Volume 506 Number 7487
Suicide watch p.131
Despite a high death toll, public-health efforts to combat suicide lag far behind those focused on preventing accidents and diseases such as cancer. A US initiative aims to redress the balance.
Number crunch p.131
The correct use of statistics is not just good for science — it is essential.
Lone wolves p.132
A declining island wolf population underlines the influence that humans have on nature.
UK rolls out terror-attack plan p.139
Front-line services being trained in new approach to dealing with decontamination of victims in direct aftermath of an event.
Iconic island study on its last legs p.140
Ecologists call for genetic rescue of Isle Royale’s inbred wolves.
Ancient genome stirs ethics debate p.142
Sequencing of DNA from Native American ‘Clovis boy’ forces researchers to rethink handling of tribal remains.
NIH makes wary return to India p.143
Some clinical trials funded by US agency resume, but strict regulations have put off others.
Medicine gets up close and personal p.144
Long-term study will monitor healthy people in detail — and encourage them to respond to the results.
Medication: The smart-pill oversell p.146
Scientific method: Statistical errors p.150
News & Views
Palaeogenomics: Genetic roots of the first Americans p.162
Cosmology: Cool start to hydrogen ionization p.163
Remote sensing: A green illusion p.165
Condensed-matter physics: History matters for a stirred superfluid p.166
Conservation: Making marine protected areas work p.167
Ocean science: Eddy effects on biogeochemistry p.168
Cold dark matter heats up p.171
A principal discovery in modern cosmology is that standard model particles comprise only 5 per cent of the mass-energy budget of the Universe. In the ΛCDM paradigm, the remaining 95 per cent consists of dark energy (Λ) and cold dark matter. ΛCDM is being challenged by its apparent inability to explain the low-density ‘cores’ of dark matter measured at the centre of galaxies, where centrally concentrated high-density ‘cusps’ were predicted. But before drawing conclusions, it is necessary to include the effect of gas and stars, historically seen as passive components of galaxies. We now understand that these can inject heat energy into the cold dark matter through a coupling based on rapid gravitational potential fluctuations, explaining the observed low central densities.
De novo mutations in schizophrenia implicate synaptic networks p.179
The authors report the largest family-trio exome sequencing study of schizophrenia to date; mutations are overrepresented in genes for glutamatergic synaptic proteins and also genes mutated in autism and intellectual disability, providing insights into aetiological mechanisms and pathopshyisology shared with other neurodevelopmental disorders.
A polygenic burden of rare disruptive mutations in schizophrenia p.185
Exome sequence analysis of more than 5,000 schizophrenia cases and controls identifies a polygenic burden primarily arising from rare, disruptive mutations distributed across many genes, among which are those encoding voltage-gated calcium ion channels and the signalling complex formed by the ARC protein of the postsynaptic density; as in autism, mutations were also found in homologues of known targets of the fragile X mental retardation protein.
Molecular control of δ-opioid receptor signalling p.191
The 1.8 Å high-resolution X-ray crystal structure of the human δ-opioid receptor is presented, with site-directed mutagenesis and functional studies revealing a crucial role for a sodium ion in mediating allosteric control in this receptor.
The observable signature of late heating of the Universe during cosmic reionization p.197
Models and simulations of the epoch of reionization predict that spectra of the 21-centimetre transition of atomic hydrogen will show a clear fluctuation peak, at a redshift and scale, respectively, that mark the central stage of reionization and the characteristic size of ionized bubbles. This is based on the assumption that the cosmic gas was heated by stellar remnants—particularly X-ray binaries—to temperatures well above the cosmic microwave background at that time (about 30 kelvin). Here we show instead that the hard spectra (that is, spectra with more high-energy photons than low-energy photons) of X-ray binaries make such heating ineffective, resulting in a delayed and spatially uniform heating that modifies the 21-centimetre signature of reionization. Rather than looking for a simple rise and fall of the large-scale fluctuations (peaking at several millikelvin), we must expect a more complex signal also featuring a distinct minimum (at less than a millikelvin) that marks the rise of the cosmic mean gas temperature above the microwave background. Observing this signal, possibly with radio telescopes in operation today, will demonstrate the presence of a cosmic background of hard X-rays at that early time.
