Nature Medicine Contents: October 2012 Volume 18 Number 10 pp 1443-1592

TABLE OF CONTENTS October 2012 Volume 18, Issue 10 Podcast Editorial News Correction Book Review Correspondence News and Views Community Corner Between Bedside and Bench Research Highlights Essays Articles Letters Technical Reports Addendum Corrigenda Japanese table of contents Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Rat Genomics and Models (3-6 December 2012) Cambridge, UK This popular conference focuses on the rat as a model for studying the etiology of complex human diseases, including hypertension, diabetes, renal failure, cancer and others. Generation and annotation of an updated rat reference genome assembly will also be covered. Abstracts by 8 October. Register by 22 October.   Advertisement Nature Medicine ePOSTER ON METABOLIC SYNDROME Published originally in 2011, the 2012 version of the ePoster features a new organ -- the pancreas -- plus updates for the existing organs to reflect key advances of the past year. www.nature.com/nm/poster Sponsored by   Advertisement Nature Insight: Gut Microbes and Health This Insight focuses on the ecological principles that govern microbiota composition; interactions of the microbiota with the immune system and metabolic processes; and genomic tools that can aid in the analysis of microbial communities. Access the Insight free online for six months. Produced with support from: Yakult Honsha   Nature Medicine Podcast  Top Medicine to the masses  How the 2012 election will affect biomedical research, and a new way to boost vaccine effectiveness in the elderly. Listen Now Editorial Top Repeat after me   p1443 doi:10.1038/nm.2978 A new initiative for ensuring the reproducibility of biomedical research is commendable, but the involvement of a for-profit company may not be the right path forward. News Top Early-stage therapies target surgery-induced erectile dysfunction   p1444 Sarah C P Williams doi:10.1038/nm1012-1444 US presidential candidates diverge on how to help biopharma   p1445 Susan Matthews doi:10.1038/nm1012-1445 Companies wager high on CD38-targeting drugs for blood cancer   p1446 Rebecca Hersher doi:10.1038/nm1012-1446a Despite quintuple disappointments, Lilly still charms investors   p1446 Kathleen Raven doi:10.1038/nm1012-1446b Proposal for San Francisco to negotiate drug prices makes waves   p1447 Kathleen Raven doi:10.1038/nm1012-1447a NCATS gains first chief and positions for industry partnerships   p1447 Susan Matthews doi:10.1038/nm1012-1447b Hantavirus treatments advance amidst outbreak in US park   p1448 Elie Dolgin doi:10.1038/nm1012-1448a Correction Top Correction   p1448 doi:10.1038/nm1012-1448b News Top Q&A Straight talk with...Mary Woolley   p1449 doi:10.1038/nm1012-1449 As the US presidential campaign heads into the final stretch before the Election Day, the nonpartisan alliance known as Research!America is working to put health research high on the political agenda. Mary Woolley, president and chief executive officer of the Washington, DC-based organization, spoke with Roxanne Khamsi about what it will take to catalyze support among lawmakers for biomedical research. News in Brief Biomedical briefing   pp1450 - 1451 doi:10.1038/nm1012-1450 News Features The new drug circuit   pp1452 - 1454 Daniel Grushkin doi:10.1038/nm1012-1452 Synthetic biology has historically relied on bacteria as a testing ground for engineering cell behavior through genetic signals. But a small group of researchers have their sights set on redesigning mammalian cells, which have more complex genetic machinery. Daniel Grushkin meets the scientists aiming to reprogram our bodies' cells for a new generation of tailor-made treatments. Bioengingeering bacteria for a cure[mdash]it's not that easy   p1454 Daniel Grushkin doi:10.1038/nm1012-1454 Book Review Top Disappearing disease   p1455 Stephen B Blount reviews Eradication: Ridding the World of Diseases Forever? by Nancy Leys Stepan doi:10.1038/nm.2887 Correspondence Top Lethal H5N1 influenza viruses are not resistant to interferon action in human, simian, porcine or chicken cells   pp1456 - 1457 John M Ngunjiri, Kareem N Mohni, Margaret J Sekellick, Stacey Schultz-Cherry, Robert G Webster and Philip I Marcus doi:10.1038/nm.2879 