The authorities must take the necessary time to remedy the slapdash introduction of a database containing the medical records of the entire population of England.
Full disclosure p.8
Regulatory agencies must demand conflict-of-interest statements for the research they use.
Track and trace p.8
Identifiers that follow researchers’ work from grant to paper will make funding more effective.
US seeks waste-research revival p.15
Radioactive leak brings nuclear repositories into the spotlight.
Japan caught up in energy dilemma p.16
As the third anniversary of the Fukushima disaster nears, the nation is faltering in its resolution to shun nuclear power.
Dust regulations trigger backlash p.18
US agency’s reassessment of silica exposure rules provokes conflict-of-interest row with senators.
Prenatal-screening companies expand scope of DNA tests p.19
But the increasingly accurate analyses carry the ethical dilemma of uncertain outcomes.
Brazil clamps down on illegal fossil trade p.20
Debate rages as collectors accused of exporting specimens face up to 20 years in jail.
Budget woes hinder clinical-trials network p.21
Costly cancer trials a challenge for revamped US programme.
Epigenetics: The sins of the father p.22
The rechargeable revolution: A better battery p.26
News & Views
Earth science: Missing link in mantle dynamics p.42
Biological techniques: Wrapped around the heart p.43
Plant science: How to switch affinity p.44
Optomechanics: Hardware for a quantum network p.45
Influenza: Prediction is worth a shot p.47
Cancer: Inflammation lights the way to metastasis p.48
Disclinations provide the missing mechanism for deforming olivine-rich rocks in the mantle p.51
Using electron backscattering diffraction maps of deformed olivine to resolve the disclinations at grain boundaries, combined with a disclination-based model of a high-angle tilt boundary in olivine, reveals the missing mechanism for describing plastic flow in polycrystalline olivine: an applied shear induces grain-boundary migration through disclination motion.
A predictive fitness model for influenza p.57
A computational approach for predicting the future evolution of the human influenza virus, based on population-genetic data of previous strains, is presented; this model holds promise for improving vaccine strain selection for seasonal influenza.
DNA interrogation by the CRISPR RNA-guided endonuclease Cas9 p.62
This study defines how a short DNA sequence, known as the PAM, is critical for target DNA interrogation by the CRISPR-associated enzyme Cas9 — DNA melting and heteroduplex formation initiate near the PAM and extend directionally through the remaining target sequence, and the PAM is also required to activate the catalytic activity of Cas9.
Molecular basis of nitrate uptake by the plant nitrate transporter NRT1.1 p.68
In Arabidopsis thaliana the phosphorylation state of the ‘dual affinity’ transporter, NRT1.1, allows the uptake of nitrate over a wide concentration range; the crystal structure and molecular basis for this is described in this study.
Crystal structure of the plant dual-affinity nitrate transporter NRT1.1 p.73
A description of the crystal structure of unphosphorylated NRT1.1 provides insights into how phosphorylation switches the nitrate transporter between the low-affinity and high-affinity states.
Change in the chemical composition of infalling gas forming a disk around a protostar p.78
IRAS 04368+2557 is a solar-type (low-mass) protostar embedded in a protostellar core (L1527) in the Taurus molecular cloud, which is only 140 parsecs away from Earth, making it the closest large star-forming region. The protostellar envelope has a flattened shape with a diameter of a thousand astronomical units (1 au is the distance from Earth to the Sun), and is infalling and rotating. It also has a protostellar disk with a radius of 90 au (ref. 6), from which a planetary system is expected to form. The interstellar gas, mainly consisting of hydrogen molecules, undergoes a change in density of about three orders of magnitude as it collapses from the envelope into the disk, while being heated from 10 kelvin to over 100 kelvin in the mid-plane, but it has hitherto not been possible to explore changes in chemical composition associated with this collapse. Here we report that the unsaturated hydrocarbon molecule cyclic-C3H2 resides in the infalling rotating envelope, whereas sulphur monoxide (SO) is enhanced in the transition zone at the radius of the centrifugal barrier (100 ± 20 au), which is the radius at which the kinetic energy of the infalling gas is converted to rotational energy. Such a drastic change in chemistry at the centrifugal barrier was not anticipated, but is probably caused by the discontinuous infalling motion at the centrifugal barrier and local heating processes there.
