Volume 505 Issue 7485


Support our buoys p.585

An international effort is needed to restore an early-warning system for the vast warming of the Pacific Ocean that leads to extreme weather worldwide.

doi: 10.1038/505585a

Open invitation p.585

Europe’s proposed climate targets fire the starting gun on the long build-up to Paris 2015.

doi: 10.1038/505585b

Crystal clear p.586

Celebrating the many achievements of crystallography.

doi: 10.1038/505586a


News Features

The crystal century p.601

From aiding drug design to analysing soil samples on Mars, crystallography has helped to propel much of modern science over the past 100 years.

doi: 10.1038/505601a

The big guns p.604

Powerful X-ray lasers are getting to the heart of matter.

doi: 10.1038/505604a

News & Views

Sources of inspiration p.620

Synchrotrons have long been the preferred X-ray sources for crystallography, but competition has arrived with the advent of X-ray free-electron lasers. A synchrotron expert and an advocate of free-electron lasers discuss the prospects of their preferred source types for applications in structural biology.

doi: 10.1038/505620a

A second layer of information in RNA p.621

Three studies have characterized the full complement of RNA folding in cells. They find large numbers of secondary structures in RNA, some of which may have functional consequences for the cell. See Letters p.696, p.701 & p.706

doi: 10.1038/505621a

Potency unchained p.622

Differentiated cells have been reprogrammed to an embryonic-like state using a physical stimulus. This treatment generates a new cell population that contributes to both the embryo and the placenta. See Article p.641 & Letter p.676

doi: 10.1038/505622a

Portrait of a dynamic neighbour p.625

Brown dwarfs are celestial objects that lack the mass to become fully fledged stars. High-resolution maps of one such object add to the evidence that these exotic worlds have highly dynamic weather and climate. See Letter p.654

doi: 10.1038/505625a

Brotherly love benefits females p.626

Mating competition between males often has harmful consequences for females. But it seems that fruit flies alter their behaviour among kin, with brothers being less aggressive and females reproducing for longer as a result. See Letter p.672

doi: 10.1038/nature12853

Polar exploration p.627

Magnetic monopoles — particles carrying a single magnetic charge — have never been seen. Analogues of these entities have now been produced in an ultracold cloud of rubidium atoms. See Letter p.657

doi: 10.1038/505627a


Solar System evolution from compositional mapping of the asteroid belt p.629

Advances in the discovery and characterization of asteroids over the past decade have revealed an unanticipated underlying structure that points to a dramatic early history of the inner Solar System. The asteroids in the main asteroid belt have been discovered to be more compositionally diverse with size and distance from the Sun than had previously been known. This implies substantial mixing through processes such as planetary migration and the subsequent dynamical processes.

doi: 10.1038/nature12908


The evolution of lncRNA repertoires and expression patterns in tetrapods p.635

Evolutionary study of long noncoding RNA (lncRNA) repertoires and expression patterns in 11 tetrapod species identifies approximately 11,000 primate-specific lncRNAs and 2,500 highly conserved lncRNAs, including approximately 400 genes that are likely to have ancient origins; many lncRNAs, particularly ancient ones, are actively regulated and may function mainly in embryonic development.

doi: 10.1038/nature12943

Stimulus-triggered fate conversion of somatic cells into pluripotency p.641

One of two papers describing a reprogramming phenomenon called stimulus-triggered acquisition of pluripotency (STAP) — in STAP, lineage-committed adult somatic cells are reprogrammed to pluripotency by transient exposure to low-pH treatment, and extensive analysis of the molecular features and developmental potential of STAP cells indicates that they represent a unique state of pluripotency.

doi: 10.1038/nature12968


A global cloud map of the nearest known brown dwarf p.654

Brown dwarfs—substellar bodies more massive than planets but not massive enough to initiate the sustained hydrogen fusion that powers self-luminous stars—are born hot and slowly cool as they age. As they cool below about 2,300 kelvin, liquid or crystalline particles composed of calcium aluminates, silicates and iron condense into atmospheric ‘dust’, which disappears at still cooler temperatures (around 1,300 kelvin). Models to explain this dust dispersal include both an abrupt sinking of the entire cloud deck into the deep, unobservable atmosphere and breakup of the cloud into scattered patches (as seen on Jupiter and Saturn). However, hitherto observations of brown dwarfs have been limited to globally integrated measurements, which can reveal surface inhomogeneities but cannot unambiguously resolve surface features. Here we report a two-dimensional map of a brown dwarf’s surface that allows identification of large-scale bright and dark features, indicative of patchy clouds. Monitoring suggests that the characteristic timescale for the evolution of global weather patterns is approximately one day.

