Nature

Current Issue:

• Flu papers warrant full publication
  Although more debate is needed, the benefits of publishing sensitive data outweigh the risks that have so far been made public.
• Turing at 100
  This year marks the centenary of the birth of Alan Turing. He deserves your attention.
• Over the line
  Dishonesty, however tempting, is the wrong way to tackle climate sceptics.
• The man behind the machine
  Alan Turing is famous for many reasons. Andrew Hodges delves into why Turing's achievements took so long to be recognized.
  Andrew Hodges
• Evolution: Lilliputian lizards come to light
  The forests of northern Madagascar harbour a dwarf chameleon that is the smallest lizard in the world in terms of total length. Adult males of the diminutive Brookesia micra reach a length of less than 24 millimetres.B. micra and three other tiny
• Biophysics: Claustrophobic DNA in tug of war
  When a long thin polymer such as DNA is forced into a confined space — say a small membrane channel — it loses some of its freedom, and hence its entropy. Regaining that entropy is a powerful driving force for escape.Chia-Fu Chou at the
• Cell signalling: Sideways activation
  Elucidation of a cell receptor's crystal structure has revealed a unique lateral docking mechanism, report Hugh Rosen of the Scripps Research Institute in La Jolla, California, and his colleagues.G-protein-coupled receptors (GPCRs) are signalling molecules that span the plasma membranes of cells and are generally
• Biology: Immunity's circadian link
  Daily patterns in the body's biochemical and physiological processes called circadian rhythms may influence immune-system function. Erol Fikrig and his colleagues at Yale University in New Haven, Connecticut, have found that the expression of an immune protein called TLR9 rises and falls with the circadian
• Stem-cell biology: Restore my beating heart
  Infusions of a patient's own cardiac stem cells may reduce scar tissue and promote heart-muscle growth after a heart attack, according to a small safety study. Eduardo Marbán of the Cedars-Sinai Heart Institute in Los Angeles, California, and his colleagues harvested heart cells from 17
• Genomics: Loss-of-function found in droves
  Genome-sequencing work has suggested that even healthy humans carry hundreds of 'loss of function' (LoF) mutations that seriously disrupt protein-coding genes. Daniel MacArthur at the Wellcome Trust Sanger Institute in Hinxton, UK, and his colleagues performed extensive analysis on 185 genomes and determined that a
• Astrophysics: Zombie star rising
  When a star suddenly brightened in 1961, many assumed it had died in a supernova — but it seems that the light has not yet gone out. Schuyler Van Dyk at the California Institute of Technology in Pasadena and Thomas Matheson at the National Optical
• Immunology: Immune system master switch
  The fetal immune system develops from stem cells in the liver, whereas the immune cells that protect adults form in the bone marrow. Moreover, early in life the immune system contains cells that quickly respond to only a limited number of foreign molecules; adult immune
• Zoology: Antifreeze's role in fish spread
  Antifreeze proteins in the bodily fluids of Antarctic fishes are a crucial adaptation to life in the freezing waters — but their appearance alone is insufficient to explain the huge diversity of the region's fish species. Thomas Near of Yale University in New Haven, Connecticut,
• Chemistry: Simple solution for tricky chemistry
  Highly read on pubs.acs.org in JanuaryChemists have invented a reagent to ease the addition of a desirable chemical group to many useful compounds. Pharmaceutical, medicinal and agricultural chemists add fluorine groups to molecules to improve certain properties — to lower toxicity, for example.
• Seven days: 17–23 February 2012
  The week in science: Animals saved from chemical safety tests; fund launched to clean up methane and black-carbon emissions; and excitement over nanopore DNA sequencing.
• Flu meeting opts for openness
  Controversial virus studies should be published and oversight of such work strengthened, conference concludes.
  Declan Butler
• Growing pains for children's study
  Door-to-door recruitment abandoned for US project.
  Meredith Wadman
• Editor’s move sparks backlash
  Bioethicists are forced to consider their purpose as leading practitioner joins controversial stem-cell company.
  David Cyranoski
• Extra scrutiny for ‘grandee grantees’
  An analysis by Nature reveals who holds the most grants from the US National Institutes of Health.
