Hot off the presses! Apr 23 Nature

The Apr 23 issue of the Nature is now up on Pubget (About Nature): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Wanted: cyber-czars
  - Nature 458(7241):945 (2009)
  The world needs stronger leadership in safeguarding the security of computation and communication networks. That includes research institutions.
• More than hot air
  - Nature 458(7241):945-946 (2009)
  The United States has finally acknowledged that global warming is a threat. It must now act on that.
• No more catch-up
  - Nature 458(7241):946 (2009)
  Regulatory agencies need to be more proactive in preparing for avant-garde products.
• Cell biology: Night vision
  - Nature 458(7241):948 (2009)
  
• Biochemistry: Hushing the flush
  - Nature 458(7241):948 (2009)
  
• Climate change: Network effects
  - Nature 458(7241):948 (2009)
  
• Population studies: China needs women
  - Nature 458(7241):948 (2009)
  
• Neuroscience: Connecting dementias
  - Nature 458(7241):948 (2009)
  
• Circadian rhythms: Magnetic clocks
  - Nature 458(7241):948-949 (2009)
  
• Cognitive psychology: Bilingual baby talk
  - Nature 458(7241):949 (2009)
  
• Climate modelling: Soot and warming
  - Nature 458(7241):949 (2009)
  
• Evolution: Bitter apple
  - Nature 458(7241):949 (2009)
  
• Microbiology: Colony collapse cured?
  - Nature 458(7241):949 (2009)
  
• Journal club
  - Nature 458(7241):949 (2009)
  
• Still strict on stem cells
  - Nature 458(7241):950-951 (2009)
  
• Pharmaceutical companies join forces on HIV
  - Nature 458(7241):950-951 (2009)
  
• Fees delay pharmed drug
  - Nature 458(7241):951 (2009)
  
• High hopes for US patent reform
  - Nature 458(7241):952-953 (2009)
  
• FANTOM sees networks in cells
  - Nature 458(7241):955 (2009)
  
• India's electioneers make bold pledges on science
  - Nature 458(7241):956-957 (2009)
  
• Snapshot: Motion detector
  - Nature 458(7241):956 (2009)
  
• French life-science alliance unveiled
  - Nature 458(7241):957 (2009)
  
• Australia launches global carbon-capture institute
  - Nature 458(7241):958 (2009)
  
• Company offering ethical reviews suspends activity
  - Nature 458(7241):958 (2009)
  
• US and Japan to collaborate on stem-cell technology
  - Nature 458(7241):958 (2009)
  
• Jailed Iranian AIDS doctors lose court appeal
  - Nature 458(7241):958 (2009)
  
• US medical institute invests in undergraduates
  - Nature 458(7241):958 (2009)
  
• Germany joins in with maize moratorium
  - Nature 458(7241):958 (2009)
  
• Personal technology: Phoning in data
  - Nature 458(7241):959-961 (2009)
  
• Stem cells: Fast and furious
  - Nature 458(7241):962-965 (2009)
  
• Open-access publishing can survive recession
  - Nature 458(7241):967 (2009)
  Your Commentaries on 'How to survive the recession' devote much discussion to the effects of the global recession on science (Nature 457, 957–963; 2009).
• Crystal growers are being forced to scatter
  - Nature 458(7241):967 (2009)
  As you indicate in your News Feature 'China's crystal cache' (Nature 457, 953–955; 2009), China and Japan provide most new single crystals for research, and the supply in the United States and Europe is becoming more and more limited. One explanation for this decline is that researchers specializing in single-crystal growth are unable to find laboratories willing to support their work.
• Struggle to translate Darwin's view of concurrency
  - Nature 458(7241):967 (2009)
  In your Editorial 'Humanity and evolution' (Nature 457, 763–764; 2009), you mention Charles Darwin's image of a fiercely competitive world.
• Big Brother has evolved
  - Nature 458(7241):968 (2009)
  Tracking someone's movements can now be done cheaply and easily, and there are few restrictions on who can monitor whom, says Jerome E. Dobson.
• This title is false
  - Nature 458(7241):969 (2009)
  Comparing gene networks to Greek philosophy could help biologists to see the truth, argue Mark Isalan and Matthew Morrison.
• Final warning from a sceptical prophet
  - Nature 458(7241):970-971 (2009)
  In his new book, James Lovelock fears that humanity faces widespread death and mass migration as Earth's systems become further unbalanced by climate change, explains Andrew Watson.
• Pursuing the infinite
  - Nature 458(7241):971-972 (2009)
  
