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Summaries of newsworthy papers include Trp’ing the copper fantastic, Compound screening gets more specific, Helium on the brane, Mechanical memories, The workings of deep brain stimulation, Foamy viruses join the gene therapy toolbox, Gene mutation affecting human brain size, The protective effects of brain damage and Gaining entry into the brain

NATURE AND THE NATURE RESEARCH JOURNALS PRESS RELEASE For papers that will be published online on 23 December 2007 This press release is copyrighted to the Nature journals mentioned below. This press release contains: · Summaries of newsworthy papers: Stem cells: Isolation from individuals – Nature Trp’ing the copper fantastic – Nature Chemical Biology Compound screening gets more specific – Nature Chemical Biology Helium on the brane – Nature Physics Mechanical memories – Nature Nanotechnology The workings of deep brain stimulation – Nature Medicine Foamy viruses join the gene therapy toolbox – Nature Medicine Gene mutation affecting human brain size – Nature Genetics The protective effects of brain damage – Nature Neuroscience Gaining entry into the brain – Nature Immunology · Mention of papers to be published at the same time with the same embargo · Geographical listing of authors PDFs of all the papers mentioned on this release can be found in the relevant journal’s section of http://press.nature.com. Press contacts for the Nature journals are listed at the end of this release. Warning: This document, and the Nature journal papers to which it refers, may contain information that is price sensitive (as legally defined, for example, in the UK Criminal Justice Act 1993 Part V) with respect to publicly quoted companies. Anyone dealing in securities using information contained in this document, or in advance copies of a Nature journal’s content, may be guilty of insider trading under the US Securities Exchange Act of 1934. PICTURES: To obtain artwork from any of the journals, you must first obtain permission from the copyright holder (if named) or author of the research paper in question (if not). NOTE: Once a paper is published, the digital object identifier (DOI) number can be used to retrieve the abstract and full text from the journal web site (abstracts are available to everyone, full text is available only to subscribers). To do this, add the DOI to the following URL: http://dx.doi.org/ (For example, http://dx.doi.org/10.1038/ng730). For more information about DOIs and Advance Online Publication, see http://www.nature.com/ng/aop/. PLEASE CITE THE SPECIFIC NATURE JOURNAL AND WEBSITE AS THE SOURCE OF THE FOLLOWING ITEMS. IF PUBLISHING ONLINE, PLEASE CARRY A HYPERLINK TO THE APPROPRIATE JOURNAL’S WEBSITE. ****************************************************NATURE************************************************ (http://www.nature.com/nature) [1] Stem cells: Isolation from individuals DOI: 10.1038/nature06534 Hot on the heels of a series of advances in stem cell research, a team demonstrate derivation of induced pluripotent stem (iPS) cells from fetal, neonatal and adult human primary cells, in a paper published online in Nature this week. Where earlier studies used established fibroblast cell lines and cells isolated from joint fluid, this group also developed a method to use cells from skin-punch biopsies from a healthy adult volunteer. The researchers suggest that this could be used to isolate patient-specific cells in culture. Recent new research has shown that human and mouse fibroblasts can be reprogrammed to an embryonic-stem-cell-like state of pluripotency, where the cells can generate all tissues in an organism. This is achieved by expressing certain recently defined transcription factors to yield iPS cells. George Daley and colleagues confirmed that human skin biopsies can be transformed to iPS cells, and also that two of the transcription factors are essential, whereas two others, KLF4 and MYC, enhance the efficiency of the technique. The human iPS cells resembled embryonic stem cells in their morphology and gene expression, and in their capacity to form teratomas. Author contact: George Daley (Children's Hospital, Boston, MA, USA) Tel: +1 