Optical detection of radio waves through a nanomechanical transducer p.81
Low-loss transmission and sensitive recovery of weak radio-frequency and microwave signals is a ubiquitous challenge, crucial in radio astronomy, medical imaging, navigation, and classical and quantum communication. Efficient up-conversion of radio-frequency signals to an optical carrier would enable their transmission through optical fibres instead of through copper wires, drastically reducing losses, and would give access to the set of established quantum optical techniques that are routinely used in quantum-limited signal detection. Research in cavity optomechanics has shown that nanomechanical oscillators can couple strongly to either microwave or optical fields. Here we demonstrate a room-temperature optoelectromechanical transducer with both these functionalities, following a recent proposal using a high-quality nanomembrane. A voltage bias of less than 10 V is sufficient to induce strong coupling between the voltage fluctuations in a radio-frequency resonance circuit and the membrane’s displacement, which is simultaneously coupled to light reflected off its surface. The radio-frequency signals are detected as an optical phase shift with quantum-limited sensitivity. The corresponding half-wave voltage is in the microvolt range, orders of magnitude less than that of standard optical modulators. The noise of the transducer—beyond the measured Johnson noise of the resonant circuit—consists of the quantum noise of light and thermal fluctuations of the membrane, dominating the noise floor in potential applications in radio astronomy and nuclear magnetic imaging. Each of these contributions is inferred to be when balanced by choosing an electromechanical cooperativity of with an optical power of 1 mW. The noise temperature of the membrane is divided by the cooperativity. For the highest observed cooperativity of , this leads to a projected noise temperature of 40 mK and a sensitivity limit of . Our approach to all-optical, ultralow-noise detection of classical electronic signals sets the stage for coherent up-conversion of low-frequency quantum signals to the optical domain.
Self-assembly of hydrogen-bonded two-dimensional quasicrystals p.86
The process of molecular self-assembly on solid surfaces is essentially one of crystallization in two dimensions, and the structures that result depend on the interplay between intermolecular forces and the interaction between adsorbates and the underlying substrate. Because a single hydrogen bond typically has an energy between 15 and 35 kilojoules per mole, hydrogen bonding can be a strong driver of molecular assembly; this is apparent from the dominant role of hydrogen bonding in nucleic-acid base pairing, as well as in the secondary structure of proteins. Carboxylic acid functional groups, which provide two hydrogen bonds, are particularly promising and reliable in creating and maintaining surface order, and self-assembled monolayers of benzoic acids produce structure that depends on the number and relative placement of carboxylic acid groups. Here we use scanning tunnelling microscopy to study self-assembled monolayers of ferrocenecarboxylic acid (FcCOOH), and find that, rather than producing dimeric or linear structures typical of carboxylic acids, FcCOOH forms highly unusual cyclic hydrogen-bonded pentamers, which combine with simultaneously formed FcCOOH dimers to form two-dimensional quasicrystallites that exhibit local five-fold symmetry and maintain translational and rotational order (without periodicity) for distances of more than 400 ångströms.
Rate of tree carbon accumulation increases continuously with tree size p.90
Forests are major components of the global carbon cycle, providing substantial feedback to atmospheric greenhouse gas concentrations. Our ability to understand and predict changes in the forest carbon cycle—particularly net primary productivity and carbon storage—increasingly relies on models that represent biological processes across several scales of biological organization, from tree leaves to forest stands. Yet, despite advances in our understanding of productivity at the scales of leaves and stands, no consensus exists about the nature of productivity at the scale of the individual tree, in part because we lack a broad empirical assessment of whether rates of absolute tree mass growth (and thus carbon accumulation) decrease, remain constant, or increase as trees increase in size and age. Here we present a global analysis of 403 tropical and temperate tree species, showing that for most species mass growth rate increases continuously with tree size. Thus, large, old trees do not act simply as senescent carbon reservoirs but actively fix large amounts of carbon compared to smaller trees; at the extreme, a single big tree can add the same amount of carbon to the forest within a year as is contained in an entire mid-sized tree. The apparent paradoxes of individual tree growth increasing with tree size despite declining leaf-level and stand-level productivity can be explained, respectively, by increases in a tree’s total leaf area that outpace declines in productivity per unit of leaf area and, among other factors, age-related reductions in population density. Our results resolve conflicting assumptions about the nature of tree growth, inform efforts to undertand and model forest carbon dynamics, and have additional implications for theories of resource allocation and plant senescence.