  Eric Hand
• Physicists raid Tevatron for parts
  Fermilab icon plundered amid tight budgets and shifting scientific aims.
  Eugenie Samuel Reich
• Wild flower blooms again after 30,000 years on ice
  Fruits hoarded by ancient ground squirrels give new life to prehistoric plants.
  Sharon Levy
• Turing at 100: Legacy of a universal mind
  From the day he was born — 23 June 1912 — Alan Mathison Turing seemed destined to solitude, misunderstanding and persecution (see page 441). As his centenary year opens, Nature hails him as one of the top scientific minds of all time (see
  Tanguy Chouard
• Computer modelling: Brain in a box
  Henry Markram wants €1 billion to model the entire human brain. Sceptics don't think he should get it.
  M. Mitchell Waldrop
• Turing centenary: The dawn of computing
  Alan Turing's bridging of logic and machines laid the foundation for digital computers, says George Dyson.
  George Dyson
• Turing centenary: Life's code script
  Turing machines and cells have much in common, argues Sydney Brenner.
  Sydney Brenner
• Turing centenary: Is the brain a good model for machine intelligence?
  To celebrate the centenary of the year of Alan Turing's birth, four scientists and entrepreneurs assess the divide between neuroscience and computing.
• Turing centenary: Pattern formation
  We are only beginning to see the impact of Turing's influential work on morphogenesis, says John Reinitz.
  John Reinitz
• Turing centenary: The incomputable reality
  The natural world's interconnectivity should inspire better models of the Universe, says Barry Cooper.
  Barry Cooper
• Neuroscience: Powerful acts
  Giovanni Frazzetto explores how theatre exerts its psychological effects on the emotions.
  Giovanni Frazzetto
• Books in brief
  The US human population is a bouillabaisse of DNA. Geneticist Bryan Sykes took on the challenge of identifying its ingredients on an epic cross-country trip. He recounts the detective work — including interviews with genealogists and fellow geneticists — and methodology behind the findings. How
• Infectious disease: Chronicles of a killer virus
  Just over 30 years after HIV/AIDS was first recognized, three accounts of its ravages intrigue Robin Weiss.
  Robin A. Weiss
• Q&A: The eternal optimist
  Peter Diamandis is the founder of the non-profit X Prize Foundation, which aims to kick-start research and development to solve humanity's biggest challenges. On the publication this week of his book Abundance, co-authored with journalist Steven Kotler, he explains how technological and social progress will enable us to provide enough food, water and energy for all.
  Nicola Jones
• Mutant flu: preparing for a pandemic
  We at the global humanitarian organization Save the Children agree that controversy over lab-created H5N1 avian influenza virus should not detract from the larger concern of global preparedness for a flu pandemic (Nature482, 131; 201210.1038/482131a).In a pandemic flu
  Eric S. Starbuck
• Mutant flu: assessing biosecurity risks
  In the ongoing controversy over the mutant H5N1 avian influenza research (Nature481, 9–10, 201210.1038/481009a), we should be wary of reducing biosecurity measures merely to assigning access rights to sensitive information and materials. A national security body made
  Johannes Rath
• Foreign drug trials: questionable use of chimpanzees
  By conducting their experiments at US chimpanzee centres, foreign scientists have been circumventing their own nations' bans on chimpanzee research since 2005 (Nature482, 132; 2012). It is important to point out that those scientists are almost all employed by foreign-based
  John J. Pippin
• Sugar: there's more to the obesity crisis
  To describe sugar as “toxic” is extreme, as is its ludicrous comparison with alcohol (Nature482, 27–29; 2012). Such sensationalism could damage the livelihoods of thousands of people working in the sugar industry worldwide, and will be felt in
  Ron Boswell
• Sugar: fruit fructose is still healthy
  Robert Lustig and colleagues argue that sugar is “toxic” (Nature482, 27–29; 2012), focusing on the “deadly effect” of the fructose moiety of sucrose. But they are directing attention away from the problem of general overconsumption.Guidelines on healthy
  John L. SievenpiperRussell J. de SouzaDavid J. A. Jenkins
• Sugar: a problem of developed countries
  The contribution of sugar towards chronic disease is more relevant to developed countries than to the developing world (Nature482, 27–29; 2012). In Asia, for example, up to 10% of the population is obese and/or diabetic (see go.nature.com/qmmoha), even