617 919 2013; E-mail: george.daley@childrens.harvard.edu *************************************NATURE CHEMICAL BIOLOGY *********************************** (http://www.nature.com/nchembio) [2] Trp’ing the copper fantastic DOI: 10.1038/nchembio.2007.57 The amino acid tryptophan has an unprecedented role in copper binding, suggests a study online this week in Nature Chemical Biology. Copper is an essential metal for life. However, because it is highly reactive and therefore could cause damage to cells, it must be ‘chaperoned’ at all times. Relatively little is known about many of the proteins that move copper around cells. Thomas O’Halloran and colleagues looked closely at a copper trafficking protein called CusF. They found that a tryptophan from the CusF protein is very close to the copper and that the interaction between the tryptophan and the copper is critical for copper binding. Tryptophan residues have been known to interact with positively charged ions, such as sodium or potassium, in what is called a ‘cation-pi’ interaction. These results now reveal that proteins can use these cation-pi interactions to delicately transport copper around cells. Author contact: Thomas O’Halloran (Northwestern University, Evanston, IL, USA) Tel: +1 847 491 5060; E-mail: t-ohalloran@northwestern.edu [3] Compound screening gets more specific DOI: 10.1038/nchembio.2007.59 A drug screening platform that can be used through the various testing and monitoring stages of the drug discovery process is reported online this week in Nature Chemical Biology. High-throughput screening for drug candidates generally involves using enzymes purified from cells for use as the drug target, but whole cells are now being used more often. Garry Nolan and colleagues show that measurement of the phosphorylation levels of intracellular signalling proteins in whole cells could be extended from single drug effects to large-scale screening efforts. In their own screens, the authors identified several compounds that, from among all of the cell types and their associated signaling pathways found in whole blood, selectivity inhibited only the B cell Jak-Stat signalling pathway — the cytokine signaling pathway that mediates cell growth, differentiation, apoptosis, and other fundamental cell functions. The strategy, called phospho flow, is therefore capable of screening compound libraries for inhibitors of specific kinase signalling pathways that target particular cell types in physiologically- and disease-relevant cell populations. Author contact: Garry Nolan (Stanford University, Stanford, CA, USA) Tel: +1 650 725 7002; E-mail: gnolan@stanford.edu Other papers from Nature Chemical Biology to be published online at the same time and with the same embargo: [4] Site selectivity of platinum anticancer therapeutics DOI: 10.1038/nchembio.2007.58 ***********************************************NATURE PHYSICS***************************************** (http://www.nature.com/naturephysics) [5] Helium on the brane (N&V) DOI: 10.1038/nphys815 Low-temperature physicists may have found a laboratory test of the ‘untestable’ string theory using two distinct phases of liquid helium, as reported online this week in Nature Physics. String theory is a multidimensional theory based on vibrating strings, as opposed to the point particles described in the Standard Model. Within string theory, a brane is a large surface embedded in higher dimensional space — our Universe could occupy such a brane. A collision between a brane and an antibrane can leave behind topological defects, including perhaps the Big Bang itself. But however elegant this theory, it makes no falsifiable predictions, or at least none using current technology. Richard Haley, George Pickett and co-workers have taken a lateral step to address this barrier. They cool helium-3 isotope to a superfluid state — that is, a quantum fluid with non-classical properties such as completely frictionless flow. Adding a magnetic field creates a second superfluid phase, and the interface between these two phases behaves like a two-dimensional brane. Indeed, the collision of a brane–antibrane pair leaves traces of a stringy residue of defects: a tangle of vortices. But