• The hidden language of cells
  - Nature 458(7241):972 (2009)
  
• Industrial strength, corroded
  - Nature 458(7241):973 (2009)
  
• Culture dish
  - Nature 458(7241):973 (2009)
  Vienna in 1900 was a place of intellectual tumult, a city at the centre of both psychiatry and modernism. The Wellcome Collection's latest exhibition Madness and Modernity, showing in London until 28 June, explores how ideas of the mind from Sigmund Freud and others influenced views of madness in a period of great change.
• Quantum chemistry: The little molecule that could
  - Nature 458(7241):975-976 (2009)
  The creation of diatomic molecules bound by roaming electrons that allow a huge internuclear distance is some achievement. It opens the door to further experimental exploitation of the principles involved.
• Schizophrenia: A point of disruption
  - Nature 458(7241):976-977 (2009)
  Much is still to be learned about the molecular basis of mental disorders. The identification of a signalling pathway that is affected in schizophrenia, and which thus provides potential therapeutic targets, is a welcome advance.
• Global change: China at the carbon crossroads
  - Nature 458(7241):977-979 (2009)
  In China, as in other nations that produce carbon dioxide from fossil fuels on a large scale, the terrestrial biosphere mops up a proportion of the emissions. Estimates of the amounts involved are now available.
• Complex systems: Cooperative network dynamics
  - Nature 458(7241):979-980 (2009)
  Nested, or hierarchically arranged, mutualisms allow ecosystems to support more species than they otherwise would. But in this and other contexts, the growth of such networks could carry a heavy price.
• Neuroscience: Optical control of reward
  - Nature 458(7241):980-981 (2009)
  Is it wishful thinking that the behaviour of an organism as complex as a mouse might be controlled by modulating its intracellular signalling with light? No: this is just what researchers have achieved with an elegant technique.
• Obituary: John Maddox (1925–2009)
  - Nature 458(7241):983-984 (2009)
  
• A Publisher's perspective
  - Nature 458(7241):984-985 (2009)
  
• Maddox by his successor
  - Nature 458(7241):985-986 (2009)
  
