Volume 505 Issue 7481


The greater good p.5

Governments, funding agencies and universities must all do their bit to ensure that research is appropriately assessed and rewarded.

doi: 10.1038/505005a


News Features

The accidental epigeneticist p.14

By studying disadvantaged children, Richard Tremblay has traced the roots of chronic aggressive behaviour back as far as infancy. Now he hopes to go back further.

doi: 10.1038/505014a

News & Views

Resistance nailed p.30

A series of in vitro, genomic, ecological and epidemiological studies has pinpointed gene mutations in the malaria parasite Plasmodium falciparum that play a key part in resistance to artemisinin-based antimalarial drugs. See Article p.50

doi: 10.1038/nature12845

Cloudy with a chance of dustballs p.31

The flat and featureless transmission spectra of two intermediate-sized extrasolar planets, observed during the planets' passage across their host stars, shed light on the properties of their atmospheres. See Letters p.66 & p.69

doi: 10.1038/505031a

Four makes a party p.32

Adding the first high-quality Neanderthal sequence to genomic comparisons of archaic and modern humans sheds light on gene flow, population structure and adaptation, and suggests the existence of an unknown group. See Article p.43

doi: 10.1038/nature12847

Clouds of uncertainty p.34

An evaluation of atmospheric convective mixing and low-level clouds in climate models suggests that Earth's climate will warm more than was thought in response to increasing levels of carbon dioxide. See Article p.37

doi: 10.1038/505034a

The beginning of the end p.35

Studies in mice and humans suggest that cellular senescence, the cessation of cell proliferation that is known to suppress cancer and promote ageing, may have evolved to regulate embryonic development.

doi: 10.1038/nature12844


Spread in model climate sensitivity traced to atmospheric convective mixing p.37

The change in global mean temperature in response to a change in external forcing is highly uncertain; here differences in the simulated strength of convective mixing between the lower and middle tropical troposphere are shown to explain about half of the variance in climate sensitivity, constraining the predicted equilibrium climate sensitivity to an increase of 3 to 5 degrees Celsius.

doi: 10.1038/nature12829

The complete genome sequence of a Neanderthal from the Altai Mountains p.43

A complete genome sequence is presented of a female Neanderthal from Siberia, providing information about interbreeding between close relatives and uncovering gene flow events among Neanderthals, Denisovans and early modern humans, as well as establishing substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.

doi: 10.1038/nature12886


Strong neutrino cooling by cycles of electron capture and β decay in neutron star crusts p.62

The temperature in the crust of an accreting neutron star, which comprises its outermost kilometre, is set by heating from nuclear reactions at large densities, neutrino cooling and heat transport from the interior. The heated crust has been thought to affect observable phenomena at shallower depths, such as thermonuclear bursts in the accreted envelope. Here we report that cycles of electron capture and its inverse, β decay, involving neutron-rich nuclei at a typical depth of about 150 metres, cool the outer neutron star crust by emitting neutrinos while also thermally decoupling the surface layers from the deeper crust. This ‘Urca’ mechanism has been studied in the context of white dwarfs and type Ia supernovae, but hitherto was not considered in neutron stars, because previous models computed the crust reactions using a zero-temperature approximation and assumed that only a single nuclear species was present at any given depth. The thermal decoupling means that X-ray bursts and other surface phenomena are largely independent of the strength of deep crustal heating. The unexpectedly short recurrence times, of the order of years, observed for very energetic thermonuclear superbursts are therefore not an indicator of a hot crust, but may point instead to an unknown local heating mechanism near the neutron star surface.

doi: 10.1038/nature12757

A featureless transmission spectrum for the Neptune-mass exoplanet GJ 436b p.66

GJ 436b is a warm—approximately 800 kelvin—exoplanet that periodically eclipses its low-mass (half the mass of the Sun) host star, and is one of the few Neptune-mass planets that is amenable to detailed characterization. Previous observations have indicated that its atmosphere has a ratio of methane to carbon monoxide that is 105 times smaller than predicted by models for hydrogen-dominated atmospheres at these temperatures. A recent study proposed that this unusual chemistry could be explained if the planet’s atmosphere is significantly enhanced in elements heavier than hydrogen and helium. Here we report observations of GJ 436b’s atmosphere obtained during transit. The data indicate that the planet’s transmission spectrum is featureless, ruling out cloud-free, hydrogen-dominated atmosphere models with an extremely high significance of 48σ. The measured spectrum is consistent with either a layer of high cloud located at a pressure level of approximately one millibar or with a relatively hydrogen-poor (three per cent hydrogen and helium mass fraction) atmospheric composition.

