Beyond compare p.501

doi: 10.1038/500501b

Hidden heat p.501

doi: 10.1038/500501a

Green fuels blast off p.509

doi: 10.1038/500509a

Brazilian citation scheme outed p.510

doi: 10.1038/500510a

Summer storms bolster Arctic ice p.512

doi: 10.1038/500512a

Biotech boom prompts fears of bust p.513

doi: 10.1038/500513a

African genes tracked back p.514

doi: 10.1038/500514a

The origins of space and time p.516

doi: 10.1038/500516a

Ancient algae crossed a threshold p.532

doi: 10.1038/500532a

Dopamine ramps up p.533

doi: 10.1038/500533a

Radioactive glow as a smoking gun p.535

doi: 10.1038/500535a

Long RNAs wire up cancer growth p.536

doi: 10.1038/nature12548

A dark cloud unveils its secrets p.537

doi: 10.1038/500537a

Wealth management in the gut p.538

doi: 10.1038/500538a

Richness of human gut microbiome correlates with metabolic markers p.541

doi: 10.1038/nature12506

A ‘kilonova’ associated with the short-duration γ-ray burst GRB 130603B p.547

Short-duration γ-ray bursts are intense flashes of cosmic γ-rays, lasting less than about two seconds, whose origin is unclear. The favoured hypothesis is that they are produced by a relativistic jet created by the merger of two compact stellar objects (specifically two neutron stars or a neutron star and a black hole). This is supported by indirect evidence such as the properties of their host galaxies, but unambiguous confirmation of the model is still lacking. Mergers of this kind are also expected to create significant quantities of neutron-rich radioactive species, whose decay should result in a faint transient, known as a ‘kilonova’, in the days following the burst. Indeed, it is speculated that this mechanism may be the predominant source of stable r-process elements in the Universe. Recent calculations suggest that much of the kilonova energy should appear in the near-infrared spectral range, because of the high optical opacity created by these heavy r-process elements. Here we report optical and near-infrared observations that provide strong evidence for such an event accompanying the short-duration γ-ray burst GRB 130603B. If this, the simplest interpretation of the data, is correct, then it confirms that compact-object mergers are the progenitors of short-duration γ-ray bursts and the sites of significant production of r-process elements. It also suggests that kilonovae offer an alternative, unbeamed electromagnetic signature of the most promising sources for direct detection of gravitational waves.

doi: 10.1038/nature12505

A rigid and weathered ice shell on Titan p.550

Several lines of evidence suggest that Saturn’s largest moon, Titan, has a global subsurface ocean beneath an outer ice shell 50 to 200 kilometres thick. If convection is occurring, the rigid portion of the shell is expected to be thin; similarly, a weak, isostatically compensated shell has been proposed to explain the observed topography. Here we report a strong inverse correlation between gravity and topography at long wavelengths that are not dominated by tides and rotation. We argue that negative gravity anomalies (mass deficits) produced by crustal thickening at the base of the ice shell overwhelm positive gravity anomalies (mass excesses) produced by the small surface topography, giving rise to this inverse correlation. We show that this situation requires a substantially rigid ice shell with an elastic thickness exceeding 40 kilometres, and hundreds of metres of surface erosion and deposition, consistent with recent estimates from local features. Our results are therefore not compatible with a geologically active, low-rigidity ice shell. After extrapolating to wavelengths that are controlled by tides and rotation, we suggest that Titan’s moment of inertia may be even higher (that is, Titan may be even less centrally condensed) than is currently thought.

doi: 10.1038/nature12400

Crystallites of magnetic charges in artificial spin ice p.553

Artificial spin ice is a class of lithographically created arrays of interacting ferromagnetic nanometre-scale islands. It was introduced to investigate many-body phenomena related to frustration and disorder in a material that could be tailored to precise specifications and imaged directly. Because of the large magnetic energy scales of these nanoscale islands, it has so far been impossible to thermally anneal artificial spin ice into desired thermodynamic ensembles; nearly all studies of artificial spin ice have either treated it as a granular material activated by alternating fields or focused on the as-grown state of the arrays. This limitation has prevented experimental investigation of novel phases that can emerge from the nominal ground states of frustrated lattices. For example, artificial kagome spin ice, in which the islands are arranged on the edges of a hexagonal net, is predicted to support states with monopolar charge order at entropies below that of the previously observed pseudo-ice manifold. Here we demonstrate a method for thermalizing artificial spin ices with square and kagome lattices by heating above the Curie temperature of the constituent material. In this manner, artificial square spin ice achieves unprecedented thermal ordering of the moments. In artificial kagome spin ice, we observe incipient crystallization of the magnetic charges embedded in pseudo-ice, with crystallites of magnetic charges whose size can be controlled by tuning the lattice constant. We find excellent agreement between experimental data and Monte Carlo simulations of emergent charge–charge interactions.

