Volume 502 Number 7470
Mind how you go p.141
The protracted battle to find cures for psychiatric illnesses is changing course, but prejudice and stigma against those with poor mental health remain a problem.
Closed question p.141
The US shutdown is damaging science, and Congress must be called to account.
Launch of an online data journal p.142
Cell transport carries off Nobel p.149
Medicine prize goes to discoverers of vesicle system that shuttles biomolecules around cells.
Higgs theorists amass physics prize p.150
François Englert and Peter Higgs rewarded with Nobel 50 years after hunt for boson began.
Congo carbon plan kicks off p.151
Democratic Republic of the Congo maps forest biomass to attract carbon credits.
Researchers split over NSA hacking p.152
Cryptographers condemn US National Security Agency’s tapping and tampering, but mathematicians shrug.
Novartis reboots brain division p.153
After years in the doldrums, research into neurological disorders is about to undergo a major change of direction.
Secrets of trial data revealed p.154
Records of side effects seen in clinical tests are missing from publicly available documents.
Neuroscience: Through the eyes of a mouse p.156
Some brain researchers are increasingly using mice to study visual processing, but others fear the move is short-sighted.
Amazon ecology: Footprints in the forest p.160
Researchers are tracking just how much impact ancient peoples had on the Amazon.
News & Views
Earth science: The timing of climate change p.174
Palaeontology: A jaw-dropping fossil fish p.175
Quantum physics: Watching the wavefunction collapse p.177
Microbiology: RNAs at fever pitch p.178
Cell biology: Molecular clearance at the cell's antenna p.180
Metabolic syndrome: F stands for fructose and fat p.181
The projected timing of climate departure from recent variability p.183
An ensemble of simulations indicates that ongoing climate change will exceed the bounds of historical climate variability some time in the mid to late twenty-first century and that the burden of rapid climate adaption will occur earliest in highly biodiverse and often economically challenged tropical areas.
A Silurian placoderm with osteichthyan-like marginal jaw bones p.188
Although the origin of jaws is one of the key episodes in the evolution of vertebrates, the jaw bones of modern bony fishes and limbed vertebrates differ so much from those in any other groups that the individual evolutionary steps in the transition are still unknown; here Entelognathus is described, an early placoderm fish with full body armour, but with marginal jaw bones similar to those of modern bony fishes and limbed vertebrates.
Functional interaction between autophagy and ciliogenesis p.194
The primary cilium is a microtubule-based organelle that functions in sensory and signal transduction; here the authors show that the primary cilium is required for activation of starvation-induced autophagy and that basal autophagy negatively regulates ciliogenesis.
Crystal structure of a Na+-bound Na+,K+-ATPase preceding the E1P state p.201
X-ray crystal structures of Na+,K+-ATPase in a transition state that precedes the phosphorylated intermediate are described, showing how this ATPase functions as a Na+-specific pump.
Evidence for a new nuclear ‘magic number’ from the level structure of 54Ca p.207
Atomic nuclei are finite quantum systems composed of two distinct types of fermion—protons and neutrons. In a manner similar to that of electrons orbiting in an atom, protons and neutrons in a nucleus form shell structures. In the case of stable, naturally occurring nuclei, large energy gaps exist between shells that fill completely when the proton or neutron number is equal to 2, 8, 20, 28, 50, 82 or 126 (ref. 1). Away from stability, however, these so-called ‘magic numbers’ are known to evolve in systems with a large imbalance of protons and neutrons. Although some of the standard shell closures can disappear, new ones are known to appear. Studies aiming to identify and understand such behaviour are of major importance in the field of experimental and theoretical nuclear physics. Here we report a spectroscopic study of the neutron-rich nucleus 54Ca (a bound system composed of 20 protons and 34 neutrons) using proton knockout reactions involving fast radioactive projectiles. The results highlight the doubly magic nature of 54Ca and provide direct experimental evidence for the onset of a sizable subshell closure at neutron number 34 in isotopes far from stability.
