Volume 498 Issue 7454


Brain blast p.271

DIY attempts at electrical brain stimulation to improve cognition are to get easier.

doi: 10.1038/498271b

Risk management p.271

A project to pool data and tools to calculate earthquake hazards is an important milestone, but it will be down to individuals to decide how to interpret and respond to those risks.

doi: 10.1038/498271a

Science prevails p.272

The US government gives up its fight to keep age restrictions on the morning-after pill.

doi: 10.1038/498272a


News Features

The quantum company p.286

D-Wave is pioneering a novel way of making quantum computers — but it is also courting controversy.

doi: 10.1038/498286a

Quake catcher p.290

With Earthquake death tolls rising, Ross Stein is building a global risk model to mitigate future disasters.

doi: 10.1038/498290a

News & Views

The seeds of ice in clouds p.302

An investigation of droplet freezing in clouds suggests that a minor component of mineral dust in the atmosphere is the main catalyst for this process. Two experts discuss the ramifications of this finding for those investigating cloud-droplet freezing, and for scientists studying atmospheric aerosols. See Letter p.355

doi: 10.1038/nature12256

Archaeology meets primate technology p.303

A study of wild capuchin monkeys that crack nuts using stone hammers reveals temporal and spatial patterning of the relics of their technological efforts, confirming that such behaviours can be studied from an archaeological perspective.

doi: 10.1038/498303a

Integration triggers death p.305

That HIV cripples the immune system by killing CD4+ T cells has long been known. It now emerges that the protein DNA-PK, activated by viral integration into the host-cell genome, is the agent of this death response. See Letter p.376

doi: 10.1038/nature12254

Flying like a fly p.306

When biologists unravelled the principles of insect flight, they inspired a generation of engineers to build on their aerodynamic feats. Thanks to a revolution in micro-manufacturing techniques, the first robotic fly now flies.

doi: 10.1038/nature12258

Heavy calcium nuclei weigh in p.307

The configurations of calcium nuclei make them good test cases for studies of nuclear properties. The measurement of the masses of two heavy calcium nuclei provides benchmarks for models of atomic nuclei. See Letter p.346

doi: 10.1038/498307a

Signalling from disordered proteins p.308

The discovery that a disordered protein can transmit signals between two binding sites calls into question the idea that communication within proteins requires a specific structural pathway linking such sites. See Letter p.390

doi: 10.1038/498308a

The virus whose family expanded p.310

The discovery of many new species of hepaciviruses and pegiviruses, which exhibit enormous genetic diversity, in wild rodent and bat populations might help us to understand the origins of the hepatitis C virus.

doi: 10.1038/498310b


Anisotropic leaky-mode modulator for holographic video displays p.313

Realizing holographic video displays is proving far from straightforward, but it is shown here that it may be possible to overcome the limitations of present displays by harnessing the desirable optical manipulation properties of anisotropic leaky-mode spatial light modulators.

doi: 10.1038/nature12217

The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis p.318

This study identifies a deubiquitinase (DUB) that specifically recognises and cleaves linear ubiquitin chains, implicating linear (de)ubiquitination in Wnt signalling and angiogenesis; mutations in gumby cause defects in angiogenesis in mice, and structural and biochemical analysis shows that gumby encodes a linear-ubiquitin-specific DUB.

doi: 10.1038/nature12296

Structural mechanism of cytosolic DNA sensing by cGAS p.332

Cytosolic DNA arising from intracellular bacterial or viral infections induces type I interferon through activation of the DNA sensor cGAS, which catalyses the synthesis of cyclic dinucleotide which in turn activates STING; here the crystal structures of a carboxy-terminal fragment of cGAS alone and in complex with UTP and DNA–ATP–GTP complex are determined.

doi: 10.1038/nature12305


The rapid assembly of an elliptical galaxy of 400 billion solar masses at a redshift of 2.3 p.338

Stellar archaeology shows that massive elliptical galaxies formed rapidly about ten billion years ago with star-formation rates of above several hundred solar masses per year. Their progenitors are probably the submillimetre bright galaxies at redshifts z greater than 2. Although the mean molecular gas mass (5 × 1010 solar masses) of the submillimetre bright galaxies can explain the formation of typical elliptical galaxies, it is inadequate to form elliptical galaxies that already have stellar masses above 2 × 1011 solar masses at z ≈ 2. Here we report multi-wavelength high-resolution observations of a rare merger of two massive submillimetre bright galaxies at z = 2.3. The system is seen to be forming stars at a rate of 2,000 solar masses per year. The star-formation efficiency is an order of magnitude greater than that of normal galaxies, so the gas reservoir will be exhausted and star formation will be quenched in only around 200 million years. At a projected separation of 19 kiloparsecs, the two massive starbursts are about to merge and form a passive elliptical galaxy with a stellar mass of about 4 × 1011 solar masses. We conclude that gas-rich major galaxy mergers with intense star formation can form the most massive elliptical galaxies by z ≈ 1.5.