News and Views Top Heat from calcium cycling melts fat   pp1458 - 1459 Leslie P Kozak and Martin E Young doi:10.1038/nm.2956 A new study in mice shows that sarcolipin, a small, regulatory protein of the intracellular calcium pump (SERCA) in skeletal muscle, is part of a nonshivering thermogenic mechanism for regulating both core body temperature and energy balance (pages 1575-1579). See also: Letter by Bal et al. A complex substitute: antibody therapy for hemophilia   pp1460 - 1461 David Lillicrap doi:10.1038/nm.2959 Deficiency of the procoagulant cofactor factor VIII (FVIII) in hemophilia A is routinely treated by protein replacement therapy with plasma-derived or recombinant FVIII. Now, a humanized bispecific antibody has been demonstrated to perform the 'scaffold' function of FVIII and could potentially function as a FVIII substitute as a treatment for this inherited bleeding condition (pages 1570-1574). See also: Letter by Kitazawa et al. Attacking the flank: targeting new pathways in SBMA   pp1461 - 1463 Diane E Merry doi:10.1038/nm.2967 Androgen withdrawal-based therapeutic strategies for spinal and bulbar muscular atrophy (SBMA) have shown limited benefit in clinical trials, and therapies for this disease still remain a considerable challenge. The finding that a class of migraine medications, the triptans, improve disease in a mouse model of SBMA suggests a new route for future investigations into SBMA therapies (pages 1531-1538). See also: Article by Minamiyama et al. LIF-ting Hippo averts metastasis   pp1463 - 1465 Stefano Piccolo doi:10.1038/nm.2955 Reactivation of 'metastasis suppressor' genes holds great promise for the treatment of incurable malignancies. To date, only a few of these genes have been identified. A new study shows that breast cancer metastasis can be blunted by leukemia inhibitory factor (LIF) signaling through regulation of the Hippo pathway, linking metastatic growth to the regulation of a pathway involved in building organs during development (pages 1511-1517). See also: Article by Chen et al. Nature Medicine JOBS of the week Faculty Position in the Department of Pharmacology University of Virginia Assistant Professor Massachusetts Institute of Technology Faculty Position-NYU Center for Genomics & Systems Biology New York University Research Assistant University of Bristol Drug Discovery Programme - Head of Biology Beatson Institute for Cancer Research Research Laboratory Manager Imperial College London Assistant / Associate / Full Professor of Cellular & Molecular Medicine Cleveland Clinic Lerner Research Institute Postdoctoral Opportunity In Cell-Cell Adhesion And Communication Northwestern Univeristy Feinberg School of Medicine Ph.D. Student in Neuroscience Goethe Universit�t Frankfurt Senior researcher in genetic evaluation Aarhus University - Denmark More Science jobs from Nature Medicine EVENT International Conference on Microelectronics, Optoelectronics, and Nanoelectronics 28.-30.11.12 Paris, France More science events from Community Corner Top Parsing the potential of a new male contraceptive   pp1466 - 1467 doi:10.1038/nm.2970 Between Bedside and Bench Top The Ongoing Battle Against Influenza: The challenge of flu transmission   pp1468 - 1470 Seema S Lakdawala and Kanta Subbarao doi:10.1038/nm.2953 Influenza viruses can cause a broad spectrum of disease severity, including devastating cases in some people. Several factors influence the epidemiological success of the virus; the mechanisms of transmission and the strategies for prevention and treatment have an impact on the disease outcome and the incidence of flu infection in the population. Understanding how and why the viruses spread so efficiently among people and determining possible ways to harness this transmission have been arduous tasks, given the limitations of flu animal models. In 'Bedside to Bench', Kanta Subbarao and Seema S. Lakdawala peruse a study that used a human challenge model to assess influenza transmission; this experimental approach shows how transmission can be studied in humans and emphasizes factors that are different compared to animals, such as distinct disease severity and incidence. Lessons can be taken to optimize animal studies. Another issue that dictates the