Nature Medicine Contents: April 2013 Volume 19 Number 5 pp 507-651

Advertisement NPG and Frontiers form alliance to further open science Frontiers is at the forefront of building the ultimate Open Science platform and is driving innovations around peer-review, article and author impact metrics and social networking for researchers. We will work together to empower researchers to change the way science is communicated. Find out more TABLE OF CONTENTS May 2013 Volume 19, Issue 5 Podcast Editorials News Book Review News and Views Community Corner Research Highlights Reviews Articles Letters Technical Report Advertisement Grant Funding for New Drug Discoveries Harrington Discovery Institute at UH Case Medical Center announces its 2013 Harrington Scholar-Innovator Grant competition, open to physician-scientists at accredited academic medical centers, research institutions and universities in the U.S. Letters of Intent due May 15, 2013. Learn more at www.HarringtonDiscovery.org. Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Cancer Pharmacogenomics and Targeted Therapies (15-17 September 2013) Welcome Trust Genome Campus, Hinxton, Cambridge, UK. This new conference is aimed at scientists and clinician-scientists and will seek to address many of the key challenges in the design, development and clinical implementation of targeted cancer therapies. Registration/abstract deadline: 28 June.   Advertisement SciBX Collections Macrocycles and constrained peptides This special collection explores the factors behind the growing interest in macrocycles and constrained peptides over the last five years and their effect on drug discovery. Click here to access the collection for free! Produced with support from: Aileron Therapeutics, Inc., Polypeptide Group, Polyphor LTD., Lanthiopharma B.V.   Advertisement Nature Genetics Focus on iCOGS Nature Genetics is pleased to present the iCOGS print and online Focus advancing our understanding of the genetic susceptibility to three common hormone-related cancers-breast, ovarian and prostate cancers. This collection of 13 papers by the COGS (Collaborative Oncological Gene-environment Study) Consortium is accompanied by editorial essays highlighting and analyzing the main themes of this milestone in genetic epidemiology. View the Focus for FREE at: www.nature.com/ng/focus/iCOGS Produced with support from Illumina   Nature Medicine Podcast  Top The skinny on brown fat We discuss the two types of brown fat newly described in people and a lab-grown kidney that can make urine after transplantation in a rat. Listen Now Editorials Top The science police   p507 doi:10.1038/nm.3191 The publication of a controversial study by a US National Institutes of Health (NIH)-funded researcher suggesting a link between the Tea Party and the tobacco industry has brought the NIH under fire by Congress. But strict policing of NIH grantees would be a waste of resources and a setback to scientific inquiry. Raising standards   p508 doi:10.1038/nm0513-508 Nature journals' updated editorial policies aim to improve transparency and reproducibility News Top Japan to offer fast-track approval path for stem cell therapies   p510 David Cyranoski doi:10.1038/nm0513-510 Delays in updates to ethics guidelines for research spark concern   p511 Alla Katsnelson doi:10.1038/nm0513-511 Biomedical journal and publisher hope to bring preprints to life   p512 Ewen Callaway doi:10.1038/nm0513-512 After food and drug scandals, China's regulator gets a makeover   p513 Felix Cheung doi:10.1038/nm0513-513a Dengue deluge highlights need for vaccine   p513 Elie Dolgin doi:10.1038/nm0513-513b Inhibitors of rogue enzyme near trials for brain and blood tumors   p514 Sarah CP Williams doi:10.1038/nm0513-514 Drug development for progeria yields insights into normal aging   p515 Kevin Jiang doi:10.1038/nm0513-515 The single biggest risk factor for the vast majority of chronic diseases is old age. For many diseases, in fact, a person's birth date is a larger red flag than all other known risk factors combined. But for too long, physicians thought that the aging process was impossible to modify or slow down. Like death and taxes, growing old[mdash]and the medical problems that come with it[mdash]was considered inevitable. That's starting to change. In this special news focus on aging, Nature Medicine looks at the