Nature Medicine Contents: October 2013 Volume 19 Number 10 pp 1191-1350

TABLE OF CONTENTS October 2013 Volume 19, Issue 10 Podcast Focus Editorial News Correction Book Review News and Views Community Corner Between Bedside and Bench Research Highlights Essays Review Articles Letters Technical Reports Advertisement   Watch 126 sessions from the leading infectious diseases and antimicrobial agents conference, ICAAC 2013. Presentations cover antimicrobial resistance, vaccine development, immunology, microbial pathogenesis, laboratory diagnostics, clinical trials, and more. Earn AMA PRA Category 1 Credits™, view abstracts, and tour the iPoster Hall. www.icaaconline.com Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Frontiers in Internal Medicine is sending out a call to active physicians and expert clinicians to help us build a dynamic, highly regarded editorial board! We're looking for Specialist Chief Editor for Nuclear Medicine, Family Medicine and Hematology, amongst other key specialities in this field. Be a part of the future of research publication.    Nature Medicine Podcast  Top Virus protection A two-drug combo guards against the deadly MERS virus in monkeys, and a set of naturally occurring immune cells could form the basis of a universal flu vaccine in people. Listen Now Editorial Top Animal research: a balancing act   p1191 doi:10.1038/nm.3382 Gains in human health come at the expense of animals in the lab. But denying those gains by hampering animal research could be far costlier. News Top Polypill improves adherence but fails to win all scientists' hearts   p1192 Alla Katsnelson doi:10.1038/nm1013-1192 First IL-6-blocking drug nears approval for rare blood disorder   p1193 Sarah C P Williams doi:10.1038/nm1013-1193 Syrian gas attack reinforces need for better anti-sarin drugs   pp1194 - 1195 Elie Dolgin doi:10.1038/nm1013-1194 Caution urged over the FDA's new breakthrough designation   p1196 Kevin Jiang doi:10.1038/nm1013-1196a Scientists express growing reluctance to share study protocols   p1196 Elizabeth Devitt doi:10.1038/nm1013-1196b Q&A Straight talk with...Daniel Levy   p1197 doi:10.1038/nm1013-1197 Thanks to the automatic cuts in US government spending, the approximately $9-million-per-year contract the Framingham Heart Study receives from the US National Heart, Lung, and Blood Institute was reduced by $4 million on 1 August. Overseeing the budget-related turbulence is Daniel Levy, a medical officer at the NHLBI who joined the FHS nearly 30 years ago and has served as the study's director since 1994. Elie Dolgin met with Levy to discuss how he's taking the new funding realities to heart. News in Brief Biomedical briefing   pp1198 - 1199 doi:10.1038/nm1013-1198 Correction Top Correction   p1199 doi:10.1038/nm1013-1199 News Top News Feature Finding the right chemistry   pp1200 - 1203 Killugudi Jayaraman doi:10.1038/nm1013-1200 Discovering the right compound that can treat an infection such as HIV is only the first piece of the drug development puzzle. The next challenge is to make the manufacturing process more efficient[mdash]and thereby cheaper. Killugudi Jayaraman meets with the 'process chemistry' experts honing these reactions to bring down the cost of antiretrovirals. Opinion Animal experiments deserve a place on drug labels   p1204 Robert Winston doi:10.1038/nm1013-1204 Drug development depends on preclinical experimentation in animal models. To make the public aware of the vital role of these studies, pharmaceutical companies should be legally obliged to make note of this on their products that came to fruition through animal research. Book Review Top Nasty priority disputes   p1205 Melissa S Anderson reviews Prize Fight: The Race and the Rivalry to be the First in Science by Morton A. Meyers doi:10.1038/nm.3292 News and Views Top Therapeutically reeducating macrophages to treat GBM   pp1207 - 1208 Christopher Garris and Mikael J Pittet doi:10.1038/nm.3355 Glioblastoma multiforme (GBM) is the most common type of aggressive malignant brain cancer. The current lack of successful therapeutics means that this disease has a dismal prognosis. However, a new study in mice offers hope for patients with GBM by demonstrating the efficacy of a novel drug that targets GBM-associated macrophages (pages 1264-1272). See also: Article by Pyonteck et al. To B or not to B[mdash]that is the question for myocardial infarction   pp1208 - 1210 Nancy D Kim and Andrew D Luster doi:10.1038/nm.3367 After myocardial infarction (MI), circulating B cells produce the chemokine Ccl7, which mobilizes inflammatory monocytes from the bone marrow into the blood, after which they are then recruited to the injured heart, a new study shows. B cell depletion after MI limits myocardial injury and improves heart function, suggesting a new approach for the management of acute MI (pages 1273-1280). See also: Article by Zouggari et al. NKT cells: the smoking gun in fungal-induced asthma?   