Sensory–motor transformations for speech occur bilaterally p.94
Historically, the study of speech processing has emphasized a strong link between auditory perceptual input and motor production output. A kind of ‘parity’ is essential, as both perception- and production-based representations must form a unified interface to facilitate access to higher-order language processes such as syntax and semantics, believed to be computed in the dominant, typically left hemisphere. Although various theories have been proposed to unite perception and production, the underlying neural mechanisms are unclear. Early models of speech and language processing proposed that perceptual processing occurred in the left posterior superior temporal gyrus (Wernicke’s area) and motor production processes occurred in the left inferior frontal gyrus (Broca’s area). Sensory activity was proposed to link to production activity through connecting fibre tracts, forming the left lateralized speech sensory–motor system. Although recent evidence indicates that speech perception occurs bilaterally, prevailing models maintain that the speech sensory–motor system is left lateralized and facilitates the transformation from sensory-based auditory representations to motor-based production representations. However, evidence for the lateralized computation of sensory–motor speech transformations is indirect and primarily comes from stroke patients that have speech repetition deficits (conduction aphasia) and studies using covert speech and haemodynamic functional imaging. Whether the speech sensory–motor system is lateralized, like higher-order language processes, or bilateral, like speech perception, is controversial. Here we use direct neural recordings in subjects performing sensory–motor tasks involving overt speech production to show that sensory–motor transformations occur bilaterally. We demonstrate that electrodes over bilateral inferior frontal, inferior parietal, superior temporal, premotor and somatosensory cortices exhibit robust sensory–motor neural responses during both perception and production in an overt word-repetition task. Using a non-word transformation task, we show that bilateral sensory–motor responses can perform transformations between speech-perception- and speech-production-based representations. These results establish a bilateral sublexical speech sensory–motor system.
Cell-autonomous correction of ring chromosomes in human induced pluripotent stem cells p.99
Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation. Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions. Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate. The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-derived iPSCs devoid of the original chromosomal aberration. Our results suggest a fundamentally different function for cellular reprogramming as a means of ‘chromosome therapy’ to reverse combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. In addition, our work provides an experimentally tractable human cellular system for studying mechanisms of chromosomal number control, which is of critical relevance to human development and disease.
Citrullination regulates pluripotency and histone H1 binding to chromatin p.104
Citrullination is the post-translational conversion of an arginine residue within a protein to the non-coded amino acid citrulline. This modification leads to the loss of a positive charge and reduction in hydrogen-bonding ability. It is carried out by a small family of tissue-specific vertebrate enzymes called peptidylarginine deiminases (PADIs) and is associated with the development of diverse pathological states such as autoimmunity, cancer, neurodegenerative disorders, prion diseases and thrombosis. Nevertheless, the physiological functions of citrullination remain ill-defined, although citrullination of core histones has been linked to transcriptional regulation and the DNA damage response. PADI4 (also called PAD4 or PADV), the only PADI with a nuclear localization signal, was previously shown to act in myeloid cells where it mediates profound chromatin decondensation during the innate immune response to infection. Here we show that the expression and enzymatic activity of Padi4 are also induced under conditions of ground-state pluripotency and during reprogramming in mouse. Padi4 is part of the pluripotency transcriptional network, binding to regulatory elements of key stem-cell genes and activating their expression. Its inhibition lowers the percentage of pluripotent cells in the early mouse embryo and significantly reduces reprogramming efficiency. Using an unbiased proteomic approach we identify linker histone H1 variants, which are involved in the generation of compact chromatin, as novel PADI4 substrates. Citrullination of a single arginine residue within the DNA-binding site of H1 results in its displacement from chromatin and global chromatin decondensation. Together, these results uncover a role for citrullination in the regulation of pluripotency and provide new mechanistic insights into how citrullination regulates chromatin compaction.
Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma p.109
Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma–endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.
Sulphoglycolysis in Escherichia coli K-12 closes a gap in the biogeochemical sulphur cycle p.114
Sulphoquinovose (SQ, 6-deoxy-6-sulphoglucose) has been known for 50 years as the polar headgroup of the plant sulpholipid in the photosynthetic membranes of all higher plants, mosses, ferns, algae and most photosynthetic bacteria. It is also found in some non-photosynthetic bacteria, and SQ is part of the surface layer of some Archaea. The estimated annual production of SQ is 10,000,000,000 tonnes (10 petagrams), thus it comprises a major portion of the organo-sulphur in nature, where SQ is degraded by bacteria. However, despite evidence for at least three different degradative pathways in bacteria, no enzymic reaction or gene in any pathway has been defined, although a sulphoglycolytic pathway has been proposed. Here we show that Escherichia coli K-12, the most widely studied prokaryotic model organism, performs sulphoglycolysis, in addition to standard glycolysis. SQ is catabolised through four newly discovered reactions that we established using purified, heterologously expressed enzymes: SQ isomerase, 6-deoxy-6-sulphofructose (SF) kinase, 6-deoxy-6-sulphofructose-1-phosphate (SFP) aldolase, and 3-sulpholactaldehyde (SLA) reductase. The enzymes are encoded in a ten-gene cluster, which probably also encodes regulation, transport and degradation of the whole sulpholipid; the gene cluster is present in almost all (>91%) available E. coli genomes, and is widespread in Enterobacteriaceae. The pathway yields dihydroxyacetone phosphate (DHAP), which powers energy conservation and growth of E. coli, and the sulphonate product 2,3-dihydroxypropane-1-sulphonate (DHPS), which is excreted. DHPS is mineralized by other bacteria, thus closing the sulphur cycle within a bacterial community.
Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse p.118
The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR–pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs.
SRA- and SET-domain-containing proteins link RNA polymerase V occupancy to DNA methylation p.124
RNA-directed DNA methylation in Arabidopsis thaliana depends on the upstream synthesis of 24-nucleotide small interfering RNAs (siRNAs) by RNA POLYMERASE IV (Pol IV) and downstream synthesis of non-coding transcripts by Pol V. Pol V transcripts are thought to interact with siRNAs which then recruit DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) to methylate DNA. The SU(VAR)3-9 homologues SUVH2 and SUVH9 act in this downstream step but the mechanism of their action is unknown. Here we show that genome-wide Pol V association with chromatin redundantly requires SUVH2 and SUVH9. Although SUVH2 and SUVH9 resemble histone methyltransferases, a crystal structure reveals that SUVH9 lacks a peptide-substrate binding cleft and lacks a properly formed S-adenosyl methionine (SAM)-binding pocket necessary for normal catalysis, consistent with a lack of methyltransferase activity for these proteins. SUVH2 and SUVH9 both contain SRA (SET- and RING-ASSOCIATED) domains capable of binding methylated DNA, suggesting that they function to recruit Pol V through DNA methylation. Consistent with this model, mutation of DNA METHYLTRANSFERASE 1 (MET1) causes loss of DNA methylation, a nearly complete loss of Pol V at its normal locations, and redistribution of Pol V to sites that become hypermethylated. Furthermore, tethering SUVH2 with a zinc finger to an unmethylated site is sufficient to recruit Pol V and establish DNA methylation and gene silencing. These results indicate that Pol V is recruited to DNA methylation through the methyl-DNA binding SUVH2 and SUVH9 proteins, and our mechanistic findings suggest a means for selectively targeting regions of plant genomes for epigenetic silencing.