doi: 10.1038/nature12955

Observation of Dirac monopoles in a synthetic magnetic field p.657

Magnetic monopoles—particles that behave as isolated north or south magnetic poles—have been the subject of speculation since the first detailed observations of magnetism several hundred years ago. Numerous theoretical investigations and hitherto unsuccessful experimental searches have followed Dirac’s 1931 development of a theory of monopoles consistent with both quantum mechanics and the gauge invariance of the electromagnetic field. The existence of even a single Dirac magnetic monopole would have far-reaching physical consequences, most famously explaining the quantization of electric charge. Although analogues of magnetic monopoles have been found in exotic spin ices and other systems, there has been no direct experimental observation of Dirac monopoles within a medium described by a quantum field, such as superfluid helium-3 (refs 10, 11, 12, 13). Here we demonstrate the controlled creation of Dirac monopoles in the synthetic magnetic field produced by a spinor Bose–Einstein condensate. Monopoles are identified, in both experiments and matching numerical simulations, at the termini of vortex lines within the condensate. By directly imaging such a vortex line, the presence of a monopole may be discerned from the experimental data alone. These real-space images provide conclusive and long-awaited experimental evidence of the existence of Dirac monopoles. Our result provides an unprecedented opportunity to observe and manipulate these quantum mechanical entities in a controlled environment.

doi: 10.1038/nature12954

Site- and energy-selective slow-electron production through intermolecular Coulombic decay p.661

Irradiation of matter with light tends to electronically excite atoms and molecules, with subsequent relaxation processes determining where the photon energy is ultimately deposited and electrons and ions produced. In weakly bound systems, intermolecular Coulombic decay (ICD) enables very efficient relaxation of electronic excitation through transfer of the excess energy to neighbouring atoms or molecules that then lose an electron and become ionized. Here we propose that the emission site and energy of the electrons released during this process can be controlled by coupling the ICD to a resonant core excitation. We illustrate this concept with ab initio many-body calculations on the argon–krypton model system, where resonant photoabsorption produces an initial or ‘parent’ excitation of the argon atom, which then triggers a resonant-Auger-ICD cascade that ends with the emission of a slow electron from the krypton atom. Our calculations show that the energy of the emitted electrons depends sensitively on the initial excited state of the argon atom. The incident energy can thus be adjusted both to produce the initial excitation in a chosen atom and to realize an excitation that will result in the emission of ICD electrons with desired energies. These properties of the decay cascade might have consequences for fundamental and applied radiation biology and could be of interest in the development of new spectroscopic techniques.

doi: 10.1038/nature12936

Resonant Auger decay driving intermolecular Coulombic decay in molecular dimers p.664

In 1997, it was predicted that an electronically excited atom or molecule placed in a loosely bound chemical system (such as a hydrogen-bonded or van-der-Waals-bonded cluster) could efficiently decay by transferring its excess energy to a neighbouring species that would then emit a low-energy electron. This intermolecular Coulombic decay (ICD) process has since been shown to be a common phenomenon, raising questions about its role in DNA damage induced by ionizing radiation, in which low-energy electrons are known to play an important part. It was recently suggested that ICD can be triggered efficiently and site-selectively by resonantly core-exciting a target atom, which then transforms through Auger decay into an ionic species with sufficiently high excitation energy to permit ICD to occur. Here we show experimentally that resonant Auger decay can indeed trigger ICD in dimers of both molecular nitrogen and carbon monoxide. By using ion and electron momentum spectroscopy to measure simultaneously the charged species created in the resonant-Auger-driven ICD cascade, we find that ICD occurs in less time than the 20 femtoseconds it would take for individual molecules to undergo dissociation. Our experimental confirmation of this process and its efficiency may trigger renewed efforts to develop resonant X-ray excitation schemes for more localized and targeted cancer radiation therapy.