how far does the analogy go? Cliff Burgess, a string theorist, comments on the broader implications of this work in an accompanying News & Views article. Author contact: Richard Haley (Lancaster University, UK) Tel: +44 1524 593224; E-mail: R.Haley@lancaster.ac.uk Cliff Burgess (Perimeter Institute, Waterloo, Ontario, Canada) N&V author Please note the author is currently based at: TH Division, CERN, Geneva, Switzerland E-mail: cburgess@perimeterinstitute.ca Other papers from Nature Physics to be published online at the same time and with the same embargo: [6] Evolution equation for quantum entanglement DOI: 10.1038/nphys826 **************************************NATURE NANOTECHNOLOGY*********************************** (http://www.nature.com/nnano) [7] Mechanical memories DOI:10.1038/nnano.2007.417 Scientists have developed a memory device that uses the mechanical motion of tiny tubes of carbon measuring just 60 billionths of a metre across, reports a paper online this week in Nature Nanotechnology. Modern data-storage media exploit a wide variety of electronic, magnetic and optical techniques to read and write information as a series of 'ones' and 'zeros'. Gehan Amaratunga and co-workers have now built a new type of memory cell in which the mechanical motion of a multiwalled carbon nanotube with respect to a nanotube-based capacitor — a simple device that is used to store electric charge — can be used to write a 'one'. Although so-called nanoelectromechanical memory devices have been demonstrated before, they have been difficult to make. The new devices can be fabricated with techniques that are compatible with those already widely used to make silicon chips. The team is currently working on ways to read the data. Author contact: Gehan Amaratunga (University of Cambridge, UK) Tel: +44 1223 748320; E-mail gaja1@cam.ac.uk Other papers from Nature Nanotechnology to be published online at the same time and with the same embargo: [8] Nanomagnetic actuation of receptor-mediated signal transduction (N&V) DOI: 10.1038/nnano.2007.418 [9] Colossal magnetic anisotropy of monatomic free and deposited platinum nanowires DOI: 10.1038/nnano.2007.419 [10] Nanoprecipitation-assisted ion current oscillations DOI: 10.1038/nnano.2007.420 *******************************************Nature MEDICINE******************************************** (http://www.nature.com/naturemedicine) [11] The workings of deep brain stimulation DOI: 10.1038/nm1693 A chemical called adenosine plays a key role in the beneficial effect of deep brain stimulation on tremor, reports a paper online this week in Nature Medicine. Neurosurgeons use deep brain stimulation to treat a variety of movement disorders, such as Parkinson’s disease and tremor, but it has been unclear how deep brain stimulation acts to improve these disorders. Maiken Nedergaard and colleagues found that deep brain stimulation causes an increase in the amount of adenosine near the site of stimulation, which decreases the excitability of nearby neurons. In an animal model of tremor, adenosine infusion into the brain was sufficient to reduce tremor. These results are consistent with the known role of caffeine, an adenosine antagonist, to induce tremor. Adenosine administration might therefore be a new way to reverse tremor and improve the effectiveness of deep brain stimulation. Author contact: Maiken Nedergaard (University of Rochester Medical Center, Rochester, NY, USA) Tel: +1 585 273 2868; E-mail: Nedergaard@urmc.rochester.edu [12] Foamy viruses join the gene therapy toolbox DOI: 10.1038/nm1695 Foamy virus vectors have been used to cure a genetic immune deficiency in dogs, suggests a paper online this week in Nature Medicine. The results indicate that they may be useful alternative vectors for curing some diseases by gene therapy. Foamy viruses are a type of integrating retrovirus found in many mammalian species. Unlike other types of retrovirus used for gene therapy, foamy viruses have never been associated with disease in humans. Dennis Hickstein and colleagues used a foamy virus vector – a modified form of the virus that acts as a delivery vehicle for a therapeutic gene – to express the gene for the white blood cell integrin