doi: 10.1038/nature12184

Volcanism on Mars controlled by early oxidation of the upper mantle p.342

Detailed information about the chemical composition and evolution of Mars has been derived principally from the SNC (shergottite–nakhlite–chassignite) meteorites, which are genetically related igneous rocks of Martian origin. They are chemically and texturally similar to terrestrial basalts and cumulates, except that they have higher concentrations of iron and volatile elements such as phosphorus and chlorine and lower concentrations of nickel and other chalcophile (sulphur-loving) elements. Most Martian meteorites have relatively young crystallization ages (1.4 billion years to 180 million years ago) and are considered to be derived from young, lightly cratered volcanic regions, such as the Tharsis plateau. Surface rocks from the Gusev crater analysed by the Spirit rover are much older (about 3.7 billion years old) and exhibit marked compositional differences from the meteorites. Although also basaltic in composition, the surface rocks are richer in nickel and sulphur and have lower manganese/iron ratios than the meteorites. This has led to doubts that Mars can be described adequately using the ‘SNC model’. Here we show, however, that the differences between the compositions of meteorites and surface rocks can be explained by differences in the oxygen fugacity during melting of the same sulphur-rich mantle. This ties the sources of Martian meteorites to those of the surface rocks through an early (>3.7 billion years ago) oxidation of the uppermost mantle that had less influence on the deeper regions, which produce the more recent volcanic rocks.

doi: 10.1038/nature12225

Masses of exotic calcium isotopes pin down nuclear forces p.346

The properties of exotic nuclei on the verge of existence play a fundamental part in our understanding of nuclear interactions. Exceedingly neutron-rich nuclei become sensitive to new aspects of nuclear forces. Calcium, with its doubly magic isotopes 40Ca and 48Ca, is an ideal test for nuclear shell evolution, from the valley of stability to the limits of existence. With a closed proton shell, the calcium isotopes mark the frontier for calculations with three-nucleon forces from chiral effective field theory. Whereas predictions for the masses of 51Ca and 52Ca have been validated by direct measurements, it is an open question as to how nuclear masses evolve for heavier calcium isotopes. Here we report the mass determination of the exotic calcium isotopes 53Ca and 54Ca, using the multi-reflection time-of-flight mass spectrometer of ISOLTRAP at CERN. The measured masses unambiguously establish a prominent shell closure at neutron number N = 32, in excellent agreement with our theoretical calculations. These results increase our understanding of neutron-rich matter and pin down the subtle components of nuclear forces that are at the forefront of theoretical developments constrained by quantum chromodynamics.

doi: 10.1038/nature12226

Defect pair separation as the controlling step in homogeneous ice melting p.350

On being heated, ice melts into liquid water. Although in practice this process tends to be heterogeneous, it can occur homogeneously inside bulk ice. The thermally induced homogeneous melting of solids is fairly well understood, and involves the formation and growth of melting nuclei. But in the case of water, resilient hydrogen bonds render ice melting more complex. We know that the first defects appearing during homogeneous ice melting are pairs of five- and seven-membered rings, which appear and disappear repeatedly and randomly in space and time in the crystalline ice structure. However, the accumulation of these defects to form an aggregate is nearly additive in energy, and results in a steep free energy increase that suppresses further growth. Here we report molecular dynamics simulations of homogeneous ice melting that identify as a crucial first step not the formation but rather the spatial separation of a defect pair. We find that once it is separated, the defect pair—either an interstitial (I) and a vacancy (V) defect pair (a Frenkel pair), or an L and a D defect pair (a Bjerrum pair)—is entropically stabilized, or ‘entangled’. In this state, defects with threefold hydrogen-bond coordination persist and grow, and thereby prepare the system for subsequent rapid melting.

doi: 10.1038/nature12190

The importance of feldspar for ice nucleation by mineral dust in mixed-phase clouds p.355

The amount of ice present in mixed-phase clouds, which contain both supercooled liquid water droplets and ice particles, affects cloud extent, lifetime, particle size and radiative properties. The freezing of cloud droplets can be catalysed by the presence of aerosol particles known as ice nuclei. One of the most important ice nuclei is thought to be mineral dust aerosol from arid regions. It is generally assumed that clay minerals, which contribute approximately two-thirds of the dust mass, dominate ice nucleation by mineral dust, and many experimental studies have therefore focused on these materials. Here we use an established droplet-freezing technique to show that feldspar minerals dominate ice nucleation by mineral dusts under mixed-phase cloud conditions, despite feldspar being a minor component of dust emitted from arid regions. We also find that clay minerals are relatively unimportant ice nuclei. Our results from a global aerosol model study suggest that feldspar ice nuclei are globally distributed and that feldspar particles may account for a large proportion of the ice nuclei in Earth’s atmosphere that contribute to freezing at temperatures below about −15 °C.

