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For life science research only. Not for use in diagnostic procedures. |  | | |  | TABLE OF CONTENTS
| | February 2012 Volume 18, Issue 2 |  | | |  |  Editorial
News
Book Review
News and Views
Community Corner
Between Bedside and Bench
Research Highlights
Commentary
Brief Communications
Articles
Letters
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We discuss a drug that disrupts HCV cell entry and how leprosy breaks down the body's defenses.
Listen Now | | Editorial | Top | | | | | Science in times of crisis p179
doi:10.1038/nm.2672
Budget cuts and administrative changes that have eliminated the Ministry of Science in Spain illustrate the need to safeguard science funding and policies in European countries immersed in the economic crisis.
Full Text | PDF | | News | Top | | | | | Congress vouches for priority review of childhood disease p181
Roxanne Palmer
doi:10.1038/nm0212-181
Full Text | PDF | | | | | India mulling stricter laws to curb unethical trials p182
Killugudi Jayaraman
doi:10.1038/nm0212-182
Full Text | PDF | | | | | With bated breath, companies await approval for inhalable drugs p183
Elie Dolgin
doi:10.1038/nm0212-183
Full Text | PDF | | | | | Spain reeling from budget and staff cuts in biomedicine p184
Michele Catanzaro
doi:10.1038/nm0212-184a
Full Text | PDF | | | | | New insight on bariatric surgery difficult to swallow pp184 - 185
Melinda Wenner Moyer
doi:10.1038/nm0212-184b
Full Text | PDF | | | | | Internet data miners strike disease detection gold p185
Rebecca Hersher
doi:10.1038/nm0212-185
Full Text | PDF | | | | | Clinicians call for greater transparency in trial recruitment p186
Rebecca Hersher
doi:10.1038/nm0212-186a
Full Text | PDF | | | | | Fifth time's the charm? p186
Rebecca Hersher
doi:10.1038/nm0212-186b
Full Text | PDF | | | | | Q&A | | | | | Straight talk with...Patrick Soon-Shiong p187
Amber Dance
doi:10.1038/nm0212-187
Patrick Soon-Shiong has only one mode of thinking: big. The South Africa-born surgeon-scientist has founded two multi-billion-dollar pharmaceutical firms and is now setting his sights on transforming the entire US biomedical system with a modern, high-speed data network. Amber Dance sat down with Soon-Shiong to talk about how uniting physicians and scientists will surmount the most pressing challenges in biomedicine and cancer research.
Abstract | Full Text | PDF | | | | | News in Brief | | | | | Biomedical briefing pp188 - 189
doi:10.1038/nm0212-188
Full Text | PDF | | | | | Correction p189
doi:10.1038/nm0212-189
Full Text | PDF | | | | | News Feature | | | | | The Ultimate Endpoint pp190 - 193
Elie Dolgin
doi:10.1038/nm0212-190
Suicide is the third leading cause of death in the US among people under the age of 45. Yet psychiatrists know remarkably little about what treatments can most effectively prevent people from killing themselves. For the most part, investigators have shied away from studying the problem head-on because designing intervention studies with suicidal subjects is fraught with difficulty. Elie Dolgin talks to the small group of mental health professionals who are hoping to put an end to that.
Full Text | PDF | | | | | Opinion | | | | | Action is required to safeguard the future of academic medicine in the UK p194
Garth M Funston and Adam M H Young
doi:10.1038/nm0212-194
The long-term decline in the number of UK doctors who conduct research is well recognized. Although some signs of recovery have been noted in the last few years, government budget cuts and the imminent rise in the tuition fee cap may make a bad situation worse.