Hysteresis in a quantized superfluid ‘atomtronic’ circuit p.200
Atomtronics is an emerging interdisciplinary field that seeks to develop new functional methods by creating devices and circuits where ultracold atoms, often superfluids, have a role analogous to that of electrons in electronics. Hysteresis is widely used in electronic circuits—it is routinely observed in superconducting circuits and is essential in radio-frequency superconducting quantum interference devices. Furthermore, it is as fundamental to superfluidity (and superconductivity) as quantized persistent currents, critical velocity and Josephson effects. Nevertheless, despite multiple theoretical predictions, hysteresis has not been previously observed in any superfluid, atomic-gas Bose–Einstein condensate. Here we directly detect hysteresis between quantized circulation states in an atomtronic circuit formed from a ring of superfluid Bose–Einstein condensate obstructed by a rotating weak link (a region of low atomic density). This contrasts with previous experiments on superfluid liquid helium where hysteresis was observed directly in systems in which the quantization of flow could not be observed, and indirectly in systems that showed quantized flow. Our techniques allow us to tune the size of the hysteresis loop and to consider the fundamental excitations that accompany hysteresis. The results suggest that the relevant excitations involved in hysteresis are vortices, and indicate that dissipation has an important role in the dynamics. Controlled hysteresis in atomtronic circuits may prove to be a crucial feature for the development of practical devices, just as it has in electronic circuits such as memories, digital noise filters (for example Schmitt triggers) and magnetometers (for example superconducting quantum interference devices).
Quantum error correction in a solid-state hybrid spin register p.204
Error correction is important in classical and quantum computation. Decoherence caused by the inevitable interaction of quantum bits with their environment leads to dephasing or even relaxation. Correction of the concomitant errors is therefore a fundamental requirement for scalable quantum computation. Although algorithms for error correction have been known for some time, experimental realizations are scarce. Here we show quantum error correction in a heterogeneous, solid-state spin system. We demonstrate that joint initialization, projective readout and fast local and non-local gate operations can all be achieved in diamond spin systems, even under ambient conditions. High-fidelity initialization of a whole spin register (99 per cent) and single-shot readout of multiple individual nuclear spins are achieved by using the ancillary electron spin of a nitrogen–vacancy defect. Implementation of a novel non-local gate generic to our electron–nuclear quantum register allows the preparation of entangled states of three nuclear spins, with fidelities exceeding 85 per cent. With these techniques, we demonstrate three-qubit phase-flip error correction. Using optimal control, all of the above operations achieve fidelities approaching those needed for fault-tolerant quantum operation, thus paving the way to large-scale quantum computation. Besides their use with diamond spin systems, our techniques can be used to improve scaling of quantum networks relying on phosphorus in silicon, quantum dots, silicon carbide or rare-earth ions in solids.
Mosaic two-lengthscale quasicrystals p.208
Over the past decade, quasicrystalline order has been observed in many soft-matter systems: in dendritic micelles, in star and tetrablock terpolymer melts and in diblock copolymer and surfactant micelles. The formation of quasicrystals from such a broad range of ‘soft’ macromolecular micelles suggests that they assemble by a generic mechanism rather than being dependent on the specific chemistry of each system. Indeed, micellar softness has been postulated and shown to lead to quasicrystalline order. Here we theoretically explore this link by studying two-dimensional hard disks decorated with step-like square-shoulder repulsion that mimics, for example, the soft alkyl shell around the aromatic core in dendritic micelles. We find a family of quasicrystals with 10-, 12-, 18- and 24-fold bond orientational order which originate from mosaics of equilateral and isosceles triangles formed by particles arranged core-to-core and shoulder-to-shoulder. The pair interaction responsible for these phases highlights the role of local packing geometry in generating quasicrystallinity in soft matter, complementing the principles that lead to quasicrystal formation in hard tetrahedra. Based on simple interparticle potentials, quasicrystalline mosaics may well find use in diverse applications ranging from improved image reproduction to advanced photonic materials.
A two-fold increase of carbon cycle sensitivity to tropical temperature variations p.212
Earth system models project that the tropical land carbon sink will decrease in size in response to an increase in warming and drought during this century, probably causing a positive climate feedback. But available data are too limited at present to test the predicted changes in the tropical carbon balance in response to climate change. Long-term atmospheric carbon dioxide data provide a global record that integrates the interannual variability of the global carbon balance. Multiple lines of evidence demonstrate that most of this variability originates in the terrestrial biosphere. In particular, the year-to-year variations in the atmospheric carbon dioxide growth rate (CGR) are thought to be the result of fluctuations in the carbon fluxes of tropical land areas. Recently, the response of CGR to tropical climate interannual variability was used to put a constraint on the sensitivity of tropical land carbon to climate change. Here we use the long-term CGR record from Mauna Loa and the South Pole to show that the sensitivity of CGR to tropical temperature interannual variability has increased by a factor of 1.9 ± 0.3 in the past five decades. We find that this sensitivity was greater when tropical land regions experienced drier conditions. This suggests that the sensitivity of CGR to interannual temperature variations is regulated by moisture conditions, even though the direct correlation between CGR and tropical precipitation is weak. We also find that present terrestrial carbon cycle models do not capture the observed enhancement in CGR sensitivity in the past five decades. More realistic model predictions of future carbon cycle and climate feedbacks require a better understanding of the processes driving the response of tropical ecosystems to drought and warming.
