Volume 503 Number 7475
Precautionary measures p.165
Major African campaigns targeting malaria and HIV could help millions, but key concerns over their long-term effects should not be forgotten.
Data deadline p.165
Time is running out to comment on the NIH’s plan for sharing genomic data.
Keep asking p.166
Prejudice, not evidence, is too often the basis for government drug policies.
Large NIH projects cut p.173
Budget woes force institutes to scrutinize expensive, non-competitive programmes.
Warsaw talks to thrash out UN climate roadmap p.174
Costs of reducing emissions may be flashpoints in path towards 2015 Paris treaty.
Physicists plan to build a bigger LHC p.177
Accelerator ring would be 100 kilometres around and run at seven times the energy of the Large Hadron Collider.
Mars mission set for launch p.178
NASA’s MAVEN orbiter aims to unravel the mystery of the red planet’s missing atmosphere.
Social scientists hit back at grant rules p.179
Researchers seek to fend off restrictions on National Science Foundation grant programmes.
Preprints come to life p.180
A dedicated website for sharing biology papers before peer review leaves journals divided.
AIDS prevention: Africa’s circumcision challenge p.182
Malaria: A race against resistance p.186
News & Views
Applied physics: A cascade laser's random walk p.200
Biochemistry: Metal ghosts in the splicing machine p.201
Solar System: Russian skyfall p.202
Stem cells: Differentiated cells in a back-up role p.204
Quantum physics: The right ambience for a single spin p.205
Biodiversity: The ecological deficit p.206
HIV: Antibodies advance the search for a cure p.207
Sound and heat revolutions in phononics p.209
The phonon is the physical particle representing mechanical vibration and is responsible for the transmission of everyday sound and heat. Understanding and controlling the phononic properties of materials provides opportunities to thermally insulate buildings, reduce environmental noise, transform waste heat into electricity and develop earthquake protection. Here I review recent progress and the development of new ideas and devices that make use of phononic properties to control both sound and heat. Advances in sonic and thermal diodes, optomechanical crystals, acoustic and thermal cloaking, hypersonic phononic crystals, thermoelectrics, and thermocrystals herald the next technological revolution in phononics.
Dedifferentiation of committed epithelial cells into stem cells in vivo p.218
Using in vivo lineage tracing in mice and sorted cells in culture, the ability of stably committed cells to dedifferentiate into basal stem cells in the mouse trachea is investigated: the findings suggest that the dedifferentiation of committed cell types into stem cells may contribute generally to regeneration in higher vertebrates in different organ and injury contexts.
Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys p.224
Treatment of SHIV-infected monkeys with potent broadly neutralizing anti-HIV-1 monoclonal antibodies resulted in rapid control of viral replication in both peripheral blood and tissues; viral rebound was linked to decreasing antibody concentrations and not the generation of escape mutations, and setpoint viral load following viral rebound remained lower than the initial baseline viral load.
RNA catalyses nuclear pre-mRNA splicing p.229
The spliceosome is shown to catalyse splicing through the RNA and not the protein components of the spliceosome; pre-messenger RNA splicing requires U6 snRNA acting by a mechanism similar to that used by group II self-splicing introns.
The trajectory, structure and origin of the Chelyabinsk asteroidal impactor p.235
Earth is continuously colliding with fragments of asteroids and comets of various sizes. The largest encounter in historical times occurred over the Tunguska river in Siberia in 1908, producing an airburst of energy equivalent to 5–15 megatons of trinitrotoluene (1 kiloton of trinitrotoluene represents an energy of 4.185 × 1012 joules). Until recently, the next most energetic airburst events occurred over Indonesia in 2009 and near the Marshall Islands in 1994, both with energies of several tens of kilotons. Here we report an analysis of selected video records of the Chelyabinsk superbolide of 15 February 2013, with energy equivalent to 500 kilotons of trinitrotoluene, and details of its atmospheric passage. We found that its orbit was similar to the orbit of the two-kilometre-diameter asteroid 86039 (1999 NC43), to a degree of statistical significance sufficient to suggest that the two were once part of the same object. The bulk strength—the ability to resist breakage—of the Chelyabinsk asteroid, of about one megapascal, was similar to that of smaller meteoroids and corresponds to a heavily fractured single stone. The asteroid broke into small pieces between the altitudes of 45 and 30 kilometres, preventing more-serious damage on the ground. The total mass of surviving fragments larger than 100 grams was lower than expected.