progress being made in drug interventions for the elderly and the hurdles that remain in the pursuit of a pharmaceutical elixir for healthy aging. With little research training, geriatricians pick clinic over the lab   p516 Megan Scudellari doi:10.1038/nm0513-516 Frailty research strengthens with biomarker and treatment leads   p517 Sarah CP Williams doi:10.1038/nm0513-517 Old mice require new experimental tricks to study aging process   pp518 - 519 Elie Dolgin doi:10.1038/nm0513-518 Sequencing of superagers offers drug targets, but fewer than hoped   p519 Kevin Jiang doi:10.1038/nm0513-519 New findings rejuvenate age-old drug development field   pp520 - 521 Cassandra Willyard doi:10.1038/nm0513-520 Living labs open door to retirees who want to join studies   p521 Roxanne Khamsi doi:10.1038/nm0513-521 News in Brief Biomedical briefing   pp522 - 523 doi:10.1038/nm0513-522 Q&A Straight talk with...: Mandana Arabi   p524 doi:10.1038/nm0513-524 Mandana Arabi leads the Sackler Institute for Nutrition Science, created in 2011 by the New York Academy of Sciences to address the massive global problem of malnutrition. She spoke with Alisa Opar about how the institute hopes to put nutrition research on the scientific map. News Feature Rethinking the formula   pp525 - 529 Roxanne Khamsi doi:10.1038/nm0513-525 Health insurance covers drugs approved by regulatory agencies, but it often doesn't pay for the products known as 'medical foods' needed to keep individuals alive and well. This lack of reimbursement means that many who cannot afford these life-saving diets suffer brain deterioration and disability[mdash]or worse. Roxanne Khamsi reports on the battle for medical foods and how it could affect the treatment of diseases as diverse as osteoporosis and Alzheimer's. Opinion Establish good genomic practice to guide medicine forward   p530 Richard W Barker, David A Brindley and Anna Schuh doi:10.1038/nm0513-530 Genomic advances, including next-generation sequencing, offer substantial opportunities and challenges for stratified and personalized medicines. However, the lack of standardization in genomic diagnostics translates into a major risk of error introduction. To ensure the integrity of such data[mdash]and their application[mdash]we suggest the development of 'good genomic practice' standards to guide the field. Book Review Top The shape of science   p531 Barry Bozeman reviews How Economics Shapes Science by Paula Stephan doi:10.1038/nm.3177 News and Views Top Meat-metabolizing bacteria in atherosclerosis   pp533 - 534 Fredrik Backhed doi:10.1038/nm.3178 L-Carnitine is a common food supplement and naturally occurs in red meat. This nutrient is metabolized into trimethyl metabolites by the gut microbiota and is associated with an elevated risk for cardiovascular disease. A recent study provides new insights into this link by exploring how the gut microbiota generates proatherogenic metabolites from L-carnitine and how the microbiota is altered in response to an omnivorous diet (pages 576-585). See also: Article by Koeth et al. A gut-heart connection in cardiometabolic regulation   pp534 - 536 Alessia Buglioni and John C Burnett Jr doi:10.1038/nm.3196 A new study establishes a link between glucagon-like peptide-1 (GLP-1) release from the gut and the cardiac hormone atrial natriuretic peptide, which lowers blood pressure. As GLP-1 receptor agonists are used to control glycemia in patients with type 2 diabetes, this new gut-heart axis suggests a role of these agents in overall cardiovascular homeostasis (pages 567-575). See also: Article by Kim et al. Peli1 sets the CNS on fire   pp536 - 538 Xinyang Song and Youcun Qian doi:10.1038/nm.3176 It has long been unknown how activation of resident macrophages in the brain, or microglia, is regulated during the inflammatory pathogenesis of multiple sclerosis. Work in a mouse model of human multiple sclerosis identifies the E3 ubiquitin ligase Peli1 as a new crucial regulator of microglia activation (pages 595-602). See also: Article by Xiao et al. Targeting RAF-MEK-ERK kinase-scaffold interactions in cancer   pp538 - 540 Darrin D Stuart and William R Sellers doi:10.1038/nm.3195 The RAS-RAF-MEK-ERK signaling kinase pathway has been the focus of intense cancer drug development efforts because of its central role in tumor cell proliferation and survival. Although