Nature Medicine Contents: December 2012 Volume 18 Number 12 pp 1717-1857

TABLE OF CONTENTS December 2012 Volume 18, Issue 12 Podcast Editorial News Correction Correspondence News and Views Community Corner Between Bedside and Bench Research Highlights Review Articles Technical Reports Corrigenda Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Miami 2013 Winter Symposium: The Molecular Basis of Metabolism and Nutrition February 10-13, 2013 - Miami, FL, USA Join leaders in this field to discuss advances in human nutrition, human genetics/epigenetics, clinical and animal studies of disease pathogenesis, inborn errors of metabolism, methyl metabolism, stem cell programming, genome stability, transcription, and developmental biology. For more information and to register, visit: www.nature.com/natureconferences/miami/mws2013   Advertisement Nature Outlook: Autism Its causes, treatments, and definition remain to be pieced together. Access the Outlook free online for six months. Produced with support from: Nancy Lurie Marks Family Foundation, The Simons Foundation, Roche, Autism Speaks, The Autism Science Foundation   Nature Medicine Podcast  Top Reaching for the SARS  We explore why a promising vaccine for SARS is proving difficult to advance further and new strategies aimed at halting the progression of Alzheimer�s and diabetes. Listen Now Editorial Top Lessons from vaccine history   p1717 doi:10.1038/nm.3039 In spite of years of effort, we still lack highly efficacious vaccines against HIV, tuberculosis, malaria and numerous other widespread pathogens. Two recent setbacks in vaccine trials suggest that it's time to rethink how new vaccines are developed and to investigate what can be learned from the existing armament of childhood vaccines. News Top Gene therapies advance, but some see manufacturing challenges   pp1718 - 1719 Elie Dolgin doi:10.1038/nm1212-1718 Greek drug shortage brings call for cost-effective approach   p1719 Anastasios Kafantaris doi:10.1038/nm1212-1719 Computer program aims to rank vaccine development decisions   p1720 Devin Powell doi:10.1038/nm1212-1720 Biomedical grant awarded by 'American Idol'-style public vote   p1721 Elie Dolgin doi:10.1038/nm1212-1721 Select-agent status could slow development of anti-SARS therapies   p1722 Susan Matthews doi:10.1038/nm1212-1722 Malaria vaccine results present infant immunization quandary   p1723 Cassandra Willyard doi:10.1038/nm1212-1723 Storm shows need for mouse backup, but costs present challenges   p1724 Susan Matthews doi:10.1038/nm1212-1724 Q&A Straight talk with...Guido Rasi   p1725 doi:10.1038/nm1212-1725 A year ago, Guido Rasi stepped into the role of executive director of the European Medicines Agency (EMA), becoming only the third person to fill that role since the inception of the continental drug advisory body, in 1995. He spoke with Roxanne Khamsi about how the EMA is working toward better safety guidance and improved transparency. News in Brief Biomedical briefing   pp1726 - 1727 doi:10.1038/nm1212-1726 Correction Top Corrections   p1727 doi:10.1038/nm1212-1727 News Top Timeline of events: A brief history of what made news this year   p1728 doi:10.1038/nm1212-1728 This year has proven to be a veritable cliff-hanger for the world of biomedicine. At the same time that the US government stands poised on the brink of the so-called 'fiscal cliff', pharmaceutical companies are stumbling with the industry's 'patent cliff' and academic researchers face the looming 'funding cliff'. But not everything in 2012 was so dire, with dozens of new drugs to hit worldwide markets and countless discoveries made to enable the next generation of medicines. What follows are a set of 'Cliff's notes' to the year that was for the field. The Yearbook   p1729 doi:10.1038/nm1212-1729 We list the key people who made headlines this year, either for public reports that overstretched their reach or for papers that almost never saw the light of day. A need for speed: Signals in drug development   pp1730 - 1731 doi:10.1038/nm1212-1730 Another year, another round of approvals, mixed reviews and high-profile failures. We look back on