Full Text | PDF | | Book Review | Top | | | | | Smallpox: the big picture pp195 - 196
Amy E. Slaton reviews Pox: An American History by Michael Willrich
doi:10.1038/nm.2662
Full Text | PDF | | News and Views | Top | | | | | | | Community Corner | Top | | | | | A delicate balance: tweaking IL-2 immunotherapy pp208 - 209
doi:10.1038/nm0212-208
Full Text | PDF | | Between Bedside and Bench | Top | | | | | Puzzling over schizophrenia: Schizophrenia as a pathway disease pp210 - 211
Patrick F Sullivan
doi:10.1038/nm.2670
Effective treatment for schizophrenia is still an unmet clinical need. Alleviating problems associated with cognitive impairment and finding the root of the disease remain priorities for clinicians and scientists. The incomplete understanding of the basis of this pathology has urged for research that will unravel the genetic origin of schizophrenia. But studies involving environmental exposure and social impact have also hinted at extrinsic factors as players in the pathogenesis of schizophrenia, which may be exploited to prevent the development of the disease. In 'Bench to Bedside', Patrick Sullivan proposes a model putting forward how genetic variants may confer risk by functioning together within the same pathway. This disease pathway hypothesis would imply a polygenetic variation affecting the same pathway and the alteration of a transcriptional network as a root for increasing schizophrenia risk. In 'Bedside to Bench', Andreas Meyer-Linderberg and Heike Tost discuss human-based population studies that suggest that environmental factors linked to development of schizophrenia can affect brain regions involved in the human social-emotional processing network. Genetic risk variants for schizophrenia can also influence similar regions in the brain, suggesting that environmental and intrinsic factors may converge in the same neural circuit.
Full Text | PDF | | | | | Puzzling over schizophrenia: Schizophrenia, social environment and the brain pp211 - 213
Heike Tost and Andreas Meyer-Lindenberg
doi:10.1038/nm.2671
Full Text | PDF | | Research Highlights | Top | | | | | Obesity: Is beige the new brown? | Antimicrobials: Mycobacterial asymmetry | Inflammation: Burning up the brain | Brain: Anxious about your meal? | Commentary | Top | | | | | Harnessing evolutionary biology to combat infectious disease pp217 - 220
Tom J Little, Judith E Allen, Simon A Babayan, Keith R Matthews and Nick Colegrave
doi:10.1038/nm.2572
Pathogens have remarkable abilities to flout therapeutic intervention. This characteristic is driven by evolution, either as a direct response to intervention (for example, the evolution of antibiotic resistance) or through long-term co-evolution that generates host or parasite traits that interact with therapy in undesirable or unpredicted ways. To make progress towards successful control of infectious diseases, the concepts and techniques of evolutionary biology must be deeply integrated with traditional approaches to immunology and pathogen biology. An interdisciplinary approach can inform our strategies to control pathogens or even the treatment of infected patients, positioning us to meet the current and future challenges of controlling infectious diseases.
Full Text | PDF | | Brief Communications | Top | | | | | Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer pp221 - 223
Clara Montagut, Alba Dalmases, Beatriz Bellosillo, Marta Crespo, Silvia Pairet, Mar Iglesias, Marta Salido, Manuel Gallen, Scot Marsters, Siao Ping Tsai, Andre Minoche, Seshagiri Somasekar, Sergi Serrano, Heinz Himmelbauer, Joaquim Bellmunt, Ana Rovira, Jeff Settleman, Francesc Bosch and Joan Albanell
doi:10.1038/nm.2609
By modeling acquired resistance to the EGFR antibody cetuximab in metastatic colorectal cancer, the authors identify a new mutation in the ectodomain of the receptor. The mutation is present in patient tumors after cetuximab therapy, confirming that it represents a clinically-relevant mechanism for therapy resistance. Moreover, the mutation does not affect the response to other EGFR antibodies, suggesting that if independently confirmed it may be a useful indicator to tailor anti-EGFR therapy.
First paragraph | Full Text | PDF
See also: News and Views by Bardelli & Janne | | | | | Prostaglandin E2 promotes intestinal tumor growth via DNA methylation pp224 - 226
Dianren Xia, Dingzhi Wang, Sun-Hee Kim, Hiroshi Katoh and Raymond N DuBois
doi:10.1038/nm.2608
This report uncovers a direct link between cancer-driving inflammation and DNA methylation by showing that PGE2 regulates the expression of DNA methylases, resulting in silencing of tumor-suppressor genes. The authors suggest that DNA methylation is an important component of the pathogenic effect of inflammatory signaling in colorectal cancer.