doi: 10.1038/nature12927

Australian tropical cyclone activity lower than at any time over the past 550–1,500 years p.667

The assessment of changes in tropical cyclone activity within the context of anthropogenically influenced climate change has been limited by the short temporal resolution of the instrumental tropical cyclone record (less than 50 years). Furthermore, controversy exists regarding the robustness of the observational record, especially before 1990. Here we show, on the basis of a new tropical cyclone activity index (CAI), that the present low levels of storm activity on the mid west and northeast coasts of Australia are unprecedented over the past 550 to 1,500 years. The CAI allows for a direct comparison between the modern instrumental record and long-term palaeotempest (prehistoric tropical cyclone) records derived from the 18O/16O ratio of seasonally accreting carbonate layers of actively growing stalagmites. Our results reveal a repeated multicentennial cycle of tropical cyclone activity, the most recent of which commenced around ad 1700. The present cycle includes a sharp decrease in activity after 1960 in Western Australia. This is in contrast to the increasing frequency and destructiveness of Northern Hemisphere tropical cyclones since 1970 in the Atlantic Ocean and the western North Pacific Ocean. Other studies project a decrease in the frequency of tropical cyclones towards the end of the twenty-first century in the southwest Pacific, southern Indian and Australian regions. Our results, although based on a limited record, suggest that this may be occurring much earlier than expected.

doi: 10.1038/nature12882

Within-group male relatedness reduces harm to females in Drosophila p.672

To resolve the mechanisms that switch competition to cooperation is key to understanding biological organization. This is particularly relevant for intrasexual competition, which often leads to males harming females. Recent theory proposes that kin selection may modulate female harm by relaxing competition among male relatives. Here we experimentally manipulate the relatedness of groups of male Drosophila melanogaster competing over females to demonstrate that, as expected, within-group relatedness inhibits male competition and female harm. Females exposed to groups of three brothers unrelated to the female had higher lifetime reproductive success and slower reproductive ageing compared to females exposed to groups of three males unrelated to each other. Triplets of brothers also fought less with each other, courted females less intensively and lived longer than triplets of unrelated males. However, associations among brothers may be vulnerable to invasion by minorities of unrelated males: when two brothers were matched with an unrelated male, the unrelated male sired on average twice as many offspring as either brother. These results demonstrate that relatedness can profoundly affect fitness through its modulation of intrasexual competition, as flies plastically adjust sexual behaviour in a manner consistent with kin-selection theory.

doi: 10.1038/nature12949

Bidirectional developmental potential in reprogrammed cells with acquired pluripotency p.676

We recently discovered an unexpected phenomenon of somatic cell reprogramming into pluripotent cells by exposure to sublethal stimuli, which we call stimulus-triggered acquisition of pluripotency (STAP). This reprogramming does not require nuclear transfer or genetic manipulation. Here we report that reprogrammed STAP cells, unlike embryonic stem (ES) cells, can contribute to both embryonic and placental tissues, as seen in a blastocyst injection assay. Mouse STAP cells lose the ability to contribute to the placenta as well as trophoblast marker expression on converting into ES-like stem cells by treatment with adrenocorticotropic hormone (ACTH) and leukaemia inhibitory factor (LIF). In contrast, when cultured with Fgf4, STAP cells give rise to proliferative stem cells with enhanced trophoblastic characteristics. Notably, unlike conventional trophoblast stem cells, the Fgf4-induced stem cells from STAP cells contribute to both embryonic and placental tissues in vivo and transform into ES-like cells when cultured with LIF-containing medium. Taken together, the developmental potential of STAP cells, shown by chimaera formation and in vitro cell conversion, indicates that they represent a unique state of pluripotency.

doi: 10.1038/nature12969

Genome-wide dissection of the quorum sensing signalling pathway in Trypanosoma brucei p.681