doi: 10.1038/nature12399

Late Miocene threshold response of marine algae to carbon dioxide limitation p.558

Coccolithophores are marine algae that use carbon for calcification and photosynthesis. The long-term adaptation of these and other marine algae to decreasing carbon dioxide levels during the Cenozoic era has resulted in modern algae capable of actively enhancing carbon dioxide at the site of photosynthesis. This enhancement occurs through the transport of dissolved bicarbonate (HCO₃−) and with the help of enzymes whose expression can be modulated by variable aqueous carbon dioxide concentration, [CO₂], in laboratory cultures. Coccolithophores preserve the geological history of this adaptation because the stable carbon and oxygen isotopic compositions of their calcite plates (coccoliths), which are preserved in the fossil record, are sensitive to active carbon uptake and transport by the cell. Here we use a model of cellular carbon fluxes and show that at low [CO₂] the increased demand for HCO₃− at the site of photosynthesis results in a diminished allocation of HCO₃− to calcification, which is most pronounced in larger cells. This results in a large divergence between the carbon isotopic compositions of small versus large coccoliths only at low [CO₂]. Our evaluation of the oxygen and carbon isotope record of size-separated fossil coccoliths reveals that this isotopic divergence first arose during the late Miocene to the earliest Pliocene epoch (about 7–5 million years ago). We interpret this to be a threshold response of the cells’ carbon acquisition strategies to decreasing [CO₂]. The documented coccolithophore response is synchronous with a global shift in terrestrial vegetation distribution between 8 and 5 Myr ago, which has been interpreted by some studies as a floral response to decreasing partial pressures of carbon dioxide () in the atmosphere. We infer a global decrease in carbon dioxide levels for this time interval that has not yet been identified in the sparse proxy record but is synchronous with global cooling and progressive glaciations.

doi: 10.1038/nature12448

Rapid, climate-driven changes in outlet glaciers on the Pacific coast of East Antarctica p.563

Observations of ocean-terminating outlet glaciers in Greenland and West Antarctica indicate that their contribution to sea level is accelerating as a result of increased velocity, thinning and retreat. Thinning has also been reported along the margin of the much larger East Antarctic ice sheet, but whether glaciers are advancing or retreating there is largely unknown, and there has been no attempt to place such changes in the context of localized mass loss or climatic or oceanic forcing. Here we present multidecadal trends in the terminus position of 175 ocean-terminating outlet glaciers along 5,400 kilometres of the margin of the East Antarctic ice sheet, and reveal widespread and synchronous changes. Despite large fluctuations between glaciers—linked to their size—three epochal patterns emerged: 63 per cent of glaciers retreated from 1974 to 1990, 72 per cent advanced from 1990 to 2000, and 58 per cent advanced from 2000 to 2010. These trends were most pronounced along the warmer western South Pacific coast, whereas glaciers along the cooler Ross Sea coast experienced no significant changes. We find that glacier change along the Pacific coast is consistent with a rapid and coherent response to air temperature and sea-ice trends, linked through the dominant mode of atmospheric variability (the Southern Annular Mode). We conclude that parts of the world’s largest ice sheet may be more vulnerable to external forcing than recognized previously.

doi: 10.1038/nature12382

Anaerobic oxidation of methane coupled to nitrate reduction in a novel archaeal lineage p.567

Anaerobic oxidation of methane (AOM) is critical for controlling the flux of methane from anoxic environments. AOM coupled to iron, manganese and sulphate reduction have been demonstrated in consortia containing anaerobic methanotrophic (ANME) archaea. More recently it has been shown that the bacterium Candidatus ‘Methylomirabilis oxyfera’ can couple AOM to nitrite reduction through an intra-aerobic methane oxidation pathway. Bioreactors capable of AOM coupled to denitrification have resulted in the enrichment of ‘M. oxyfera’ and a novel ANME lineage, ANME-2d. However, as ‘M. oxyfera’ can independently couple AOM to denitrification, the role of ANME-2d in the process is unresolved. Here, a bioreactor fed with nitrate, ammonium and methane was dominated by a single ANME-2d population performing nitrate-driven AOM. Metagenomic, single-cell genomic and metatranscriptomic analyses combined with bioreactor performance and 13C- and 15N-labelling experiments show that ANME-2d is capable of independent AOM through reverse methanogenesis using nitrate as the terminal electron acceptor. Comparative analyses reveal that the genes for nitrate reduction were transferred laterally from a bacterial donor, suggesting selection for this novel process within ANME-2d. Nitrite produced by ANME-2d is reduced to dinitrogen gas through a syntrophic relationship with an anaerobic ammonium-oxidizing bacterium, effectively outcompeting ‘M. oxyfera’ in the system. We propose the name Candidatus ‘Methanoperedens nitroreducens’ for the ANME-2d population and the family Candidatus ‘Methanoperedenaceae’ for the ANME-2d lineage. We predict that ‘M. nitroreducens’ and other members of the ‘Methanoperedenaceae’ have an important role in linking the global carbon and nitrogen cycles in anoxic environments.

