The right to speak out p.137
Controversy over the results touted by a genetic-ancestry firm has highlighted the need for reform of the United Kingdom’s restrictive libel law.
Energy crossroads p.137
Everyone should wish Germany well in its great experiment in renewable energy.
Time for plan B p.138
A court ruling to remove age limits on access to emergency contraception must prevail.
Urgent search for flu source p.145
Researchers suspect H7N9 virus is in bird markets as human cases rise rapidly.
Wild weather can send greenhouse gases spiraling p.147
Researchers get to grips with effects of heat, drought and storms on carbon release.
Stem cells boom in vet clinics p.148
Horses, dogs and even a tiger have received the unproven therapies. Now, drug regulators plan to weigh in.
Budget forces tough look at biodefence p.149
US supply stockpile for combating bioterror attacks and pandemics feels the strain of funding cuts.
Gene patents in the dock p.150
As US Supreme Court justices prepare to hear arguments in Myriad Genetics case, observers are debating the impact of the outcome on personal genomics.
See-through brains clarify connections p.151
Technique to make tissue transparent offers three-dimensional view of neural networks.
Genetics: A gene of rare effect p.152
Renewable power: Germany’s energy gamble p.156
News & Views
Cognitive neuroscience: Sensory noise drives bad decisions p.172
Optical devices: Photonic insulators with a twist p.173
Neuroscience: Anxiety is the sum of its parts p.174
Microbiology: Intraterrestrial lifestyles p.176
Structural biology: A solution to the telomerase puzzle p.177
Solar system: Saturn's ring rain p.178
Glucose–TOR signalling reprograms the transcriptome and activates meristems p.181
The authors show that photosynthetically derived glucose drives target-of-rapamycin signalling, resulting in transcriptional reprogramming of genes involved in cell cycle regulation.
The architecture of Tetrahymena telomerase holoenzyme p.187
The long-awaited structure of a telomerase holoenzyme, from Tetrahymena, has been obtained by electron microscopy; affinity labelling of subunits and modelling with NMR and crystal structures of various components allowed the identification of the catalytic core and subunit interactions, and the functional role of the subunits in telomerase processivity was enabled by performing the first reconstitution of the holoenzyme in vitro.
The domination of Saturn’s low-latitude ionosphere by ring ‘rain’ p.193
Saturn’s ionosphere is produced when the otherwise neutral atmosphere is exposed to a flow of energetic charged particles or solar radiation. At low latitudes the solar radiation should result in a weak planet-wide glow in the infrared, corresponding to the planet’s uniform illumination by the Sun. The observed electron density of the low-latitude ionosphere, however, is lower and its temperature higher than predicted by models. A planet-to-ring magnetic connection has been previously suggested, in which an influx of water from the rings could explain the lower-than-expected electron densities in Saturn’s atmosphere. Here we report the detection of a pattern of features, extending across a broad latitude band from 25 to 60 degrees, that is superposed on the lower-latitude background glow, with peaks in emission that map along the planet’s magnetic field lines to gaps in Saturn’s rings. This pattern implies the transfer of charged species derived from water from the ring-plane to the ionosphere, an influx on a global scale, flooding between 30 to 43 per cent of the surface of Saturn’s upper atmosphere. This ring ‘rain’ is important in modulating ionospheric emissions and suppressing electron densities.