which medicines made the headlines. Notable advances 2012   pp1732 - 1734 doi:10.1038/nm1212-1732 From the microbiome to the microenvironment, certain areas of biomedicine saw fast-paced discovery this year. Here's a rundown of the papers that helped these fields advance quickly in 2012. Opinion Global health needs to fill the innovation gap   p1735 Trevor Mundel doi:10.1038/nm1212-1735 In recent years, the pharmaceutical industry has struggled to deliver new therapies, especially for diseases that affect the most vulnerable in developing countries. The global health community can fill this vacuum by catalyzing innovative partnerships across academia, government and the private sector, fostering a more rigorous environment for scientific decision making and creating the tools and infrastructure to conduct effective translational research. Correspondence Top Reproducibility concerns   pp1736 - 1737 John P A Ioannidis, Brian Nosek and Elizabeth Iorns doi:10.1038/nm.3020 News and Views Top A marriage made to last in drug design   pp1737 - 1738 Marcelo O Dietrich and Tamas L Horvath doi:10.1038/nm.3018 Many mechanisms can contribute to complex diseases such as metabolic diseases; thus, combination therapies may be required to target individual underlying pathological mechanisms. A new study combines glucagon-like peptide-1 (GLP1) and estrogen in a single molecule, allowing selective targeting of this conjugate to cells that express the GLP1 receptor. This strategy improves the metabolic profile of obese mice without the adverse side effects associated with estrogen therapy (pages 1847-1856). See also: Technical Report by Finan et al. Metabolic jet lag when the fat clock is out of sync   pp1738 - 1740 Ingrid Wernstedt Asterholm and Philipp E Scherer doi:10.1038/nm.3010 There is a growing appreciation of the importance of circadian regulation in energy homeostasis, and the dysregulation of the circadian clock has been associated with obesity and metabolic abnormalities. A new study shows that adipocyte-specific deletion of a core circadian clock gene, Arntl (Bmal1), in mice shifts the timing of their feeding behavior, resulting in obesity (pages 1768-1777). See also: Article by Paschos et al. Enhancing hematopoietic growth factor performance   pp1740 - 1741 Yen-Michael S Hsu and Daniel C Link doi:10.1038/nm.3022 Delayed blood count recovery is a major cause of morbidity and mortality in people undergoing stem cell transplantation or intensive chemotherapy. Treatment with hematopoietic growth factors can accelerate hematopoiesis, but prolonged cytopenias still occur. A new study shows that inhibition of dipeptidylpeptidase IV augments the activity of certain hematopoietic growth factors, providing a new approach to potentially treat cytopenias (pages 1786-1796). See also: Article by Broxmeyer et al. Can't get there from here: cilia and hydrocephalus   pp1742 - 1743 Bethany N Sotak and Joseph G Gleeson doi:10.1038/nm.3011 Hydrocephalus describes an expansion of the cerebral ventricles that is associated with decreased cerebral volume and compromised neurological function. Although hydrocephalus mostly occurs sporadically, it is frequently associated with diseases caused by defective cilia function, including Bardet-Biedl syndrome (BBS). A new study reveals that hydrocephalus in a mouse model of BBS is related to defective proliferation and apoptosis of neural progenitor cells (NPCs) and can be rescued with lithium treatment (pages 1797-1804). See also: Article by Carter et al. Ion channels boost axonal injury in multiple sclerosis   pp1743 - 1745 Reinhard Hohlfeld doi:10.1038/nm.3021 In neuroinflammatory diseases such as multiple sclerosis, ion channels may fan the embers of neurodegeneration. A new study shows that the cation channel TRPM4 (transient receptor potential melastatin 4) crucially contributes to axonal loss in an animal model of multiple sclerosis (pages 1805-1811). See also: Article by Schattling et al. Nature Medicine JOBS of the week Drug Discovery for Helminths Aroian Group, University of California, San Diego Assistant / Associate Professor- Chemical Biology / Medicinal