  Christiani Jeyakumar HenryViren Ranawana
• Sugar: other ‘toxic’ factors play a part
  Regulating products based on a scientific risk analysis is a worthy goal, but I contend that Robert Lustig and colleagues oversimplify the “toxic” truth about refined carbohydrates (Nature482, 27–29; 2012). Rather than demonizing sugar, the authors would have
  Saleem H. Ali
• Australia: small steps to control invasives
  We believe that there are more obvious and less destructive options for controlling gamba grass and other invasive weeds in Australia than introducing mega-herbivores such as elephants (Nature482, 30; 2012).Biological control using carefully screened host-specific arthropods or pathogens, combined
  Bruce L. WebberJohn K. ScottRaphael K. Didham
• Australia: better solutions to wildfires
  Among David Bowman's more outlandish suggestions for dealing with Australia's massive problems of wildfires, feral animals and weeds, there are some workable ideas (Nature482, 30; 2012).Some of these are already being implemented, such as the reinstatement of Aboriginal fire
  Richard J. Hobbs
• Australia: a case for Aboriginal rangers
  David Bowman makes a strong case for employing Aboriginal people to manage their own land and to reinstate traditional fire practices in Australia (Nature482, 30; 2012). This strategy could form the basis of a coordinated, long-term conservation service.It would
  Clive R. McMahon
• Australia: no price on cutting fire risk
  David Bowman proposes that elephants should be introduced into Australia as a cost-effective way to control invasive gamba grass, a major source of wildfire fuel (Nature482, 30; 2012). But managing the elephants could be more expensive than, say, launching a
  P. J. Nico de BruynAndrew B. Davies
• Education: Outside the box
  A European industrial doctorate could help students to break out of academia, but applied science is not for everyone.
  Quirin Schiermeier
• Turning point: Christopher Wilson
  After finding virtual particles, a physicist turns to proteomics.
  Virginia Gewin
• Ghost in the machine
  Computer love.
  Grace Tang
• Geometry and scale in species–area relationships
  Arising from F. He & S. P. Hubbell Nature473, 368–371 (2011).He and Hubbell developed a sampling theory for the species–area relationship (SAR) and the endemics–area relationship (EAR). They argued that the number of extinctions after habitat loss is described by the EAR and that extinction rates in previous studies are overestimates because the EAR is always lower than the SAR. Here we show that their conclusion is not general and depends on the geometry of habitat destruction and the scale of the SAR. We also question their critique of the Millennium Ecosystem Assessment estimates, as those estimates are not dependent on the SAR only, although important uncertainties remain due to other methodological issues.
  Henrique Miguel PereiraLuís Borda-de-ÁguaInês Santos Martins
• Extinction and climate change
  Arising from F. He & S. P. Hubbell Nature473, 368–371 ()(2011).Statistical relationships between habitat area and the number of species observed (species–area relationships, SARs) are sometimes used to assess extinction risks following habitat destruction or loss of climatic suitability. He and Hubbell argue that the numbers of species confined to—rather than observed in—different areas (endemics–area relationships, EARs) should be used instead of SARs, and that SAR-based extinction estimates in the literature are too high. We suggest that He and Hubbell’s SAR estimates are biased, that the empirical data they use are not appropriate to calculate extinction risks, and that their statements about extinction risks from climate change do not take into account non-SAR-based estimates or recent observations. Species have already responded to climate change in a manner consistent with high future extinction risks.
  Chris D. ThomasMark Williamson
• He and Hubbell reply
  Replying to H. M. Pereira, L. Borda-de-Água & I. Santos Martins Nature482, 10.1038/nature10857; C. D. Thomas & M. Williamson Nature482, 10.1038/nature10858Pereira et al. argue that our conclusion that species–area relationships (SARs) always overestimate extinction is not general because the spatial configuration of landscape destruction can influence the results. Thomas and Williamson argue that there are many other causes of extinction besides habitat loss. We agree with the latter comment, but show that the arguments of Pereira et al. are not substantiated.