First paragraph | Full Text | PDF | | Articles | Top | | | | | A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20 pp227 - 234
Michael Blank, Yi Tang, Motozo Yamashita, Sandra S Burkett, Steven Y Cheng and Ying E Zhang
doi:10.1038/nm.2596
The authors identify a new tumor suppressor role for Smurf2 that is linked to its regulation of histone modifications through RNF20. In the absence of Smurf2 in mice, and potentially also when its nuclear function is compromised in human tumors, higher levels of histone ubiquitination lead to a relaxation of chromatin structure, and alterations in DNA repair result in compromised genomic instability and increased tumorigenesis in aging mice. The findings suggest that loss of Smurf2 function may underlie tumor initiation by reshaping the epigenetic landscape of cells.
Abstract | Full Text | PDF
See also: News and Views by Wang & Roberts | | | | | Cidea is an essential transcriptional coactivator regulating mammary gland secretion of milk lipids pp235 - 243
Wenshan Wang, Na Lv, Shasha Zhang, Guanghou Shui, Hui Qian, Jingfeng Zhang, Yuanying Chen, Jing Ye, Yuansheng Xie, Yuemao Shen, Markus R Wenk and Peng Li
doi:10.1038/nm.2614
Cidea is typically thought of as a lipid droplet-associated cytoplasmic protein in brown adipose tissue. Peng Li and colleagues now show that it is also in the nucleus, and in mammary gland epithelial cells it acts as an essential transcriptional coactivator of C/EBP[beta] to regulate the expression of genes involved in milk lipid secretion during lactation.
Abstract | Full Text | PDF | | | | | AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation pp244 - 251
Johanna T Lanner, Dimitra K Georgiou, Adan Dagnino-Acosta, Alina Ainbinder, Qing Cheng, Aditya D Joshi, Zanwen Chen, Viktor Yarotskyy, Joshua M Oakes, Chang Seok Lee, Tanner O Monroe, Arturo Santillan, Keke Dong, Laurie Goodyear, Iskander I Ismailov, George G Rodney, Robert T Dirksen and Susan L Hamilton
doi:10.1038/nm.2598
Mutations in the type I ryanodine receptor (RYR1), a calcium channel, leads to stimulus-induced pathological muscle contractions, including malignant hyperthermia. Currently there are no pharmacological agents to protect against this condition, but Susan Hamilton and her colleagues have now identified AICAR as one possible candidate compound. To date, AICAR has been thought to be an AMPK activator, but her group shows that in a mouse model of malignant hyperthermia it does not target this kinase, but rather RYR1, to prevent improper calcium leakage and pathology.
Abstract | Full Text | PDF | | | | | cGMP-Prkg1 signaling and Pde5 inhibition shelter cochlear hair cells and hearing function pp252 - 259
Mirko Jaumann, Juliane Dettling, Martin Gubelt, Ulrike Zimmermann, Andrea Gerling, Francois Paquet-Durand, Susanne Feil, Stephan Wolpert, Christoph Franz, Ksenya Varakina, Hao Xiong, Niels Brandt, Stephanie Kuhn, Hyun-Soon Geisler, Karin Rohbock, Peter Ruth, Jens Schlossmann, Joachim Hutter, Peter Sandner, Robert Feil, Jutta Engel, Marlies Knipper and Lukas Ruttiger
doi:10.1038/nm.2634
Noise-induced hearing loss (NIHL) is a prevalent problem in the industrialized world. Now, Lukas Ruttiger and colleagues show that the phosphodiesterase inhibitor vardenafil can prevent NIHL in rats and mice.