Photonic Floquet topological insulators p.196
Topological insulators are a new phase of matter, with the striking property that conduction of electrons occurs only on their surfaces. In two dimensions, electrons on the surface of a topological insulator are not scattered despite defects and disorder, providing robustness akin to that of superconductors. Topological insulators are predicted to have wide-ranging applications in fault-tolerant quantum computing and spintronics. Substantial effort has been directed towards realizing topological insulators for electromagnetic waves. One-dimensional systems with topological edge states have been demonstrated, but these states are zero-dimensional and therefore exhibit no transport properties. Topological protection of microwaves has been observed using a mechanism similar to the quantum Hall effect, by placing a gyromagnetic photonic crystal in an external magnetic field. But because magnetic effects are very weak at optical frequencies, realizing photonic topological insulators with scatter-free edge states requires a fundamentally different mechanism—one that is free of magnetic fields. A number of proposals for photonic topological transport have been put forward recently. One suggested temporal modulation of a photonic crystal, thus breaking time-reversal symmetry and inducing one-way edge states. This is in the spirit of the proposed Floquet topological insulators, in which temporal variations in solid-state systems induce topological edge states. Here we propose and experimentally demonstrate a photonic topological insulator free of external fields and with scatter-free edge transport—a photonic lattice exhibiting topologically protected transport of visible light on the lattice edges. Our system is composed of an array of evanescently coupled helical waveguides arranged in a graphene-like honeycomb lattice. Paraxial diffraction of light is described by a Schrödinger equation where the propagation coordinate (z) acts as ‘time’. Thus the helicity of the waveguides breaks z-reversal symmetry as proposed for Floquet topological insulators. This structure results in one-way edge states that are topologically protected from scattering.
Recent temperature extremes at high northern latitudes unprecedented in the past 600 years p.201
Recently observed extreme temperatures at high northern latitudes are rare by definition, making the longer time span afforded by climate proxies important for assessing how the frequency of such extremes may be changing. Previous reconstructions of past temperature variability have demonstrated that recent warmth is anomalous relative to preceding centuries or millennia, but extreme events can be more thoroughly evaluated using a spatially resolved approach that provides an ensemble of possible temperature histories. Here, using a hierarchical Bayesian analysis of instrumental, tree-ring, ice-core and lake-sediment records, we show that the magnitude and frequency of recent warm temperature extremes at high northern latitudes are unprecedented in the past 600 years. The summers of 2005, 2007, 2010 and 2011 were warmer than those of all prior years back to 1400 (probability P > 0.95), in terms of the spatial average. The summer of 2010 was the warmest in the previous 600 years in western Russia (P > 0.99) and probably the warmest in western Greenland and the Canadian Arctic as well (P > 0.90). These and other recent extremes greatly exceed those expected from a stationary climate, but can be understood as resulting from constant space–time variability about an increased mean temperature.
Climatic control of bedrock river incision p.206
Bedrock river incision drives the development of much of Earth’s surface topography, and thereby shapes the structure of mountain belts and modulates Earth’s habitability through its effects on soil erosion, nutrient fluxes and global climate. Although it has long been expected that river incision rates should depend strongly on precipitation rates, quantifying the effects of precipitation rates on bedrock river incision rates has proved difficult, partly because river incision rates are difficult to measure and partly because non-climatic factors can obscure climatic effects at sites where river incision rates have been measured. Here we present measurements of river incision rates across one of Earth’s steepest rainfall gradients, which show that precipitation rates do indeed influence long-term bedrock river incision rates. We apply a widely used empirical law for bedrock river incision to a series of rivers on the Hawaiian island of Kaua‘i, where mean annual precipitation ranges from 0.5 metres to 9.5 metres (ref. 12)—over 70 per cent of the global range—and river incision rates averaged over millions of years can be inferred from the depth of river canyons and the age of the volcanic bedrock. Both a time-averaged analysis and numerical modelling of transient river incision reveal that the long-term efficiency of bedrock river incision across Kaua‘i is positively correlated with upstream-averaged mean annual precipitation rates. We provide theoretical context for this result by demonstrating that our measurements are consistent with a linear dependence of river incision rates on stream power, the rate of energy expenditure by the flow on the riverbed. These observations provide rare empirical evidence for the long-proposed coupling between climate and river incision, suggesting that previously proposed feedbacks among topography, climate and tectonics may occur.