ITGB2 in blood stem cells from dogs with canine leukocyte adhesion deficiency. CLAD dogs normally lack this protein and their immune cells consequently fail to migrate to sites of infection. After reinfusion of the corrected stem cells, the dogs showed complete reversal of disease symptoms, lasting more than two years. The authors also looked at where the foamy virus had integrated into the host cell genome, and found that, compared with gammaretroviral vectors, there was a decreased risk of integration near oncogenes Author contact: Dennis Hickstein (National Cancer Institute, Bethesda, MD, USA) Tel: +1 301 594 1718; E-mail: hicksted@mail.nih.gov Other papers from Nature Medicine to be published online at the same time and with the same embargo: [13] Langerhans cell histiocytosis reveals a novel IL-17A-dependent pathway of dendritic cell fusion DOI: 10.1038/nm1694 [14] Rapid conditional targeted ablation of cells expressing human CD59 in transgenic mice by intermedilysin DOI: 10.1038/nm1674 ***********************************************NATURE GENETICS ************************************** (http://www.nature.com/naturegenetics) [15] Gene mutation affecting human brain size DOI: 10.1038/ng.2007.80 Scientists have identified mutations in a gene that cause reduced brain and body size, reports a paper to be published online this week in Nature Genetics. Andrew Jackson and colleagues studied individuals with Seckel syndrome, which is characterized by growth retardation in the womb, severe proportionate short stature, and markedly reduced brain size or microcephaly. They had previously shown that some affected individuals have mutations in a gene called ATR, but these mutations did not account for everyone with the syndrome. The authors found mutations in a gene called PCNT, encoding a protein called pericentrin, in two families with Seckel syndrome. Pericentrin is a component of the centrosome, which organizes the cellular apparatus that ensures proper segregation of chromosomes during cell division. Other genes involved in centrosomal function have previously been found to be mutated in different forms of microcephaly, suggesting that it is essential for determining human brain size. Author contact: Andrew Jackson (Human Genetics Unit, Western General Hospital, Edinburgh, UK) Tel: +44 131 332 2471; E-mail: andrew.jackson@hgu.mrc.ac.uk Other papers from Nature Genetics to be published online at the same time and with the same embargo: [16] Closing gaps in the human genome with fosmid resources generated from multiple individuals DOI: 10.1038/ng.2007.34 [17] Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2 DOI: 10.1038/ng.2007.45 [18] Identification and characterization of high-flux-control genes of yeast through competition analyses in continuous cultures DOI: 10.1038/ng.2007.49 *******************************************NATURE NEUROSCIENCE *********************************** (http://www.nature.com/natureneuroscience) [19] The protective effects of brain damage DOI: 10.1038/nn2032 Combat veterans with certain types of brain damage are less likely to develop post-traumatic stress disorder (PTSD), reports a study in the February issue of Nature Neuroscience. This finding indicates that certain brain regions are important for the development of this disorder. PTSD is an anxiety disorder characterized by recurrent distressing memories of traumatic events, such as combat, which can significantly impair day-to-day functioning. Previous functional imaging studies found that PTSD is associated with reduced activity in a part of the brain known as the ventromedial prefrontal cortex. PTSD is also associated with increased activity in another part of the brain, the amygdala, which is involved in processing fear. Thus, its excessive activity in PTSD is consistent with patients responding fearfully to normally harmless stimuli. However, functional imaging cannot prove that changes in activity in these regions actually cause PTSD, as both could be an effect of some other process. Jordan Grafman and colleagues now take steps toward proving this causal link by studying a unique sample of Vietnam war veterans who had suffered brain injury, as well as a