Observing single quantum trajectories of a superconducting quantum bit p.211
The length of time that a quantum system can exist in a superposition state is determined by how strongly it interacts with its environment. This interaction entangles the quantum state with the inherent fluctuations of the environment. If these fluctuations are not measured, the environment can be viewed as a source of noise, causing random evolution of the quantum system from an initially pure state into a statistical mixture—a process known as decoherence. However, by accurately measuring the environment in real time, the quantum system can be maintained in a pure state and its time evolution described by a ‘quantum trajectory’ determined by the measurement outcome. Here we use weak measurements to monitor a microwave cavity containing a superconducting quantum bit (qubit), and track the individual quantum trajectories of the system. In this set-up, the environment is dominated by the fluctuations of a single electromagnetic mode of the cavity. Using a near-quantum-limited parametric amplifier, we selectively measure either the phase or the amplitude of the cavity field, and thereby confine trajectories to either the equator or a meridian of the Bloch sphere. We perform quantum state tomography at discrete times along the trajectory to verify that we have faithfully tracked the state of the quantum system as it diffuses on the surface of the Bloch sphere. Our results demonstrate that decoherence can be mitigated by environmental monitoring, and validate the foundation of quantum feedback approaches based on Bayesian statistics. Moreover, our experiments suggest a new means of implementing ‘quantum steering’—the harnessing of action at a distance to manipulate quantum states through measurement.
Quasicrystalline structure formation in a classical crystalline thin-film system p.215
The discovery of quasicrystals—crystalline structures that show order while lacking periodicity—forced a paradigm shift in crystallography. Initially limited to intermetallic systems, the observation of quasicrystalline structures has recently expanded to include ‘soft’ quasicrystals in the fields of colloidal and supermolecular chemistry. Here we report an aperiodic oxide that grows as a two-dimensional quasicrystal on a periodic single-element substrate. On a Pt(111) substrate with 3-fold symmetry, the perovskite barium titanate BaTiO3 forms a high-temperature interface-driven structure with 12-fold symmetry. The building blocks of this dodecagonal structure assemble with the theoretically predicted Stampfli–Gähler tiling having a fundamental length-scale of 0.69 nm. This example of interface-driven formation of ultrathin quasicrystals from a typical periodic perovskite oxide potentially extends the quasicrystal concept to a broader range of materials. In addition, it demonstrates that frustration at the interface between two periodic materials can drive a thin film into an aperiodic quasicrystalline phase, as proposed previously. Such structures might also find use as ultrathin buffer layers for the accommodation of large lattice mismatches in conventional epitaxy.
Bottom-up control of geomagnetic secular variation by the Earth’s inner core p.219
Temporal changes in the Earth’s magnetic field, known as geomagnetic secular variation, occur most prominently at low latitudes in the Atlantic hemisphere (that is, from −90 degrees east to 90 degrees east), whereas in the Pacific hemisphere there is comparatively little activity. This is a consequence of the geographical localization of intense, westward drifting, equatorial magnetic flux patches at the core surface. Despite successes in explaining the morphology of the geomagnetic field, numerical models of the geodynamo have so far failed to account systematically for this striking pattern of geomagnetic secular variation. Here we show that it can be reproduced provided that two mechanisms relying on the inner core are jointly considered. First, gravitational coupling aligns the inner core with the mantle, forcing the flow of liquid metal in the outer core into a giant, westward drifting, sheet-like gyre. The resulting shear concentrates azimuthal magnetic flux at low latitudes close to the core–mantle boundary, where it is expelled by core convection and subsequently transported westward. Second, differential inner-core growth, fastest below Indonesia, causes an asymmetric buoyancy release in the outer core which in turn distorts the gyre, forcing it to become eccentric, in agreement with recent core flow inversions. This bottom-up heterogeneous driving of core convection dominates top-down driving from mantle thermal heterogeneities, and localizes magnetic variations in a longitudinal sector centred beneath the Atlantic, where the eccentric gyre reaches the core surface. To match the observed pattern of geomagnetic secular variation, the solid material forming the inner core must now be in a state of differential growth rather than one of growth and melting induced by convective translation.
Key role of symbiotic dinitrogen fixation in tropical forest secondary succession p.224
Forests contribute a significant portion of the land carbon sink, but their ability to sequester CO2 may be constrained by nitrogen, a major plant-limiting nutrient. Many tropical forests possess tree species capable of fixing atmospheric dinitrogen (N2), but it is unclear whether this functional group can supply the nitrogen needed as forests recover from disturbance or previous land use, or expand in response to rising CO2 (refs 6, 8). Here we identify a powerful feedback mechanism in which N2 fixation can overcome ecosystem-scale deficiencies in nitrogen that emerge during periods of rapid biomass accumulation in tropical forests. Over a 300-year chronosequence in Panama, N2-fixing tree species accumulated carbon up to nine times faster per individual than their non-fixing neighbours (greatest difference in youngest forests), and showed species-specific differences in the amount and timing of fixation. As a result of fast growth and high fixation, fixers provided a large fraction of the nitrogen needed to support net forest growth (50,000 kg carbon per hectare) in the first 12 years. A key element of ecosystem functional diversity was ensured by the presence of different N2-fixing tree species across the entire forest age sequence. These findings show that symbiotic N2 fixation can have a central role in nitrogen cycling during tropical forest stand development, with potentially important implications for the ability of tropical forests to sequester CO2.
