Volume 506 Issue 7488


Not so neutral p.265

Switzerland’s science landscape is under threat after a narrow majority of citizens voted for tighter immigration rules that could restrict the number of foreign scientists who work in the country.

doi: 10.1038/506265a

Intelligent testing p.265

Science has a part to play in ensuring protection for defendants with intellectual disabilities.

doi: 10.1038/506265b

Helium high p.266

Many bemoan the shortage of helium for the lab, but for geologists, its true value is in the ground.

doi: 10.1038/506266a


Fight against smog ramps up p.273

Chinese government to provide incentives for heavy polluters to go green, but analysts question whether its wider air-quality strategy goes far enough.

doi: 10.1038/506273a

News Features

Death of a comet p.281

Before it shattered near the Sun, Comet ISON became a scientific celebrity. Now researchers are trying to piece together its lessons.

doi: 10.1038/506281a

Smart enough to die? p.284

The US Supreme Court years ago ruled against applying the death penalty to people unable to understand the legal process. Now it must grapple with the science of how intellectual disability is measured.

doi: 10.1038/506284a

News & Views

Lopsided stellar death p.298

Observations of the supernova remnant Cassiopeia A offer an unprecedented look back at the centre of this explosion, and support the hypothesis that spatial asymmetry is key to explaining the event. See Letter p.339

doi: 10.1038/506298a

Take the brakes off for liver repair p.299

A protein produced by endothelial cells that line blood vessels has been found to regulate the timing of cell proliferation following liver injury, further demonstrating the role of vascular signals in tissue regeneration.

doi: 10.1038/506299a

Persistence of leukaemic ancestors p.300

The early development of acute leukaemias is assumed for the most part to be clinically silent and transient. But it now seems that ancestral precancerous cells are identifiable and persistent. See Article p.328

doi: 10.1038/nature13056

A promising advance in nuclear fusion p.302

Experiments conducted at the US National Ignition Facility have cleared a hurdle on the road to nuclear fusion in the laboratory, encouraging fusion scientists around the world. See Letter p.343

doi: 10.1038/nature13057

Protein binding cannot subdue a lively RNA p.303

Ribosomes, the cell's protein-synthesis machines, are assembled from their components in a defined order. It emerges that the first assembly step must overcome dynamic structural rearrangements. See Article p.334

doi: 10.1038/nature13055

Genetic rejuvenation of old muscle p.304

In advanced age, the stem cells responsible for muscle regeneration switch from reversible quiescence to irreversible senescence. Targeting a driver of senescence revives muscle stem cells and restores regeneration. See Article p.316

doi: 10.1038/nature13058


The rise of oxygen in Earth’s early ocean and atmosphere p.307

The rapid increase of carbon dioxide concentration in Earth’s modern atmosphere is a matter of major concern. But for the atmosphere of roughly two-and-half billion years ago, interest centres on a different gas: free oxygen (O2) spawned by early biological production. The initial increase of O2 in the atmosphere, its delayed build-up in the ocean, its increase to near-modern levels in the sea and air two billion years later, and its cause-and-effect relationship with life are among the most compelling stories in Earth’s history.

doi: 10.1038/nature13068


In situ identification of bipotent stem cells in the mammary gland p.322

Through the use of a novel three-dimensional imaging technique, used in conjunction with a multicolour reporter that allows lineage tracing and cell tracking of entire mammary ducts in vivo, bipotent stem cells are shown to have a central role in both puberty and long-term maintenance; in addition, long-lived luminal progenitor cells with a prominent role in ductal expansion are identified.

doi: 10.1038/nature12948

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia p.328

The authors identify pre-leukaemic haematopoietic stem cells (HSCs) in patients with acute myeloid leukaemia; these pre-leukaemic HSCs have the capacity of normal multi-lineage haematopoietic differentiation with a competitive growth advantage over wild-type HSCs, and owing to their persistence may serve as a reservoir for therapeutic resistance and relapse.

doi: 10.1038/nature13038

Protein-guided RNA dynamics during early ribosome assembly p.334

Three-colour fluorescence resonance energy transfer and molecular dynamics simulations are used to study the events occurring early in assembly of the 30S ribosome; within a non-native intermediate S4 ribosomal protein–16S RNA structure, S4 is capable of altering the RNA helix dynamics to facilitate conformation changes that enable subsequent protein binding.

doi: 10.1038/nature13039


Asymmetries in core-collapse supernovae from maps of radioactive 44Ti in Cassiopeia A p.339