traumatic emotional event. They used structural magnetic resonance imaging to produce a detailed picture of the brains of this group, and then compared veterans with PTSD to those without the illness. This comparison identifies differences in a bilateral frontal area (including the ventromedial prefrontal cortex) and an anterior area including the amygdala. Damage to either of these regions was associated with reduced occurrence of PTSD. These results confirm that the ventromedial prefrontal cortex and the amygdala are critically involved in the processes that lead to PTSD. Author contact: Jordan Grafman (National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA) Tel: +1 301 496 0220; E-mail: grafmanj@ninds.nih.gov Other papers from Nature Neuroscience to be published online at the same time and with the same embargo: [20] Bilateral olfactory sensory input enhances chemotaxis behavior DOI: 10.1038/nn2031 *******************************************NATURE IMMUNOLOGY ************************************ (http://www.nature.com/natureimmunology) [21] Gaining entry into the brain DOI: 10.1038/ni1551 Researchers have identified a protein used by aggressive immune cells seeking to breach the blood-brain barrier, reports a paper published online this week in Nature Immunology. Normally few immune cells enter the brains of healthy animals. However, neuroinflammatory disorders result in weakening of the blood-brain barrier, and entry of potentially dangerous immune cells into the central nervous system. Alexandre Prat and colleagues show that the adhesion protein ALCAM acts as a ‘foothold’ for immune cells moving between blood-brain barrier endothelial cells. Blockade of ALCAM reduced the severity and slowed the progression of experimental autoimmune encephalomyelitis, a mouse model of human multiple sclerosis, and ALCAM worked synergistically with another adhesion molecule, ICAM1, to move immune cells across the blood-brain barrier. Future work is needed to determine whether ALCAM blockade holds therapeutic utility in treating established human neuroinflammatory diseases. Author contact: Alexandre Prat (CHUM-Notre-Dame Hospital, Montreal, Canada) Tel: +1 514­­ 890 8000 ext 24735; E-mail: aprat@umontreal.ca Other papers from Nature Immunology to be published online at the same time and with the same embargo: [22] Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer DOI: 10.1038/ni1549 [23] Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice DOI: 10.1038/ni1552 *************************************************************************************************************** Items from other Nature journals to be published online at the same time and with the same embargo: NATURE GEOSCIENCE (http://www.nature.com/ngeo) [24] Decreased abundance of crustose coralline algae due to ocean acidification DOI: 10.1038/ngeo100 NATURE MATERIALS (http://www.nature.com/naturematerials) [25] Mechanical annealing and source-limited deformation in submicrometre-diameter Ni crystals DOI: 10.1038/nmat2085 [26] High-capacity hydrogen storage in lithium and sodium amidoboranes DOI: 10.1038/nmat2081 Nature BIOTECHNOLOGY (http://www.nature.com/naturebiotechnology) [27] Fluorogen-activating single-chain antibodies for imaging cell surface proteins DOI: 10.1038/nbt1368 [28] Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor DOI: 10.1038/nbt1376 [29] In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags DOI: 10.1038/nbt1377 Nature STRUCTURAL & MOLECULAR BIOLOGY (http://www.nature.com/natstructmolbiol) [30] TER1, the RNA subunit of fission yeast telomerase DOI: 10.1038/nsmb1343 [31] Identification and characterization of the Schizosaccharomyces pombe TER1 telomerase RNA DOI: 10.1038/nsmb1354 [32] tRNA–mRNA mimicry drives translation initiation from a viral IRES DOI: 10.1038/nsmb1351 [33] RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes DOI: 10.1038/nsmb1352 [34] The structure of a DnaB-family replicative helicase and its interactions with primase DOI: 10.1038/nsmb1356 NATURE CELL BIOLOGY (http://www.nature.com/naturecellbiology) [35] Developmentally regulated transcription of mammalian telomeres by DNA dependent RNA polymerase II DOI: 10.1038/ncb1685 [36] A