Peiying Yu, Crisanto Escano, Susette C. Mueller, Laureano Asico, Annabelle Pascua, Quansheng Lu, Xiaoyan Wang, Van Anthony M. Villar, John E. Jones, Zheng Wang, Ammasi Periasamy, Yuen-Sum Lau, Patricio Soares-da-Silva, Karen Creswell, Gaétan Guillemette, David R. Sibley, Gilbert Eisner, John J. Gildea, Robin A. Felder, Pedro A. Jose http://www.jci.org/articles/view/33637C1 info:doi/10.1172/JCI33637C1 American Society for Clinical Investigation Yosuke Kawasaki, Fumitaka Kugimiya, Hirotaka Chikuda, Satoru Kamekura, Toshiyuki Ikeda, Naohiro Kawamura, Taku Saito, Yusuke Shinoda, Akiro Higashikawa, Fumiko Yano, Toru Ogasawara, Naoshi Ogata, Kazuto Hoshi, Franz Hofmann, James R. Woodgett, Kozo Nakamura, Ung-il Chung, Hiroshi Kawaguchi http://www.jci.org/articles/view/35243E1 info:doi/10.1172/JCI35243E1 American Society for Clinical Investigation