Genome-wide signatures of convergent evolution in echolocating mammals OPEN p.228
Evolution is typically thought to proceed through divergence of genes, proteins and ultimately phenotypes. However, similar traits might also evolve convergently in unrelated taxa owing to similar selection pressures. Adaptive phenotypic convergence is widespread in nature, and recent results from several genes have suggested that this phenomenon is powerful enough to also drive recurrent evolution at the sequence level. Where homoplasious substitutions do occur these have long been considered the result of neutral processes. However, recent studies have demonstrated that adaptive convergent sequence evolution can be detected in vertebrates using statistical methods that model parallel evolution, although the extent to which sequence convergence between genera occurs across genomes is unknown. Here we analyse genomic sequence data in mammals that have independently evolved echolocation and show that convergence is not a rare process restricted to several loci but is instead widespread, continuously distributed and commonly driven by natural selection acting on a small number of sites per locus. Systematic analyses of convergent sequence evolution in 805,053 amino acids within 2,326 orthologous coding gene sequences compared across 22 mammals (including four newly sequenced bat genomes) revealed signatures consistent with convergence in nearly 200 loci. Strong and significant support for convergence among bats and the bottlenose dolphin was seen in numerous genes linked to hearing or deafness, consistent with an involvement in echolocation. Unexpectedly, we also found convergence in many genes linked to vision: the convergent signal of many sensory genes was robustly correlated with the strength of natural selection. This first attempt to detect genome-wide convergent sequence evolution across divergent taxa reveals the phenomenon to be much more pervasive than previously recognized.
Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy p.232
The blood system is maintained by a small pool of haematopoietic stem cells (HSCs), which are required and sufficient for replenishing all human blood cell lineages at millions of cells per second throughout life. Megakaryocytes in the bone marrow are responsible for the continuous production of platelets in the blood, crucial for preventing bleeding—a common and life-threatening side effect of many cancer therapies—and major efforts are focused at identifying the most suitable cellular and molecular targets to enhance platelet production after bone marrow transplantation or chemotherapy. Although it has become clear that distinct HSC subsets exist that are stably biased towards the generation of lymphoid or myeloid blood cells, we are yet to learn whether other types of lineage-biased HSC exist or understand their inter-relationships and how differently lineage-biased HSCs are generated and maintained. The functional relevance of notable phenotypic and molecular similarities between megakaryocytes and bone marrow cells with an HSC cell-surface phenotype remains unclear. Here we identify and prospectively isolate a molecularly and functionally distinct mouse HSC subset primed for platelet-specific gene expression, with enhanced propensity for short- and long-term reconstitution of platelets. Maintenance of platelet-biased HSCs crucially depends on thrombopoietin, the primary extrinsic regulator of platelet development. Platelet-primed HSCs also frequently have a long-term myeloid lineage bias, can self-renew and give rise to lymphoid-biased HSCs. These findings show that HSC subtypes can be organized into a cellular hierarchy, with platelet-primed HSCs at the apex. They also demonstrate that molecular and functional priming for platelet development initiates already in a distinct HSC population. The identification of a platelet-primed HSC population should enable the rational design of therapies enhancing platelet output.
Temperature triggers immune evasion by Neisseria meningitidis p.237
Neisseria meningitidis has several strategies to evade complement-mediated killing, and these contribute to its ability to cause septicaemic disease and meningitis. However, the meningococcus is primarily an obligate commensal of the human nasopharynx, and it is unclear why the bacterium has evolved exquisite mechanisms to avoid host immunity. Here we demonstrate that mechanisms of meningococcal immune evasion and resistance against complement increase in response to an increase in ambient temperature. We have identified three independent RNA thermosensors located in the 5′ untranslated regions of genes necessary for capsule biosynthesis, the expression of factor H binding protein, and sialylation of lipopolysaccharide, which are essential for meningococcal resistance against immune killing. Therefore increased temperature (which occurs during inflammation) acts as a ‘danger signal’ for the meningococcus, enhancing its defence against human immune killing. Infection with viral pathogens, such as influenza, leads to inflammation in the nasopharynx with an increased temperature and recruitment of immune effectors. Thermoregulation of immune defence could offer an adaptive advantage to the meningococcus during co-infection with other pathogens, and promote the emergence of virulence in an otherwise commensal bacterium.
