Volume 497 Number 7449
Science in schools p.287
The US National Center for Science Education teaches researchers how to fight for their cause.
Privacy in the digital age p.287
The proposed European Data Protection Regulation will rightly preserve people’s privacy — but, without exceptions for scientific research, it could hinder or prevent medical discoveries.
Together we stand p.288
To reach a sustainable future, we must merge economic and environmental agendas.
Human stem cells created by cloning p.295
Breakthrough sets up showdown with induced adult lines.
Magnetar found at giant black hole p.296
Magnetized neutron star could test Einstein’s theory.
Chinese project probes the genetics of genius p.297
Bid to unravel the secrets of brainpower faces scepticism.
Hawking decision fuels Israel debate p.299
Physicist’s stance a ‘turning point’, claim supporters.
Meeting targets lab lapses p.300
Attendees search for ways to tackle misconduct and sloppy science.
Neanderthal culture: Old masters p.302
Invasive species: The 18-km2 rat trap p.306
News & Views
Fisheries: Climate change at the dinner table p.320
Microbiology: Bacterial communities as capitalist economies p.321
Planetary science: Plumbing the depths of Uranus and Neptune p.323
Metallurgy: Iron production electrified p.324
Evolution: Stuck between the teeth p.325
Inferring ancient divergences requires genes with strong phylogenetic signals p.327
Determining major branches in the tree of life generally relies on concatenating as much genetic information as possible, but, as shown here, phylogenomic analysis often produces results that are incongruent with the results of concatenation; a method that gives credence to genes or internodes with high average internode support reduces the incongruence.
Structural and molecular interrogation of intact biological systems p.332
High-resolution imaging has traditionally required thin sectioning, a process that disrupts long-range connectivity in the case of brains: here, intact mouse brains and human brain samples have been made fully transparent and macromolecule permeable using a new method termed CLARITY, which allows for intact-tissue imaging as well as repeated antibody labelling and in situ hybridization of non-sectioned tissue.
Structure of the human smoothened receptor bound to an antitumour agent p.338
The crystal structure of the human smoothened (SMO) receptor is presented in complex with a small-molecule antitumour agent; this represents the first example of a non-class-A, 7-transmembrane (7TM) receptor structure, revealing different conserved motifs common within class frizzled 7TM receptors and an unusually complex arrangement of long extracellular loops stabilized by disulphide bonds.
Atmospheric confinement of jet streams on Uranus and Neptune p.344
The observed cloud-level atmospheric circulation on the outer planets of the Solar System is dominated by strong east–west jet streams. The depth of these winds is a crucial unknown in constraining their overall dynamics, energetics and internal structures. There are two approaches to explaining the existence of these strong winds. The first suggests that the jets are driven by shallow atmospheric processes near the surface, whereas the second suggests that the atmospheric dynamics extend deeply into the planetary interiors. Here we report that on Uranus and Neptune the depth of the atmospheric dynamics can be revealed by the planets’ respective gravity fields. We show that the measured fourth-order gravity harmonic, J4, constrains the dynamics to the outermost 0.15 per cent of the total mass of Uranus and the outermost 0.2 per cent of the total mass of Neptune. This provides a stronger limit to the depth of the dynamical atmosphere than previously suggested, and shows that the dynamics are confined to a thin weather layer no more than about 1,000 kilometres deep on both planets.
An electrically pumped polariton laser p.348
Conventional semiconductor laser emission relies on stimulated emission of photons, which sets stringent requirements on the minimum amount of energy necessary for its operation. In comparison, exciton–polaritons in strongly coupled quantum well microcavities can undergo stimulated scattering that promises more energy-efficient generation of coherent light by ‘polariton lasers’. Polariton laser operation has been demonstrated in optically pumped semiconductor microcavities at temperatures up to room temperature, and such lasers can outperform their weak-coupling counterparts in that they have a lower threshold density. Even though polariton diodes have been realized, electrically pumped polariton laser operation, which is essential for practical applications, has not been achieved until now. Here we present an electrically pumped polariton laser based on a microcavity containing multiple quantum wells. To prove polariton laser emission unambiguously, we apply a magnetic field and probe the hybrid light–matter nature of the polaritons. Our results represent an important step towards the practical implementation of polaritonic light sources and electrically injected condensates, and can be extended to room-temperature operation using wide-bandgap materials.