beta-catenin gradient links the clock and wavefront systems in mouse embryo segmentation DOI: 10.1038/ncb1679 NATURE METHODS (http://www.nature.com/nmeth) [37] GraFix: sample preparation for single-particle electron cryomicroscopy DOI: 10.1038/nmeth1139 [38] Targeted patch-clamp recordings and single-cell electroporation of unlabeled neurons in vivo DOI: 10.1038/nmeth1150 *************************************************************************************************************** GEOGRAPHICAL LISTING OF AUTHORS The following list of places refers to the whereabouts of authors on the papers numbered in this release. The listing may be for an author's main affiliation, or for a place where they are working temporarily. Please see the PDF of the paper for full details. ARGENTINA San Martin: 9 AUSTRIA Vienna: 37 BELGIUM Liege: 17 Leuven: 17 BERMUDA St George’s: 24 BRAZIL Rio de Janeiro: 6 CANADA: Montreal: 21 Ottawa: 21 FINLAND Helsinki: 5 FRANCE Lyon: 13 Pierre Benite: 13 GERMANY Aachen: 6 Berlin: 17 Cologne: 17 Dresden: 6 Freiburg: 6 Goettingen: 37 Heidelberg: 38 ITALY Palermo: 13 Trieste: 9 JAPAN Gunma: 28 Kyoto: 36 Osaka: 38 Saitama: 38 Tokyo: 38 KOREA Suwon: 7 Yongin: 7 NETHERLANDS Leiden: 13 Nijmegen: 17 OMAN Muscat: 17 RUSSIA Voronezh: 9 SINGAPORE Singapore: 4, 26 SOUTH AFRICA Durban: 6 SPAIN Madrid: 35 SWEDEN Solna: 13 Stockholm: 9, 13 SWITZERLAND Lausanne: 20 Zurich: 21 UNITED KINGDOM Aberystwyth: 18 Cambridge: 7, 18 Chilton: 26 Lancaster: 5 London: 17, 38 Manchester: 18 Oxford: 26 UNITED STATES OF AMERICA Alabama Birmingham: 23 California Berkeley: 8, 25, 32 Irvine: 10 Los Angeles: 34 Santa Clara: 16 Stanford: 3 Thousand Oaks: 10 Colorado Aurora: 32, 33 Boulder: 33 Florida St Petersburg: 24 Georgia Atlanta: 29 Hawaii Honolulu: 24 Kaneohe: 24 Illinois Chicago: 2, 10 Evanston: 2 Maryland Bethesda: 11, 12, 14, 19, 36 Frederick: 36 Germantown: 19 Massachusetts Beverly: 16 Boston: 1, 8, 14 Cambridge: 1, 8, 14 Michigan Ann Arbor: 2 Warren: 25 Minnesota Minneapolis: 25 Missouri Kansas City: 30, 36 St Louis: 17 New Jersey Princeton: 31 New York New York: 20 Rochester: 11 Oklahoma Oklahoma City: 14 Pennsylvania Philadelphia: 22, 36 Pittsburgh: 23, 27 University Park: Tennessee Memphis: 23 Texas Houston: 30 Washington Richland: 26 Seattle: 2, 12, 16 PRESS CONTACTS… For media inquiries relating to embargo policy for all the Nature Research Journals: Katherine Anderson (Nature London) Tel: +44 20 7843 4502; E-mail: k.anderson@nature.com Ruth Francis (Senior Press Officer, Nature, London) Tel: +44 20 7843 4562; E-mail: r.francis@nature.com For media inquiries relating to editorial content/policy for the Nature Research Journals, please contact the journals individually: Nature Biotechnology (New York) Peter Hare Tel: +1 212 726 9284; E-mail: biotech@natureny.com Nature Cell Biology (London) Bernd Pulverer Tel: +44 20 7843 4892; E-mail: cellbio@nature.com Nature Chemical Biology (Boston) Andrea Garvey Tel: +1 617 475 9241, E-mail: chembio@boston.nature.com Nature Genetics (New York) Orli Bahcall Tel: +1 212 726 9311; E-mail: natgen@natureny.com Nature Geoscience (London) Heike Langenberg Tel: +44 20 7843 4042; E-mail: h.langenberg@nature.com Nature Immunology (New York) Laurie Dempsey Tel: +1 212 726 9372; E-mail: immunology@natureny.com Nature Materials (London) Fabio Pulizzi Tel: +44 207 014 4024; E-mail: materials@nature.com Nature Medicine (New York) Juan Carlos Lopez Tel: +1 212 726 9325; E-mail: medicine@natureny.com Nature Methods (New York) Allison Doerr Tel: +1 212 726 9393; E-mail: methods@natureny.com Nature Nanotechnology (London) Peter Rodgers Tel: +44 20 7014 4019; Email: p.rodgers@nature.com Nature Neuroscience (New York) Sandra Aamodt (based in California) Tel: +1 530 795 3256; E-mail: neurosci@natureny.com Nature Physics (London) Alison Wright Tel: +44 20 7843 4555; E-mail: a.wright@nature.com Nature Structural & Molecular Biology (New York) Michelle Montoya Tel: +1 212 726 9326; E-mail: nsmb@natureny.com About Nature Publishing Group Nature Publishing Group (NPG) is a division of Macmillan Publishers Ltd, dedicated to serving the academic, professional scientific and medical communities. 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