• Mantle skewness and ridge segmentation
  - Nature 458(7241):E11 (2009)
  Arising from: D. R. Toomey, D. Jousselin, R. A. Dunn, W. S. D. Wilcock & R. S. Detrick Nature 446, 409–414 (2007); Toomey et al. reply Mantle upwelling is generally assumed to be symmetric. Toomey et al. 1 observe low seismic-wave velocity in off-axis mantle, and suggest that mantle upwelling is skewed, which has important implications for asthenospheric flow, ridge segmentation, crustal accretion, and volcanic, tectonic and hydrothermal vent activities along the ridge axis. However, we point out here that the mantle low-velocity zone (MLVZ) presented by Toomey et al. 1 is not constrained by their data. We conclude that inferences pertaining to ridge segmentation and mantle flow are not reliable.
• Toomey et al. reply
  - Nature 458(7241):E12 (2009)
  Replying to: S. S. Singh & K. C. Macdonald Nature 458, 10.1038/nature07887 (2009) We think that the Singh and Macdonald 1 description of the experimental uncertainties in our data2 is a misrepresentation of what we have done, and that they are incorrect in stating that our results2 on the structure of the uppermost mantle in the subaxial region beneath the East Pacific Rise are unconstrained by data.
• Genome-wide analysis of Notch signalling in Drosophila by transgenic RNAi
  - Nature 458(7241):987-992 (2009)
  Genome-wide RNA interference (RNAi) screens have identified near-complete sets of genes involved in cellular processes. However, this methodology has not yet been used to study complex developmental processes in a tissue-specific manner. Here we report the use of a library of Drosophila strains expressing inducible hairpin RNAi constructs to study the Notch signalling pathway during external sensory organ development. We assigned putative loss-of-function phenotypes to 21.2% of the protein-coding Drosophila genes. Using secondary assays, we identified 6 new genes involved in asymmetric cell division and 23 novel genes regulating the Notch signalling pathway. By integrating our phenotypic results with protein interaction data, we constructed a genome-wide, functionally validated interaction network governing Notch signalling and asymmetric cell division. We used clustering algorithms to identify nuclear import pathways and the COP9 signallosome as Notch regulators. Our ! results show that complex developmental processes can be analysed on a genome-wide level and provide a unique resource for functional annotation of the Drosophila genome.
• Solar wind as the origin of rapid reddening of asteroid surfaces
  - Nature 458(7241):993-995 (2009)
  A comparison of the laboratory reflectance spectra of meteorites with observations of asteroids revealed that the latter are much 'redder', with the spectral difference explained by 'space weathering'1, 2, though the actual processes and timescales involved have remained controversial3, 4. A recent study5 of young asteroid families concluded that they suffered only minimal space weathering. Here we report additional observations of those families, revealing that space weathering must be a very rapid process—the final colour of a silicate-rich asteroid is acquired shortly after its 'birth' (within 106 years of undergoing a catastrophic collision). This rapid timescale favours solar wind implantation as the main mechanism of space weathering, as laboratory experiments have shown that it is the most rapid of several competing processes. We further demonstrate the necessity to take account of composition when evaluating weathering effectiveness, as both laboratory and as! teroid data show an apparent dependence of weathering on olivine abundance. The rapid colour change that we find implies that colour trends seen among asteroids are most probably due to compositional or surface-particle-size properties, rather than to different relative ages. Apparently fresh surfaces most frequently seen among small near-Earth asteroids may be the result of tidal shaking that rejuvenates their surfaces during planetary encounters6, 7.
• Optimized dynamical decoupling in a model quantum memory
  - Nature 458(7241):996-1000 (2009)
  Any quantum system, such as those used in quantum information or magnetic resonance, is subject to random phase errors that can dramatically affect the fidelity of a desired quantum operation or measurement1. In the context of quantum information, quantum error correction techniques have been developed to correct these errors, but resource requirements are extraordinary. The realization of a physically tractable quantum information system will therefore be facilitated if qubit (quantum bit) error rates are far below the so-called fault-tolerance error threshold1, predicted to be of the order of 10-3–10-6. The need to realize such low error rates motivates a search for alternative strategies to suppress dephasing in quantum systems2. Here we experimentally demonstrate massive suppression of qubit error rates by the application of optimized dynamical decoupling3, 