doi: 10.1038/nature12278

A Jurassic avialan dinosaur from China resolves the early phylogenetic history of birds p.359

The recent discovery of small paravian theropod dinosaurs with well-preserved feathers in the Middle–Late Jurassic Tiaojishan Formation of Liaoning Province (northeastern China) has challenged the pivotal position of Archaeopteryx, regarded from its discovery to be the most basal bird. Removing Archaeopteryx from the base of Avialae to nest within Deinonychosauria implies that typical bird flight, powered by the forelimbs only, either evolved at least twice, or was subsequently lost or modified in some deinonychosaurians. Here we describe the complete skeleton of a new paravian from the Tiaojishan Formation of Liaoning Province, China. Including this new taxon in a comprehensive phylogenetic analysis for basal Paraves does the following: (1) it recovers it as the basal-most avialan; (2) it confirms the avialan status of Archaeopteryx; (3) it places Troodontidae as the sister-group to Avialae; (4) it supports a single origin of powered flight within Paraves; and (5) it implies that the early diversification of Paraves and Avialae took place in the Middle–Late Jurassic period.

doi: 10.1038/nature12168

Distinct behavioural and network correlates of two interneuron types in prefrontal cortex p.363

Neurons in the prefrontal cortex exhibit diverse behavioural correlates, an observation that has been attributed to cell-type diversity. To link identified neuron types with network and behavioural functions, we recorded from the two largest genetically defined inhibitory interneuron classes, the perisomatically targeting parvalbumin (PV) and the dendritically targeting somatostatin (SOM) neurons in anterior cingulate cortex of mice performing a reward foraging task. Here we show that PV and a subtype of SOM neurons form functionally homogeneous populations showing a double dissociation between both their inhibitory effects and behavioural correlates. Out of several events pertaining to behaviour, a subtype of SOM neurons selectively responded at reward approach, whereas PV neurons responded at reward leaving and encoded preceding stay duration. These behavioural correlates of PV and SOM neurons defined a behavioural epoch and a decision variable important for foraging (whether to stay or to leave), a crucial function attributed to the anterior cingulate cortex. Furthermore, PV neurons could fire in millisecond synchrony, exerting fast and powerful inhibition on principal cell firing, whereas the inhibitory effect of SOM neurons on firing output was weak and more variable, consistent with the idea that they respectively control the outputs of, and inputs to, principal neurons. These results suggest a connection between the circuit-level function of different interneuron types in regulating the flow of information and the behavioural functions served by the cortical circuits. Moreover, these observations bolster the hope that functional response diversity during behaviour can in part be explained by cell-type diversity.

doi: 10.1038/nature12176

Topographic diversity of fungal and bacterial communities in human skin p.367

Traditional culture-based methods have incompletely defined the microbial landscape of common recalcitrant human fungal skin diseases, including athlete’s foot and toenail infections. Skin protects humans from invasion by pathogenic microorganisms and provides a home for diverse commensal microbiota. Bacterial genomic sequence data have generated novel hypotheses about species and community structures underlying human disorders. However, microbial diversity is not limited to bacteria; microorganisms such as fungi also have major roles in microbial community stability, human health and disease. Genomic methodologies to identify fungal species and communities have been limited compared with those that are available for bacteria. Fungal evolution can be reconstructed with phylogenetic markers, including ribosomal RNA gene regions and other highly conserved genes. Here we sequenced and analysed fungal communities of 14 skin sites in 10 healthy adults. Eleven core-body and arm sites were dominated by fungi of the genus Malassezia, with only species-level classifications revealing fungal-community composition differences between sites. By contrast, three foot sites—plantar heel, toenail and toe web—showed high fungal diversity. Concurrent analysis of bacterial and fungal communities demonstrated that physiologic attributes and topography of skin differentially shape these two microbial communities. These results provide a framework for future investigation of the contribution of interactions between pathogenic and commensal fungal and bacterial communities to the maintainenace of human health and to disease pathogenesis.

doi: 10.1038/nature12171

Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo p.371

Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects. The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration, but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue.

doi: 10.1038/nature12175

HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration p.376

Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide, ultimately the consequence of cytolytic infection of CD4+ T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia, yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4+ T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4+ T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals.