The protozoan parasites Trypanosoma brucei spp. cause important human and livestock diseases in sub-Saharan Africa. In mammalian blood, two developmental forms of the parasite exist: proliferative ‘slender’ forms and arrested ‘stumpy’ forms that are responsible for transmission to tsetse flies. The slender to stumpy differentiation is a density-dependent response that resembles quorum sensing in microbial systems and is crucial for the parasite life cycle, ensuring both infection chronicity and disease transmission. This response is triggered by an elusive ‘stumpy induction factor’ (SIF) whose intracellular signalling pathway is also uncharacterized. Laboratory-adapted (monomorphic) trypanosome strains respond inefficiently to SIF but can generate forms with stumpy characteristics when exposed to cell-permeable cAMP and AMP analogues. Exploiting this, we have used a genome-wide RNA interference library screen to identify the signalling components driving stumpy formation. In separate screens, monomorphic parasites were exposed to 8-(4-chlorophenylthio)-cAMP (pCPT-cAMP) or 8-pCPT-2′-O-methyl-5′-AMP to select cells that were unresponsive to these signals and hence remained proliferative. Genome-wide Ion Torrent based RNAi target sequencing identified cohorts of genes implicated in each step of the signalling pathway, from purine metabolism, through signal transducers (kinases, phosphatases) to gene expression regulators. Genes at each step were independently validated in cells naturally capable of stumpy formation, confirming their role in density sensing in vivo. The putative RNA-binding protein, RBP7, was required for normal quorum sensing and promoted cell-cycle arrest and transmission competence when overexpressed. This study reveals that quorum sensing signalling in trypanosomes shares similarities to fundamental quiescence pathways in eukaryotic cells, its components providing targets for quorum-sensing interference-based therapeutics.

doi: 10.1038/nature12864

Mutational and fitness landscapes of an RNA virus revealed through population sequencing p.686

RNA viruses exist as genetically diverse populations. It is thought that diversity and genetic structure of viral populations determine the rapid adaptation observed in RNA viruses and hence their pathogenesis. However, our understanding of the mechanisms underlying virus evolution has been limited by the inability to accurately describe the genetic structure of virus populations. Next-generation sequencing technologies generate data of sufficient depth to characterize virus populations, but are limited in their utility because most variants are present at very low frequencies and are thus indistinguishable from next-generation sequencing errors. Here we present an approach that reduces next-generation sequencing errors and allows the description of virus populations with unprecedented accuracy. Using this approach, we define the mutation rates of poliovirus and uncover the mutation landscape of the population. Furthermore, by monitoring changes in variant frequencies on serially passaged populations, we determined fitness values for thousands of mutations across the viral genome. Mapping of these fitness values onto three-dimensional structures of viral proteins offers a powerful approach for exploring structure–function relationships and potentially uncovering new functions. To our knowledge, our study provides the first single-nucleotide fitness landscape of an evolving RNA virus and establishes a general experimental platform for studying the genetic changes underlying the evolution of virus populations.

doi: 10.1038/nature12861

Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity p.691

The type I interferon (IFN) response protects cells from viral infection by inducing hundreds of interferon-stimulated genes (ISGs), some of which encode direct antiviral effectors. Recent screening studies have begun to catalogue ISGs with antiviral activity against several RNA and DNA viruses. However, antiviral ISG specificity across multiple distinct classes of viruses remains largely unexplored. Here we used an ectopic expression assay to screen a library of more than 350 human ISGs for effects on 14 viruses representing 7 families and 11 genera. We show that 47 genes inhibit one or more viruses, and 25 genes enhance virus infectivity. Comparative analysis reveals that the screened ISGs target positive-sense single-stranded RNA viruses more effectively than negative-sense single-stranded RNA viruses. Gene clustering highlights the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS, also known as MB21D1) as a gene whose expression also broadly inhibits several RNA viruses. In vitro, lentiviral delivery of enzymatically active cGAS triggers a STING-dependent, IRF3-mediated antiviral program that functions independently of canonical IFN/STAT1 signalling. In vivo, genetic ablation of murine cGAS reveals its requirement in the antiviral response to two DNA viruses, and an unappreciated contribution to the innate control of an RNA virus. These studies uncover new paradigms for the preferential specificity of IFN-mediated antiviral pathways spanning several virus families.

doi: 10.1038/nature12862

In vivo genome-wide profiling of RNA secondary structure reveals novel regulatory features p.696

