Nature Medicine Contents: July 2013 Volume 19 Number 7 pp 791-945

Advertisement Collaborate. Co-Develop. Commercialize.  Built to strengthen your companion diagnostic development, World CDx will ensure every step is as smooth as the next. Join the World CDx community to maximize the impact of your collaborations. Improve your clinical biomarker validation, embed genomic technologies into your development and achieve successful Rx/Dx co-development. www.world-cdx.com TABLE OF CONTENTS July 2013 Volume 19, Issue 7 Podcast Editorials News Book Review Correspondence News and Views Community Corner Between Bedside and Bench Research Highlights Reviews Focus Perspective Brief Communication Articles Letters Technical Report Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Regenerative Medicine: From biology to therapy (30 October-1 November 2013)  Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. This exciting new Wellcome Trust conference is aimed at scientists involved in developmental and regenerative biology, stem cell research, translational medicine, or clinical trials. Abstracts due 13 September. Register by 2 October.     Advertisement Nature Reprint Collection MicroRNAs from bench to clinic This Nature Reprint Collection presents some of the recent advances in moving microRNAs from basic research into the clinic both as diagnostic biomarkers and therapeutic targets.  Click here to access the Collection for free!   Produced with support from:      Nature Medicine Podcast  Top African antidote We discuss Africa's first drug development hub and a new assay for personalizing cystic fibrosis therapy. Listen Now Editorials Top A brighter future in the fight against hepatitis   p791 doi:10.1038/nm.3269 Public health and research efforts directed at managing and targeting viral hepatitis have borne fruit in recent decades. However, more work is necessary to meet the goals of preventing transmission and treating infection to eliminate the enormous burden of hepatitis worldwide. A victory for genes   p792 doi:10.1038/nm.3279 The ability to patent human genes has been costly to researchers and patients, and has restricted competition in the biotech marketplace. The recent US Supreme Court decision making isolated human genes unpatentable will bring freedom of choice to the patient, and level the playing field for research and development. News Top New tools automatically match patients with clinical trials   p793 Alisa Opar doi:10.1038/nm0713-793 Companies go toe to toe, as topical treatments for nail fungus bloom   pp794 - 795 Cassandra Willyard doi:10.1038/nm0713-794 Publication checklist proposed to boost rigor of pilot trials   pp795 - 796 Elie Dolgin doi:10.1038/nm0713-795 Transparency battle resurfaces as EU trial revamp wraps up   p797 David Holmes doi:10.1038/nm0713-797 State stem cell agency floats idea of [dollar]70 million 'Alpha' clinics   p798 Elie Dolgin doi:10.1038/nm0713-798a Tuberculosis trials, already struggling, hit hard by US sequester   pp798 - 799 Trevor Quirk doi:10.1038/nm0713-798b Gene expression database scales up, providing baseline data   p799 Susan Matthews doi:10.1038/nm0713-799 News in Brief Biomedical briefing   pp800 - 801 doi:10.1038/nm0713-800 Q&A Straight talk with...Doris Meder and Geert Van Minnebruggen   p802 doi:10.1038/nm0713-802 Doris Meder and Geert Van Minnebruggen had a dream to team up core facilities across the EU so that institutes could pool resources to buy state-of-the-art machines as soon as the tools became available. To that end, they founded Core for Life (C4L), a pan-European project that formally launched on 14 May. Katharine Sanderson spoke with Meder and Van Minnebruggen about how they hope to democratize access to the very latest technologies for life scientists. News Feature Made in Africa   pp803 - 806 Linda Nordling doi:10.1038/nm0713-803 The resource-poor countries of Africa have traditionally relied on Western nations for their drug supply, but a new drug development center with a promising antimalarial agent could pave the way for a homegrown pharmaceutical pipeline. Linda Nordling investigates how this one facility at the southern tip of the continent promises to embolden an entire African drug industry. Opinion Three isn't the magic number   p807 Michael Houghton doi:10.1038/nm0713-807 Most research prizes in biomedicine, from the Nobels to the Laskers, are restricted to three recipients. But in an age of big science, when much larger teams are generally needed to make important research discoveries, all the people who provide seminal contributions deserve to