A 500-kiloton airburst over Chelyabinsk and an enhanced hazard from small impactors p.238
Most large (over a kilometre in diameter) near-Earth asteroids are now known, but recognition that airbursts (or fireballs resulting from nuclear-weapon-sized detonations of meteoroids in the atmosphere) have the potential to do greater damage than previously thought has shifted an increasing portion of the residual impact risk (the risk of impact from an unknown object) to smaller objects. Above the threshold size of impactor at which the atmosphere absorbs sufficient energy to prevent a ground impact, most of the damage is thought to be caused by the airburst shock wave, but owing to lack of observations this is uncertain. Here we report an analysis of the damage from the airburst of an asteroid about 19 metres (17 to 20 metres) in diameter southeast of Chelyabinsk, Russia, on 15 February 2013, estimated to have an energy equivalent of approximately 500 (±100) kilotons of trinitrotoluene (TNT, where 1 kiloton of TNT = 4.185×1012 joules). We show that a widely referenced technique of estimating airburst damage does not reproduce the observations, and that the mathematical relations based on the effects of nuclear weapons—almost always used with this technique—overestimate blast damage. This suggests that earlier damage estimates near the threshold impactor size are too high. We performed a global survey of airbursts of a kiloton or more (including Chelyabinsk), and find that the number of impactors with diameters of tens of metres may be an order of magnitude higher than estimates based on other techniques. This suggests a non-equilibrium (if the population were in a long-term collisional steady state the size-frequency distribution would either follow a single power law or there must be a size-dependent bias in other surveys) in the near-Earth asteroid population for objects 10 to 50 metres in diameter, and shifts more of the residual impact risk to these sizes.
Stabilizing the magnetic moment of single holmium atoms by symmetry p.242
Single magnetic atoms, and assemblies of such atoms, on non-magnetic surfaces have recently attracted attention owing to their potential use in high-density magnetic data storage and as a platform for quantum computing. A fundamental problem resulting from their quantum mechanical nature is that the localized magnetic moments of these atoms are easily destabilized by interactions with electrons, nuclear spins and lattice vibrations of the substrate. Even when large magnetic fields are applied to stabilize the magnetic moment, the observed lifetimes remain rather short (less than a microsecond). Several routes for stabilizing the magnetic moment against fluctuations have been suggested, such as using thin insulating layers between the magnetic atom and the substrate to suppress the interactions with the substrate’s conduction electrons, or coupling several magnetic moments together to reduce their quantum mechanical fluctuations. Here we show that the magnetic moments of single holmium atoms on a highly conductive metallic substrate can reach lifetimes of the order of minutes. The necessary decoupling from the thermal bath of electrons, nuclear spins and lattice vibrations is achieved by a remarkable combination of several symmetries intrinsic to the system: time reversal symmetry, the internal symmetries of the total angular momentum and the point symmetry of the local environment of the magnetic atom.