A new anode material for oxygen evolution in molten oxide electrolysis p.353
Molten oxide electrolysis (MOE) is an electrometallurgical technique that enables the direct production of metal in the liquid state from oxide feedstock, and compared with traditional methods of extractive metallurgy offers both a substantial simplification of the process and a significant reduction in energy consumption. MOE is also considered a promising route for mitigation of CO2 emissions in steelmaking, production of metals free of carbon, and generation of oxygen for extra-terrestrial exploration. Until now, MOE has been demonstrated using anode materials that are consumable (graphite for use with ferro-alloys and titanium) or unaffordable for terrestrial applications (iridium for use with iron). To enable metal production without process carbon, MOE requires an anode material that resists depletion while sustaining oxygen evolution. The challenges for iron production are threefold. First, the process temperature is in excess of 1,538 degrees Celsius (ref. 10). Second, under anodic polarization most metals inevitably corrode in such conditions. Third, iron oxide undergoes spontaneous reduction on contact with most refractory metals and even carbon. Here we show that anodes comprising chromium-based alloys exhibit limited consumption during iron extraction and oxygen evolution by MOE. The anode stability is due to the formation of an electronically conductive solid solution of chromium(iii) and aluminium oxides in the corundum structure. These findings make practicable larger-scale evaluation of MOE for the production of steel, and potentially provide a key material component enabling mitigation of greenhouse-gas emissions while producing metal of superior metallurgical quality.
Deep fracture fluids isolated in the crust since the Precambrian era p.357
Fluids trapped as inclusions within minerals can be billions of years old and preserve a record of the fluid chemistry and environment at the time of mineralization. Aqueous fluids that have had a similar residence time at mineral interfaces and in fractures (fracture fluids) have not been previously identified. Expulsion of fracture fluids from basement systems with low connectivity occurs through deformation and fracturing of the brittle crust. The fractal nature of this process must, at some scale, preserve pockets of interconnected fluid from the earliest crustal history. In one such system, 2.8 kilometres below the surface in a South African gold mine, extant chemoautotrophic microbes have been identified in fluids isolated from the photosphere on timescales of tens of millions of years. Deep fracture fluids with similar chemistry have been found in a mine in the Timmins, Ontario, area of the Canadian Precambrian Shield. Here we show that excesses of 124Xe, 126Xe and 128Xe in the Timmins mine fluids can be linked to xenon isotope changes in the ancient atmosphere and used to calculate a minimum mean residence time for this fluid of about 1.5 billion years. Further evidence of an ancient fluid system is found in 129Xe excesses that, owing to the absence of any identifiable mantle input, are probably sourced in sediments and extracted by fluid migration processes operating during or shortly after mineralization at around 2.64 billion years ago. We also provide closed-system radiogenic noble-gas (4He, 21Ne, 40Ar, 136Xe) residence times. Together, the different noble gases show that ancient pockets of water can survive the crustal fracturing process and remain in the crust for billions of years.
Adaptive dynamics under development-based genotype–phenotype maps p.361
It is not known whether natural selection can encounter any given phenotype that can be produced by genetic variation. There has been a long-lasting debate about the processes that limit adaptation and, consequently, about how well adapted phenotypes are. Here we examine how development may affect adaptation, by decomposing the genotype–fitness map—the association between each genotype and its fitness—into two: one mapping genotype to phenotype by means of a computational model of organ development, and one mapping phenotype to fitness. In the map of phenotype and fitness, the fitness of each individual is based on the similarity between realized morphology and optimal morphology. We use three different simulations to map phenotype to fitness, and these differ in the way in which similarity is calculated: similarity is calculated for each trait (in terms of each cell position individually), for a large or a small number of phenotypic landmarks (the ‘many-traits’ and ‘few-traits’ phenotype–fitness maps), and by measuring the overall surface roughness of morphology (the ‘roughness’ phenotype–fitness map). Evolution is simulated by applying the genotype–phenotype map and one phenotype–fitness map to each individual in the population, as well as random mutation and drift. We show that the complexity of the genotype–phenotype map prevents substantial adaptation in some of the phenotype–fitness maps: sustained adaptation is only possible using ‘roughness’ or ‘few-traits’ phenotype–fitness maps. The results contribute developmental understanding to the long-standing question of which aspects of phenotype can be effectively optimized by natural selection.
Signature of ocean warming in global fisheries catch p.365
Marine fishes and invertebrates respond to ocean warming through distribution shifts, generally to higher latitudes and deeper waters. Consequently, fisheries should be affected by ‘tropicalization’ of catch (increasing dominance of warm-water species). However, a signature of such climate-change effects on global fisheries catch has so far not been detected. Here we report such an index, the mean temperature of the catch (MTC), that is calculated from the average inferred temperature preference of exploited species weighted by their annual catch. Our results show that, after accounting for the effects of fishing and large-scale oceanographic variability, global MTC increased at a rate of 0.19 degrees Celsius per decade between 1970 and 2006, and non-tropical MTC increased at a rate of 0.23 degrees Celsius per decade. In tropical areas, MTC increased initially because of the reduction in the proportion of subtropical species catches, but subsequently stabilized as scope for further tropicalization of communities became limited. Changes in MTC in 52 large marine ecosystems, covering the majority of the world’s coastal and shelf areas, are significantly and positively related to regional changes in sea surface temperature. This study shows that ocean warming has already affected global fisheries in the past four decades, highlighting the immediate need to develop adaptation plans to minimize the effect of such warming on the economy and food security of coastal communities, particularly in tropical regions.
Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4 p.369
Postnatal/adult neural stem cells (NSCs) within the rodent subventricular zone (SVZ; also called subependymal zone) generate doublecortin (Dcx)+ neuroblasts that migrate and integrate into olfactory bulb circuitry. Continuous production of neuroblasts is controlled by the SVZ microenvironmental niche. It is generally thought that enhancing the neurogenic activities of endogenous NSCs may provide needed therapeutic options for disease states and after brain injury. However, SVZ NSCs can also differentiate into astrocytes. It remains unclear whether there are conditions that favour astrogenesis over neurogenesis in the SVZ niche, and whether astrocytes produced there have different properties compared with astrocytes produced elsewhere in the brain. Here we show in mice that SVZ-generated astrocytes express high levels of thrombospondin 4 (Thbs4), a secreted homopentameric glycoprotein, in contrast to cortical astrocytes, which express low levels of Thbs4. We found that localized photothrombotic/ischaemic cortical injury initiates a marked increase in Thbs4hi astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-creERtm4 lineage tracing demonstrated that it is these SVZ-generated Thbs4hi astrocytes, and not Dcx+ neuroblasts, that home-in on the injured cortex. This robust post-injury astrogenic response required SVZ Notch activation modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to activate downstream signals, including increased Nfia transcription factor expression important for glia production. Consequently, Thbs4 homozygous knockout mice (Thbs4KO/KO) showed severe defects in cortical-injury-induced SVZ astrogenesis, instead producing cells expressing Dcx migrating from SVZ to the injury sites. These alterations in cellular responses resulted in abnormal glial scar formation after injury, and significantly increased microvascular haemorrhage into the brain parenchyma of Thbs4KO/KO mice. Taken together, these findings have important implications for post-injury applications of endogenous and transplanted NSCs in the therapeutic setting, as well as disease states where Thbs family members have important roles.
X-ray phase-contrast in vivo microtomography probes new aspects of Xenopus gastrulation p.374
An ambitious goal in biology is to understand the behaviour of cells during development by imaging—in vivo and with subcellular resolution—changes of the embryonic structure. Important morphogenetic movements occur throughout embryogenesis, but in particular during gastrulation when a series of dramatic, coordinated cell movements drives the reorganization of a simple ball or sheet of cells into a complex multi-layered organism. In Xenopus laevis, the South African clawed frog and also in zebrafish, cell and tissue movements have been studied in explants, in fixed embryos, in vivo using fluorescence microscopy or microscopic magnetic resonance imaging. None of these methods allows cell behaviours to be observed with micrometre-scale resolution throughout the optically opaque, living embryo over developmental time. Here we use non-invasive in vivo, time-lapse X-ray microtomography, based on single-distance phase contrast and combined with motion analysis, to examine the course of embryonic development. We demonstrate that this powerful four-dimensional imaging technique provides high-resolution views of gastrulation processes in wild-type X. laevis embryos, including vegetal endoderm rotation, archenteron formation, changes in the volumes of cavities within the porous interstitial tissue between archenteron and blastocoel, migration/confrontation of mesendoderm and closure of the blastopore. Differential flow analysis separates collective from relative cell motion to assign propulsion mechanisms. Moreover, digitally determined volume balances confirm that early archenteron inflation occurs through the uptake of external water. A transient ectodermal ridge, formed in association with the confrontation of ventral and head mesendoderm on the blastocoel roof, is identified. When combined with perturbation experiments to investigate molecular and biomechanical underpinnings of morphogenesis, our technique should help to advance our understanding of the fundamentals of development.
The shaping and functional consequences of the microRNA landscape in breast cancer p.378
MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1,302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture, suggesting an important role for post-transcriptional regulation. The key clinical parameters and cellular pathways related to the miRNA landscape are characterized, revealing context-dependent interactions, for example with regards to cell adhesion and Wnt signalling. Notably, only prognostic miRNA signatures derived from breast tumours devoid of somatic copy-number aberrations (CNA-devoid) are consistently prognostic across several other subtypes and can be validated in external cohorts. We then use a data-driven approach to seek the effects of miRNAs associated with differential co-expression of mRNAs, and find that miRNAs act as modulators of mRNA–mRNA interactions rather than as on–off molecular switches. We demonstrate such an important modulatory role for miRNAs in the biology of CNA-devoid breast cancers, a common subtype in which the immune response is prominent. These findings represent a new framework for studying the biology of miRNAs in human breast cancer.
EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2 p.383
MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at the post-transcriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in the regulation of cellular response to a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumour. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumour cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here we show that epidermal growth factor receptor (EGFR), which is the product of a well-characterized oncogene in human cancers, suppresses the maturation of specific tumour-suppressor-like miRNAs in response to hypoxic stress through phosphorylation of argonaute 2 (AGO2) at Tyr 393. The association between EGFR and AGO2 is enhanced by hypoxia, leading to elevated AGO2-Y393 phosphorylation, which in turn reduces the binding of Dicer to AGO2 and inhibits miRNA processing from precursor miRNAs to mature miRNAs. We also identify a long-loop structure in precursor miRNAs as a critical regulatory element in phospho-Y393-AGO2-mediated miRNA maturation. Furthermore, AGO2-Y393 phosphorylation mediates EGFR-enhanced cell survival and invasiveness under hypoxia, and correlates with poorer overall survival in breast cancer patients. Our study reveals a previously unrecognized function of EGFR in miRNA maturation and demonstrates how EGFR is likely to function as a regulator of AGO2 through novel post-translational modification. These findings suggest that modulation of miRNA biogenesis is important for stress response in tumour cells and has potential clinical implications.
Psl trails guide exploration and microcolony formation in Pseudomonas aeruginosa biofilms p.388
Bacterial biofilms are surface-associated, multicellular, morphologically complex microbial communities. Biofilm-forming bacteria such as the opportunistic pathogen Pseudomonas aeruginosa are phenotypically distinct from their free-swimming, planktonic counterparts. Much work has focused on factors affecting surface adhesion, and it is known that P. aeruginosa secretes the Psl exopolysaccharide, which promotes surface attachment by acting as ‘molecular glue’. However, how individual surface-attached bacteria self-organize into microcolonies, the first step in communal biofilm organization, is not well understood. Here we identify a new role for Psl in early biofilm development using a massively parallel cell-tracking algorithm to extract the motility history of every cell on a newly colonized surface. By combining this technique with fluorescent Psl staining and computer simulations, we show that P. aeruginosa deposits a trail of Psl as it moves on a surface, which influences the surface motility of subsequent cells that encounter these trails and thus generates positive feedback. Both experiments and simulations indicate that the web of secreted Psl controls the distribution of surface visit frequencies, which can be approximated by a power law. This Pareto-type behaviour indicates that the bacterial community self-organizes in a manner analogous to a capitalist economic system, a ‘rich-get-richer’ mechanism of Psl accumulation that results in a small number of ‘elite’ cells becoming extremely enriched in communally produced Psl. Using engineered strains with inducible Psl production, we show that local Psl concentrations determine post-division cell fates and that high local Psl concentrations ultimately allow elite cells to serve as the founding population for initial microcolony development.
Receptor binding by a ferret-transmissible H5 avian influenza virus p.392
Cell-surface-receptor binding by influenza viruses is a key determinant of their transmissibility, both from avian and animal species to humans as well as from human to human. Highly pathogenic avian H5N1 viruses that are a threat to public health have been observed to acquire affinity for human receptors, and transmissible-mutant-selection experiments have identified a virus that is transmissible in ferrets, the generally accepted experimental model for influenza in humans. Here, our quantitative biophysical measurements of the receptor-binding properties of haemagglutinin (HA) from the transmissible mutant indicate a small increase in affinity for human receptor and a marked decrease in affinity for avian receptor. From analysis of virus and HA binding data we have derived an algorithm that predicts virus avidity from the affinity of individual HA–receptor interactions. It reveals that the transmissible-mutant virus has a 200-fold preference for binding human over avian receptors. The crystal structure of the transmissible-mutant HA in complex with receptor analogues shows that it has acquired the ability to bind human receptor in the same folded-back conformation as seen for HA from the 1918, 1957 (ref. 4), 1968 (ref. 5) and 2009 (ref. 6) pandemic viruses. This binding mode is substantially different from that by which non-transmissible wild-type H5 virus HA binds human receptor. The structure of the complex also explains how the change in preference from avian to human receptors arises from the Gln226Leu substitution, which facilitates binding to human receptor but restricts binding to avian receptor. Both features probably contribute to the acquisition of transmissibility by this mutant virus.