Chemistry / Drug Discovery Wayne State University Associate Professor in Drug Discovery (fixed-term) The University of Nottingham Key Postdoctoral Position at Wits Advanced Drug Delivery Platform Available Immediately University of the Witwatersrand, Johannesburg, South Africa PhD Position: Functionalized Inorganic Materials for Water Remediation and Drug Delivery University of Southern Denmark, Department of Physics, Chemistry and Pharmacy More Science jobs from Nature Medicine EVENT Taking X-Ray Phase Contrast Imaging into Mainstream Applications 06.12.12 London, UK More science events from Community Corner Top Trialing targeted therapies for autism   pp1746 - 1747 doi:10.1038/nm.3027 Between Bedside and Bench Top Hiding Under the Skin: Interleukin-17-producing [gamma][delta] T cells go under the skin?   pp1748 - 1750 Burkhard Becher and Stanislav Pantelyushin doi:10.1038/nm.3016 Despite the irrefutable role of inflammation in psoriasis, a complete knowledge of what immune cells and cytokines are involved during initiation and progression of this skin disease is lacking. Moreover, the complexities of the immune cell network and potential differences between mice and humans have led to translational failures. It is therefore important that we acquire in-depth understanding of what inflammatory players, of the many involved, are crucial, if we wish to develop effective therapies. In 'Bedside to Bench', James Krueger discusses how a subset of T cells, TH17 cells, which release interleukin-17 in humans, seem to be essential for pathogenesis of psoriasis. The interplay between interleukin-17 and other cytokines that may potentially be involved in psoriasis also needs further investigation. Additionally, there are open questions as to what subset of T cells, other than TH17, also produce interleukin-17 and when. In 'Bench to Bedside', Burkhard Becher and Stanislav Pantelyushin examine this issue by looking at a mouse model of skin inflammation that resembles psoriasis in humans. A class of skin-invading innate immune cells called [gamma][delta] T cells was shown to drive skin inflammation in this model, particularly during the early stages of the disease, suggesting that innate immunity plays an important part in the initiation of psoriasis Hiding Under the Skin: A welcome surprise in psoriasis   pp1750 - 1751 James G Krueger doi:10.1038/nm.3025 Research Highlights Top Neuroscience: A new genetic form of autism | Cancer: The importance of editing | Cancer: Antitumor duality of ApoE | Immunology: Beyond tolerance | Autoimmunity: NET loss in lupus | Kidney: Going with the flow | Metabolism: Fine-tuning iron | New from NPG Review Top Mechanisms of implantation: strategies for successful pregnancy   pp1754 - 1767 Jeeyeon Cha, Xiaofei Sun and Sudhansu K Dey doi:10.1038/nm.3012 Articles Top Obesity in mice with adipocyte-specific deletion of clock component Arntl    pp1768 - 1777 Georgios K Paschos, Salam Ibrahim, Wen-Liang Song, Takeshige Kunieda, Gregory Grant, Teresa M Reyes, Christopher A Bradfield, Cheryl H Vaughan, Michael Eiden, Mojgan Masoodi, Julian L Griffin, Fenfen Wang, John A Lawson and Garret A FitzGerald doi:10.1038/nm.2979 A molecular mechanism in the brain and individual tissues allows mammals to adapt to a 24-hour clock. Garret FitzGerald and colleagues now show that genetic deletion of one member of this pathway specifically in the fat of mice results in acutely altered lipid profiles that, in turn, result in increased feeding and obesity. This could explain why human night-shift workers are at an increased risk for obesity and metabolic disease. See also: News and Views by Asterholm & Scherer Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways   pp1778 - 1785 Jian Huang, Michelle Nguyen-McCarty, Elizabeth O Hexner, Gwenn Danet-Desnoyers and Peter S Klein doi:10.1038/nm.2984 Hematopoietic stem cells are difficult to maintain in vitro, hampering their clinical use. Jian Huang et al. show that mouse and human hematopoietic stem cells can be maintained in culture in the absence of exogenous cytokines by combined treatment with agents that activate Wnt and inhibit mTOR signaling, two major signaling pathways implicated in stem cell homeostasis. Moreover, treatment with two such compounds used clinically increases the number of hematopoietic stem cells in mice in vivo. Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis   pp1786 - 1796 Hal E Broxmeyer, Jonathan Hoggatt, Heather A O'Leary, Charlie Mantel, Brahmananda R Chitteti, Scott Cooper, Steven Messina-Graham, Giao Hangoc, Sherif Farag, Sara L Rohrabaugh, Xuan Ou, Jennifer Speth, Louis M Pelus, Edward F Srour and Timothy B Campbell doi:10.1038/nm.2991 The peptidase DPP4 has a wide variety of target proteins, including the chemokine SDF-1 and the hormone GLP-1. Hal Broxmeyer and his coworkers now identify colony-stimulating factors as a new class of DPP4 substrates, including GM-CSF, G-CSF, IL-3 and erythropoietin. Treatment of mice with a clinically approved, orally available DPP4 inhibitor improved hematopoietic recovery after radiation or chemotherapeutic drug administration, pointing to potential clinical applications of these findings. See also: News and Views by Hsu & Link Abnormal development of NG2+PDGFR-[alpha]+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model   pp1797 - 1804 Calvin S Carter, Timothy W Vogel, Qihong Zhang, Seongjin Seo, Ruth E Swiderski, Thomas O Moninger, Martin D Cassell, Daniel R Thedens, Kim M Keppler-Noreuil, Peggy Nopoulos, Darryl Y Nishimura, Charles C Searby, Kevin Bugge and Val C Sheffield doi:10.1038/nm.2996 Hydrocephalus is a neurological disorder characterized by expansion of the ventricles. In a mouse model, the authors identified a role for neural progenitors and for platelet-derived growth factor signaling in the pathogenesis of neonatal hydrocephalus. Targeting this pathway reduced ventricular volume, pointing to a new therapeutic target for this condition. See also: News and Views by Sotak & Gleeson TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis   pp1805 - 1811 Benjamin Schattling, Karin Steinbach, Edda Thies, Martin Kruse, Aurelie Menigoz, Friederike Ufer, Veit Flockerzi, Wolfgang Bruck, Olaf Pongs, Rudi Vennekens, Matthias Kneussel, Marc Freichel, Doron Merkler and Manuel A Friese doi:10.1038/nm.3015 Axonal and neuronal damage are commonly seen in patients with multiple sclerosis. Manuel A. Friese and his colleagues now report that the cation channel transient receptor potential melastatin 4 (TRPM4) is upregulated in multiple sclerosis lesions in patients and contributes to disease in vivo. Genetic deletion or pharmacological inhibition of TRPM4 in a mouse model of multiple sclerosis reduces clinical scores and is neuroprotective, suggesting this may represent a novel therapeutic target. See also: News and Views by Hohlfeld Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline   pp1812 - 1819 Johannes vom Berg, Stefan Prokop, Kelly R Miller, Juliane Obst, Roland E Kalin, Ileana Lopategui-Cabezas, Anja Wegner, Florian Mair, Carola G Schipke, Oliver Peters, York Winter, Burkhard Becher and Frank L Heppner doi:10.1038/nm.2965 Proinflammatory cytokine expression increases as a result of amyloid deposition in Alzheimer's disease. Frank L. Heppner and colleagues show that genetic and pharmacological inhibition of IL-12 and IL-23 signaling reduces plaque load and improves cognitive deficits in mouse models of Alzheimer's disease. As the concentration of p40 is also increased in the cerebrospinal fluid of individuals with Alzheimer's disease, this suggests that this pathway may be targeted therapeutically in patients. A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease   pp1820 - 1826 Rachel L Graham, Michelle M Becker, Lance D Eckerle, Meagan Bolles, Mark R Denison and Ralph S Baric doi:10.1038/nm.2972 Attenuated viruses can be highly effective vaccines. In this issue, Ralph Baric and colleagues report that inactivating mutations in the exonuclease ExoN of a mouse-adapted SARS coronavirus impair replication fidelity and cause a mutator phenotype. The resulting attenuated virus protected mice against a lethal coronavirus challenge. NK cells impede glioblastoma virotherapy through NKp30 and NKp46 natural cytotoxicity