Guided hierarchical co-assembly of soft patchy nanoparticles p.247
The concept of hierarchical bottom-up structuring commonly encountered in natural materials provides inspiration for the design of complex artificial materials with advanced functionalities. Natural processes have achieved the orchestration of multicomponent systems across many length scales with very high precision, but man-made self-assemblies still face obstacles in realizing well-defined hierarchical structures. In particle-based self-assembly, the challenge is to program symmetries and periodicities of superstructures by providing monodisperse building blocks with suitable shape anisotropy or anisotropic interaction patterns (‘patches’). Irregularities in particle architecture are intolerable because they generate defects that amplify throughout the hierarchical levels. For patchy microscopic hard colloids, this challenge has been approached by using top-down methods (such as metal shading or microcontact printing), enabling molecule-like directionality during aggregation. However, both top-down procedures and particulate systems based on molecular assembly struggle to fabricate patchy particles controllably in the desired size regime (10–100 nm). Here we introduce the co-assembly of dynamic patchy nanoparticles—that is, soft patchy nanoparticles that are intrinsically self-assembled and monodisperse—as a modular approach for producing well-ordered binary and ternary supracolloidal hierarchical assemblies. We bridge up to three hierarchical levels by guiding triblock terpolymers (length scale ∼10 nm) to form soft patchy nanoparticles (20–50 nm) of different symmetries that, in combination, co-assemble into substructured, compartmentalized materials (>10 μm) with predictable and tunable nanoscale periodicities. We establish how molecular control over polymer composition programs the building block symmetries and regulates particle positioning, offering a route to well-ordered mixed mesostructures of high complexity.
Evidence for high salinity of Early Cretaceous sea water from the Chesapeake Bay crater p.252
High-salinity groundwater more than 1,000 metres deep in the Atlantic coastal plain of the USA has been documented in several locations, most recently within the 35-million-year-old Chesapeake Bay impact crater. Suggestions for the origin of increased salinity in the crater have included evaporite dissolution, osmosis and evaporation from heating associated with the bolide impact. Here we present chemical, isotopic and physical evidence that together indicate that groundwater in the Chesapeake crater is remnant Early Cretaceous North Atlantic (ECNA) sea water. We find that the sea water is probably 100–145 million years old and that it has an average salinity of about 70 per mil, which is twice that of modern sea water and consistent with the nearly closed ECNA basin. Previous evidence for temperature and salinity levels of ancient oceans have been estimated indirectly from geochemical, isotopic and palaeontological analyses of solid materials in deep sediment cores. In contrast, our study identifies ancient sea water in situ and provides a direct estimate of its age and salinity. Moreover, we suggest that it is likely that remnants of ECNA sea water persist in deep sediments at many locations along the Atlantic margin.
The earliest known holometabolous insects p.257
The Eumetabola (Endopterygota (also known as Holometabola) plus Paraneoptera) have the highest number of species of any clade, and greatly contribute to animal species biodiversity. The palaeoecological circumstances that favoured their emergence and success remain an intriguing question. Recent molecular phylogenetic analyses have suggested a wide range of dates for the initial appearance of the Holometabola, from the Middle Devonian epoch (391 million years (Myr) ago) to the Late Pennsylvanian epoch (311 Myr ago), and Hemiptera (310 Myr ago). Palaeoenvironments greatly changed over these periods, with global cooling and increasing complexity of green forests. The Pennsylvanian-period crown-eumetabolan fossil record remains notably incomplete, particularly as several fossils have been erroneously considered to be stem Holometabola (Supplementary Information); the earliest definitive beetles are from the start of the Permian period. The emergence of the hymenopterids, sister group to other Holometabola, is dated between 350 and 309 Myr ago, incongruent with their current earliest record (Middle Triassic epoch). Here we describe five fossils— a Gzhelian-age stem coleopterid, a holometabolous larva of uncertain ordinal affinity, a stem hymenopterid, and early Hemiptera and Psocodea, all from the Moscovian age—and reveal a notable penecontemporaneous breadth of early eumetabolan insects. These discoveries are more congruent with current hypotheses of clade divergence. Eumetabola experienced episodes of diversification during the Bashkirian–Moscovian and the Kasimovian–Gzhelian ages. This cladogenetic activity is perhaps related to notable episodes of drying resulting from glaciations, leading to the eventual demise in Euramerica of coal-swamp ecosystems, evidenced by floral turnover during this interval. These ancient species were of very small size, living in the shadow of Palaeozoic-era ‘giant’ insects. Although these discoveries reveal unexpected Pennsylvanian eumetabolan diversity, the lineage radiated more successfully only after the mass extinctions at the end of the Permian period, giving rise to the familiar crown groups of their respective clades.