doi: 10.1038/nature12375

Pervasive genetic hitchhiking and clonal interference in forty evolving yeast populations p.571

The dynamics of adaptation determine which mutations fix in a population, and hence how reproducible evolution will be. This is central to understanding the spectra of mutations recovered in the evolution of antibiotic resistance, the response of pathogens to immune selection, and the dynamics of cancer progression. In laboratory evolution experiments, demonstrably beneficial mutations are found repeatedly, but are often accompanied by other mutations with no obvious benefit. Here we use whole-genome whole-population sequencing to examine the dynamics of genome sequence evolution at high temporal resolution in 40 replicate Saccharomyces cerevisiae populations growing in rich medium for 1,000 generations. We find pervasive genetic hitchhiking: multiple mutations arise and move synchronously through the population as mutational ‘cohorts’. Multiple clonal cohorts are often present simultaneously, competing with each other in the same population. Our results show that patterns of sequence evolution are driven by a balance between these chance effects of hitchhiking and interference, which increase stochastic variation in evolutionary outcomes, and the deterministic action of selection on individual mutations, which favours parallel evolutionary solutions in replicate populations.

doi: 10.1038/nature12344

Prolonged dopamine signalling in striatum signals proximity and value of distant rewards p.575

Predictions about future rewarding events have a powerful influence on behaviour. The phasic spike activity of dopamine-containing neurons, and corresponding dopamine transients in the striatum, are thought to underlie these predictions, encoding positive and negative reward prediction errors. However, many behaviours are directed towards distant goals, for which transient signals may fail to provide sustained drive. Here we report an extended mode of reward-predictive dopamine signalling in the striatum that emerged as rats moved towards distant goals. These dopamine signals, which were detected with fast-scan cyclic voltammetry (FSCV), gradually increased or—in rare instances—decreased as the animals navigated mazes to reach remote rewards, rather than having phasic or steady tonic profiles. These dopamine increases (ramps) scaled flexibly with both the distance and size of the rewards. During learning, these dopamine signals showed spatial preferences for goals in different locations and readily changed in magnitude to reflect changing values of the distant rewards. Such prolonged dopamine signalling could provide sustained motivational drive, a control mechanism that may be important for normal behaviour and that can be impaired in a range of neurologic and neuropsychiatric disorders.

doi: 10.1038/nature12475

A gustatory receptor paralogue controls rapid warmth avoidance in Drosophila p.580

Behavioural responses to temperature are critical for survival, and animals from insects to humans show strong preferences for specific temperatures. Preferred temperature selection promotes avoidance of adverse thermal environments in the short term and maintenance of optimal body temperatures over the long term, but its molecular and cellular basis is largely unknown. Recent studies have generated conflicting views of thermal preference in Drosophila, attributing importance to either internal or peripheral warmth sensors. Here we reconcile these views by showing that thermal preference is not a singular response, but involves multiple systems relevant in different contexts. We found previously that the transient receptor potential channel TRPA1 acts internally to control the slowly developing preference response of flies exposed to a shallow thermal gradient. We now find that the rapid response of flies exposed to a steep warmth gradient does not require TRPA1; rather, the gustatory receptor GR28B(D) drives this behaviour through peripheral thermosensors. Gustatory receptors are a large gene family, widely studied in insect gustation and olfaction, and are implicated in host-seeking by insect disease vectors, but have not previously been implicated in thermosensation. At the molecular level, GR28B(D) misexpression confers thermosensitivity upon diverse cell types, suggesting that it is a warmth sensor. These data reveal a new type of thermosensory molecule and uncover a functional distinction between peripheral and internal warmth sensors in this tiny ectotherm reminiscent of thermoregulatory systems in larger, endothermic animals. The use of multiple, distinct molecules to respond to a given temperature, as observed here, may facilitate independent tuning of an animal’s distinct thermosensory responses.

doi: 10.1038/nature12390

Dietary intervention impact on gut microbial gene richness p.585

Complex gene–environment interactions are considered important in the development of obesity. The composition of the gut microbiota can determine the efficacy of energy harvest from food and changes in dietary composition have been associated with changes in the composition of gut microbial populations. The capacity to explore microbiota composition was markedly improved by the development of metagenomic approaches, which have already allowed production of the first human gut microbial gene catalogue and stratifying individuals by their gut genomic profile into different enterotypes, but the analyses were carried out mainly in non-intervention settings. To investigate the temporal relationships between food intake, gut microbiota and metabolic and inflammatory phenotypes, we conducted diet-induced weight-loss and weight-stabilization interventions in a study sample of 38 obese and 11 overweight individuals. Here we report that individuals with reduced microbial gene richness (40%) present more pronounced dys-metabolism and low-grade inflammation, as observed concomitantly in the accompanying paper. Dietary intervention improves low gene richness and clinical phenotypes, but seems to be less efficient for inflammation variables in individuals with lower gene richness. Low gene richness may therefore have predictive potential for the efficacy of intervention.