severity of flu episodes is the potential emergence of drug-resistant strains in treated individuals. In 'Bench to Bedside', Anne Kelso and Aeron C. Hurt discuss another concern[mdash]the presence of drug-resistant viruses with additional permissive mutations that make them fit to infect and compete with wild-type strains. The fact that these strains can be found in untreated people and can spread poses a public health concern and a challenge for scientists to find new drugs and assess antiviral combinations. The Ongoing Battle Against Influenza: Drug-resistant influenza viruses: why fitness matters   pp1470 - 1471 Anne Kelso and Aeron C Hurt doi:10.1038/nm.2954 Research Highlights Top Neurodegeneration: A translational block | Diabetes: Dedifferentiation, not death | Immunology: Commensals under attack | Cancer: Finding fusions Essays Top 2012 Albert Lasker Medical Research Awards Paradigm shifts in science: insights from the arts   pp1473 - 1477 Joseph L Goldstein doi:10.1038/nm.2923 2012 Albert Lasker Medical Research Awards One path to understanding energy transduction in biological systems   pp1478 - 1482 James A Spudich doi:10.1038/nm.2924 2012 Albert Lasker Medical Research Awards Following nature's challenges   pp1483 - 1485 Michael P Sheetz and William R. Kenan doi:10.1038/nm.2957 2012 Albert Lasker Medical Research Awards How lucky can one be? A perspective from a young scientist at the right place at the right time   pp1486 - 1488 Ronald D Vale doi:10.1038/nm.2925 2012 Albert Lasker Medical Research Awards The long reach of liver transplantation   pp1489 - 1492 Thomas E Starzl doi:10.1038/nm.2927 2012 Albert Lasker Medical Research Awards “It can't be done”   pp1493 - 1495 Roy Y Calne doi:10.1038/nm.2926 2012 Albert Lasker Medical Research Awards Developmental biology using purified genes   pp1496 - 1498 Donald D Brown doi:10.1038/nm.2929 2012 Albert Lasker Medical Research Awards On the road from classical to modern molecular biology   pp1499 - 1502 Tom Maniatis doi:10.1038/nm.2931 Articles Top Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma   pp1503 - 1510 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/nm.2941 NRAS-driven melanomas have limited therapeutic options. Combining genetically engineered models and oncogenic signaling inhibitors with rational systems-biology approaches, the authors compare the effects of genetic extinction of NRAS to that of chemical pathway inhibition targeting downstream MEK. The differences provide actionable targets by revealing that NRAS signaling operates as a gated output and that MEK inhibition, although inducing apoptosis, is not able to achieve further inhibition of NRAS-induced outputs such as cell-cycle progression. A combination of MEK and CDK4 inhibitors provides a more complete inhibition of NRAS signaling and a more effective antitumor effect in vivo. LIFR is a breast cancer metastasis suppressor upstream of the Hippo-YAP pathway and a prognostic marker   pp1511 - 1517 Dahu Chen, Yutong Sun, Yongkun Wei, Peijing Zhang, Abdol Hossein Rezaeian, Julie Teruya-Feldstein, Sumeet Gupta, Han Liang, Hui-Kuan Lin, Mien-Chie Hung and Li Ma doi:10.1038/nm.2940 The authors identify LIFR as a breast cancer metastasis suppressor by showing how its loss promotes metastasis without substantial effect on primary tumor growth. This function of LIFR involves promoting the membrane localization of Scribble and enabling the cytoplasmic sequestration of Hippo pathway transducers, thus involving this signaling pathway in metastasis control. LIFR loss is also observed in human breast tumors, where it correlates with poor prognosis. See also: News and Views by Piccolo Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity   pp1518 - 1524 Guangjin Li, Mingcan Yu, Won-Woo Lee, Michael Tsang, Eswar Krishnan, Cornelia M Weyand and Jorg J Goronzy doi:10.1038/nm.2963 Human T cell function declines with age, reducing the ability of vaccines to protect the elderly against infectious disease. In this issue, Jorg Goronzy and his colleagues shed light on the mechanism by which naive CD4+ T cell responses are impaired in elderly individuals. The researchers show that miR-181a is reduced in these cells in older individuals. This results in increased expression of DUSP6, a phosphatase that dampens ERK signaling, which is necessary for optimal T cell receptor sensitivity to antigen. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma   pp1525 - 1530 Nandini Krishnamoorthy, Anupriya Khare, Timothy B Oriss, Mahesh Raundhal, Christina Morse, Manohar Yarlagadda, Sally E Wenzel, Martin L Moore, R Stokes Peebles Jr, Anuradha Ray and Prabir Ray doi:10.1038/nm.2896 Recurrent infections with respiratory syncytial virus (RSV) early in life increase susceptibility to asthma. Nandini Krishnamoorthy et al. show that RSV infection of young mice impairs maternally transferred tolerance to allergens. Regulatory T (Treg) cells in infected mice have impaired suppressor function and adopt a TH2-like phenotype. Naratriptan mitigates CGRP1-associated motor neuron degeneration caused by an expanded polyglutamine repeat tract   pp1531 - 1538 Makoto Minamiyama, Masahisa Katsuno, Hiroaki Adachi, Hideki Doi, Naohide Kondo, Madoka Iida, Shinsuke Ishigaki, Yusuke Fujioka, Shinjiro Matsumoto, Yu Miyazaki, Fumiaki Tanaka, Hiroki Kurihara and Gen Sobue doi:10.1038/nm.2932 Spinal and bulbar musclar atrophy (SBMA) is caused by expanded polyglutamine repeats in the androgen receptor, leading to motor neuron degeneration. Gen Sobue and his colleagues describe a molecular cascade whereby mutant androgen receptor upregulates CGRP in neuronal cells, promoting JNK activation and degeneration. The 5-HT1B/1D receptor agonist naratriptan, which is approved for the treatment of migraine, decreases CGRP expression and improves motor performance in a mouse model of SBMA, suggesting a novel therapeutic strategy for SBMA. See also: News and Views by Merry MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity   pp1539 - 1549 Christine M Kusminski, William L Holland, Kai Sun, Jiyoung Park, Stephen B Spurgin, Ying Lin, G Roger Askew, Judith A Simcox, Don A McClain, Cai Li and Philipp E Scherer doi:10.1038/nm.2899 Obesity is often associated with mitochondrial dysfunction. What is not clear, however, is whether this is a cause or a consequence of the condition and its detrimental effects on metabolic health. Phil Scherer and colleagues now show that by manipulating a key protein involved in mitochondrial function specifically in adipocytes the mitochondria is crucial in maintaining proper lipid levels and whole-body insulin sensitivity. Interactions among HCLS1, HAX1 and LEF-1 proteins are essential for G-CSF-triggered granulopoiesis   pp1550 - 1559 Julia Skokowa, Maxim Klimiankou, Olga Klimenkova, Dan Lan, Kshama Gupta, Kais Hussein, Esteban Carrizosa, Inna Kusnetsova, Zhixiong Li, Claudio Sustmann, Arnold Ganser, Cornelia Zeidler, Hans-Heinrich Kreipe, Janis Burkhardt, Rudolf Grosschedl and Karl Welte doi:10.1038/nm.2958 In congenital neutropenia, myeloid-lineage differentiation in response to the cytokine G-CSF is defective. Julia Skokowa et al. now show that an interplay among three proteins[mdash]the adapter proteins HCLS1 and HAX1 and the transcription factor LEF-1[mdash]is required for G-CSF-triggered granulocytic differentiation, and they provide evidence that this pathway is dysregulated in both congenital neutropenia and acute myeloid leukemia. Endothelial PI3K-C2[alpha], a class II PI3K, has an essential role in angiogenesis and vascular barrier function   pp1560 - 1569 Kazuaki Yoshioka, Kotaro Yoshida, Hong Cui, Tomohiko Wakayama, Noriko Takuwa, Yasuo Okamoto, Wa Du, Xun Qi, Ken Asanuma, Kazushi Sugihara, Sho Aki, Hidekazu Miyazawa, Kuntal Biswas, Chisa Nagakura, Masaya Ueno, Shoichi Iseki, Robert J Schwartz, Hiroshi Okamoto, Takehiko Sasaki, Osamu Matsui, Masahide Asano, Ralf H Adams, Nobuyuki Takakura and Yoh Takuwa doi:10.1038/nm.2928 Although type I phosphatidylinositol 3-kinases (PI3Ks) are well studied signaling proteins, the functions of other PI3Ks are more enigmatic. Kazuaki Yoshioka et al. find that the type II PI3K-2[alpha] isoform regulates endosomal trafficking and cell signaling in endothelial cells. Angiogenic and vascular permeability responses are attenuated in mice lacking PI3K-2[alpha], pointing to this enzyme as a potential target for treating vascular disease. Letters Top A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model   pp1570 - 1574 Takehisa