pp1210 - 1211 Dale I Godfrey, Daniel G Pellicci and Jamie Rossjohn doi:10.1038/nm.3360 Aspergillus fumigatus is a fungus that is associated with a severe form of asthma, although the precise immunological basis for this disease is unclear. A new study in mice shows that natural killer T (NKT) cells are crucial for progression of A. fumigatus-induced asthma and also identifies a glycolipid antigen from this fungus that seems to drive this NKT cell-mediated inflammatory response (pages 1297-1304). See also: Article by Albacker et al. Akt2 relaxes podocytes in chronic kidney disease   pp1212 - 1213 Jochen Reiser doi:10.1038/nm.3357 A signaling cascade is activated in podocytes to induce survival and cope with stress during advanced glomerular disease, a new study shows. The findings may also explain why the immunosuppressor sirolimus, an inhibitor of this pathway, can cause proteinuria in a subset of patients with chronic kidney disease (pages 1288-1296). See also: Article by Canaud et al. Nature Medicine JOBS of the week Postdoctoral Fellow Johns Hopkins Hospital Postdoctoral Research Assistant University of Edinburgh PhD Scholarship NUI Galway PhD Student Position University of Geneva More Science jobs from Nature Medicine EVENT NanoBio-Europe Congress 2014 02.06.14 M�nster, Germany More science events from Community Corner Top Semagacestat's fall: where next for AD therapies?   pp1214 - 1215 doi:10.1038/nm.3365 Between Bedside and Bench Top Metabolic Disease Puts Up a Fight: Are diet and exercise helpful for the heart?   pp1216 - 1217 Julie A Lovshin and Daniel J Drucker doi:10.1038/nm.3370 Given the multisystemic nature of the metabolic syndrome, the field is now aiming at perusing both intrinsic and environmental factors from a biological and therapeutic standpoint. Physicians often advise obese individuals suffering from type 2 diabetes to lose weight through exercise and healthy diets. Although it may be an obvious recommendation, a large study has recently shown that weight loss achieved through these lifestyle changes does not significantly reduce cardiovascular disease events in these patients compared to conventional diabetes care. In 'Bedside to Bench', Julie A. Lovshin and Daniel J. Drucker discuss the limitations of this study, the conclusions that can be drawn regarding the true benefit of weight loss in this context and the molecular factors that deserve further attention at the bench in light of this trial. In 'Bench to Bedside', Eleftheria Maratos-Flier examines the role of antidiabetic drugs in both host and gut microbiota metabolism. These effects in the intestinal flora support advocating an increase in our understanding of how the gut microbiome affects obesity for finding the means to harness its therapeutic potential. Metabolic Disease Puts Up a Fight: Microbes, metabolism and medications   pp1218 - 1219 Eleftheria Maratos-Flier doi:10.1038/nm.3373 Research Highlights Top Metabolism: REG[gamma]ulating lipid metabolism | Diseases of the nervous system: The complexity of compensation | Inflammatory diseases: Blocking lymphocyte access | Bone metastases: Bad to the bone | New from NPG | Inflammation: Monocytes on the clock | Myeloproliferative disease: Leukemic cells hijack the niche Essays Top Juxtapositions in Trafalgar Square: tip-offs to creativity in art and science   pp1222 - 1226 Joseph L Goldstein doi:10.1038/nm.3329 A molecular machine for neurotransmitter release: synaptotagmin and beyond   pp1227 - 1231 Thomas C Sudhof doi:10.1038/nm.3338 In search of the molecular mechanism of intracellular membrane fusion and neurotransmitter release   pp1232 - 1235 Richard H Scheller doi:10.1038/nm.3339 The multichannel cochlear implant for severe-to-profound hearing loss   pp1236 - 1239 Graeme M Clark doi:10.1038/nm.3340 The importance of being flexible   pp1240 - 1244 Ingeborg Hochmair doi:10.1038/nm.3341 Toward better representations of sound with cochlear implants   pp1245 - 1248 Blake S Wilson doi:10.1038/nm.3343 An interview with Bill and Melinda Gates   pp1249 - 1251 doi:10.1038/nm.3331 Bill and Melinda Gates have led a profound transformation in the way we view the world's most pressing health concerns, looking for effective ways to improve the lives of millions of people. Claire Pomeroy, president of the Albert and Mary Lasker Foundation, spoke with them about their current concerns and plans to advance their agenda. Review Top Brown and beige fat: development, function