  Fangliang HeStephen P. Hubbell
• Clarification
  The table in the News story 'Obama shoots for science increase' (Nature482, 283–285; 2012) was unclear about the make-up of the Food and Drug Administration's budget. Obama's request leaves the government's input nearly flat, but a rise in user fees from
• Cell biology: Collagen secretion explained
  Cells package proteins into vesicles for secretion to the extracellular milieu. A study has now identified an enzyme that modifies the packaging machinery to encapsulate unusually large proteins, such as collagen. See Article p.495
  David J. Stephens
• Astrophysics: First results from Planck observatory
  Early data from the Planck space satellite provide information about dust in distant galaxies, as well as in the Milky Way, and on the properties of gas in some of the largest clusters of galaxies in the Universe.
  Uroš Seljak
• Fluid mechanics: Mist opportunities
  Fluid mechanics: Mist opportunities Nature 482, 7386 (2012). doi:10.1038/482476a Author: Rosamund Daw
  Rosamund Daw
• Materials science: Cell environments programmed with light
  A combination of two light-induced reactions has been used to attach peptides to a polymeric gel, and then to detach them from it. This feat opens up opportunities for studying the effects of signalling molecules on cell behaviour in vitro.
  Matthias P. Lutolf
• Quantum computing: A topological route to error correction
  Quantum computing is plagued by noise and small errors. An approach based on topological techniques reduces the sensitivity to errors and boosts the prospects for building practical quantum computers. See Article p.489
  James D. Franson
• 50 & 100 years ago
  50 Years AgoAlthough the annual figures for carriage-rates of all pathogenic staphylococci follow no particular course, evidence from many sources in industrialized countries shows that this is not the case with regard to the proportions of penicillin-resistant organisms ... These findings raise many questions
• Structural biology: Muscarinic receptors become crystal clear
  Muscarinic acetylcholine receptors mediate many physiological responses of the nervous system. Structures of two of these receptors yield insight into how they bind drugs and their mechanism of action. See Letters p.547 & 552
  Rebecca L. KowNeil M. Nathanson
• Cancer genetics: Evolution after tumour spread
  A genetic study of brain cancers in mice and humans reveals distinct mutations in primary tumours and their metastases, suggesting that the two disease 'compartments' may require different treatments.
  Steven C. Clifford
• Climate change: Shrinking glaciers under scrutiny
  Melting glaciers contribute to sea-level rise, but measuring their mass loss over time is difficult. An analysis of satellite data on Earth's changing gravity field does just that, and delivers some unexpected results.
  Jonathan Bamber
• The case for open computer programs
  Scientific communication relies on evidence that cannot be entirely included in publications, but the rise of computational science has added a new layer of inaccessibility. Although it is now accepted that data should be made available on request, the current regulations regarding the availability of software are inconsistent. We argue that, with some exceptions, anything less than the release of source programs is intolerable for results that depend on computation. The vagaries of hardware, software and natural language will always ensure that exact reproducibility remains uncertain, but withholding code increases the chances that efforts to reproduce results will fail.