Abstract | Full Text | PDF
See also: News and Views by Layman & Zuo | | | | | An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection pp260 - 266
Fei Chen, Zhugong Liu, Wenhui Wu, Cristina Rozo, Scott Bowdridge, Ariel Millman, Nico Van Rooijen, Joseph F Urban Jr, Thomas A Wynn and William C Gause
doi:10.1038/nm.2628
Protective T helper 2 (TH2)-type responses are induced by parasite infection and can control inflammation and induce parasite expulsion. In this issue, Chen et al. report that in a mouse model of helminth infection, TH2-type responses protect against acute lung tissue damage by both suppressing inflammation and promoting macrophage-associated wound healing.
Abstract | Full Text | PDF | | | | | MicroRNA-21 targets the vitamin D-dependent antimicrobial pathway in leprosy pp267 - 273
Philip T Liu, Matthew Wheelwright, Rosane Teles, Evangelia Komisopoulou, Kristina Edfeldt, Benjamin Ferguson, Manali D Mehta, Aria Vazirnia, Thomas H Rea, Euzenir N Sarno, Thomas G Graeber and Robert L Modlin
doi:10.1038/nm.2584
The ability of Mycobacterium leprae to upregulate miRNA-21 provides an effective mechanism for the pathogen to escape from the vitamin D-dependent antimicrobial pathway.
Abstract | Full Text | PDF | | | | | Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans pp274 - 280
Tom M Wilkinson, Chris K F Li, Cecilia S C Chui, Arthur K Y Huang, Molly Perkins, Julia C Liebner, Rob Lambkin-Williams, Anthony Gilbert, John Oxford, Ben Nicholas, Karl J Staples, Tao Dong, Daniel C Douek, Andrew J McMichael and Xiao-Ning Xu
doi:10.1038/nm.2612
The role of T cells in modulating the course of influenza infection in humans is not clear. Wilkinson et al. now report that, in the absence of strain-specific humoral immunity, preexisting cytotoxic CD4+ T cells limit the severity and duration of symptoms in humans challenged with influenza virus and suggest these CD4+ T cell responses might be harnessed in vaccine development.
Abstract | Full Text | PDF
See also: News and Views by Kelso | | Letters | Top | | | | | Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor pp281 - 285
Bruno Sainz Jr, Naina Barretto, Danyelle N Martin, Nobuhiko Hiraga, Michio Imamura, Snawar Hussain, Katherine A Marsh, Xuemei Yu, Kazuaki Chayama, Waddah A Alrefai and Susan L Uprichard
doi:10.1038/nm.2581
The Niemann-Pick C1-like 1 cholesterol uptake receptor is an entry factor for the hepatitis C virus, according to this report. Ezetimibe, a drug that targets this receptor and is approved for use in humans, inhibits infection by the hepatitis C virus in a mouse model, highlighting the therapeutic potential of this discovery.
First paragraph | Full Text | PDF | | | | | Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension pp286 - 290
Oleksandra Prysyazhna, Olena Rudyk and Philip Eaton
doi:10.1038/nm.2603
Using mice with an amino substitution in the kinase PKG, a key regulator of blood vessel tone, Oleksandra Prysyazhna et al. provide evidence for the physiological importance of PKG oxidation and disulfide formation in maintaining normal blood pressure. These results clarify the nature of an enigmatic vasodilatory activity termed endothelium-derived hyperpolarizing factor and suggest that vascular oxidative stress can have blood pressure-lowering effects.
First paragraph | Full Text | PDF | | | | | Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export pp291 - 295
Peng Lei, Scott Ayton, David I Finkelstein, Loredana Spoerri, Giuseppe D Ciccotosto, David K Wright, Bruce X W Wong, Paul A Adlard, Robert A Cherny, Linh Q Lam, Blaine R Roberts, Irene Volitakis, Gary F Egan, Catriona A McLean, Roberto Cappai, James A Duce and Ashley I Bush
doi:10.1038/nm.2613
Tau aggregation is associated with neurodegenerative diseases called tauopathies. Ashley Bush and colleagues now report that aged tau-deficient mice develop motor and cognitive dysfunction that is linked to elevated iron levels in the brains of the mice.