Embryology of Early Jurassic dinosaur from China with evidence of preserved organic remains p.210
Fossil dinosaur embryos are surprisingly rare, being almost entirely restricted to Upper Cretaceous strata that record the late stages of non-avian dinosaur evolution. Notable exceptions are the oldest known embryos from the Early Jurassic South African sauropodomorph Massospondylus and Late Jurassic embryos of a theropod from Portugal. The fact that dinosaur embryos are rare and typically enclosed in eggshells limits their availability for tissue and cellular level investigations of development. Consequently, little is known about growth patterns in dinosaur embryos, even though post-hatching ontogeny has been studied in several taxa. Here we report the discovery of an embryonic dinosaur bone bed from the Lower Jurassic of China, the oldest such occurrence in the fossil record. The embryos are similar in geological age to those of Massospondylus and are also assignable to a sauropodomorph dinosaur, probably Lufengosaurus. The preservation of numerous disarticulated skeletal elements and eggshells in this monotaxic bone bed, representing different stages of incubation and therefore derived from different nests, provides opportunities for new investigations of dinosaur embryology in a clade noted for gigantism. For example, comparisons among embryonic femora of different sizes and developmental stages reveal a consistently rapid rate of growth throughout development, possibly indicating that short incubation times were characteristic of sauropodomorphs. In addition, asymmetric radial growth of the femoral shaft and rapid expansion of the fourth trochanter suggest that embryonic muscle activation played an important role in the pre-hatching ontogeny of these dinosaurs. This discovery also provides the oldest evidence of in situ preservation of complex organic remains in a terrestrial vertebrate.
Predominant archaea in marine sediments degrade detrital proteins p.215
Half of the microbial cells in the Earth’s oceans are found in sediments. Many of these cells are members of the Archaea, single-celled prokaryotes in a domain of life separate from Bacteria and Eukaryota. However, most of these archaea lack cultured representatives, leaving their physiologies and placement on the tree of life uncertain. Here we show that the uncultured miscellaneous crenarchaeotal group (MCG) and marine benthic group-D (MBG-D) are among the most numerous archaea in the marine sub-sea floor. Single-cell genomic sequencing of one cell of MCG and three cells of MBG-D indicated that they form new branches basal to the archaeal phyla Thaumarchaeota and Aigarchaeota, for MCG, and the order Thermoplasmatales, for MBG-D. All four cells encoded extracellular protein-degrading enzymes such as gingipain and clostripain that are known to be effective in environments chemically similar to marine sediments. Furthermore, we found these two types of peptidase to be abundant and active in marine sediments, indicating that uncultured archaea may have a previously undiscovered role in protein remineralization in anoxic marine sediments.
Diverging neural pathways assemble a behavioural state from separable features in anxiety p.219
Behavioural states in mammals, such as the anxious state, are characterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations). Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety. Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optogenetics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features. First, two BNST subregions were unexpectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state features, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features. Notably, we found that three distinct anterodorsal BNST efferent projections—to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area—each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxiogenic environments. These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projections, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.
Distinct extended amygdala circuits for divergent motivational states p.224
The co-morbidity of anxiety and dysfunctional reward processing in illnesses such as addiction and depression suggests that common neural circuitry contributes to these disparate neuropsychiatric symptoms. The extended amygdala, including the bed nucleus of the stria terminalis (BNST), modulates fear and anxiety, but also projects to the ventral tegmental area (VTA), a region implicated in reward and aversion, thus providing a candidate neural substrate for integrating diverse emotional states. However, the precise functional connectivity between distinct BNST projection neurons and their postsynaptic targets in the VTA, as well as the role of this circuit in controlling motivational states, have not been described. Here we record and manipulate the activity of genetically and neurochemically identified VTA-projecting BNST neurons in freely behaving mice. Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons. By contrast, in vivo optically identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic (γ-aminobutyric acid-containing) projection neurons was suppressed. Channelrhodopsin-2-assisted circuit mapping revealed that both BNST glutamatergic and GABAergic projections preferentially innervate postsynaptic non-dopaminergic VTA neurons, thus providing a mechanistic framework for in vivo circuit perturbations. In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioural phenotypes. Conversely, activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes, which were also recapitulated by direct inhibition of VTA GABAergic neurons. These data demonstrate that functionally opposing BNST to VTA circuits regulate rewarding and aversive motivational states, and may serve as a crucial circuit node for bidirectionally normalizing maladaptive behaviours.