Feature detection and orientation tuning in the Drosophila central complex p.262
Many animals, including insects, are known to use visual landmarks to orient in their environment. In Drosophila melanogaster, behavioural genetics studies have identified a higher brain structure called the central complex as being required for the fly’s innate responses to vertical visual features and its short- and long-term memory for visual patterns. But whether and how neurons of the fly central complex represent visual features are unknown. Here we use two-photon calcium imaging in head-fixed walking and flying flies to probe visuomotor responses of ring neurons—a class of central complex neurons that have been implicated in landmark-driven spatial memory in walking flies and memory for visual patterns in tethered flying flies. We show that dendrites of ring neurons are visually responsive and arranged retinotopically. Ring neuron receptive fields comprise both excitatory and inhibitory subfields, resembling those of simple cells in the mammalian primary visual cortex. Ring neurons show strong and, in some cases, direction-selective orientation tuning, with a notable preference for vertically oriented features similar to those that evoke innate responses in flies. Visual responses were diminished during flight, but, in contrast with the hypothesized role of the central complex in the control of locomotion, not modulated during walking. Taken together, these results indicate that ring neurons represent behaviourally relevant visual features in the fly’s environment, enabling downstream central complex circuits to produce appropriate motor commands. More broadly, this study opens the door to mechanistic investigations of circuit computations underlying visually guided action selection in the Drosophila central complex.
SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients p.267
Phelan–McDermid syndrome (PMDS) is a complex neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and an increased risk of autism spectrum disorders (ASDs). PMDS is caused by heterozygous deletions of chromosome 22q13.3. Among the genes in the deleted region is SHANK3, which encodes a protein in the postsynaptic density (PSD). Rare mutations in SHANK3 have been associated with idiopathic ASDs, non-syndromic intellectual disability, and schizophrenia. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem (iPS) cells from individuals with PMDS and autism and used them to produce functional neurons. We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of mature excitatory synapses that lack SHANK3 but contain PSD95 and N-methyl-d-aspartate (NMDA) receptors with fast deactivation kinetics. Our findings provide direct evidence for a disruption in the ratio of cellular excitation and inhibition in PMDS neurons, and point to a molecular pathway that can be recruited to restore it.
Paneth cells as a site of origin for intestinal inflammation p.272
The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn’s disease. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1HM mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn’s disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1ΔIEC) or autophagy function (Atg16l1ΔIEC or Atg7ΔIEC) in intestinal epithelial cells results in each other’s compensatory engagement, and severe spontaneous Crohn’s-disease-like transmural ileitis if both mechanisms are compromised. Xbp1ΔIEC mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn’s disease as a specific disorder of Paneth cells.
Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia p.277
Neutralizing antibodies can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS. However, earlier studies of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies administered to infected individuals or humanized mice reported poor control of virus replication and the rapid emergence of resistant variants. A new generation of anti-HIV-1 monoclonal antibodies, possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals. These neutralizing antibodies target different regions of the HIV-1 envelope glycoprotein including the CD4-binding site, glycans located in the V1/V2, V3 and V4 regions, and the membrane proximal external region of gp41 (refs 9, 10, 11, 12, 13, 14). Here we have examined two of the new antibodies, directed to the CD4-binding site and the V3 region (3BNC117 and 10-1074, respectively), for their ability to block infection and suppress viraemia in macaques infected with the R5 tropic simian–human immunodeficiency virus (SHIV)-AD8, which emulates many of the pathogenic and immunogenic properties of HIV-1 during infections of rhesus macaques. Either antibody alone can potently block virus acquisition. When administered individually to recently infected macaques, the 10-1074 antibody caused a rapid decline in virus load to undetectable levels for 4–7 days, followed by virus rebound during which neutralization-resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viraemia for 3–5 weeks in some long-term chronically SHIV-infected animals with low CD4+ T-cell levels. A second cycle of anti-HIV-1 monoclonal antibody therapy, administered to two previously treated animals, successfully controlled virus rebound. These results indicate that immunotherapy or a combination of immunotherapy plus conventional antiretroviral drugs might be useful as a treatment for chronically HIV-1-infected individuals experiencing immune dysfunction.