4, 5, 6, 7, 8 pulse sequences, using a model quantum system capable of simulating a variety of qubit techno! logies. We demonstrate an analytically derived pulse sequence9, UDD, and find novel sequences through active, real-time experimental feedback. The latter sequences are tailored to maximize error suppression without the need for a priori knowledge of the ambient noise environment, and are capable of suppressing errors by orders of magnitude compared to other existing sequences (including the benchmark multi-pulse spin echo10, 11). Our work includes the extension of a treatment to predict qubit decoherence12, 13 under realistic conditions, yielding strong agreement between experimental data and theory for arbitrary pulse sequences incorporating nonidealized control pulses. These results demonstrate the robustness of qubit memory error suppression through dynamical decoupling techniques across a variety of qubit technologies11, 14, 15, 16.
• Universal transduction scheme for nanomechanical systems based on dielectric forces
  - Nature 458(7241):1001-1004 (2009)
  Any polarizable body placed in an inhomogeneous electric field experiences a dielectric force. This phenomenon is well known from the macroscopic world: a water jet is deflected when approached by a charged object. This fundamental mechanism is exploited in a variety of contexts—for example, trapping microscopic particles in an optical tweezer1, where the trapping force is controlled via the intensity of a laser beam, or dielectrophoresis2, where electric fields are used to manipulate particles in liquids. Here we extend the underlying concept to the rapidly evolving field of nanoelectromechanical systems3, 4 (NEMS). A broad range of possible applications are anticipated for these systems5, 6, 7, but drive and detection schemes for nanomechanical motion still need to be optimized8, 9. Our approach is based on the application of dielectric gradient forces for the controlled and local transduction of NEMS. Using a set of on-chip electrodes to create an electric field g! radient, we polarize a dielectric resonator and subject it to an attractive force that can be modulated at high frequencies. This universal actuation scheme is efficient, broadband and scalable. It also separates the driving scheme from the driven mechanical element, allowing for arbitrary polarizable materials and thus potentially ultralow dissipation NEMS10. In addition, it enables simple voltage tuning of the mechanical resonance over a wide frequency range, because the dielectric force depends strongly on the resonator–electrode separation. We use the modulation of the resonance frequency to demonstrate parametric actuation11, 12. Moreover, we reverse the actuation principle to realize dielectric detection, thus allowing universal transduction of NEMS. We expect this combination to be useful both in the study of fundamental principles and in applications such as signal processing and sensing.
• Observation of ultralong-range Rydberg molecules
  - Nature 458(7241):1005-1008 (2009)
  Rydberg atoms have an electron in a state with a very high principal quantum number, and as a result can exhibit unusually long-range interactions. One example is the bonding of two such atoms by multipole forces to form Rydberg–Rydberg molecules with very large internuclear distances1, 2, 3. Notably, bonding interactions can also arise from the low-energy scattering of a Rydberg electron with negative scattering length from a ground-state atom4, 5. In this case, the scattering-induced attractive interaction binds the ground-state atom to the Rydberg atom at a well-localized position within the Rydberg electron wavefunction and thereby yields giant molecules that can have internuclear separations of several thousand Bohr radii6, 7, 8. Here we report the spectroscopic characterization of such exotic molecular states formed by rubidium Rydberg atoms that are in the spherically symmetric s state and have principal quantum numbers, n, between 34 and 40. We find that the ! spectra of the vibrational ground state and of the first excited state of the Rydberg molecule, the rubidium dimer Rb(5s)–Rb(ns), agree well with simple model predictions. The data allow us to extract the s-wave scattering length for scattering between the Rydberg electron and the ground-state atom, Rb(5s), in the low-energy regime (kinetic energy, <100 meV), and to determine the lifetimes and the polarizabilities of the Rydberg molecules. Given our successful characterization of s-wave bound Rydberg states, we anticipate that p-wave bound states9, trimer states10 and bound states involving a Rydberg electron with large angular momentum—so-called trilobite molecules5—will also be realized and directly probed in the near future.
• The carbon balance of terrestrial ecosystems in China
  - Nature 458(7241):1009-1013 (2009)