Asymmetry is required by most numerical simulations of stellar core-collapse explosions, but the form it takes differs significantly among models. The spatial distribution of radioactive 44Ti, synthesized in an exploding star near the boundary between material falling back onto the collapsing core and that ejected into the surrounding medium, directly probes the explosion asymmetries. Cassiopeia A is a young, nearby, core-collapse remnant from which 44Ti emission has previously been detected but not imaged. Asymmetries in the explosion have been indirectly inferred from a high ratio of observed 44Ti emission to estimated 56Ni emission, from optical light echoes, and from jet-like features seen in the X-ray and optical ejecta. Here we report spatial maps and spectral properties of the 44Ti in Cassiopeia A. This may explain the unexpected lack of correlation between the 44Ti and iron X-ray emission, the latter being visible only in shock-heated material. The observed spatial distribution rules out symmetric explosions even with a high level of convective mixing, as well as highly asymmetric bipolar explosions resulting from a fast-rotating progenitor. Instead, these observations provide strong evidence for the development of low-mode convective instabilities in core-collapse supernovae.

doi: 10.1038/nature12997

Fuel gain exceeding unity in an inertially confined fusion implosion p.343

Ignition is needed to make fusion energy a viable alternative energy source, but has yet to be achieved. A key step on the way to ignition is to have the energy generated through fusion reactions in an inertially confined fusion plasma exceed the amount of energy deposited into the deuterium–tritium fusion fuel and hotspot during the implosion process, resulting in a fuel gain greater than unity. Here we report the achievement of fusion fuel gains exceeding unity on the US National Ignition Facility using a ‘high-foot’ implosion method, which is a manipulation of the laser pulse shape in a way that reduces instability in the implosion. These experiments show an order-of-magnitude improvement in yield performance over past deuterium–tritium implosion experiments. We also see a significant contribution to the yield from α-particle self-heating and evidence for the ‘bootstrapping’ required to accelerate the deuterium–tritium fusion burn to eventually ‘run away’ and ignite.

doi: 10.1038/nature13008

Exceptional ballistic transport in epitaxial graphene nanoribbons p.349

Graphene nanoribbons will be essential components in future graphene nanoelectronics. However, in typical nanoribbons produced from lithographically patterned exfoliated graphene, the charge carriers travel only about ten nanometres between scattering events, resulting in minimum sheet resistances of about one kilohm per square. Here we show that 40-nanometre-wide graphene nanoribbons epitaxially grown on silicon carbide are single-channel room-temperature ballistic conductors on a length scale greater than ten micrometres, which is similar to the performance of metallic carbon nanotubes. This is equivalent to sheet resistances below 1 ohm per square, surpassing theoretical predictions for perfect graphene by at least an order of magnitude. In neutral graphene ribbons, we show that transport is dominated by two modes. One is ballistic and temperature independent; the other is thermally activated. Transport is protected from back-scattering, possibly reflecting ground-state properties of neutral graphene. At room temperature, the resistance of both modes is found to increase abruptly at a particular length—the ballistic mode at 16 micrometres and the other at 160 nanometres. Our epitaxial graphene nanoribbons will be important not only in fundamental science, but also—because they can be readily produced in thousands—in advanced nanoelectronics, which can make use of their room-temperature ballistic transport properties.

doi: 10.1038/nature12952

Prodigious degassing of a billion years of accumulated radiogenic helium at Yellowstone p.355

Helium is used as a critical tracer throughout the Earth sciences, where its relatively simple isotopic systematics is used to trace degassing from the mantle, to date groundwater and to time the rise of continents. The hydrothermal system at Yellowstone National Park is famous for its high helium-3/helium-4 isotope ratio, commonly cited as evidence for a deep mantle source for the Yellowstone hotspot. However, much of the helium emitted from this region is actually radiogenic helium-4 produced within the crust by α-decay of uranium and thorium. Here we show, by combining gas emission rates with chemistry and isotopic analyses, that crustal helium-4 emission rates from Yellowstone exceed (by orders of magnitude) any conceivable rate of generation within the crust. It seems that helium has accumulated for (at least) many hundreds of millions of years in Archaean (more than 2.5 billion years old) cratonic rocks beneath Yellowstone, only to be liberated over the past two million years by intense crustal metamorphism induced by the Yellowstone hotspot. Our results demonstrate the extremes in variability of crustal helium efflux on geologic timescales and imply crustal-scale open-system behaviour of helium in tectonically and magmatically active regions.

doi: 10.1038/nature12992

Species coexistence and the dynamics of phenotypic evolution in adaptive radiation p.359