inhibitors of RAF and MEK provide therapeutic validation, tumor resistance challenges their effectiveness. Targeting scaffolding proteins such as IQGAP1 may be a new approach (pages 626-630). See also: Letter by Jameson et al. How brown is brown fat? It depends where you look   pp540 - 541 Jan Nedergaard and Barbara Cannon doi:10.1038/nm.3187 Although it is now accepted that adult humans possess active brown adipose tissue, it has been questioned whether this is genuine classical brown adipose tissue. Two new studies provide evidence that humans, both as babies and adults, do have classical brown tissue and also indicate that there is heterogeneity in the composition of brown fat depots in humans, as in mice (pages 631-634 and 635-639). See also: Letter by Lidell et al. | Letter by Cypess et al. Bad versus good cholesterol in the bone marrow   pp541 - 543 Eugene A Podrez doi:10.1038/nm.3188 A study now links platelet generation and cholesterol metabolism, providing new understanding of the mechanisms involved in thrombocytosis and atherogenesis. The authors show that the cholesterol transporter ABCG4 is highly expressed in bone marrow megakaryocyte progenitors, and in its absence, these cells have defective cholesterol efflux and increased proliferation, leading to increased megakaryocyte production, thrombocytosis and accelerated atherogenesis in atherosclerosis-prone mice (pages 586-594). See also: Article by Murphy et al. Nature Medicine JOBS of the week Postdoctoral Fellow Icahn School of Medcine at Mount Sinai Post Doctoral Research Associate King's College London PhD scholarships Danish Diabetes Academy Post Doctoral Position Inserm (French Institute of Health and Medical Research) More Science jobs from Nature Medicine EVENT More science events from Community Corner Top How antibiotics kill bacteria: new models needed?   pp544 - 545 doi:10.1038/nm.3198 Research Highlights Top Viral infection: Cloaked in a stolen envelope | Viral infection: Therapeutic micromanagement | Cancer microenvironment: p53 acts in the hood | Cancer therapy: A Notch further with SERCA | New from NPG | Innate immunity: Immune cells muscle up | Cytokines: Dual functions for interferons | Allergy: Basophils meet monocytes Reviews Top Fetomaternal immune cross-talk and its consequences for maternal and offspring's health   pp548 - 556 Petra C Arck and Kurt Hecher doi:10.1038/nm.3160 This Review discusses recent developments in understanding the immune processes that occur at the fetomaternal interface to ensure fetal tolerance during pregnancy, including the roles of fetal trophoblasts, epigenetically modified decidual stromal cells and maternal innate and adaptive immune cells. The authors also explain how impairments in the maternal immune adaptation to pregnancy might influence pregnancy complication,s such as spontaneous miscarriage, as well as postnatal health of the child. PPAR[gamma] signaling and metabolism: the good, the bad and the future   pp557 - 566 Maryam Ahmadian, Jae Myoung Suh, Nasun Hah, Christopher Liddle, Annette R Atkins, Michael Downes and Ronald M Evans doi:10.1038/nm.3159 Thiazolidinediones (TZDs), which act through the nuclear receptor peroxisome proliferator activated receptor-[gamma] (PPAR[gamma]), are a widely prescribed class of drugs for type 2 diabetes; however, their use has been challenged by a number of side effects. Here the authors outline recent advances in our understanding of the modulation of the PPAR[gamma] pathway in metabolism and discuss how these insights might be used to explain the adverse side effects of TZD therapy and develop a new generation of safer PPAR[gamma]-targeting drugs. Articles Top GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure   pp567 - 575 Minsuk Kim, Mathew J Platt, Tadao Shibasaki, Susan E Quaggin, Peter H Backx, Susumu Seino, Jeremy A Simpson and Daniel J Drucker doi:10.1038/nm.3128 The peptide hormone GLP-1 has both antidiabetic and antihypertensive effects. Daniel Drucker and his colleagues now show that GLP-1 lowers blood pressure through indirect mechanisms involving the heart: GLP-1 acts on its receptor in atrial cardiomyocytes to stimulate secretion of the peptide hormone ANP, which in turn lowers blood pressure through direct effects on the vasculature and kidney. See also: News and Views by Buglioni & Burnett Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis   pp576 - 585 Robert A Koeth, Zeneng Wang, Bruce S Levison, Jennifer A Buffa, Elin Org, Brendan T Sheehy, Earl B Britt, Xiaoming Fu, Yuping Wu, Lin Li, Jonathan D Smith, Joseph A DiDonato, Jun Chen, Hongzhe Li, Gary D Wu, James D Lewis, Manya Warrier, J Mark Brown, Ronald M Krauss, W H Wilson Tang, Frederic D Bushman, Aldons J Lusis and Stanley L Hazen doi:10.1038/nm.3145 The long-noted association of red meat with an increased risk of cardiovascular disease may be due to ingestion of a specific compound found in red meat, l-carnitine. The ability of this compound to promote atherosclerosis in mice requires that it be further metabolized by the gut microbiota. In humans, omnivores but not vegans or vegetarians metabolize l-carnitine in this manner, a difference which may be explained by effects of diet on the presence of specific types of bacteria in the gut. See also: News and Views by Backhed Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombocytosis   pp586 - 594 Andrew J Murphy, Nora Bijl, Laurent Yvan-Charvet, Carrie B Welch, Neha Bhagwat, Adili Reheman, Yiming Wang, James A Shaw, Ross L Levine, Heyu Ni, Alan R Tall and Nan Wang doi:10.1038/nm.3150 Nan Wang and colleagues uncover a new function for HDL that may contribute to its anti-atherosclerotic effects. In the bone marrow, HDL removes cholesterol from megakaryocyte progenitor cells in a process requiring the cholesterol transporter ABCG4, thereby dampening megakaryocyte and platelet production. See also: News and Views by Podrez Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation   pp595 - 602 Yichuan Xiao, Jin Jin, Mikyoung Chang, Jae-Hoon Chang, Hongbo Hu, Xiaofei Zhou, George C Brittain, Christine Stansberg, Oivind Torkildsen, Xiaodong Wang, Robert Brink, Xuhong Cheng and Shao-Cong Sun doi:10.1038/nm.3111 Microglia are activated in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here Shao-Cong Sun and colleagues demonstrate that the E3 ubiquitin ligase Peli1 is expressed in microglia and is required for their activation and expression of inflammatory cytokines and chemokines after the induction of EAE. Disease severity is reduced in Peli1-deficient mice, partly through the effects of Peli1 on TLR signaling and Traf3 degradation. See also: News and Views by Song & Qian Letters Top Targeting the endocannabinoid system in the treatment of fragile X syndrome   pp603 - 607 Arnau Busquets-Garcia, Maria Gomis-Gonzalez, Thomas Guegan, Carmen Agustin-Pavon, Antoni Pastor, Susana Mato, Alberto Perez-Samartin, Carlos Matute, Rafael de la Torre, Mara Dierssen, Rafael Maldonado and Andres Ozaita doi:10.1038/nm.3127 Fragile X syndrome is a type of mental retardation caused by mutations in the Fmr1 gene. Now Andres Ozaita and colleagues show that blocking cannabinoid signaling can restore learning in these mice, suggesting a potential therapeutic approach to this disease. PPAR[beta]/[delta] governs Wnt signaling and bone turnover   pp608 - 613 Carina Scholtysek, Julia Katzenbeisser, He Fu, Stefan Uderhardt, Natacha Ipseiz, Cornelia Stoll, Mario M Zaiss, Michael Stock, Laura Donhauser, Christina Bohm, Arnd Kleyer, Andreas Hess, Klaus Engelke, Jean-Pierre David, Farida Djouad, Jan Peter Tuckermann, Beatrice Desvergne, Georg Schett and Gerhard Kronke doi:10.1038/nm.3146 Gerhard Kronke and his colleagues show that PPAR[beta]/[delta] regulates Wnt signaling in osteoblasts, which in turn determines the proper ratio of OPG to RANKL and thus bone homeostasis. They go on to show that pharmacological activation of this receptor normalizes bone density in a mouse model of osteoporosis. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions   pp614 - 618 Felipe De Sousa E Melo, Xin Wang, Marnix Jansen, Evelyn Fessler, Anne Trinh, Laura P M H de Rooij, Joan H de Jong, Onno J de Boer, Ronald van Leersum, Maarten F Bijlsma, Hans Rodermond, Maartje van der Heijden, Carel J M van Noesel, Jurriaan B Tuynman, Evelien Dekker, Florian Markowetz, Jan Paul Medema and Louis Vermeulen doi:10.1038/nm.3174 Analysis of gene-expression profiles led to the identification of three molecularly distinct subtypes of colon cancer. One of these subtypes is new, and its identification is of clinical interest because it tends to have a particularly unfavorable prognosis and is refractory to existing targeted