and therapeutic potential   pp1252 - 1263 Matthew Harms and Patrick Seale doi:10.1038/nm.3361 There is much interest in brown and beige adipocytes, as their thermogenic activities can suppress weight gain and metabolic disease in rodent models. The authors review recent data that have provided new insights into the development and biology of brown and beige adipocytes and critically assess the possibilities for manipulating these cells to combat obesity and its associated diseases. Articles Top CSF-1R inhibition alters macrophage polarization and blocks glioma progression   pp1264 - 1272 Stephanie M Pyonteck, Leila Akkari, Alberto J Schuhmacher, Robert L Bowman, Lisa Sevenich et al. doi:10.1038/nm.3337 The authors provide preclinical testing of a CSFR-1 inhibitor in proneural glioma models. The compound targets macrophages in the tumor microenvironment rather than tumor cells themselves and is shown to portend considerable antitumor effects. Its activity relies on re-education of tumor-associated macrophages without affecting their survival, reverting their tumor-promoting phenotype. Moreover, gene signatures capturing the tumorigenic features of macrophages can predict survival in human patients with glioma, underscoring the potential relevance of this strategy as a glioma therapy. See also: News and Views by Garris & Pittet B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction   pp1273 - 1280 Yasmine Zouggari, Hafid Ait-Oufella, Philippe Bonnin, Tabassome Simon, Andrew P Sage et al. doi:10.1038/nm.3284 After myocardial infarction, inflammatory cells are rapidly recruited to the heart and strongly affect the course of recovery. Ziad Mallat and his colleagues uncover a pathogenic role for B cells after myocardial infarction, showing that infarction triggers B cell secretion of the chemokine Ccl7, which mobilizes monocytes from the bone marrow, increases their recruitment to the heart and impairs heart function. See also: News and Views by Kim & Luster Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor   pp1281 - 1287 Takehiro Torisu, Kumiko Torisu, In Hye Lee, Jie Liu, Daniela Malide et al. doi:10.1038/nm.3288 In the process of autophagy, cellular constituents are degraded and recycled. Toren Finkel and his colleagues show that this process also regulates the secretion of a key blood-clotting protein by endothelial cells, such that transient inhibition of autophagy might be therapeutically useful for treating thrombotic disorders. AKT2 is essential to maintain podocyte viability and function during chronic kidney disease   pp1288 - 1296 Guillaume Canaud, Frank Bienaime, Amandine Viau, Caroline Treins, William Baron et al. doi:10.1038/nm.3313 Rapamycin (also known as sirolimus) is a potent immunosuppressive drug that is often used after organ transplant to prevent rejection, but it also can cause kidney dysfunction. Fabiola Terzi and her colleagues now show this side effect of rapamycin is due to targeting of mTORC2 and suppression of AKT2 activity in podocytes. They also show that AKT2 normally acts to maintain podocyte viability and structure during chronic kidney disease. See also: News and Views by Reiser Invariant natural killer T cells recognize a fungal glycosphingolipid that can induce airway hyperreactivity   pp1297 - 1304 Lee A Albacker, Vinod Chaudhary, Ya-Jen Chang, Hye Young Kim, Ya-Ting Chuang et al. doi:10.1038/nm.3321 Sensitization to the fungus Aspergillus fumigatus is associated with allergic airway disease and asthma. Now Dale Umetsu and colleagues report that invariant natural killer T (iNKT) cells directly recognize the glycosphingolipid asperamide B derived from A. fumigatus. Asperamide B stains and activates mouse and human iNKT cells and induces airway hyper-reactivity in mice, suggesting that fungi can be directly detected by iNKT cells. See also: News and Views by Godfrey et al. Cellular immune correlates of protection against symptomatic pandemic influenza   pp1305 - 1312 Saranya Sridhar, Shaima Begom, Alison Bermingham, Katja Hoschler, Walt Adamson et al. doi:10.1038/nm.3350 The correlates of protection against illness caused by natural influenza infection in seronegative individuals is important for the design of vaccines capable of conferring immunity against different influenza virus strains. Sridhar et al. now report their analysis of individuals infected by the 2009 H1N1 pandemic influenza virus and show that the presence of pre-existing CD8+ T cell responses to conserved influenza epitopes is associated with reduced severity of illness. The findings support the importance of developing universal influenza vaccines that are capable of inducing crossreactive T cell responses to mitigate