Nature Medicine Contents: December 2013 Volume 19 Number 12 pp 1547-1673

TABLE OF CONTENTS December 2013 Volume 19, Issue 12 Podcast Editorial News Book Review News and Views Community Corner Between Bedside and Bench Research Highlights Reviews Articles Letters Technical Reports Retraction Advertisement Roche's X-tremeGENE Transfection Reagents Efficiently transfect difficult cells, including more than 100 cancer cell lines. Free sample and protocols at www.x-tremegene.roche.com   For life science research only. Not for use in diagnostic procedures. Subscribe   Facebook   RSS   Recommend to library   Twitter   Podcast Advertisement Emerging therapeutic targets for T2DM  Type 2 diabetes mellitus (T2DM) is one of the most prevalent noncommunicable diseases in the world. New therapeutic targets for T2DM have been uncovered in the past decade, some of which have reached clinical application. This Nature Reviews Endocrinology collection gives an overview of the emerging therapeutic targets for T2DM, discussing promising avenues uncovered from basic, translational and clinical research. The collection is free for 6 months thanks to support from    Nature Medicine Podcast  Top Fair share We talk with the founders of shared lab facilities and ask why genetic differences in blood clotting may underlie racial disparities in heart disease. Listen Now Editorial Top Retraction blues   pp1547 - 1548 doi:10.1038/nm.3426 Advocacy for the integrity of the scientific record is stronger than ever. Paradoxically, retracting a flawed paper is getting more and more difficult. News Top Drugs with dual-hormone action gain attention in diabetes field   p1549 Veronica Hackethal doi:10.1038/nm1213-1549 Kinesin inhibitor marches toward first-in-class pivotal trial   p1550 Brian Owens doi:10.1038/nm1213-1550a Correction   p1550 doi:10.1038/nm1213-1550b Alzheimer's imaging agents struggle to find a market outside trials   p1551 Sarah CP Williams doi:10.1038/nm1213-1551 Adolescent perceptions of drug advertising come under review   p1552 Arielle Duhaime-Ross doi:10.1038/nm1213-1552 Q&A Straight talk with...BT Slingsby   p1553 doi:10.1038/nm1213-1553 This year saw the launch of the Global Health Innovative Technology (GHIT) Fund—a new public-private partnership between five Japanese pharmaceutical companies, two government ministries and the Bill & Melinda Gates Foundation. In November, the Tokyo-based fund announced its first round of awards totaling $5.7 million. Leading the new $120 million, five-year initiative is BT Slingsby, a US-born scholar of the Japanese healthcare industry. He met with Cassandra Willyard to discuss the new fund and how Japan can help drive the development of medicines and vaccines for diseases of the developing world. News in Brief Biomedical briefing   pp1554 - 1555 doi:10.1038/nm1213-1554 News Feature Thanks for sharing   pp1556 - 1558 Elie Dolgin doi:10.1038/nm1213-1556 Co-working spaces in which many entrepreneurs share a common environment have been a hallmark of the computer startup industry for decades. Now, the life sciences sector is beginning to do the same. Elie Dolgin talks with the pioneers helping to bring affordable wet-lab space—plus the infrastructure and support needed to launch a successful commercial enterprise—to the next generation of biotech innovators. Opinions Advancing women in R&D will help accelerate medicine   p1559 Annalisa Jenkins doi:10.1038/nm1213-1559 Enabling women to serve at the highest leadership levels in pharmaceutical R&D will help advance science to offer a broader array of medicines to patients. But in an industry dominated by men in the most senior-level roles, women have a long way to go to get to the top. Timeline of events: A brief history of what made news this year   p1560 doi:10.1038/nm1213-1560 Biomedical research in 2013 saw some dramatic developments, with unprecedented government action in the US ranging from the budget sequester in the spring to a dramatic government shutdown in autumn. But throughout the year, bright spots in science around the globe continued to dazzle, including multimillion-dollar partnerships to advance drug discovery and the go-ahead for highly anticipated trials of regenerative medicine. The Yearbook   p1561 doi:10.1038/nm1213-1561 Our list of newsmakers this year includes everyone from thought leaders with brainy plans for the future to individuals who influenced rules and regulations—even