be awarded. Book Review Top Racial profiling in medicine   p808 Aravinda Chakravarti reviews Race in a Bottle: The Story of BiDil and Racialized Medicine in a Post-Genomic Age by Jonathan Kahn doi:10.1038/nm.3254 Correspondence Top Regarding the mechanism of action of a proposed peptide agonist of the bone morphogenetic protein receptor activin-like kinase 3   pp809 - 810 Malcolm Whitman, Vicki Rosen, Ali H Brivanlou, Jay C Groppe and Walter Sebald et al. doi:10.1038/nm.3080 Reply to Regarding the mechanism of action of a proposed peptide agonist of the bone morphogenetic protein receptor activin-like kinase 3   pp810 - 811 Hikaru Sugimoto, Valerie S LeBleu, Dattatreyamurty Bosukonda, Peter Keck and Gangadhar Taduri et al. doi:10.1038/nm.3081 MSCs: science and trials   p811 Mark F Pittenger doi:10.1038/nm.3219 MSCs: science and trials   p812 Donald G Phinney, Jacques Galipeau, Mauro Krampera, Ivan Martin and Yufang Shi et al. doi:10.1038/nm.3220 MSCs: science and trials   pp812 - 813 Willem E Fibbe, Francesco Dazzi and Katarina LeBlanc doi:10.1038/nm.3222 Reply to MSCs: science and trials   pp813 - 814 Paolo Bianco doi:10.1038/nm.3255 Finding ways to improve the use of biobanks   pp814 - 815 Pascal Puchois doi:10.1038/nm.3257 Finding ways to improve the use of biobanks   p815 Angelo Paradiso and Mats Hansson doi:10.1038/nm.3256 News and Views Top BCAT1 defines gliomas by IDH status   pp816 - 817 Jared R Mayers and Matthew G Vander Heiden doi:10.1038/nm.3263 Metabolic alterations, such as those caused by mutations in the enzyme isocitrate dehydrogenase (IDH), define a clinically distinct subset of primary brain cancers. Expression of BCAT1 is now reported as a new metabolic change defining brain cancers without IDH mutations (pages 901-908). See also: Article by Tonjes et al. Migrating melanocyte stem cells: masters of disaster?   pp818 - 819 Ralf Paus doi:10.1038/nm.3264 A new study provides an example of the delicate balance between stem cell migration, differentiation and maintenance in the context of skin wounding. In mice, wounding or ultraviolet irradiation induces melanocyte stem cells in the hair follicle to leave their niche before cell division and migrate up the follicle to differentiate into functional melanocytes, thus providing a protective pigmented barrier (pages 924-929). See also: Letter by Chou et al. Medicine JOBS of the week Chemical Biology in Cellular and Molecular Medicine University of Leuven (Belgium) Chair of Pharmacogenomics or Personalised Medicine University of Sydney Postdoctoral fellowship Institute of Experimental Medicine - Hungarian Academy of Sciences The Joan and Jack Craig Chair in Autism Research Dalhousie University Research Assistant / Technicial in Analytical Chemistry Felipe Cava More Science jobs from Medicine EVENT Molecular Medicine Congress September 3, 2013 Frankfurt, Germany More science events from Community Corner Top A new route to human embryonic stem cells   pp820 - 821 doi:10.1038/nm.3266 Between Bedside and Bench Top How Cytokine Networks Fuel Inflammation: Toward a cytokine-based disease taxonomy   pp822 - 824 Georg Schett, Dirk Elewaut, Iain B. McInnes, Jean-Michel Dayer and Markus F. Neurath doi:10.1038/nm.3260 Discerning which mediators drive pathogenesis in chronic inflammatory diseases can be complex: immune cells can release various pathogenic cytokines, and numerous cytokines may either cause one specific disease or many. Human validation and mechanistic studies will be necessary to identify the key immune cells and cytokines for a given inflammatory disorder and to pinpoint which cytokine might be the appropriate target for tackling each disease. In 'Bedside to Bench', Georg Schett et al. discuss how human trials targeting different cytokines suggest the existence of a hierarchical framework of cytokines that defines groups of chronic inflamatory diseases rather differently from the homogenous molecular disease pattern previously assumed. In 'Bench to Bedside', Vijay Kuchroo and Dominique Baeten peruse the role of interleukin-17A as drug target in several autoimmune diseases to highlight how success in the clinic will need understanding of pathogenic pathways and the immunological and tissue context of each inflammatory disease. How Cytokine Networks Fuel Inflammation: Interleukin-17 and a tale of two autoimmune diseases   pp824 - 825 Dominique L. P. Baeten and Vijay K. Kuchroo doi:10.1038/nm.3268 Research Highlights Top T cells: Bending the rules of restriction | T cells: Reprogramming regulatory T cells | Cancer therapy: Fueling resistance | Alzheimer's disease: Micrological modulation | New from NPG | Autoimmunity: Be more sensitive | Tumor suppressors: A new PTEN translational variant Reviews Top Induced regeneration[mdash]the progress and promise of direct reprogramming for heart repair   pp829 - 836 Russell C Addis and Jonathan A Epstein doi:10.1038/nm.3225 There is much interest in the area of cardiac regeneration to replace cardiomyocytes lost in a heart attack. A number of recent studies have shown the feasibility of direct reprogramming, which allows one cell type to be directly converted into another cell type without going through a pluripotent intermediate step. In this Review, the authors review developments in direct reprogramming to cardiac cells in vitro and in vivo and compare the utility of these methods with pluripotent stem cell-mediated approaches. Focus on Hepatitis Understanding the hepatitis C virus life cycle paves the way for highly effective therapies   pp837 - 849 Troels K H Scheel and Charles M Rice doi:10.1038/nm.3248 A new wave of antivirals to fight hepatitis C infection has helped patients achieve a good quality of life, but drug resistance, side effects and a lack of pan-viral genotype coverage still remains a problem. This Review discusses current clinical studies and potential targets of the virus life cycle to tackle these issues and puts forward a paradigm to develop second-generation effective antivirals and drug combinations for achieving the ideal regimen of an all-oral, interferon-free therapeutic cocktail. Focus on Hepatitis Global control of hepatitis C: where challenge meets opportunity   pp850 - 858 David L Thomas doi:10.1038/nm.3184 In this Review, David L. Thomas discusses how recent therapeutic and diagnostic advances could be implemented in public health strategies to prevent viral hepatitis infections and treat existing infected patients. Despite the still increasing incidence and prevalence of hepatitis C infection, available tools may bring viral eradication a step closer toward becoming a reality. Focus on Hepatitis Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells   pp859 - 868 Barbara Rehermann doi:10.1038/nm.3251 During chronic infection caused by hepatitis C and B viruses, effector adaptive immune cells are exhausted and incapable of clearing the virus, but they can still contribute to liver inflammation in this setting. This Review discusses the regulatory role of nonspecific immune natural killer (NK) cells, which, along with other immune regulatory signals, help the host counteract liver disease progression and immunopathology by controlling virus-specific immunity. Focus on Hepatitis Current progress in development of hepatitis C virus vaccines   pp869 - 878 T Jake Liang doi:10.1038/nm.3183 Ongoing investigational studies aim to uncover new strategies to develop an effective vaccine to prevent hepatitis C infection. Advances have moved forward vaccine candidates, but technical and biological barriers posed by the virus still exist. This Review discusses how to better design vaccine trials and evaluate key components of protective immunity to achieve a working preventive vaccine. Perspective - Focus on Hepatitis Top Regulation of hepatic innate immunity by hepatitis C virus   pp879 - 888 Stacy M Horner and Michael Gale Jr doi:10.1038/nm.3253 Persistence of hepatitis C virus contributes to chronic infection, which can lead to liver fibrosis and even liver cancer. Different factors, such as host genetics and immunity and viral immune evasion strategies, account for the outcome of the infection and the patient response to antivirals. This Perspective discusses how the interaction of these factors modulates viral immunity and how they might be used to identify the key targets to mount an effective immune response that will clear the virus and improve drug response. Brief Communication Top A largely random AAV integration profile after LPLD gene therapy   pp889 - 891 Christine Kaeppel, Stuart G Beattie, Raffaele Fronza, Richard van Logtenstein and Florence Salmon et al. doi:10.1038/nm.3230 An adeno-associated virus (AAV) vector encoding a variant of human lipoprotein lipase was recently approved in Europe as the first gene therapy for the treatment of LPL deficiency. Here Manfred Schmidt and his colleagues report their analysis of AAV integration sites after injection of the gene therapy construct in LPL-deficient patients and in mice. Articles Top MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion   pp892 - 900 James Soh, Jahangir Iqbal, Joyce Queiroz, Carlos Fernandez-Hernando and M Mahmood Hussain doi:10.1038/nm.3200 This study identifies miR-30c as a regulator of both microsomal triglyceride transfer protein, needed for the secretion of APOB-containing lipoproteins such as low-density lipoproteins, and a number of other genes involved in lipid biosynthesis. In mice, miR-30c regulates hepatic lipid biosynthesis and lipoprotein secretion such that hepatic overexpression of miR-30c reduces plasma cholesterol and triglyceride concentrations and decreases atherosclerotic plaque burden. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1   pp901 - 908 Martje Tonjes, Sebastian Barbus, Yoon Jung Park, Wei Wang and Magdalena Schlotter et al. doi:10.1038/nm.3217 Branched-chain amino acid transaminase 1, the enzyme that initiates the catabolism of branched-chain amino acids, is involved in glioma pathogenesis, making it a potential therapeutic target. See also: News and Views by Mayers & Vander Heiden Inflammasome-derived IL-1[beta] production induces nitric oxide-mediated resistance to Leishmania    pp909 - 915 Djalma S Lima-Junior, Diego L Costa, Vanessa Carregaro, Larissa D Cunha and Alexandre L N Silva et al. doi:10.1038/nm.3221 Activation of inflammasomes has been implicated in sensing pathogens. Now Dario Zamboni and colleagues report that the Nlrp3 inflammasome has a key role in restricting replication of Leishmania parasites in macrophages and in mice by triggering interleukin-1A-dependent induction of nitric oxide, a crucial mediator of defense against Leishmania. Fgf9 from dermal [gamma][delta] T cells induces hair follicle neogenesis after wounding   pp916 - 923 Denise Gay, Ohsang Kwon, Zhikun Zhang, Michelle Spata and Maksim V Plikus et al. doi:10.1038/nm.3181 Humans lack robust regeneration of hair follicles after skin wounding. George Cotsarelis and colleagues now show that [gamma][delta] T cells are not present at high levels in human skin, that in mice they are a key initial source of the protein fibroblast growth factor 9 and that this factor modulates hair follicle regeneration during skin wound healing. These results suggest a possible topical clinical treatment to regrow hair after wounding and perhaps for other conditions of hair loss. Letters Top Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling   pp924 - 929 Wei Chin Chou, Makoto Takeo, Piul Rabbani, Hai Hu and Wendy Lee et al. doi:10.1038/nm.3194 Mayumi Ito and her colleagues show that during skin wounding in mice, melanocyte stem cells in the hair follicle are induced by melanocortin 1 receptor (Mc1r) signaling to migrate towards the epidermis and differentiate into mature pigment-producing cells. This mechanism allows for protection of the healing skin from ultraviolet light-induced damage. See also: News and Views by Paus Association of HLA-DRB1-restricted CD4+ T cell responses with HIV immune control   pp930 - 933 Srinika Ranasinghe, Sam Cutler, Isaiah Davis, Richard Lu and Damien Z Soghoian et al. doi:10.1038/nm.3229 CD8+ T cell responses have been associated with control of HIV replication, but the role of CD4+ T cells in protecting against this virus is unclear. In an analysis of HLA class II-restricted CD4+ T cell responses in HIV-infected individuals, Hendrik Streeck and his colleagues now report that certain HLA-DRB1 variants are associated with low viremia and can present a wide breadth of peptides, suggesting that CD4+ T cell responses in infected individuals may help control HIV. Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs   pp934 - 938 Erich Gulbins, Monica Palmada, Martin Reichel, Anja Luth and Christoph Bohmer et al. doi:10.1038/nm.3214 Depression is a debilitating condition for which new treatments are sorely needed. Now, Erich Gulbins and his colleagues report that reducing ceramide levels in the brain has antidepressant effects in mouse models of the disease. Technical Report Top A functional CFTR assay using primary cystic fibrosis intestinal organoids   pp939 - 945 Johanna F Dekkers, Caroline L Wiegerinck, Hugo R de Jonge, Inez Bronsveld and Hettie M Janssens et al. doi:10.1038/nm.3201 Building on earlier work, Dekkers et al. describe the first application of their intestinal organoid culture technology to the study of human disease, in this case cystic fibrosis. These so called 'mini-guts', which recapitulate the essential in vivo intestinal tissue architecture in vitro, are used to develop a rapid and quantitative assay to measure mutant cystic fibrosis transmembrane conductance regulator (CFTR) function, as well as test the efficacy of correctors and potentiators of mutant CFTR. 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