Global conservation outcomes depend on marine protected areas with five key features p.216
In line with global targets agreed under the Convention on Biological Diversity, the number of marine protected areas (MPAs) is increasing rapidly, yet socio-economic benefits generated by MPAs remain difficult to predict and under debate. MPAs often fail to reach their full potential as a consequence of factors such as illegal harvesting, regulations that legally allow detrimental harvesting, or emigration of animals outside boundaries because of continuous habitat or inadequate size of reserve. Here we show that the conservation benefits of 87 MPAs investigated worldwide increase exponentially with the accumulation of five key features: no take, well enforced, old (>10 years), large (>100 km2), and isolated by deep water or sand. Using effective MPAs with four or five key features as an unfished standard, comparisons of underwater survey data from effective MPAs with predictions based on survey data from fished coasts indicate that total fish biomass has declined about two-thirds from historical baselines as a result of fishing. Effective MPAs also had twice as many large (>250 mm total length) fish species per transect, five times more large fish biomass, and fourteen times more shark biomass than fished areas. Most (59%) of the MPAs studied had only one or two key features and were not ecologically distinguishable from fished sites. Our results show that global conservation targets based on area alone will not optimize protection of marine biodiversity. More emphasis is needed on better MPA design, durable management and compliance to ensure that MPAs achieve their desired conservation value.
Amazon forests maintain consistent canopy structure and greenness during the dry season p.221
The seasonality of sunlight and rainfall regulates net primary production in tropical forests. Previous studies have suggested that light is more limiting than water for tropical forest productivity, consistent with greening of Amazon forests during the dry season in satellite data. We evaluated four potential mechanisms for the seasonal green-up phenomenon, including increases in leaf area or leaf reflectance, using a sophisticated radiative transfer model and independent satellite observations from lidar and optical sensors. Here we show that the apparent green up of Amazon forests in optical remote sensing data resulted from seasonal changes in near-infrared reflectance, an artefact of variations in sun-sensor geometry. Correcting this bidirectional reflectance effect eliminated seasonal changes in surface reflectance, consistent with independent lidar observations and model simulations with unchanging canopy properties. The stability of Amazon forest structure and reflectance over seasonal timescales challenges the paradigm of light-limited net primary production in Amazon forests and enhanced forest growth during drought conditions. Correcting optical remote sensing data for artefacts of sun-sensor geometry is essential to isolate the response of global vegetation to seasonal and interannual climate variability.
The genome of a Late Pleistocene human from a Clovis burial site in western Montana p.225
Clovis, with its distinctive biface, blade and osseous technologies, is the oldest widespread archaeological complex defined in North America, dating from 11,100 to 10,700 14C years before present (bp) (13,000 to 12,600 calendar years bp). Nearly 50 years of archaeological research point to the Clovis complex as having developed south of the North American ice sheets from an ancestral technology. However, both the origins and the genetic legacy of the people who manufactured Clovis tools remain under debate. It is generally believed that these people ultimately derived from Asia and were directly related to contemporary Native Americans. An alternative, Solutrean, hypothesis posits that the Clovis predecessors emigrated from southwestern Europe during the Last Glacial Maximum. Here we report the genome sequence of a male infant (Anzick-1) recovered from the Anzick burial site in western Montana. The human bones date to 10,705 ± 35 14C years bp (approximately 12,707–12,556 calendar years bp) and were directly associated with Clovis tools. We sequenced the genome to an average depth of 14.4× and show that the gene flow from the Siberian Upper Palaeolithic Mal’ta population into Native American ancestors is also shared by the Anzick-1 individual and thus happened before 12,600 years bp. We also show that the Anzick-1 individual is more closely related to all indigenous American populations than to any other group. Our data are compatible with the hypothesis that Anzick-1 belonged to a population directly ancestral to many contemporary Native Americans. Finally, we find evidence of a deep divergence in Native American populations that predates the Anzick-1 individual.