First paragraph | Full Text | PDF
See also: News and Views by Stankowski et al. | | | | | Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia pp298 - 303
Panagiotis Ntziachristos, Aristotelis Tsirigos, Pieter Van Vlierberghe, Jelena Nedjic, Thomas Trimarchi, Maria Sol Flaherty, Dolors Ferres-Marco, Vanina da Ros, Zuojian Tang, Jasmin Siegle, Patrik Asp, Michael Hadler, Isaura Rigo, Kim De Keersmaecker, Jay Patel, Tien Huynh, Filippo Utro, Sandrine Poglio, Jeremy B Samon, Elisabeth Paietta, Janis Racevskis, Jacob M Rowe, Raul Rabadan, Ross L Levine, Stuart Brown, Francoise Pflumio, Maria Dominguez, Adolfo Ferrando and Iannis Aifantis
doi:10.1038/nm.2651
T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3) by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.
Full Text | PDF | | Technical Reports | Top | | | | | Magnetic resonance imaging of glutamate pp302 - 306
Kejia Cai, Mohammad Haris, Anup Singh, Feliks Kogan, Joel H Greenberg, Hari Hariharan, John A Detre and Ravinder Reddy
doi:10.1038/nm.2615
Kejia Cai et al. describe a method to non-invasively detect glutamate (Glu) concentrations in the brain with MRI at high resolution. The approach is based on the pH-dependent chemical exchange saturation transfer (CEST) effect between the amino group of Glu and bulk water and offers advantages over proton magnetic resonance spectroscopy. Feasibility of GluCEST was demonstrated in rat brain after middle cerebral artery occlusion stroke and in a rat brain tumor model, as well as in healthy human brain at 7 Tesla.
Abstract | Full Text | PDF | | | | | A delivery system targeting bone formation surfaces to facilitate RNAi-based anabolic therapy pp307 - 314
Ge Zhang, Baosheng Guo, Heng Wu, Tao Tang, Bao-Ting Zhang, Lizhen Zheng, Yixin He, Zhijun Yang, Xiaohua Pan, Heelum Chow, Kinwah To, Yaping Li, Dahu Li, Xinluan Wang, Yixiang Wang, Kwongman Lee, Zhibo Hou, Nan Dong, Gang Li, Kwoksui Leung, Leungkim Hung, Fuchu He, Lingqiang Zhang and Ling Qin
doi:10.1038/nm.2617
Zhang and colleagues have developed a new targeted delivery system for RNA interference-based bone anabolic therapy. Using dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine (AspSerSer)6, the system provided selective enrichment of the encapsulated osteogenic siRNA in osteogenic lineage cells at the bone formation surface and the subsequent depletion of the target gene, encoding the bone formation inhibitor casein kinase-2 interacting protein-1 (PLEKHO1, also known as CKIP-1), leading to the promotion of bone formation in healthy and osteoporotic rats.
Abstract | Full Text | PDF
See also: News and Views by Rosen | | | | | Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett's esophagus pp315 - 321
Elizabeth L Bird-Lieberman, Andre A Neves, Pierre Lao-Sirieix, Maria O'Donovan, Marco Novelli, Laurence B Lovat, William S Eng, Lara K Mahal, Kevin M Brindle and Rebecca C Fitzgerald
doi:10.1038/nm.2616
Cell-surface glycans are known to alter as Barrett's esophagus progresses to adenocarcinoma, leading to specific changes in lectin binding patterns. Bird-Lieberman and her colleagues have exploited this knowledge to develop a new endoscopic approach that uses fluorescent-labeled lectins to visualize pre-cancerous, high-grade dysplastic lesions in Barrett's esophagus that cannot be detected by conventional endoscopy. The method uses commonly available endoscopic equipment, provides a wide field of view and is shown here in ex vivo esophageal tissue.
Abstract | Full Text | PDF | | | Top | |  | | Advertisement | | | 
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