  Global terrestrial ecosystems absorbed carbon at a rate of 1–4 Pg yr-1 during the 1980s and 1990s, offsetting 10–60 per cent of the fossil-fuel emissions1, 2. The regional patterns and causes of terrestrial carbon sources and sinks, however, remain uncertain1, 2, 3. With increasing scientific and political interest in regional aspects of the global carbon cycle, there is a strong impetus to better understand the carbon balance of China1, 2, 3. This is not only because China is the world's most populous country and the largest emitter of fossil-fuel CO2 into the atmosphere4, but also because it has experienced regionally distinct land-use histories and climate trends1, which together control the carbon budget of its ecosystems. Here we analyse the current terrestrial carbon balance of China and its driving mechanisms during the 1980s and 1990s using three different methods: biomass and soil carbon inventories extrapolated by satellite greenness measurements, ecosyst! em models and atmospheric inversions. The three methods produce similar estimates of a net carbon sink in the range of 0.19–0.26 Pg carbon (PgC) per year, which is smaller than that in the conterminous United States5 but comparable to that in geographic Europe6. We find that northeast China is a net source of CO2 to the atmosphere owing to overharvesting and degradation of forests. By contrast, southern China accounts for more than 65 per cent of the carbon sink, which can be attributed to regional climate change, large-scale plantation programmes active since the 1980s and shrub recovery. Shrub recovery is identified as the most uncertain factor contributing to the carbon sink. Our data and model results together indicate that China's terrestrial ecosystems absorbed 28–37 per cent of its cumulated fossil carbon emissions during the 1980s and 1990s.
• Impact of changes in diffuse radiation on the global land carbon sink
  - Nature 458(7241):1014-1017 (2009)
  Plant photosynthesis tends to increase with irradiance. However, recent theoretical and observational studies have demonstrated that photosynthesis is also more efficient under diffuse light conditions1, 2, 3, 4, 5. Changes in cloud cover or atmospheric aerosol loadings, arising from either volcanic or anthropogenic emissions, alter both the total photosynthetically active radiation reaching the surface and the fraction of this radiation that is diffuse, with uncertain overall effects on global plant productivity and the land carbon sink. Here we estimate the impact of variations in diffuse fraction on the land carbon sink using a global model modified to account for the effects of variations in both direct and diffuse radiation on canopy photosynthesis. We estimate that variations in diffuse fraction, associated largely with the 'global dimming' period6, 7, 8, enhanced the land carbon sink by approximately one-quarter between 1960 and 1999. However, under a climate mi! tigation scenario for the twenty-first century in which sulphate aerosols decline before atmospheric CO2 is stabilized, this 'diffuse-radiation' fertilization effect declines rapidly to near zero by the end of the twenty-first century.
• The architecture of mutualistic networks minimizes competition and increases biodiversity
  - Nature 458(7241):1018-1020 (2009)
  The main theories of biodiversity either neglect species interactions1, 2 or assume that species interact randomly with each other3, 4. However, recent empirical work has revealed that ecological networks are highly structured5, 6, 7, and the lack of a theory that takes into account the structure of interactions precludes further assessment of the implications of such network patterns for biodiversity. Here we use a combination of analytical and empirical approaches to quantify the influence of network architecture on the number of coexisting species. As a case study we consider mutualistic networks between plants and their animal pollinators or seed dispersers5, 8, 9, 10, 11. These networks have been found to be highly nested5, with the more specialist species interacting only with proper subsets of the species that interact with the more generalist. We show that nestedness reduces effective interspecific competition and enhances the number of coexisting species. Furt! hermore, we show that a nested network will naturally emerge if new species are more likely to enter the community where they have minimal competitive load. Nested networks seem to occur in many biological and social contexts12, 13, 14, suggesting that our results are relevant in a wide range of fields.
• A semi-aquatic Arctic mammalian carnivore from the Miocene epoch and origin of Pinnipedia
  - Nature 458(7241):1021-1024 (2009)