  Darrel C. InceLeslie HattonJohn Graham-Cumming
• Experimental demonstration of topological error correction
  Scalable quantum computing can be achieved only if quantum bits are manipulated in a fault-tolerant fashion. Topological error correction—a method that combines topological quantum computation with quantum error correction—has the highest known tolerable error rate for a local architecture. The technique makes use of cluster
  Xing-Can YaoTian-Xiong WangHao-Ze ChenWei-Bo GaoAustin G. FowlerRobert RaussendorfZeng-Bing ChenNai-Le LiuChao-Yang LuYou-Jin DengYu-Ao ChenJian-Wei Pan
• Ubiquitin-dependent regulation of COPII coat size and function
  Packaging of proteins from the endoplasmic reticulum into COPII vesicles is essential for secretion. In cells, most COPII vesicles are approximately 60–80 nm in diameter, yet some must increase their size to accommodate 300–400 nm procollagen fibres or chylomicrons. Impaired COPII function results in collagen deposition defects,
  Lingyan JinKanika Bajaj PahujaKatherine E. WickliffeAmita GorurChristine BaumgärtelRandy SchekmanMichael Rape
• Structural basis of highly conserved ribosome recycling in eukaryotes and archaea
  Ribosome-driven protein biosynthesis is comprised of four phases: initiation, elongation, termination and recycling. In bacteria, ribosome recycling requires ribosome recycling factor and elongation factor G, and several structures of bacterial recycling complexes have been determined. In the eukaryotic and archaeal kingdoms, however, recycling involves the
  Thomas BeckerSibylle FranckenbergStephan WicklesChristopher J. ShoemakerAndreas M. AngerJean-Paul ArmacheHeidemarie SieberCharlotte UngewickellOtto BerninghausenIngo DaberkowAnnette KarcherMichael ThommKarl-Peter HopfnerRachel GreenRoland Beckmann
• Abrupt acceleration of a ‘cold’ ultrarelativistic wind from the Crab pulsar
  Pulsars are thought to eject electron–positron winds that energize the surrounding environment, with the formation of a pulsar wind nebula. The pulsar wind originates close to the light cylinder, the surface at which the pulsar co-rotation velocity equals the speed of light, and carries away much of the rotational energy lost by the pulsar. Initially the wind is dominated by electromagnetic energy (Poynting flux) but later this is converted to the kinetic energy of bulk motion. It is unclear exactly where this takes place and to what speed the wind is accelerated. Although some preferred models imply a gradual acceleration over the entire distance from the magnetosphere to the point at which the wind terminates, a rapid acceleration close to the light cylinder cannot be excluded. Here we report that the recent observations of pulsed, very high-energy γ-ray emission from the Crab pulsar are explained by the presence of a cold (in the sense of the low energy of the electrons in the frame of the moving plasma) ultrarelativistic wind dominated by kinetic energy. The conversion of the Poynting flux to kinetic energy should take place abruptly in the narrow cylindrical zone of radius between 20 and 50 light-cylinder radii centred on the axis of rotation of the pulsar, and should accelerate the wind to a Lorentz factor of (0.5–1.0) × 106. Although the ultrarelativistic nature of the wind does support the general model of pulsars, the requirement of the very high acceleration of the wind in a narrow zone not far from the light cylinder challenges current models.
  F. A. AharonianS. V. BogovalovD. Khangulyan
• Wetting of flexible fibre arrays
  Fibrous media are functional and versatile materials, as demonstrated by their ubiquity both in natural systems such as feathers and adhesive pads and in engineered systems from nanotextured surfaces to textile products, where they offer benefits in filtration, insulation, wetting and colouring. The elasticity and high aspect ratios of the fibres allow deformation under capillary forces, which cause mechanical damage, matting self-assembly or colour changes, with many industrial and ecological consequences. Attempts to understand these systems have mostly focused on the wetting of rigid fibres or on elastocapillary effects in planar geometries and on a fibre brush withdrawn from an infinite bath. Here we consider the frequently encountered case of a liquid drop deposited on a flexible fibre array and show that flexibility, fibre geometry and drop volume are the crucial parameters that are necessary to understand the various observations referred to above. We identify the conditions required for a drop to remain compact with minimal spreading or to cause a pair of elastic fibres to coalesce. We find that there is a critical volume of liquid, and, hence, a critical drop size, above which this coalescence does not occur. We also identify a drop size that maximizes liquid capture. For both wetting and deformation of the substrates, we present rules that are deduced from the geometric and material properties of the fibres and the volume of the drop. These ideas are applicable to a wide range of fibrous materials, as we illustrate with examples for feathers, beetle tarsi, sprays and microfabricated systems.