doi: 10.1038/nature12274

cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING p.380

Detection of cytoplasmic DNA represents one of the most fundamental mechanisms of the innate immune system to sense the presence of microbial pathogens. Moreover, erroneous detection of endogenous DNA by the same sensing mechanisms has an important pathophysiological role in certain sterile inflammatory conditions. The endoplasmic-reticulum-resident protein STING is critically required for the initiation of type I interferon signalling upon detection of cytosolic DNA of both exogenous and endogenous origin. Next to its pivotal role in DNA sensing, STING also serves as a direct receptor for the detection of cyclic dinucleotides, which function as second messenger molecules in bacteria. DNA recognition, however, is triggered in an indirect fashion that depends on a recently characterized cytoplasmic nucleotidyl transferase, termed cGAMP synthase (cGAS), which upon interaction with DNA synthesizes a dinucleotide molecule that in turn binds to and activates STING. We here show in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides. Using a combinatorial approach based on mass spectrometry, enzymatic digestion, NMR analysis and chemical synthesis we demonstrate that cGAS produces a cyclic GMP-AMP dinucleotide, which comprises a 2′-5′ and a 3′-5′ phosphodiester linkage >Gp(2′-5′)Ap(3′-5′)>. We found that the presence of this 2′-5′ linkage was required to exert potent activation of human STING. Moreover, we show that cGAS first catalyses the synthesis of a linear 2′-5′-linked dinucleotide, which is then subject to cGAS-dependent cyclization in a second step through a 3′-5′ phosphodiester linkage. This 13-membered ring structure defines a novel class of second messenger molecules, extending the family of 2′-5′-linked antiviral biomolecules.

doi: 10.1038/nature12306

Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1 p.385

DNA methylation is an epigenetic modification that has critical roles in gene silencing, development and genome integrity. In Arabidopsis, DNA methylation is established by DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) and targeted by 24-nucleotide small interfering RNAs (siRNAs) through a pathway termed RNA-directed DNA methylation (RdDM). This pathway requires two plant-specific RNA polymerases: Pol-IV, which functions to initiate siRNA biogenesis, and Pol-V, which functions to generate scaffold transcripts that recruit downstream RdDM factors. To understand the mechanisms controlling Pol-IV targeting we investigated the function of SAWADEE HOMEODOMAIN HOMOLOG 1 (SHH1), a Pol-IV-interacting protein. Here we show that SHH1 acts upstream in the RdDM pathway to enable siRNA production from a large subset of the most active RdDM targets, and that SHH1 is required for Pol-IV occupancy at these same loci. We also show that the SHH1 SAWADEE domain is a novel chromatin-binding module that adopts a unique tandem Tudor-like fold and functions as a dual lysine reader, probing for both unmethylated K4 and methylated K9 modifications on the histone 3 (H3) tail. Finally, we show that key residues within both lysine-binding pockets of SHH1 are required in vivo to maintain siRNA and DNA methylation levels as well as Pol-IV occupancy at RdDM targets, demonstrating a central role for methylated H3K9 binding in SHH1 function and providing the first insights into the mechanism of Pol-IV targeting. Given the parallels between methylation systems in plants and mammals, a further understanding of this early targeting step may aid our ability to control the expression of endogenous and newly introduced genes, which has broad implications for agriculture and gene therapy.

doi: 10.1038/nature12178

Modulation of allostery by protein intrinsic disorder p.390

Allostery is an intrinsic property of many globular proteins and enzymes that is indispensable for cellular regulatory and feedback mechanisms. Recent theoretical and empirical observations indicate that allostery is also manifest in intrinsically disordered proteins, which account for a substantial proportion of the proteome. Many intrinsically disordered proteins are promiscuous binders that interact with multiple partners and frequently function as molecular hubs in protein interaction networks. The adenovirus early region 1A (E1A) oncoprotein is a prime example of a molecular hub intrinsically disordered protein. E1A can induce marked epigenetic reprogramming of the cell within hours after infection, through interactions with a diverse set of partners that include key host regulators such as the general transcriptional coactivator CREB binding protein (CBP), its paralogue p300, and the retinoblastoma protein (pRb; also called RB1). Little is known about the allosteric effects at play in E1A–CBP–pRb interactions, or more generally in hub intrinsically disordered protein interaction networks. Here we used single-molecule fluorescence resonance energy transfer (smFRET) to study coupled binding and folding processes in the ternary E1A system. The low concentrations used in these high-sensitivity experiments proved to be essential for these studies, which are challenging owing to a combination of E1A aggregation propensity and high-affinity binding interactions. Our data revealed that E1A–CBP–pRb interactions have either positive or negative cooperativity, depending on the available E1A interaction sites. This striking cooperativity switch enables fine-tuning of the thermodynamic accessibility of the ternary versus binary E1A complexes, and may permit a context-specific tuning of associated downstream signalling outputs. Such a modulation of allosteric interactions is probably a common mechanism in molecular hub intrinsically disordered protein function.

doi: 10.1038/nature12294