doi: 10.1038/nature12887

Clouds in the atmosphere of the super-Earth exoplanet GJ 1214b p.69

Recent surveys have revealed that planets intermediate in size between Earth and Neptune (‘super-Earths’) are among the most common planets in the Galaxy. Atmospheric studies are the next step towards developing a comprehensive understanding of this new class of object. Much effort has been focused on using transmission spectroscopy to characterize the atmosphere of the super-Earth archetype GJ 1214b (refs 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17), but previous observations did not have sufficient precision to distinguish between two interpretations for the atmosphere. The planet’s atmosphere could be dominated by relatively heavy molecules, such as water (for example, a 100 per cent water vapour composition), or it could contain high-altitude clouds that obscure its lower layers. Here we report a measurement of the transmission spectrum of GJ 1214b at near-infrared wavelengths that definitively resolves this ambiguity. The data, obtained with the Hubble Space Telescope, are sufficiently precise to detect absorption features from a high mean-molecular-mass atmosphere. The observed spectrum, however, is featureless. We rule out cloud-free atmospheric models with compositions dominated by water, methane, carbon monoxide, nitrogen or carbon dioxide at greater than 5σ confidence. The planet’s atmosphere must contain clouds to be consistent with the data.

doi: 10.1038/nature12888

DNA-mediated nanoparticle crystallization into Wulff polyhedra p.73

Crystallization is a fundamental and ubiquitous process much studied over the centuries. But although the crystallization of atoms is fairly well understood, it remains challenging to predict reliably the outcome of molecular crystallization processes that are complicated by various molecular interactions and solvent involvement. This difficulty also applies to nanoparticles: high-quality three-dimensional crystals are mostly produced using drying and sedimentation techniques that are often impossible to rationalize and control to give a desired crystal symmetry, lattice spacing and habit (crystal shape). In principle, DNA-mediated assembly of nanoparticles offers an ideal opportunity for studying nanoparticle crystallization: a well-defined set of rules have been developed to target desired lattice symmetries and lattice constants, and the occurrence of features such as grain boundaries and twinning in DNA superlattices and traditional crystals comprised of molecular or atomic building blocks suggests that similar principles govern their crystallization. But the presence of charged biomolecules, interparticle spacings of tens of nanometres, and the realization so far of only polycrystalline DNA-interconnected nanoparticle superlattices, all suggest that DNA-guided crystallization may differ from traditional crystal growth. Here we show that very slow cooling, over several days, of solutions of complementary-DNA-modified nanoparticles through the melting temperature of the system gives the thermodynamic product with a specific and uniform crystal habit. We find that our nanoparticle assemblies have the Wulff equilibrium crystal structure that is predicted from theoretical considerations and molecular dynamics simulations, thus establishing that DNA hybridization can direct nanoparticle assembly along a pathway that mimics atomic crystallization.

doi: 10.1038/nature12739

Increasing subtropical North Pacific Ocean nitrogen fixation since the Little Ice Age p.78

The North Pacific subtropical gyre (NPSG) plays a major part in the export of carbon and other nutrients to the deep ocean. Primary production in the NPSG has increased in recent decades despite a reduction in nutrient supply to surface waters. It is thought that this apparent paradox can be explained by a shift in plankton community structure from mostly eukaryotes to mostly nitrogen-fixing prokaryotes. It remains uncertain, however, whether the plankton community domain shift can be linked to cyclical climate variability or a long-term global warming trend. Here we analyse records of bulk and amino-acid-specific 15N/14N isotopic ratios (δ15N) preserved in the skeletons of long-lived deep-sea proteinaceous corals collected from the Hawaiian archipelago; these isotopic records serve as a proxy for the source of nitrogen-supported export production through time. We find that the recent increase in nitrogen fixation is the continuation of a much larger, centennial-scale trend. After a millennium of relatively minor fluctuation, δ15N decreases between 1850 and the present. The total shift in δ15N of −2 per mil over this period is comparable to the total change in global mean sedimentary δ15N across the Pleistocene–Holocene transition, but it is happening an order of magnitude faster. We use a steady-state model and find that the isotopic mass balance between nitrate and nitrogen fixation implies a 17 to 27 per cent increase in nitrogen fixation over this time period. A comparison with independent records suggests that the increase in nitrogen fixation might be linked to Northern Hemisphere climate change since the end of the Little Ice Age.

doi: 10.1038/nature12784

Low investment in sexual reproduction threatens plants adapted to phosphorus limitation p.82

Plant species diversity in Eurasian wetlands and grasslands depends not only on productivity but also on the relative availability of nutrients, particularly of nitrogen and phosphorus. Here we show that the impacts of nitrogen:phosphorus stoichiometry on plant species richness can be explained by selected plant life-history traits, notably by plant investments in growth versus reproduction. In 599 Eurasian sites with herbaceous vegetation we examined the relationship between the local nutrient conditions and community-mean life-history traits. We found that compared with plants in nitrogen-limited communities, plants in phosphorus-limited communities invest little in sexual reproduction (for example, less investment in seed, shorter flowering period, longer lifespan) and have conservative leaf economy traits (that is, a low specific leaf area and a high leaf dry-matter content). Endangered species were more frequent in phosphorus-limited ecosystems and they too invested little in sexual reproduction. The results provide new insight into how plant adaptations to nutrient conditions can drive the distribution of plant species in natural ecosystems and can account for the vulnerability of endangered species.