  C. DupratS. ProtièreA. Y. BeebeH. A. Stone
• Recent contributions of glaciers and ice caps to sea level rise
  Glaciers and ice caps (GICs) are important contributors to present-day global mean sea level rise. Most previous global mass balance estimates for GICs rely on extrapolation of sparse mass balance measurements representing only a small fraction of the GIC area, leaving their overall contribution to sea level rise unclear. Here we show that GICs, excluding the Greenland and Antarctic peripheral GICs, lost mass at a rate of 148 ± 30 Gt yr−1 from January 2003 to December 2010, contributing 0.41 ± 0.08 mm yr−1 to sea level rise. Our results are based on a global, simultaneous inversion of monthly GRACE-derived satellite gravity fields, from which we calculate the mass change over all ice-covered regions greater in area than 100 km2. The GIC rate for 2003–2010 is about 30 per cent smaller than the previous mass balance estimate that most closely matches our study period. The high mountains of Asia, in particular, show a mass loss of only 4 ± 20 Gt yr−1 for 2003–2010, compared with 47–55 Gt yr−1 in previously published estimates. For completeness, we also estimate that the Greenland and Antarctic ice sheets, including their peripheral GICs, contributed 1.06 ± 0.19 mm yr−1 to sea level rise over the same time period. The total contribution to sea level rise from all ice-covered regions is thus 1.48 ± 0.26 mm −1, which agrees well with independent estimates of sea level rise originating from land ice loss and other terrestrial sources.
  Thomas JacobJohn WahrW. Tad PfefferSean Swenson
• The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila
  Human neurodegenerative diseases have the temporal hallmark of afflicting the elderly population. Ageing is one of the most prominent factors to influence disease onset and progression, yet little is known about the molecular pathways that connect these processes. To understand this connection it is necessary to identify the pathways that functionally integrate ageing, chronic maintenance of the brain and modulation of neurodegenerative disease. MicroRNAs (miRNA) are emerging as critical factors in gene regulation during development; however, their role in adult-onset, age-associated processes is only beginning to be revealed. Here we report that the conserved miRNA miR-34 regulates age-associated events and long-term brain integrity in Drosophila, providing a molecular link between ageing and neurodegeneration. Fly mir-34 expression exhibits adult-onset, brain-enriched and age-modulated characteristics. Whereas mir-34 loss triggers a gene profile of accelerated brain ageing, late-onset brain degeneration and a catastrophic decline in survival, mir-34 upregulation extends median lifespan and mitigates neurodegeneration induced by human pathogenic polyglutamine disease protein. Some of the age-associated effects of miR-34 require adult-onset translational repression of Eip74EF, an essential ETS domain transcription factor involved in steroid hormone pathways. Our studies indicate that miRNA-dependent pathways may have an impact on adult-onset, age-associated events by silencing developmental genes that later have a deleterious influence on adult life cycle and disease, and highlight fly miR-34 as a key miRNA with a role in this process.
  Nan LiuMichael LandrehKajia CaoMasashi AbeGert-Jan HendriksJason R. KennerdellYongqing ZhuLi-San WangNancy M. Bonini
• Maintenance of muscle stem-cell quiescence by microRNA-489
  Among the key properties that distinguish adult mammalian stem cells from their more differentiated progeny is the ability of stem cells to remain in a quiescent state for prolonged periods of time. However, the molecular pathways for the maintenance of stem-cell quiescence remain elusive. Here we use adult mouse muscle stem cells (satellite cells) as a model system and show that the microRNA (miRNA) pathway is essential for the maintenance of the quiescent state. Satellite cells that lack a functional miRNA pathway spontaneously exit quiescence and enter the cell cycle. We identified quiescence-specific miRNAs in the satellite-cell lineage by microarray analysis. Among these, miRNA-489 (miR-489) is highly expressed in quiescent satellite cells and is quickly downregulated during satellite-cell activation. Further analysis revealed that miR-489 functions as a regulator of satellite-cell quiescence, as it post-transcriptionally suppresses the oncogene Dek, the protein product of which localizes to the more differentiated daughter cell during asymmetric division of satellite cells and promotes the transient proliferative expansion of myogenic progenitors. Our results provide evidence of the miRNA pathway in general, and of a specific miRNA, miR-489, in actively maintaining the quiescent state of an adult stem-cell population.
  Tom H. CheungNavaline L. QuachGregory W. CharvilleLing LiuLidia ParkAbdolhossein EdalatiBryan YooPhuong HoangThomas A. Rando
• Clonal selection drives genetic divergence of metastatic medulloblastoma
  Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.