influenza illness. Letters Top Treatment with interferon-[alpha]2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques   pp1313 - 1317 Darryl Falzarano, Emmie de Wit, Angela L Rasmussen, Friederike Feldmann, Atsushi Okumura et al. doi:10.1038/nm.3362 The Middle East respiratory syndrome coronavirus (MERS-CoV) has killed [sim]50% of individuals known to be infected, making understanding its mechanisms of transmission and pathogenesis and identifying candidate treatments a high priority. Heinz Feldmann, Vincent J. Munster and Michael G. Katze and their colleagues now report that treating MERS-CoV-infected rhesus macaques with interferon-[alpha]2b and ribavirin reduced virus replication and infection severity, suggesting the potential use of this combination for the clinical treatment of infected humans. Endogenous factor VIII synthesis from the intron 22-inverted F8 locus may modulate the immunogenicity of replacement therapy for hemophilia A   pp1318 - 1324 Gouri Shankar Pandey, Chen Yanover, Lisa M Miller-Jenkins, Susan Garfield, Shelley A Cole et al. doi:10.1038/nm.3270 Patients with hemophilia lacking functional coagulation factor VIII (FVIII) are treated with replacement FVIII proteins. The development of neutralizing antibodies to the replacement FVIII, a major clinical problem, depends on the nature of the mutation in the gene encoding FVIII. The authors find that a prevalent inversion allele can unexpectedly produce FVIII protein, explaining why individuals with this allele do not frequently develop neutralizing antibodies. Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes   pp1325 - 1330 Cullen M Taniguchi, Elizabeth C Finger, Adam J Krieg, Colleen Wu, Anh N Diep et al. doi:10.1038/nm.3294 In two separate studies, Amato Giaccia and Calvin Kuo and colleagues show that targeting of hypoxia-inducible factor-2[alpha] to increase its expression results in elevation of a key downstream effector of insulin signaling and thus improved insulin sensitivity in a mouse model of type 2 diabetes. A liver Hif-2[alpha]-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition   pp1331 - 1337 Kevin Wei, Stephanie M Piecewicz, Lisa M McGinnis, Cullen M Taniguchi, Stanley J Wiegand et al. doi:10.1038/nm.3295 In two separate studies, Amato Giaccia and Calvin Kuo and colleagues show that targeting of hypoxia-inducible factor-2[alpha] to increase its expression results in elevation of a key downstream effector of insulin signaling and thus improved insulin sensitivity in a mouse model of type 2 diabetes. Technical Reports Top Tracking adipogenesis during white adipose tissue development, expansion and regeneration   pp1338 - 1344 Qiong A Wang, Caroline Tao, Rana K Gupta and Philipp E Scherer doi:10.1038/nm.3324 Qiong Wang and colleagues introduce the AdipoChaser mouse, an in vivo tool to track the formation and turnover of adipocytes. They use this inducible mature adipocyte lineage-tracing system to monitor adipogenesis and follow the formation of white and beige adipocytes under different conditions: high-fat diet, cold exposure and [beta]-adrenergic stimulation. The system produced some interesting findings on in vivo adipogenesis, including that beige adipocytes differentiate de novo from specialized precursors rather than by transdifferentiation of mature white adipocytes. Quantitative imaging of disease signatures through radioactive decay signal conversion   pp1345 - 1350 Daniel L J Thorek, Anuja Ogirala, Bradley J Beattie and Jan Grimm doi:10.1038/nm.3323 Thorek et al. describe an activatable imaging agent based on a radioactive decay signal through the Cerenkov luminescence effect, which is light produced by [beta]-particle-emitting radionuclides, such as clinically available PET tracers. The approach offers a means of simultaneously investigating multiple disease-relevant biological activities in vivo[mdash]the radioluminescent readout providing a quantitative measure of enzymatic activation with reduced background. Top Advertisement Nature Medicine and Eli Lilly and Company present: Shifting Paradigms on Alzheimer's Disease December 3, 2013 Lilly Corporate Center, Indianapolis, IN, USA  Click here to register for this symposium today!     Natureevents is a fully searchable, multi-disciplinary database designed to maximise exposure for events organisers. The contents of the Natureevents Directory are now live. The digital version is available here. Find the latest scientific conferences, courses, meetings and symposia on natureevents.com. For event advertising opportunities across the Nature Publishing Group portfolio please contact natureevents@nature.com More Nature Events

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