from beyond the grave. Drugs that made headlines in 2013   pp1562 - 1563 doi:10.1038/nm1213-1562 As immunotherapies and even newer strategies such as antisense therapy march ahead, the drug development pipeline took an interesting turn this year. Here, we look back at the compounds that made the cut, as well as those that got cut. Notable advances 2013   pp1564 - 1565 doi:10.1038/nm1213-1564 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 2013. Book Review Top The war on ADHD   p1566 Mark Stein reviews Hyperactive: The Controversial History of ADHD by Matthew Smith doi:10.1038/nm.3419 News and Views Top It has to be the αv: myofibroblast integrins activate latent TGF-β1   pp1567 - 1568 Boris Hinz doi:10.1038/nm.3421 Cell-mediated activation of latent TGF-β1 is a key promoting event in fibrosis in all organs. A new study shows that specific targeting of the αv subunit of integrins in fibrogenic myofibroblasts effectively reduces developing and established fibrosis in liver, kidneys and lungs (pages 1617-1624). See also: Article by Henderson et al. Poker face no more: cancer recurrence reveals its hand   pp1569 - 1570 Christopher J Chan and Lisa M Coussens doi:10.1038/nm.3410 Recurrent disease after apparent 'cure' of primary tumors is a common factor that contributes to cancer-associated mortality. A new study suggests that an inflammatory cytokine signature may provide a clinical indication of emergent recurrent disease and, accordingly, may suggest how to select and deliver therapy targeted against the secondary tumor (pages 1625-1631). See also: Article by Kottke et al. Metformin trims fats to restore insulin sensitivity   pp1570 - 1572 Reuben J Shaw doi:10.1038/nm.3414 Despite metformin being one of the most commonly prescribed drugs for the treatment of diabetes, how it elicits its therapeutic effects has remained mysterious. A new study in mice shows that inhibitory phosphorylation of acetyl-coA carboxylases Acc1 and Acc2 by the AMP-activated protein kinase (AMPK) is essential for the ability of metformin to improve insulin sensitivity and lower blood glucose in obesity (pages 1649-1654). See also: Letter by Fullerton et al. Reassessing the role of astrocytes in ammonia neurotoxicity   pp1572 - 1574 Tore Eid and Tih-Shih W Lee doi:10.1038/nm.3420 High blood ammonia, as seen in severe liver disease and urea cycle disorders, is neurotoxic and difficult to treat. A new study shows that the toxic effects are caused by impaired astrocyte potassium buffering—not astrocyte swelling, as previously thought—and can be partially blocked by the diuretic bumetanide (pages 1643-1648). See also: Letter by Thrane et al. Nature Medicine JOBS of the week Bioinformatician Institute for Molecular Medicine Finland (FIMM) PhD Studentship MRC-University of Glasgow Centre for Virus Research Post-Doctoral Research Fellow University Frankfurt Research Fellow South Australian Health & Medical Research Institute More Science jobs from Nature Medicine EVENT Alzheimer's Research UK Drug Discovery Institute 14.02.14 UK More science events from Community Corner Top Another HIV vaccine failure: where to next?   pp1576 - 1577 doi:10.1038/nm.3413 Between Bedside and Bench Top Harnessing the Stem Cell Potential: The path to prevent mitochondrial disease   pp1578 - 1579 Akemi J Tanaka, Mark V Sauer, Dieter Egli and Daniel H Kort doi:10.1038/nm.3422 Although stem cells were initially thought to be the magic bullet for numerous diseases, translation of a stem cell-based cure into the clinic is still a work in progress. Basic research is shedding light into the potential of stem cells, and different research fronts are now exploring how to exploit this potential to tackle diverse conditions. In 'Bench to Bedside', Akemi Tanaka, Mark Sauer, Dieter Egli and Daniel Kort discuss how genome transfer from eggs of mothers with mutated mitochondria into an enucleated egg from a healthy female donor at an early developmental stage can eliminate mitochondrial disease. The negligible mutant mitochondrial DNA carryover and the differentiation of subsequent embryonic stem cells into various cell types with healthy mitochondrial DNA content suggest this could be used to prevent transmission of mitochondrial disease to the offspring. The authors discuss safety concerns and remaining technical questions that need to be resolved to make way for this new technology in the clinic. In 'Bedside to Bench', Nan