doi: 10.1038/nature12480

Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor p.589

Co-development of the cardiovascular and pulmonary systems is a recent evolutionary adaption to terrestrial life that couples cardiac output with the gas exchange function of the lung. Here we show that the murine pulmonary vasculature develops even in the absence of lung development. We have identified a population of multipotent cardiopulmonary mesoderm progenitors (CPPs) within the posterior pole of the heart that are marked by the expression of Wnt2, Gli1 and Isl1. We show that CPPs arise from cardiac progenitors before lung development. Lineage tracing and clonal analysis demonstrates that CPPs generate the mesoderm lineages within the cardiac inflow tract and lung including cardiomyocytes, pulmonary vascular and airway smooth muscle, proximal vascular endothelium, and pericyte-like cells. CPPs are regulated by hedgehog expression from the foregut endoderm, which is required for connection of the pulmonary vasculature to the heart. Together, these studies identify a novel population of multipotent cardiopulmonary progenitors that coordinates heart and lung co-development that is required for adaptation to terrestrial existence.

doi: 10.1038/nature12358

Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing p.593

Mammalian pre-implantation development is a complex process involving dramatic changes in the transcriptional architecture. We report here a comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos, using single-cell RNA sequencing. Based on single-nucleotide variants in human blastomere messenger RNAs and paternal-specific single-nucleotide polymorphisms, we identify novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). By weighted gene co-expression network analysis, we find that each developmental stage can be delineated concisely by a small number of functional modules of co-expressed genes. This result indicates a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism, acting in a step-wise fashion from cleavage to morula. Cross-species comparisons with mouse pre-implantation embryos reveal that the majority of human stage-specific modules (7 out of 9) are notably preserved, but developmental specificity and timing differ between human and mouse. Furthermore, we identify conserved key members (or hub genes) of the human and mouse networks. These genes represent novel candidates that are likely to be key in driving mammalian pre-implantation development. Together, the results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos.

doi: 10.1038/nature12364

lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs p.598

Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In ‘resistant’ prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours.

doi: 10.1038/nature12451

Mitotic trigger waves and the spatial coordination of the Xenopus cell cycle p.603

Despite the large size of the Xenopus laevis egg (approximately 1.2 mm diameter), a fertilized egg rapidly proceeds through mitosis in a spatially coordinated fashion. Mitosis is initiated by a bistable system of regulatory proteins centred on Cdk1 (refs 1, 2), raising the possibility that this spatial coordination could be achieved through trigger waves of Cdk1 activity. Using an extract system that performs cell cycles in vitro, here we show that mitosis does spread through Xenopus cytoplasm via trigger waves, propagating at a linear speed of approximately 60 µm min−1. Perturbing the feedback loops that give rise to the bistability of Cdk1 changes the speed and dynamics of the waves. Time-lapse imaging of intact eggs argues that trigger waves of Cdk1 activation are responsible for surface contraction waves, ripples in the cell cortex that precede cytokinesis. These findings indicate that Cdk1 trigger waves help ensure the spatiotemporal coordination of mitosis in large eggs. Trigger waves may be an important general mechanism for coordinating biochemical events over large distances.

doi: 10.1038/nature12321

Avoiding chromosome pathology when replication forks collide p.608

Chromosome duplication normally initiates through the assembly of replication fork complexes at defined origins. DNA synthesis by any one fork is thought to cease when it meets another travelling in the opposite direction, at which stage the replication machinery may simply dissociate before the nascent strands are finally ligated. But what actually happens is not clear. Here we present evidence consistent with the idea that every fork collision has the potential to threaten genomic integrity. In Escherichia coli this threat is kept at bay by RecG DNA translocase and by single-strand DNA exonucleases. Without RecG, replication initiates where forks meet through a replisome assembly mechanism normally associated with fork repair, replication restart and recombination, establishing new forks with the potential to sustain cell growth and division without an active origin. This potential is realized when roadblocks to fork progression are reduced or eliminated. It relies on the chromosome being circular, reinforcing the idea that replication initiation is triggered repeatedly by fork collision. The results reported raise the question of whether replication fork collisions have pathogenic potential for organisms that exploit several origins to replicate each chromosome.

doi: 10.1038/nature12312