The genesis and source of the H7N9 influenza viruses causing human infections in China p.241
A novel H7N9 influenza A virus first detected in March 2013 has since caused more than 130 human infections in China, resulting in 40 deaths. Preliminary analyses suggest that the virus is a reassortant of H7, N9 and H9N2 avian influenza viruses, and carries some amino acids associated with mammalian receptor binding, raising concerns of a new pandemic. However, neither the source populations of the H7N9 outbreak lineage nor the conditions for its genesis are fully known. Using a combination of active surveillance, screening of virus archives, and evolutionary analyses, here we show that H7 viruses probably transferred from domestic duck to chicken populations in China on at least two independent occasions. We show that the H7 viruses subsequently reassorted with enzootic H9N2 viruses to generate the H7N9 outbreak lineage, and a related previously unrecognized H7N7 lineage. The H7N9 outbreak lineage has spread over a large geographic region and is prevalent in chickens at live poultry markets, which are thought to be the immediate source of human infections. Whether the H7N9 outbreak lineage has, or will, become enzootic in China and neighbouring regions requires further investigation. The discovery here of a related H7N7 influenza virus in chickens that has the ability to infect mammals experimentally, suggests that H7 viruses may pose threats beyond the current outbreak. The continuing prevalence of H7 viruses in poultry could lead to the generation of highly pathogenic variants and further sporadic human infections, with a continued risk of the virus acquiring human-to-human transmissibility.
Type 2 innate lymphoid cells control eosinophil homeostasis p.245
Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago, and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins mediate eosinophil development and survival, and tissue recruitment, respectively, the processes underlying the basal regulation of these signals remain unknown. Here we show that serum IL-5 levels are maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 cells secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive, ILC2 cells co-express IL-5 and IL-13; this co-expression is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide also stimulates ILC2 cells through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 cells regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.
Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication p.249
Faithful propagation of DNA methylation patterns during DNA replication is critical for maintaining cellular phenotypes of individual differentiated cells. Although it is well established that Uhrf1 (ubiquitin-like with PHD and ring finger domains 1; also known as Np95 and ICBP90) specifically binds to hemi-methylated DNA through its SRA (SET and RING finger associated) domain and has an essential role in maintenance of DNA methylation by recruiting Dnmt1 to hemi-methylated DNA sites, the mechanism by which Uhrf1 coordinates the maintenance of DNA methylation and DNA replication is largely unknown. Here we show that Uhrf1-dependent histone H3 ubiquitylation has a prerequisite role in the maintenance DNA methylation. Using Xenopus egg extracts, we successfully reproduce maintenance DNA methylation in vitro. Dnmt1 depletion results in a marked accumulation of Uhrf1-dependent ubiquitylation of histone H3 at lysine 23. Dnmt1 preferentially associates with ubiquitylated H3 in vitro though a region previously identified as a replication foci targeting sequence. The RING finger mutant of Uhrf1 fails to recruit Dnmt1 to DNA replication sites and maintain DNA methylation in mammalian cultured cells. Our findings represent the first evidence, to our knowledge, of the mechanistic link between DNA methylation and DNA replication through histone H3 ubiquitylation.
Autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites p.254
The primary cilium is a microtubule-based organelle that functions in sensory and signalling pathways. Defects in ciliogenesis can lead to a group of genetic syndromes known as ciliopathies. However, the regulatory mechanisms of primary ciliogenesis in normal and cancer cells are incompletely understood. Here we demonstrate that autophagic degradation of a ciliopathy protein, OFD1 (oral-facial-digital syndrome 1), at centriolar satellites promotes primary cilium biogenesis. Autophagy is a catabolic pathway in which cytosol, damaged organelles and protein aggregates are engulfed in autophagosomes and delivered to lysosomes for destruction. We show that the population of OFD1 at the centriolar satellites is rapidly degraded by autophagy upon serum starvation. In autophagy-deficient Atg5 or Atg3 null mouse embryonic fibroblasts, OFD1 accumulates at centriolar satellites, leading to fewer and shorter primary cilia and a defective recruitment of BBS4 (Bardet–Biedl syndrome 4) to cilia. These defects are fully rescued by OFD1 partial knockdown that reduces the population of OFD1 at centriolar satellites. More strikingly, OFD1 depletion at centriolar satellites promotes cilia formation in both cycling cells and transformed breast cancer MCF7 cells that normally do not form cilia. This work reveals that removal of OFD1 by autophagy at centriolar satellites represents a general mechanism to promote ciliogenesis in mammalian cells. These findings define a newly recognized role of autophagy in organelle biogenesis.