Interactions between species can promote evolutionary divergence of ecological traits and social signals, a process widely assumed to generate species differences in adaptive radiation. However, an alternative view is that lineages typically interact when relatively old, by which time selection for divergence is weak and potentially exceeded by convergent selection acting on traits mediating interspecific competition. Few studies have tested these contrasting predictions across large radiations, or by controlling for evolutionary time. Thus the role of species interactions in driving broad-scale patterns of trait divergence is unclear. Here we use phylogenetic estimates of divergence times to show that increased trait differences among coexisting lineages of ovenbirds (Furnariidae) are explained by their greater evolutionary age in relation to non-interacting lineages, and that—when these temporal biases are accounted for—the only significant effect of coexistence is convergence in a social signal (song). Our results conflict with the conventional view that coexistence promotes trait divergence among co-occurring organisms at macroevolutionary scales, and instead provide evidence that species interactions can drive phenotypic convergence across entire radiations, a pattern generally concealed by biases in age.

doi: 10.1038/nature12874

Disease associations between honeybees and bumblebees as a threat to wild pollinators p.364

Emerging infectious diseases (EIDs) pose a risk to human welfare, both directly and indirectly, by affecting managed livestock and wildlife that provide valuable resources and ecosystem services, such as the pollination of crops. Honeybees (Apis mellifera), the prevailing managed insect crop pollinator, suffer from a range of emerging and exotic high-impact pathogens, and population maintenance requires active management by beekeepers to control them. Wild pollinators such as bumblebees (Bombus spp.) are in global decline, one cause of which may be pathogen spillover from managed pollinators like honeybees or commercial colonies of bumblebees. Here we use a combination of infection experiments and landscape-scale field data to show that honeybee EIDs are indeed widespread infectious agents within the pollinator assemblage. The prevalence of deformed wing virus (DWV) and the exotic parasite Nosema ceranae in honeybees and bumblebees is linked; as honeybees have higher DWV prevalence, and sympatric bumblebees and honeybees are infected by the same DWV strains, Apis is the likely source of at least one major EID in wild pollinators. Lessons learned from vertebrates highlight the need for increased pathogen control in managed bee species to maintain wild pollinators, as declines in native pollinators may be caused by interspecies pathogen transmission originating from managed pollinators.

doi: 10.1038/nature12977

Unidirectional pulmonary airflow patterns in the savannah monitor lizard p.367

The unidirectional airflow patterns in the lungs of birds have long been considered a unique and specialized trait associated with the oxygen demands of flying, their endothermic metabolism and unusual pulmonary architecture. However, the discovery of similar flow patterns in the lungs of crocodilians indicates that this character is probably ancestral for all archosaurs—the group that includes extant birds and crocodilians as well as their extinct relatives, such as pterosaurs and dinosaurs. Unidirectional flow in birds results from aerodynamic valves, rather than from sphincters or other physical mechanisms, and similar aerodynamic valves seem to be present in crocodilians. The anatomical and developmental similarities in the primary and secondary bronchi of birds and crocodilians suggest that these structures and airflow patterns may be homologous. The origin of this pattern is at least as old as the split between crocodilians and birds, which occurred in the Triassic period. Alternatively, this pattern of flow may be even older; this hypothesis can be tested by investigating patterns of airflow in members of the outgroup to birds and crocodilians, the Lepidosauromorpha (tuatara, lizards and snakes). Here we demonstrate region-specific unidirectional airflow in the lungs of the savannah monitor lizard (Varanus exanthematicus). The presence of unidirectional flow in the lungs of V. exanthematicus thus gives rise to two possible evolutionary scenarios: either unidirectional airflow evolved independently in archosaurs and monitor lizards, or these flow patterns are homologous in archosaurs and V. exanthematicus, having evolved only once in ancestral diapsids (the clade encompassing snakes, lizards, crocodilians and birds). If unidirectional airflow is plesiomorphic for Diapsida, this respiratory character can be reconstructed for extinct diapsids, and evolved in a small ectothermic tetrapod during the Palaeozoic era at least a hundred million years before the origin of birds.

doi: 10.1038/nature12871

Landscape of genomic alterations in cervical carcinomas p.371

Cervical cancer is responsible for 10–15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma–normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour–normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.

doi: 10.1038/nature12881

Genetics of rheumatoid arthritis contributes to biology and drug discovery p.376

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ∼10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

doi: 10.1038/nature12873

Selection and evaluation of clinically relevant AAV variants in a xenograft liver model p.382