RNA structure has critical roles in processes ranging from ligand sensing to the regulation of translation, polyadenylation and splicing. However, a lack of genome-wide in vivo RNA structural data has limited our understanding of how RNA structure regulates gene expression in living cells. Here we present a high-throughput, genome-wide in vivo RNA structure probing method, structure-seq, in which dimethyl sulphate methylation of unprotected adenines and cytosines is identified by next-generation sequencing. Application of this method to Arabidopsis thaliana seedlings yielded the first in vivo genome-wide RNA structure map at nucleotide resolution for any organism, with quantitative structural information across more than 10,000 transcripts. Our analysis reveals a three-nucleotide periodic repeat pattern in the structure of coding regions, as well as a less-structured region immediately upstream of the start codon, and shows that these features are strongly correlated with translation efficiency. We also find patterns of strong and weak secondary structure at sites of alternative polyadenylation, as well as strong secondary structure at 5′ splice sites that correlates with unspliced events. Notably, in vivo structures of messenger RNAs annotated for stress responses are poorly predicted in silico, whereas mRNA structures of genes related to cell function maintenance are well predicted. Global comparison of several structural features between these two categories shows that the mRNAs associated with stress responses tend to have more single-strandedness, longer maximal loop length and higher free energy per nucleotide, features that may allow these RNAs to undergo conformational changes in response to environmental conditions. Structure-seq allows the RNA structurome and its biological roles to be interrogated on a genome-wide scale and should be applicable to any organism.

doi: 10.1038/nature12756

Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo p.701

RNA has a dual role as an informational molecule and a direct effector of biological tasks. The latter function is enabled by RNA’s ability to adopt complex secondary and tertiary folds and thus has motivated extensive computational and experimental efforts for determining RNA structures. Existing approaches for evaluating RNA structure have been largely limited to in vitro systems, yet the thermodynamic forces which drive RNA folding in vitro may not be sufficient to predict stable RNA structures in vivo. Indeed, the presence of RNA-binding proteins and ATP-dependent helicases can influence which structures are present inside cells. Here we present an approach for globally monitoring RNA structure in native conditions in vivo with single-nucleotide precision. This method is based on in vivo modification with dimethyl sulphate (DMS), which reacts with unpaired adenine and cytosine residues, followed by deep sequencing to monitor modifications. Our data from yeast and mammalian cells are in excellent agreement with known messenger RNA structures and with the high-resolution crystal structure of the Saccharomyces cerevisiae ribosome. Comparison between in vivo and in vitro data reveals that in rapidly dividing cells there are vastly fewer structured mRNA regions in vivo than in vitro. Even thermostable RNA structures are often denatured in cells, highlighting the importance of cellular processes in regulating RNA structure. Indeed, analysis of mRNA structure under ATP-depleted conditions in yeast shows that energy-dependent processes strongly contribute to the predominantly unfolded state of mRNAs inside cells. Our studies broadly enable the functional analysis of physiological RNA structures and reveal that, in contrast to the Anfinsen view of protein folding whereby the structure formed is the most thermodynamically favourable, thermodynamics have an incomplete role in determining mRNA structure in vivo.

doi: 10.1038/nature12894

Landscape and variation of RNA secondary structure across the human transcriptome p.706

In parallel to the genetic code for protein synthesis, a second layer of information is embedded in all RNA transcripts in the form of RNA structure. RNA structure influences practically every step in the gene expression program. However, the nature of most RNA structures or effects of sequence variation on structure are not known. Here we report the initial landscape and variation of RNA secondary structures (RSSs) in a human family trio (mother, father and their child). This provides a comprehensive RSS map of human coding and non-coding RNAs. We identify unique RSS signatures that demarcate open reading frames and splicing junctions, and define authentic microRNA-binding sites. Comparison of native deproteinized RNA isolated from cells versus refolded purified RNA suggests that the majority of the RSS information is encoded within RNA sequence. Over 1,900 transcribed single nucleotide variants (approximately 15% of all transcribed single nucleotide variants) alter local RNA structure. We discover simple sequence and spacing rules that determine the ability of point mutations to impact RSSs. Selective depletion of ‘riboSNitches’ versus structurally synonymous variants at precise locations suggests selection for specific RNA shapes at thousands of sites, including 3′ untranslated regions, binding sites of microRNAs and RNA-binding proteins genome-wide. These results highlight the potentially broad contribution of RNA structure and its variation to gene regulation.

doi: 10.1038/nature12946