  Modern pinnipeds (seals, sea lions and the walrus) are semi-aquatic, generally marine carnivores the limbs of which have been modified into flippers. Recent phylogenetic studies using morphological and molecular evidence support pinniped monophyly, and suggest a sister relationship with ursoids1, 2 (for example bears) or musteloids3, 4, 5, 6, 7 (the clade that includes skunks, badgers, weasels and otters). Although the position of pinnipeds within modern carnivores appears moderately well resolved, fossil evidence of the morphological steps leading from a terrestrial ancestor to the modern marine forms has been weak or contentious. The earliest well-represented fossil pinniped is Enaliarctos, a marine form with flippers, which had appeared on the northwestern shores of North America by the early Miocene epoch8, 9. Here we report the discovery of a nearly complete skeleton of a new semi-aquatic carnivore from an early Miocene lake deposit in Nunavut, Canada, that repres! ents a morphological link in early pinniped evolution. The new taxon retains a long tail and the proportions of its fore- and hindlimbs are more similar to those of modern terrestrial carnivores than to modern pinnipeds. Morphological traits indicative of semi-aquatic adaptation include a forelimb with a prominent deltopectoral ridge on the humerus, a posterodorsally expanded scapula, a pelvis with relatively short ilium, a shortened femur and flattened phalanges, suggestive of webbing. The new fossil shows evidence of pinniped affinities and similarities to the early Oligocene Amphicticeps from Asia and the late Oligocene and Miocene Potamotherium from Europe. The discovery suggests that the evolution of pinnipeds included a freshwater transitional phase, and may support the hypothesis that the Arctic was an early centre of pinniped evolution.
• Temporally precise in vivo control of intracellular signalling
  Airan RD Thompson KR Fenno LE Bernstein H Deisseroth K - Nature 458(7241):1025-1029 (2009)
  In the study of complex mammalian behaviours, technological limitations have prevented spatiotemporally precise control over intracellular signalling processes. Here we report the development of a versatile family of genetically encoded optical tools ('optoXRs') that leverage common structure–function relationships1 among G-protein-coupled receptors (GPCRs) to recruit and control, with high spatiotemporal precision, receptor-initiated biochemical signalling pathways. In particular, we have developed and characterized two optoXRs that selectively recruit distinct, targeted signalling pathways in response to light. The two optoXRs exerted opposing effects on spike firing in nucleus accumbens in vivo, and precisely timed optoXR photostimulation in nucleus accumbens by itself sufficed to drive conditioned place preference in freely moving mice. The optoXR approach allows testing of hypotheses regarding the causal impact of biochemical signalling in behaving mammals, in a! targetable and temporally precise manner.
• Natural variation in a neural globin tunes oxygen sensing in wild Caenorhabditis elegans
  Persson A Gross E Laurent P Busch KE Bretes H de Bono M - Nature 458(7241):1030-1033 (2009)
  Behaviours evolve by iterations of natural selection, but we have few insights into the molecular and neural mechanisms involved. Here we show that some Caenorhabditis elegans wild strains switch between two foraging behaviours in response to subtle changes in ambient oxygen. This finely tuned switch is conferred by a naturally variable hexacoordinated globin, GLB-5. GLB-5 acts with the atypical soluble guanylate cyclases1, 2, 3, which are a different type of oxygen binding protein, to tune the dynamic range of oxygen-sensing neurons close to atmospheric (21%) concentrations. Calcium imaging indicates that one group of these neurons is activated when oxygen rises towards 21%, and is inhibited as oxygen drops below 21%. The soluble guanylate cyclase GCY-35 is required for high oxygen to activate the neurons; GLB-5 provides inhibitory input when oxygen decreases below 21%. Together, these oxygen binding proteins tune neuronal and behavioural responses to a narrow oxygen ! concentration range close to atmospheric levels. The effect of the glb-5 gene on oxygen sensing and foraging is modified by the naturally variable neuropeptide receptor npr-1 (refs 4, 5), providing insights into how polygenic variation reshapes neural circuit function.
• Glycerol monolaurate prevents mucosal SIV transmission
  - Nature 458(7241):1034-1038 (2009)
  Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection1, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission2, 3, 4. Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)–rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry5, 6. Here we show in this SIV–macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3alpha (also known as CCL20), plasmacytoid dendritic cells and CCR5+ cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in bot! h cervix and vagina, recruits CD4+ T cells to fuel this obligate expansion. We then show that glycerol monolaurate—a widely used antimicrobial compound7 with inhibitory activity against the production of MIP-3alpha and other proinflammatory cytokines8—can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission.
• Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease
  - Nature 458(7241):1039-1042 (2009)
  Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype1. To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-kappaB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearanc! e from the airway, but also less inflammation and disease—a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.
• Germline-encoded amino acids in the alphabeta T-cell receptor control thymic selection
  - Nature 458(7241):1043-1046 (2009)
  An alphabeta T-cell response depends on the recognition of antigen plus major histocompatibility complex (MHC) proteins1 by its antigen receptor (TCR). The ability of peripheral alphabeta T cells to recognize MHC is at least partly determined by MHC-dependent thymic selection, by which an immature T cell survives only if its TCR can recognize self MHC2, 3, 4, 5, 6, 7. This process may allow MHC-reactive TCRs to be selected from a repertoire with completely random and unbiased specificities. However, analysis of thymocytes before positive selection indicated that TCR proteins might have a predetermined ability to bind MHC8, 9, 10, 11. Here we show that specific germline-encoded amino acids in the TCR promote 'generic' MHC recognition and control thymic selection. In mice expressing single, rearranged TCR beta-chains, individual mutation of amino acids in the complementarity-determining region (CDR) 2beta to Ala reduced development of the entire TCR repertoire. Altogethe! r, these results show that thymic selection is controlled by germline-encoded MHC contact points in the alphabeta TCR and indicate that the diversity of the peripheral T-cell repertoire is enhanced by this 'built-in' specificity.
• Discovery of insect and human dengue virus host factors
  - Nature 458(7241):1047-1050 (2009)
  Dengue fever is the most frequent arthropod-borne viral disease of humans, with almost half of the world's population at risk of infection1. The high prevalence, lack of an effective vaccine, and absence of specific treatment conspire to make dengue fever a global public health threat1, 2. Given their compact genomes, dengue viruses (DENV-1–4) and other flaviviruses probably require an extensive number of host factors; however, only a limited number of human, and an even smaller number of insect host factors, have been identified3, 4, 5, 6, 7, 8, 9, 10. Here we identify insect host factors required for DENV-2 propagation, by carrying out a genome-wide RNA interference screen in Drosophila melanogaster cells using a well-established 22,632 double-stranded RNA library. This screen identified 116 candidate dengue virus host factors (DVHFs). Although some were previously associated with flaviviruses (for example, V-ATPases and alpha-glucosidases)3, 4, 5, 7, 9, 10, most o! f the DVHFs were newly implicated in dengue virus propagation. The dipteran DVHFs had 82 readily recognizable human homologues and, using a targeted short-interfering-RNA screen, we showed that 42 of these are human DVHFs. This indicates notable conservation of required factors between dipteran and human hosts. This work suggests new approaches to control infection in the insect vector and the mammalian host.
• Directional Delta and Notch trafficking in Sara endosomes during asymmetric cell division
  Coumailleau F Fürthauer M Knoblich JA González-Gaitán M - Nature 458(7241):1051-1055 (2009)
  Endocytosis has a crucial role during Notch signalling after the asymmetric division of fly sensory organ precursors (SOPs): directional signalling is mediated by differential endocytosis of the ligand Delta and the Notch effector Sanpodo in one of the SOP daughters, pIIb1, 2, 3. Here we show a new mechanism of directional signalling on the basis of the trafficking of Delta and Notch molecules already internalized in the SOP and subsequently targeted to the other daughter cell, pIIa. Internalized Delta and Notch traffic to an endosome marked by the protein Sara4, 5. During SOP mitosis, Sara endosomes containing Notch and Delta move to the central spindle and then to pIIa. Subsequently, in pIIa (but not in pIIb) Notch appears cleaved in Sara endosomes in a gamma-secretase- and Delta internalization-dependent manner, indicating that the release of the intracellular Notch tail to activate Notch target genes has occurred. We thus uncover a new mechanism to bias signalling ! even before asymmetric endocytosis of Sanpodo and Delta takes place in the daughter cells: already during SOP mitosis, asymmetric targeting of Delta and Notch-containing Sara endosomes will increase Notch signalling in pIIa and decrease it in pIIb.
• AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
  - Nature 458(7241):1056-1060 (2009)
  AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio1. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin2, 3, thiazolidinediones4 and exercise5, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP1. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordinati! on with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.
• Outsourced
  - Nature 458(7241):1066 (2009)
  Equal opportunities?