receptors   pp1827 - 1834 Christopher A Alvarez-Breckenridge, Jianhua Yu, Richard Price, Jeffrey Wojton, Jason Pradarelli, Hsiaoyin Mao, Min Wei, Yan Wang, Shun He, Jayson Hardcastle, Soledad A Fernandez, Balveen Kaur, Sean E Lawler, Eric Vivier, Ofer Mandelboim, Alessandro Moretta, Michael A Caligiuri and E Antonio Chiocca doi:10.1038/nm.3013 Oncolytic virotherapy has been tested in cancer patients, but its efficacy is uncertain. Alvarez-Breckenridge et al. now report that in mouse models of glioblastoma, an antiviral response mediated by natural killer (NK) cells may impair the anticancer efficacy of oncolytic virotherapy. Their findings suggest that limiting the cytolytic activity of NK cells might enhance replication of oncolytic viruses and increase tumor cell killing. Technical Reports Top Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy   pp1835 - 1840 Huilin Shao, Jaehoon Chung, Leonora Balaj, Alain Charest, Darell D Bigner, Bob S Carter, Fred H Hochberg, Xandra O Breakefield, Ralph Weissleder and Hakho Lee doi:10.1038/nm.2994 Cancer cells shed large numbers of small, membrane-bound microvesicles (MVs) into the circulation, which have diagnostic potential but have proved difficult to analyze in a point-of-care setting. Huilin Shao and colleagues have developed a microfluidic chip with an integrated NMR detection system for the rapid profiling of circulating MVs directly from blood samples of patients with glioblastoma. The system was used to distinguish cancer cell-derived MVs from host cell-derived MVs and to measure treatment effects in vivo. Multifunctional in vivo vascular imaging using near-infrared II fluorescence   pp1841 - 1846 Guosong Hong, Jerry C Lee, Joshua T Robinson, Uwe Raaz, Liming Xie, Ngan F Huang, John P Cooke and Hongjie Dai doi:10.1038/nm.2995 Currently there is no single imaging system that can offer adequate spatial and temporal resolution to accurately assess many of the important factors involved in peripheral arterial diseases. Here, an epifluorescence imaging approach is offered that overcomes many of the current limitations and uses the near-infrared fluorescence of single-walled carbon nanotubes as fluorophores in the second near-infrared window (beyond 1,000 nm). Its use is demonstrated for imaging blood vessels in mouse hindlimb vasculatures millimeters deep in vivo. Targeted estrogen delivery reverses the metabolic syndrome   pp1847 - 1856 Brian Finan, Bin Yang, Nickki Ottaway, Kerstin Stemmer, Timo D Muller, Chun-Xia Yi, Kirk Habegger, Sonja C Schriever, Cristina Garcia-Caceres, Dhiraj G Kabra, Jazzminn Hembree, Jenna Holland, Christine Raver, Randy J Seeley, Wolfgang Hans, Martin Irmler, Johannes Beckers, Martin Hrabe de Angelis, Joseph P Tiano, Franck Mauvais-Jarvis, Diego Perez-Tilve, Paul Pfluger, Lianshan Zhang, Vasily Gelfanov, Richard D DiMarchi and Matthias H Tschop doi:10.1038/nm.3009 Estrogen is beneficial for obesity and type 2 diabetes, though its use is limited by important side effects. In a new study, Matthias Tschop and colleagues avoid this issue by chemically linking estrogen to the hormone GLP-1 to selectively target metabolically relevant tissue and show that the conjugated compound corrects obesity, hyperglycemia and dyslipidemia in mice. This approach could be used for other hormone pairs to treat other diseases. See also: News and Views by Dietrich & Horvath Corrigenda Top Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma   p1857 Lawrence N Kwong, James C Costello, Huiyun Liu, Shan Jiang, Timothy L Helms, Aliete E Langsdorf, David Jakubosky, Giannicola Genovese, Florian L Muller, Joseph H Jeong, Ryan P Bender, Gerald C Chu, Keith T Flaherty, Jennifer A Wargo, James J Collins and Lynda Chin doi:10.1038/nm1212-1857a Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals   p1857 Naresh C Bal, Santosh K Maurya, Danesh H Sopariwala, Sanjaya K Sahoo, Subash C Gupta, Sana A Shaikh, Meghna Pant, Leslie A Rowland, Sanjeewa A Goonasekera, Jeffery D Molkentin and Muthu Periasamy doi:10.1038/nm1212-1857b Top 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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