therapies. A colorectal cancer classification system that associates cellular phenotype and responses to therapy   pp619 - 625 Anguraj Sadanandam, Costas A Lyssiotis, Krisztian Homicsko, Eric A Collisson, William J Gibb, Stephan Wullschleger, Liliane C Gonzalez Ostos, William A Lannon, Carsten Grotzinger, Maguy Del Rio, Benoit Lhermitte, Adam B Olshen, Bertram Wiedenmann, Lewis C Cantley, Joe W Gray and Douglas Hanahan doi:10.1038/nm.3175 Gene-expression profiles from over 1,000 colorectal tumors define six subtypes with specific phenotypical features, responses to therapy and clinical progression. IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors   pp626 - 630 Katherine L Jameson, Pawel K Mazur, Ashley M Zehnder, Jiajing Zhang, Brian Zarnegar, Julien Sage and Paul A Khavari doi:10.1038/nm.3165 The MAPK cascade scaffolding protein IQGAP1, although dispensable for normal epithelial homeostasis, is required for RAS- and RAF-driven tumorigenesis in mouse tumor models. Accordingly, peptide-specific disruption of the interaction between IQGAP1 and ERK1/2 can bypass acquired resistance of vemurafenib-treated BRAF-mutant melanomas and extend the life span of tumor-bearing mice. See also: News and Views by Stuart & Sellers Evidence for two types of brown adipose tissue in humans   pp631 - 634 Martin E Lidell, Matthias J Betz, Olof Dahlqvist Leinhard, Mikael Heglind, Louise Elander, Marc Slawik, Thomas Mussack, Daniel Nilsson, Thobias Romu, Pirjo Nuutila, Kirsi A Virtanen, Felix Beuschlein, Anders Persson, Magnus Borga and Sven Enerback doi:10.1038/nm.3017 Brown fat is a thermogenically active organ that burns energy instead of storing it and has been the focus of intense research recently in the hopes of harnessing this activity to combat obesity. Sven Enerback and his colleagues now show that human neonates possess a classical form of this type of fat, suggesting hope that its expansion in adults may indeed be an avenue of therapy to treat obesity. See also: News and Views by Nedergaard & Cannon | Letter by Cypess et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat   pp635 - 639 Aaron M Cypess, Andrew P White, Cecile Vernochet, Tim J Schulz, Ruidan Xue, Christina A Sass, Tian Liang Huang, Carla Roberts-Toler, Lauren S Weiner, Cathy Sze, Aron T Chacko, Laura N Deschamps, Lindsay M Herder, Nathan Truchan, Allison L Glasgow, Ashley R Holman, Alina Gavrila, Per-Olof Hasselgren, Marcelo A Mori, Michael Molla and Yu-Hua Tseng doi:10.1038/nm.3112 Brown adipose tissue (BAT) burns, rather than stores, energy and has thus been explored as a way to combat obesity. Aaron Cypess and his colleagues isolate neck fat from adult humans and show that BAT exists in this region, define its anatomical localization in the neck relative to white adipose tissue and demonstrate that it is functional. See also: News and Views by Nedergaard & Cannon | Letter by Lidell et al. Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation   pp640 - 645 Zhuo-Xian Meng, Siming Li, Lin Wang, Hwi Jin Ko, Yongjin Lee, Dae Young Jung, Mitsuharu Okutsu, Zhen Yan, Jason K Kim and Jiandie D Lin doi:10.1038/nm.3144 It has been thought that a switch by the muscle from oxidative phosphorylation to glycolysis is associated with the development of insulin resistance. Jiandie Lin and colleagues now show that transgenic mice that undergo this switch, due to modest overexpression of Baf60c, are actually more glucose tolerant and insulin sensitive compared to wild-type mice when both are placed on a high-fat diet, suggesting the switch is actually an adaptive process. Technical Report Top Regeneration and experimental orthotopic transplantation of a bioengineered kidney   pp646 - 651 Jeremy J Song, Jacques P Guyette, Sarah E Gilpin, Gabriel Gonzalez, Joseph P Vacanti and Harald C Ott doi:10.1038/nm.3154 Building on their earlier work on heart and lung organ engineering, Jeremy Song and his colleagues have now adapted the technology of using decellularized scaffolds to develop bioengineered kidneys for transplantation. When reseeded with endothelial and epithelial cells, and after orthotopic transplantation in rats, the grafts became perfused by the recipient's circulation, produced urine and provided clearance of metabolites. 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. 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