doi: 10.1038/nature12733

Upper Palaeolithic Siberian genome reveals dual ancestry of Native Americans p.87

The origins of the First Americans remain contentious. Although Native Americans seem to be genetically most closely related to east Asians, there is no consensus with regard to which specific Old World populations they are closest to. Here we sequence the draft genome of an approximately 24,000-year-old individual (MA-1), from Mal’ta in south-central Siberia, to an average depth of 1×. To our knowledge this is the oldest anatomically modern human genome reported to date. The MA-1 mitochondrial genome belongs to haplogroup U, which has also been found at high frequency among Upper Palaeolithic and Mesolithic European hunter-gatherers, and the Y chromosome of MA-1 is basal to modern-day western Eurasians and near the root of most Native American lineages. Similarly, we find autosomal evidence that MA-1 is basal to modern-day western Eurasians and genetically closely related to modern-day Native Americans, with no close affinity to east Asians. This suggests that populations related to contemporary western Eurasians had a more north-easterly distribution 24,000 years ago than commonly thought. Furthermore, we estimate that 14 to 38% of Native American ancestry may originate through gene flow from this ancient population. This is likely to have occurred after the divergence of Native American ancestors from east Asian ancestors, but before the diversification of Native American populations in the New World. Gene flow from the MA-1 lineage into Native American ancestors could explain why several crania from the First Americans have been reported as bearing morphological characteristics that do not resemble those of east Asians. Sequencing of another south-central Siberian, Afontova Gora-2 dating to approximately 17,000 years ago, revealed similar autosomal genetic signatures as MA-1, suggesting that the region was continuously occupied by humans throughout the Last Glacial Maximum. Our findings reveal that western Eurasian genetic signatures in modern-day Native Americans derive not only from post-Columbian admixture, as commonly thought, but also from a mixed ancestry of the First Americans.

doi: 10.1038/nature12736

Prefrontal parvalbumin interneurons shape neuronal activity to drive fear expression p.92

Synchronization of spiking activity in neuronal networks is a fundamental process that enables the precise transmission of information to drive behavioural responses. In cortical areas, synchronization of principal-neuron spiking activity is an effective mechanism for information coding that is regulated by GABA (γ-aminobutyric acid)-ergic interneurons through the generation of neuronal oscillations. Although neuronal synchrony has been demonstrated to be crucial for sensory, motor and cognitive processing, it has not been investigated at the level of defined circuits involved in the control of emotional behaviour. Converging evidence indicates that fear behaviour is regulated by the dorsomedial prefrontal cortex (dmPFC). This control over fear behaviour relies on the activation of specific prefrontal projections to the basolateral complex of the amygdala (BLA), a structure that encodes associative fear memories. However, it remains to be established how the precise temporal control of fear behaviour is achieved at the level of prefrontal circuits. Here we use single-unit recordings and optogenetic manipulations in behaving mice to show that fear expression is causally related to the phasic inhibition of prefrontal parvalbumin interneurons (PVINs). Inhibition of PVIN activity disinhibits prefrontal projection neurons and synchronizes their firing by resetting local theta oscillations, leading to fear expression. Our results identify two complementary neuronal mechanisms mediated by PVINs that precisely coordinate and enhance the neuronal activity of prefrontal projection neurons to drive fear expression.