Diverse and heritable lineage imprinting of early haematopoietic progenitors p.229
Haematopoietic stem cells (HSCs) and their subsequent progenitors produce blood cells, but the precise nature and kinetics of this production is a contentious issue. In one model, lymphoid and myeloid production branch after the lymphoid-primed multipotent progenitor (LMPP), with both branches subsequently producing dendritic cells. However, this model is based mainly on in vitro clonal assays and population-based tracking in vivo, which could miss in vivo single-cell complexity. Here we avoid these issues by using a new quantitative version of ‘cellular barcoding’ to trace the in vivo fate of hundreds of LMPPs and HSCs at the single-cell level. These data demonstrate that LMPPs are highly heterogeneous in the cell types that they produce, separating into combinations of lymphoid-, myeloid- and dendritic-cell-biased producers. Conversely, although we observe a known lineage bias of some HSCs, most cellular output is derived from a small number of HSCs that each generates all cell types. Crucially, in vivo analysis of the output of sibling cells derived from single LMPPs shows that they often share a similar fate, suggesting that the fate of these progenitors was imprinted. Furthermore, as this imprinting is also observed for dendritic-cell-biased LMPPs, dendritic cells may be considered a distinct lineage on the basis of separate ancestry. These data suggest a ‘graded commitment’ model of haematopoiesis, in which heritable and diverse lineage imprinting occurs earlier than previously thought.
Manipulation of small Rho GTPases is a pathogen-induced process detected by NOD1 p.233
Our innate immune system distinguishes microbes from self by detecting conserved pathogen-associated molecular patterns. However, these are produced by all microbes, regardless of their pathogenic potential. To distinguish virulent microbes from those with lower disease-causing potential the innate immune system detects conserved pathogen-induced processes, such as the presence of microbial products in the host cytosol, by mechanisms that are not fully resolved. Here we show that NOD1 senses cytosolic microbial products by monitoring the activation state of small Rho GTPases. Activation of RAC1 and CDC42 by bacterial delivery or ectopic expression of SopE, a virulence factor of the enteric pathogen Salmonella, triggered the NOD1 signalling pathway, with consequent RIP2 (also known as RIPK2)-mediated induction of NF-κB-dependent inflammatory responses. Similarly, activation of the NOD1 signalling pathway by peptidoglycan required RAC1 activity. Furthermore, constitutively active forms of RAC1, CDC42 and RHOA activated the NOD1 signalling pathway. Our data identify the activation of small Rho GTPases as a pathogen-induced process sensed through the NOD1 signalling pathway.
Succinate is an inflammatory signal that induces IL-1β through HIF-1α p.238
Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the ‘GABA (γ-aminobutyric acid) shunt’ pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.
Structural and energetic basis of folded-protein transport by the FimD usher p.243
Type 1 pili, produced by uropathogenic Escherichia coli, are multisubunit fibres crucial in recognition of and adhesion to host tissues. During pilus biogenesis, subunits are recruited to an outer membrane assembly platform, the FimD usher, which catalyses their polymerization and mediates pilus secretion. The recent determination of the crystal structure of an initiation complex provided insight into the initiation step of pilus biogenesis resulting in pore activation, but very little is known about the elongation steps that follow. Here, to address this question, we determine the structure of an elongation complex in which the tip complex assembly composed of FimC, FimF, FimG and FimH passes through FimD. This structure demonstrates the conformational changes required to prevent backsliding of the nascent pilus through the FimD pore and also reveals unexpected properties of the usher pore. We show that the circular binding interface between the pore lumen and the folded substrate participates in transport by defining a low-energy pathway along which the nascent pilus polymer is guided during secretion.
Structural basis for the drug extrusion mechanism by a MATE multidrug transporter p.247
Multidrug and toxic compound extrusion (MATE) family transporters are conserved in the three primary domains of life (Archaea, Bacteria and Eukarya), and export xenobiotics using an electrochemical gradient of H+ or Na+ across the membrane. MATE transporters confer multidrug resistance to bacterial pathogens and cancer cells, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs, respectively. Therefore, the development of MATE inhibitors has long been awaited in the field of clinical medicine. Here we present the crystal structures of the H+-driven MATE transporter from Pyrococcus furiosus in two distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 2.1–3.0 Å resolutions. The structures, combined with functional analyses, show that the protonation of Asp 41 on the amino (N)-terminal lobe induces the bending of TM1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities. The strongest inhibitory peptide that occupies the N-lobe cavity may pave the way towards the development of efficient inhibitors against MATE transporters.