Kitazawa, Tomoyuki Igawa, Zenjiro Sampei, Atsushi Muto, Tetsuo Kojima, Tetsuhiro Soeda, Kazutaka Yoshihashi, Yukiko Okuyama-Nishida, Hiroyuki Saito, Hiroyuki Tsunoda, Tsukasa Suzuki, Hideki Adachi, Taro Miyazaki, Shinya Ishii, Mika Kamata-Sakurai, Takeo Iida, Aya Harada, Keiko Esaki, Miho Funaki, Chifumi Moriyama, Eriko Tanaka, Yasufumi Kikuchi, Tetsuya Wakabayashi, Manabu Wada, Masaaki Goto, Takeshi Toyoda, Atsunori Ueyama, Sachiyo Suzuki, Kenta Haraya, Tatsuhiko Tachibana, Yoshiki Kawabe, Midori Shima, Akira Yoshioka and Kunihiro Hattori doi:10.1038/nm.2942 Individuals with hemophilia A lack the coagulation factor FVIII and are treated with frequent intravenous injections of FVIII agents. However, many individuals develop antibodies to FVIII and can no longer be treated by FVIII injection. Takehisa Kitazawa and his colleagues report the development of a bispecific antibody to FIXa and FX that mimics the function of FVIII. This antibody reduces bleeding in a nonhuman primate model of hemophilia A, is resistant to the inhibitory effects of FVIII-specific antibodies and has a long half-life after subcutaneous injection. See also: News and Views by Lillicrap Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals   pp1575 - 1579 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/nm.2897 Animals use their muscles to shiver to generate heat when exposed to the cold. But this is a short-term adaptation. Long term, it is believed the body relies on the brown adipose tissue (BAT) to generate heat in a nonshivering fashion. New work from Muthu Periasamy and colleagues challenge this BAT-centric view by showing that the muscle is also a key site of nonshivering thermogenesis. See also: News and Views by Kozak & Young Technical Reports Top In vivo photodynamic therapy using upconversion nanoparticles as remote-controlled nanotransducers   pp1580 - 1585 Niagara Muhammad Idris, Muthu Kumara Gnanasammandhan, Jing Zhang, Paul C Ho, Ratha Mahendran and Yong Zhang doi:10.1038/nm.2933 A limitation of photodynamic therapy (PDT) is the depth of penetration of visible light needed for activation of the photosensitizers, restricting treatment to tumors on or just under the skin’s surface or those lining internal organs and cavities. Niagara Muhammad Idris and colleagues have addressed this issue by developing upconversion fluorescent nanoparticles (UNCs) that convert deeper penetrating near-infrared light to visible wavelengths without sacrificing efficacy for singlet oxygen (1O2) production. The group tested the UNCs in vivo in a subcutaneous mouse tumor model using a dual-sensitizer approach for greater PDT efficacy. Annotating MYC status with 89Zr-transferrin imaging   pp1586 - 1591 Jason P Holland, Michael J Evans, Samuel L Rice, John Wongvipat, Charles L Sawyers and Jason S Lewis doi:10.1038/nm.2935 By exploiting the relationship between the transcription factor MYC and the transferrin receptor, where the level of transferrin receptor 1 expression may indicate activation of the MYC oncogenic pathway, Jason Holland and his colleagues have developed a novel PET radiotracer to quantitatively and noninvasively measure MYC activity. The 89Zr-desferrioxamine transferrin PET radiotracer was tested in several murine models of inflammation and MYC-driven prostate cancer. Addendum Top Editorial note: Lethal H5N1 influenza viruses escape host antiviral cytokine responses   p1592 Sang Heui Seo, Erich Hoffmann and Robert G Webster doi:10.1038/nm1012-1592a Corrigenda Top Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-[gamma] agonists   p1592 Kengo Shimono, Wei-en Tung, Christine Macolino, Amber Hsu-Tsai Chi, Johanna H Didizian, Christina Mundy, Roshantha A Chandraratna, Yuji Mishina, Motomi Enomoto-Iwamoto, Maurizio Pacifici and Masahiro Iwamoto doi:10.1038/nm1012-1592b Multigenerational epigenetic adaptation of the hepatic wound-healing response   p1592 Mujdat Zeybel, Timothy Hardy, Yi K Wong, John C Mathers, Christopher R Fox, Agata Gackowska, Fiona Oakley, Alastair D Burt, Caroline L Wilson, Quentin M Anstee, Matt J Barter, Steven Masson, Ahmed M Elsharkawy, Derek A Mann and Jelena Mann doi:10.1038/nm1012-1592c 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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