doi: 10.1038/nature12755

Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis p.97

Chemical or traumatic damage to the liver is frequently associated with aberrant healing (fibrosis) that overrides liver regeneration. The mechanism by which hepatic niche cells differentially modulate regeneration and fibrosis during liver repair remains to be defined. Hepatic vascular niche predominantly represented by liver sinusoidal endothelial cells deploys paracrine trophogens, known as angiocrine factors, to stimulate regeneration. Nevertheless, it is not known how pro-regenerative angiocrine signals from liver sinusoidal endothelial cells is subverted to promote fibrosis. Here, by combining an inducible endothelial-cell-specific mouse gene deletion strategy and complementary models of acute and chronic liver injury, we show that divergent angiocrine signals from liver sinusoidal endothelial cells stimulate regeneration after immediate injury and provoke fibrosis after chronic insult. The pro-fibrotic transition of vascular niche results from differential expression of stromal-derived factor-1 receptors, CXCR7 and CXCR4 (refs 18, 19, 20, 21), in liver sinusoidal endothelial cells. After acute injury, CXCR7 upregulation in liver sinusoidal endothelial cells acts with CXCR4 to induce transcription factor Id1, deploying pro-regenerative angiocrine factors and triggering regeneration. Inducible deletion of Cxcr7 in sinusoidal endothelial cells (Cxcr7iΔEC/iΔEC) from the adult mouse liver impaired liver regeneration by diminishing Id1-mediated production of angiocrine factors. By contrast, after chronic injury inflicted by iterative hepatotoxin (carbon tetrachloride) injection and bile duct ligation, constitutive FGFR1 signalling in liver sinusoidal endothelial cells counterbalanced CXCR7-dependent pro-regenerative response and augmented CXCR4 expression. This predominance of CXCR4 over CXCR7 expression shifted angiocrine response of liver sinusoidal endothelial cells, stimulating proliferation of desmin+ hepatic stellate-like cells and enforcing a pro-fibrotic vascular niche. Endothelial-cell-specific ablation of either Fgfr1 (Fgfr1iΔEC/iΔEC) or Cxcr4 (Cxcr4iΔEC/iΔEC) in mice restored the pro-regenerative pathway and prevented FGFR1-mediated maladaptive subversion of angiocrine factors. Similarly, selective CXCR7 activation in liver sinusoidal endothelial cells abrogated fibrogenesis. Thus, we demonstrate that in response to liver injury, differential recruitment of pro-regenerative CXCR7-Id1 versus pro-fibrotic FGFR1–CXCR4 angiocrine pathways in vascular niche balances regeneration and fibrosis. These results provide a therapeutic roadmap to achieve hepatic regeneration without provoking fibrosis.

doi: 10.1038/nature12681

Antibacterial membrane attack by a pore-forming intestinal C-type lectin p.103

Human body-surface epithelia coexist in close association with complex bacterial communities and are protected by a variety of antibacterial proteins. C-type lectins of the RegIII family are bactericidal proteins that limit direct contact between bacteria and the intestinal epithelium and thus promote tolerance to the intestinal microbiota. RegIII lectins recognize their bacterial targets by binding peptidoglycan carbohydrate, but the mechanism by which they kill bacteria is unknown. Here we elucidate the mechanistic basis for RegIII bactericidal activity. We show that human RegIIIα (also known as HIP/PAP) binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore. We derive a three-dimensional model of the RegIIIα pore by docking the RegIIIα crystal structure into a cryo-electron microscopic map of the pore complex, and show that the model accords with experimentally determined properties of the pore. Lipopolysaccharide inhibits RegIIIα pore-forming activity, explaining why RegIIIα is bactericidal for Gram-positive but not Gram-negative bacteria. Our findings identify C-type lectins as mediators of membrane attack in the mucosal immune system, and provide detailed insight into an antibacterial mechanism that promotes mutualism with the resident microbiota.

doi: 10.1038/nature12729

Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A p.108

Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral β-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open β-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties.

doi: 10.1038/nature12732

Coupled GTPase and remodelling ATPase activities form a checkpoint for ribosome export p.112

Eukaryotic ribosomes are assembled by a complex pathway that extends from the nucleolus to the cytoplasm and is powered by many energy-consuming enzymes. Nuclear export is a key, irreversible step in pre-ribosome maturation, but mechanisms underlying the timely acquisition of export competence remain poorly understood. Here we show that a conserved Saccharomyces cerevisiae GTPase Nug2 (also known as Nog2, and as NGP-1, GNL2 or nucleostemin 2 in human) has a key role in the timing of export competence. Nug2 binds the inter-subunit face of maturing, nucleoplasmic pre-60S particles, and the location clashes with the position of Nmd3, a key pre-60S export adaptor. Nug2 and Nmd3 are not present on the same pre-60S particles, with Nug2 binding before Nmd3. Depletion of Nug2 causes premature Nmd3 binding to the pre-60S particles, whereas mutations in the G-domain of Nug2 block Nmd3 recruitment, resulting in severe 60S export defects. Two pre-60S remodelling factors, the Rea1 ATPase and its co-substrate Rsa4, are present on Nug2-associated particles, and both show synthetic lethal interactions with nug2 mutants. Release of Nug2 from pre-60S particles requires both its K+-dependent GTPase activity and the remodelling ATPase activity of Rea1. We conclude that Nug2 is a regulatory GTPase that monitors pre-60S maturation, with release from its placeholder site linked to recruitment of the nuclear export machinery.

doi: 10.1038/nature12731

N6-methyladenosine-dependent regulation of messenger RNA stability p.117

N6-methyladenosine (m6A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, the exact role of m6A modification remains to be determined. The recent discovery of two m6A demethylases in mammalian cells highlighted the importance of m6A in basic biological functions and disease. Here we show that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) ‘reader’ protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m6A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m6A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2–mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m6A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.

doi: 10.1038/nature12730