Recombinant adeno-associated viral (rAAV) vectors have shown early promise in clinical trials. The therapeutic transgene cassette can be packaged in different AAV capsid pseudotypes, each having a unique transduction profile. At present, rAAV capsid serotype selection for a specific clinical trial is based on effectiveness in animal models. However, preclinical animal studies are not always predictive of human outcome. Here, in an attempt to further our understanding of these discrepancies, we used a chimaeric human–murine liver model to compare directly the relative efficiency of rAAV transduction in human versus mouse hepatocytes in vivo. As predicted from preclinical and clinical studies, rAAV2 vectors functionally transduced mouse and human hepatocytes at equivalent but relatively low levels. However, rAAV8 vectors, which are very effective in many animal models, transduced human hepatocytes rather poorly—approximately 20 times less efficiently than mouse hepatocytes. In light of the limitations of the rAAV vectors currently used in clinical studies, we used the same murine chimaeric liver model to perform serial selection using a human-specific replication-competent viral library composed of DNA-shuffled AAV capsids. One chimaeric capsid composed of five different parental AAV capsids was found to transduce human primary hepatocytes at high efficiency in vitro and in vivo, and provided species-selected transduction in primary liver, cultured cells and a hepatocellular carcinoma xenograft model. This vector is an ideal clinical candidate and a reagent for gene modification of human xenotransplants in mouse models of human diseases. More importantly, our results suggest that humanized murine models may represent a more precise approach for both selecting and evaluating clinically relevant rAAV serotypes for gene therapeutic applications.

doi: 10.1038/nature12875

Convergent evolution of a fused sexual cycle promotes the haploid lifestyle p.387

Sexual reproduction is restricted to eukaryotic species and involves the fusion of haploid gametes to form a diploid cell that subsequently undergoes meiosis to generate recombinant haploid forms. This process has been extensively studied in the unicellular yeast Saccharomyces cerevisiae, which exhibits separate regulatory control over mating and meiosis. Here we address the mechanism of sexual reproduction in the related hemiascomycete species Candida lusitaniae. We demonstrate that, in contrast to S. cerevisiae, C. lusitaniae exhibits a highly integrated sexual program in which the programs regulating mating and meiosis have fused. Profiling of the C. lusitaniae sexual cycle revealed that gene expression patterns during mating and meiosis were overlapping, indicative of co-C. lusitaniae. Furthermore, genetic analysis showed that the orthologue of IME2, a ‘diploid-specific’ factor in S. cerevisiae, and STE12, the master regulator of S. cerevisiae mating, were each required for progression through both mating and meiosis in C. lusitaniae. Together, our results establish that sexual reproduction has undergone significant rewiring between S. cerevisiae and C. lusitaniae, and that a concerted sexual cycle operates in C. lusitaniae that is more reminiscent of the distantly related ascomycete, Schizosaccharomyces pombe. We discuss these results in light of the evolution of sexual reproduction in yeast, and propose that regulatory coupling of mating and meiosis has evolved multiple times as an adaptation to promote the haploid lifestyle.

doi: 10.1038/nature12891

Structure of a Naegleria Tet-like dioxygenase in complex with 5-methylcytosine DNA p.391

Cytosine residues in mammalian DNA occur in five forms: cytosine (C), 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). The ten-eleven translocation (Tet) dioxygenases convert 5mC to 5hmC, 5fC and 5caC in three consecutive, Fe(ii)- and α-ketoglutarate-dependent oxidation reactions. The Tet family of dioxygenases is widely distributed across the tree of life, including in the heterolobosean amoeboflagellate Naegleria gruberi. The genome of Naegleria encodes homologues of mammalian DNA methyltransferase and Tet proteins. Here we study biochemically and structurally one of the Naegleria Tet-like proteins (NgTet1), which shares significant sequence conservation (approximately 14% identity or 39% similarity) with mammalian Tet1. Like mammalian Tet proteins, NgTet1 acts on 5mC and generates 5hmC, 5fC and 5caC. The crystal structure of NgTet1 in complex with DNA containing a 5mCpG site revealed that NgTet1 uses a base-flipping mechanism to access 5mC. The DNA is contacted from the minor groove and bent towards the major groove. The flipped 5mC is positioned in the active-site pocket with planar stacking contacts, Watson–Crick polar hydrogen bonds and van der Waals interactions specific for 5mC. The sequence conservation between NgTet1 and mammalian Tet1, including residues involved in structural integrity and functional significance, suggests structural conservation across phyla.

doi: 10.1038/nature12905