Inhibitory signalling to the Arp2/3 complex steers cell migration p.281
Cell migration requires the generation of branched actin networks that power the protrusion of the plasma membrane in lamellipodia. The actin-related proteins 2 and 3 (Arp2/3) complex is the molecular machine that nucleates these branched actin networks. This machine is activated at the leading edge of migrating cells by Wiskott–Aldrich syndrome protein (WASP)-family verprolin-homologous protein (WAVE, also known as SCAR). The WAVE complex is itself directly activated by the small GTPase Rac, which induces lamellipodia. However, how cells regulate the directionality of migration is poorly understood. Here we identify a new protein, Arpin, that inhibits the Arp2/3 complex in vitro, and show that Rac signalling recruits and activates Arpin at the lamellipodial tip, like WAVE. Consistently, after depletion of the inhibitory Arpin, lamellipodia protrude faster and cells migrate faster. A major role of this inhibitory circuit, however, is to control directional persistence of migration. Indeed, Arpin depletion in both mammalian cells and Dictyostelium discoideum amoeba resulted in straighter trajectories, whereas Arpin microinjection in fish keratocytes, one of the most persistent systems of cell migration, induced these cells to turn. The coexistence of the Rac–Arpin–Arp2/3 inhibitory circuit with the Rac–WAVE–Arp2/3 activatory circuit can account for this conserved role of Arpin in steering cell migration.
Directional tissue migration through a self-generated chemokine gradient p.285
The directed migration of cell collectives is a driving force of embryogenesis. The predominant view in the field is that cells in embryos navigate along pre-patterned chemoattractant gradients. One hypothetical way to free migrating collectives from the requirement of long-range gradients would be through the self-generation of local gradients that travel with them, a strategy that potentially allows self-determined directionality. However, a lack of tools for the visualization of endogenous guidance cues has prevented the demonstration of such self-generated gradients in vivo. Here we define the in vivo dynamics of one key guidance molecule, the chemokine Cxcl12a, by applying a fluorescent timer approach to measure ligand-triggered receptor turnover in living animals. Using the zebrafish lateral line primordium as a model, we show that migrating cell collectives can self-generate gradients of chemokine activity across their length via polarized receptor-mediated internalization. Finally, by engineering an external source of the atypical receptor Cxcr7 that moves with the primordium, we show that a self-generated gradient mechanism is sufficient to direct robust collective migration. This study thus provides, to our knowledge, the first in vivo proof for self-directed tissue migration through local shaping of an extracellular cue and provides a framework for investigating self-directed migration in many other contexts including cancer invasion.
A high-resolution map of the three-dimensional chromatin interactome in human cells p.290
A large number of cis-regulatory sequences have been annotated in the human genome, but defining their target genes remains a challenge. One strategy is to identify the long-range looping interactions at these elements with the use of chromosome conformation capture (3C)-based techniques. However, previous studies lack either the resolution or coverage to permit a whole-genome, unbiased view of chromatin interactions. Here we report a comprehensive chromatin interaction map generated in human fibroblasts using a genome-wide 3C analysis method (Hi-C). We determined over one million long-range chromatin interactions at 5–10-kb resolution, and uncovered general principles of chromatin organization at different types of genomic features. We also characterized the dynamics of promoter–enhancer contacts after TNF-α signalling in these cells. Unexpectedly, we found that TNF-α-responsive enhancers are already in contact with their target promoters before signalling. Such pre-existing chromatin looping, which also exists in other cell types with different extracellular signalling, is a strong predictor of gene induction. Our observations suggest that the three-dimensional chromatin landscape, once established in a particular cell type, is relatively stable and could influence the selection or activation of target genes by a ubiquitous transcription activator in a cell-specific manner.
Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs p.295
The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known. Here we determine binding sites, bound conformations and specific drug–receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation–π interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15 Å from the classical, ‘orthosteric’ ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator’s allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.