Yang and Marius Wernig peruse a small study of children with a myelin disorder showing that transplantation of human neural stem cells leads to engraftment and donor cell-derived myelination. Harnessing the Stem Cell Potential: A case for neural stem cell therapy   pp1580 - 1581 Nan Yang and Marius Wernig doi:10.1038/nm.3425 Research Highlights Top Metabolic disease: Obesity-associated mutations | Mitochondrial disease: Rapamycin to the rescue | Infectious disease: Blocking bacteria | Innate immunity: HIV undercover Reviews Top Development, maintenance and disruption of the blood-brain barrier   pp1584 - 1596 Birgit Obermeier, Richard Daneman and Richard M Ransohoff doi:10.1038/nm.3407 The blood-brain barrier (BBB) has a key role in maintaining brain homeostasis and, thus, brain function. This Review outlines recent advances in understanding the development and maintenance of the BBB and the contribution of BBB disruption to various neurological diseases. It also discusses how such insights might be used to design new therapeutic strategies for BBB repair. Key roles of adjuvants in modern vaccines   pp1597 - 1608 Steven G Reed, Mark T Orr and Christopher B Fox doi:10.1038/nm.3409 Adjuvants play an important part in vaccines, as they can enhance and shape antigen-specific immune responses. This Review discusses the benefits of adjuvants and recent advances in understanding their mechanisms of action. The authors also set out the clinical barriers to development of new adjuvants and offer suggestions for overcoming these hurdles to the advancement of next-generation vaccines. Advertisement "Frontiers has taken open access a step further" Andy Bhattacharjee In this video, Andy Bhattacharjee tells us what he likes about publishing at Frontiers - open access and interactive peer review. Find Andy on the Frontiers Research Network   Articles Top Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c    pp1609 - 1616 Leonard C Edelstein, Lukas M Simon, Raul Teruel Montoya, Michael Holinstat, Edward S Chen et al. doi:10.1038/nm.3385 In exploring the possibility that racial differences in platelet function might exist, Paul Bray and his colleagues report that platelets from blacks have a greater propensity to aggregate than those from whites in response to activation of the PAR4 thrombin receptor. Mechanistically, this difference in platelet function seems to reflect differences in the expression of the microRNA miR-376c and its target, the enzyme phosphatidylcholine transfer protein. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs   pp1617 - 1624 Neil C Henderson, Thomas D Arnold, Yoshio Katamura, Marilyn M Giacomini, Juan D Rodriguez et al. doi:10.1038/nm.3282 Dean Sheppard and his colleagues show that genetic or pharmacological inhibition of αv integrin signaling ameliorates fibrosis in several solid organs. See also: News and Views by Hinz Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence   pp1625 - 1631 Timothy Kottke, Nicolas Boisgerault, Rosa Maria Diaz, Oliver Donnelly, Diana Rommelfanger-Konkol et al. doi:10.1038/nm.3397 Detecting tumor recurrences early and developing therapies capable of targeting recurrences that resist frontline therapy could be of enormous benefit to patients with cancer. Using mouse tumor models, Richard Vile and colleagues find a cytokine signature associated with very early stage recurrences, as well as evidence that the recurrent tumors are resistant to innate immune responses. By targeting the altered phenotype of the recurrent tumors, the researchers cured the mice of cancer, suggesting new avenues for research into human cancer recurrence. See also: News and Views by Chan & Coussens CD28 and ITK signals regulate autoreactive T cell trafficking   pp1632 - 1637 Nitya Jain, Bing Miu, Jian-kang Jiang, Kai K McKinstry, Amanda Prince et al. doi:10.1038/nm.3393 Autoimmunity is triggered by trafficking of self-reactive T cells into tissues. Joonsoo Kang and colleagues show that the kinase ITK regulates T cell trafficking. ITK inhibition or genetic ablation prevents homing of autoreactive T cells into tissues and reduces islet destruction in models of type 1 diabetes without affecting T cell activation or antiviral T cell responses, suggesting that this kinase may be targeted in autoimmune disease. Letters Top Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection   pp1638 - 1642 Su-Hyung Park, Naga Suresh Veerapu, Eui-Cheol Shin, Angelique Biancotto, J Philip McCoy et al. doi:10.1038/nm.3408 T cells specific for hepatitis C virus (HCV) have been reported in some individuals who have been repeatedly exposed to virus, yet have never had detectable HCV or HCV-specific antibodies. These findings suggest that T cells in these individuals may protect against infection by HCV. Barbara Rehermann and colleagues now test this assumption in a nonhuman primate study exposing animals to a very low dose of HCV. Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering   pp1643 - 1648 Vinita Rangroo Thrane, Alexander S Thrane, Fushun Wang, Maria L Cotrina, Nathan A Smith et al. doi:10.1038/nm.3400 Excess ammonia in the blood can cause neurologic dysfunction and seizures. Although previous studies have suggested that astrocyte swelling and brain edema are associated with hyperammonemia, the authors show that ammonia compromises potassium buffering by astrocytes, increasing extracellular potassium concentrations and resulting in cortical disinhibition. Pharmacological or genetic inhibition of NKCC1 attenuates ammonia-induced neurologic impairment and seizures, suggesting hyperammonemia may be treated by targeting NKCC1. See also: News and Views by Eid & Lee Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin   pp1649 - 1654 Morgan D Fullerton, Sandra Galic, Katarina Marcinko, Sarah Sikkema, Thomas Pulinilkunnil et al. doi:10.1038/nm.3372 Metformin is one of the most widely prescribed therapeutics for type 2 diabetes. But exactly how it works is still unclear. Gregory Steinberg and colleagues now show that it does so by activation of the enzyme AMP-activated protein kinase (Ampk) and Ampk's obligate targeting of two key enzymes involved in lipid homeostasis. See also: News and Views by Shaw Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression   pp1655 - 1660 Matteo Trudu, Sylvie Janas, Chiara Lanzani, Huguette Debaix, Celine Schaeffer et al. doi:10.1038/nm.3384 Variation in the promoter of the gene encoding uromodulin, the most abundant protein in urine, affects the individual risk of developing hypertension or chronic kidney disease. Luca Rampoldi, Olivier Devuyst and their colleagues show that the uromodulin risk alleles are associated with higher levels of uromodulin expression. This can promote hypertension, by stimulating sodium reabsorption by the loop of Henle in the kidney, and kidney damage in both mice and humans. Technical Reports Top Tracking the fate of glomerular epithelial cells in vivo using serial multiphoton imaging in new mouse models with fluorescent lineage tags   pp1661 - 1666 Matthias J Hackl, James L Burford, Karie Villanueva, Lisa Lam, Katalin Susztak et al. doi:10.1038/nm.3405 Matthias Hackl and his colleagues develop a new serial multiphoton microscopy approach to track migrating podocytes and parietal epithelial cells over time in vivo in the intact kidney. Use of this new approach is demonstrated in several mouse models and should help answer questions surrounding podocyte proliferation and migration to other (peri)glomerular regions, thus shedding light on the mechanisms of glomerular injury and regeneration. Quantifying the local tissue volume and composition in individual brains with magnetic resonance imaging   pp1667 - 1672 Aviv Mezer, Jason D Yeatman, Nikola Stikov, Kendrick N Kay, Nam-Joon Cho et al. doi:10.1038/nm.3390 There is an urgent need for quantitative magnetic resonance approaches for assessing brain development, as well as for studying the effects of drugs on neural tissue inflammation. Aviv Mezer and colleagues have developed a neuroimaging method for the quantification of local tissue volume and tissue-surface interaction, producing reliable quantitative measurements across a range of scanners. They apply their method to both the healthy brain and individuals with relapsing-remitting multiple sclerosis. Retraction Top Retraction: Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease   p1673 Xuebin Liu, Stewart Leung, Chunxia Wang, Zhu Tan, Ji Wang et al. doi:10.1038/nm.2077 Top Advertisement 8th annual Salk Institute, Fondation IPSEN, and Nature Symposium on Biological Complexity: Genes and Physiology January 29-31, 2014 Salk Institute for Biological Studies La Jolla, CA, USA  Click here for more information or to register for this conference 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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