  Xiaochong WuPaul A. NorthcottAdrian DubucAdam J. DupuyDavid J. H. ShihHendrik WittSidney CroulEric BouffetDaniel W. FultsCharles G. EberhartLivia GarziaTimothy Van MeterDavid ZagzagNada JabadoJeremy SchwartzentruberJacek MajewskiTodd E. ScheetzStefan M. PfisterAndrey KorshunovXiao-Nan LiStephen W. SchererYoon-Jae ChoKeiko AkagiTobey J. MacDonaldJan KosterMartin G. McCabeAaron L. SarverV. Peter CollinsWilliam A. WeissDavid A. LargaespadaLara S. CollierMichael D. Taylor
• DCC constrains tumour progression via its dependence receptor activity
  The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis.
  Marie CastetsLaura BroutierYann MolinMarie BrevetGuillaume ChazotNicolas GadotArmelle PaquetLaetitia MazelinLoraine Jarrosson-WuillemeJean-Yves ScoazecAgnès BernetPatrick Mehlen
• Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours
  Since its discovery in the early 1990s the deleted in colorectal cancer (DCC) gene, located on chromosome 18q21, has been proposed as a tumour suppressor gene as its loss is implicated in the majority of advanced colorectal and many other cancers. DCC belongs to the family of netrin 1 receptors, which function as dependence receptors as they control survival or apoptosis depending on ligand binding. However, the role of DCC as a tumour suppressor remains controversial because of the rarity of DCC-specific mutations and the presence of other tumour suppressor genes in the same chromosomal region. Here we show that in a mouse model of mammary carcinoma based on somatic inactivation of p53, additional loss of DCC promotes metastasis formation without affecting the primary tumour phenotype. Furthermore, we demonstrate that in cell cultures derived from p53-deficient mouse mammary tumours DCC expression controls netrin-1-dependent cell survival, providing a mechanistic basis for the enhanced metastatic capacity of tumour cells lacking DCC. Consistent with this idea, in vivo tumour-cell survival is enhanced by DCC loss. Together, our data support the function of DCC as a context-dependent tumour suppressor that limits survival of disseminated tumour cells.
  Paul KrimpenfortJi-Ying SongNatalie ProostJohn ZevenhovenJos JonkersAnton Berns
• The same pocket in menin binds both MLL and JUND but has opposite effects on transcription
  Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs. Menin interacts with many proteins and is involved in a variety of cellular processes. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity. Several MEN1 missense mutations disrupt the menin–JUND interaction, suggesting a correlation between the tumour-suppressor function of menin and its suppression of JUND-activated transcription. Menin also interacts with mixed lineage leukaemia protein 1 (MLL1), a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription and promote MLL1-fusion-protein-induced leukaemogenesis. A recent report on the tethering of MLL1 to chromatin binding factor lens epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions of multiple proteins. Despite its importance, how menin interacts with many distinct partners and regulates their functions remains poorly understood. Here we present the crystal structures of human menin in its free form and in complexes with MLL1 or with JUND, or with an MLL1–LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin–JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.
  Jing HuangBuddha GurungBingbing WanSmita MatkarNatalia A. VeniaminovaKe WanJuanita L. MerchantXianxin HuaMing Lei
• Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist
  The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.
  Kazuko HagaAndrew C. KruseHidetsugu AsadaTakami Yurugi-KobayashiMitsunori ShiroishiCheng ZhangWilliam I. WeisTetsuji OkadaBrian K. KobilkaTatsuya HagaTakuya Kobayashi
• Structure and dynamics of the M3 muscarinic acetylcholine receptor
  Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1–M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. We describe here the structure of the Gq/11-coupled M3 mAChR (‘M3 receptor’, from rat) bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the Gi/o-coupled M2 receptor, offers possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provide additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.
  Andrew C. KruseJianxin HuAlbert C. PanDaniel H. ArlowDaniel M. RosenbaumErica RosemondHillary F. GreenTong LiuPil Seok ChaeRon O. DrorDavid E. ShawWilliam I. WeisJürgen WessBrian K. Kobilka