Intranasal epidermal growth factor treatment rescues neonatal brain injury p.230
There are no clinically relevant treatments available that improve function in the growing population of very preterm infants (less than 32 weeks’ gestation) with neonatal brain injury. Diffuse white matter injury (DWMI) is a common finding in these children and results in chronic neurodevelopmental impairments. As shown recently, failure in oligodendrocyte progenitor cell maturation contributes to DWMI. We demonstrated previously that the epidermal growth factor receptor (EGFR) has an important role in oligodendrocyte development. Here we examine whether enhanced EGFR signalling stimulates the endogenous response of EGFR-expressing progenitor cells during a critical period after brain injury, and promotes cellular and behavioural recovery in the developing brain. Using an established mouse model of very preterm brain injury, we demonstrate that selective overexpression of human EGFR in oligodendrocyte lineage cells or the administration of intranasal heparin-binding EGF immediately after injury decreases oligodendroglia death, enhances generation of new oligodendrocytes from progenitor cells and promotes functional recovery. Furthermore, these interventions diminish ultrastructural abnormalities and alleviate behavioural deficits on white-matter-specific paradigms. Inhibition of EGFR signalling with a molecularly targeted agent used for cancer therapy demonstrates that EGFR activation is an important contributor to oligodendrocyte regeneration and functional recovery after DWMI. Thus, our study provides direct evidence that targeting EGFR in oligodendrocyte progenitor cells at a specific time after injury is clinically feasible and potentially applicable to the treatment of premature children with white matter injury.
C/EBPα poises B cells for rapid reprogramming into induced pluripotent stem cells p.235
CCAAT/enhancer binding protein-α (C/EBPα) induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem (iPS) cells when co-expressed with the transcription factors Oct4 (Pou5f1), Sox2, Klf4 and Myc (hereafter called OSKM). However, how C/EBPα accomplishes these effects is unclear. Here we find that in mouse primary B cells transient C/EBPα expression followed by OSKM activation induces a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population. During this conversion, pluripotency and epithelial–mesenchymal transition genes become markedly upregulated, and 60% of the cells express Oct4 within 2 days. C/EBPα acts as a ‘path-breaker’ as it transiently makes the chromatin of pluripotency genes more accessible to DNase I. C/EBPα also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated after OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM-induced B-cell reprogramming. Because the enzyme is also required for efficient C/EBPα-induced immune cell conversion, our data indicate that Tet2 provides a mechanistic link between iPS cell reprogramming and B-cell transdifferentiation. The rapid iPS reprogramming approach described here should help to fully elucidate the process and has potential clinical applications.
Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts p.240
Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of β-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased β-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.
RNA viruses can hijack vertebrate microRNAs to suppress innate immunity p.245
Currently, there is little evidence for a notable role of the vertebrate microRNA (miRNA) system in the pathogenesis of RNA viruses. This is primarily attributed to the ease with which these viruses mutate to disrupt recognition and growth suppression by host miRNAs. Here we report that the haematopoietic-cell-specific miRNA miR-142-3p potently restricts the replication of the mosquito-borne North American eastern equine encephalitis virus in myeloid-lineage cells by binding to sites in the 3′ non-translated region of its RNA genome. However, by limiting myeloid cell tropism and consequent innate immunity induction, this restriction directly promotes neurologic disease manifestations characteristic of eastern equine encephalitis virus infection in humans. Furthermore, the region containing the miR-142-3p binding sites is essential for efficient virus infection of mosquito vectors. We propose that RNA viruses can adapt to use antiviral properties of vertebrate miRNAs to limit replication in particular cell types and that this restriction can lead to exacerbation of disease severity.
RecA bundles mediate homology pairing between distant sisters during DNA break repair p.249
DNA double-strand break (DSB) repair by homologous recombination has evolved to maintain genetic integrity in all organisms. Although many reactions that occur during homologous recombination are known, it is unclear where, when and how they occur in cells. Here, by using conventional and super-resolution microscopy, we describe the progression of DSB repair in live Escherichia coli. Specifically, we investigate whether homologous recombination can occur efficiently between distant sister loci that have segregated to opposite halves of an E. coli cell. We show that a site-specific DSB in one sister can be repaired efficiently using distant sister homology. After RecBCD processing of the DSB, RecA is recruited to the cut locus, where it nucleates into a bundle that contains many more RecA molecules than can associate with the two single-stranded DNA regions that form at the DSB. Mature bundles extend along the long axis of the cell, in the space between the bulk nucleoid and the inner membrane. Bundle formation is followed by pairing, in which the two ends of the cut locus relocate at the periphery of the nucleoid and together move rapidly towards the homology of the uncut sister. After sister locus pairing, RecA bundles disassemble and proteins that act late in homologous recombination are recruited to give viable recombinants 1–2-generation-time equivalents after formation of the initial DSB. Mutated RecA proteins that do not form bundles are defective in sister pairing and in DSB-induced repair. This work reveals an unanticipated role of RecA bundles in channelling the movement of the DNA DSB ends, thereby facilitating the long-range homology search that occurs before the strand invasion and transfer reactions.