Volume 498 Number 7453
No dishonour in depression p.137
The stigma associated with mental illness discourages investment in finding cures — even though the burden of the disorders on society is immense.
Track the trackers p.137
Oversight and public debate about access to personal data are crucial to preserving privacy.
Young upstarts p.138
Lucrative prizes emulating the Nobels bring welcome money and publicity for science.
China gets tough on carbon p.145
Cap-and-trade pilot schemes set stage for nationwide roll-out.
‘Master protocol’ aims to revamp cancer trials p.146
Pilot project will bring drug companies together to test targeted lung-cancer therapies.
FDA gets to grips with faeces p.147
Regulator triggers efforts to standardize faecal transplants.
Light flips transistor switch p.149
Photons emerge as competitors to electrons in computer circuits.
Speed test for wild cheetahs p.150
State-of-the-art collar reveals animal’s quick reflexes and phenomenal acceleration.
UK scientists fear further cuts p.151
Funding jitters rife ahead of government spending review.
Science prizes: The new Nobels p.152
Drones in science: Fly, and bring me data p.156
News & Views
Stem cells: Cloning human embryos p.174
Condensed-matter physics: Spintronics, the atomic way p.175
Stem cells: Regulation by alternative splicing p.176
Malaria: The vector as protector p.177
Cosmology: Hydrogen wisps reveal dark energy p.179
Conservation: Spare our restored soil p.180
Earth science: Water may be a damp squib p.181
Structural biology: Ion channel twists to open p.182
Locomotion dynamics of hunting in wild cheetahs p.185
A novel tracking collar provides highly precise location, speed and acceleration data from 367 runs by five cheetahs in the wild; although a top speed of 58 m.p.h. was reported, few runs were above 45 m.p.h. with the average run around 31 m.p.h., and hunting success depended on grip, manoeuvrability and muscle power rather than outright speed.
X-ray structure of the mammalian GIRK2–βγ G-protein complex p.190
An X-ray structure and electrophysiological analysis of mammalian G-protein-gated inward rectifier potassium channel GIRK2 in complex with βγ reveals a pre-open channel structure consistent with channel activation by membrane delimited G-protein subunits.
Sodium content as a predictor of the advanced evolution of globular cluster stars p.198
The asymptotic giant branch (AGB) phase is the final stage of nuclear burning for low-mass stars. Although Milky Way globular clusters are now known to harbour (at least) two generations of stars, they still provide relatively homogeneous samples of stars that are used to constrain stellar evolution theory. It is predicted by stellar models that the majority of cluster stars with masses around the current turn-off mass (that is, the mass of the stars that are currently leaving the main sequence phase) will evolve through the AGB phase. Here we report that all of the second-generation stars in the globular cluster NGC 6752—70 per cent of the cluster population—fail to reach the AGB phase. Through spectroscopic abundance measurements, we found that every AGB star in our sample has a low sodium abundance, indicating that they are exclusively first-generation stars. This implies that many clusters cannot reliably be used for star counts to test stellar evolution timescales if the AGB population is included. We have no clear explanation for this observation.
The spin Hall effect in a quantum gas p.201
Electronic properties such as current flow are generally independent of the electron’s spin angular momentum, an internal degree of freedom possessed by quantum particles. The spin Hall effect, first proposed 40 years ago, is an unusual class of phenomena in which flowing particles experience orthogonally directed, spin-dependent forces—analogous to the conventional Lorentz force that gives the Hall effect, but opposite in sign for two spin states. Spin Hall effects have been observed for electrons flowing in spin–orbit-coupled materials such as GaAs and InGaAs (refs 2, 3) and for laser light traversing dielectric junctions. Here we observe the spin Hall effect in a quantum-degenerate Bose gas, and use the resulting spin-dependent Lorentz forces to realize a cold-atom spin transistor. By engineering a spatially inhomogeneous spin–orbit coupling field for our quantum gas, we explicitly introduce and measure the requisite spin-dependent Lorentz forces, finding them to be in excellent agreement with our calculations. This ‘atomtronic’ transistor behaves as a type of velocity-insensitive adiabatic spin selector, with potential application in devices such as magnetic or inertial sensors. In addition, such techniques for creating and measuring the spin Hall effect are clear prerequisites for engineering topological insulators and detecting their associated quantized spin Hall effects in quantum gases. As implemented, our system realizes a laser-actuated analogue to the archetypal semiconductor spintronic device, the Datta–Das spin transistor.
A temporal cloak at telecommunication data rate p.205
Through advances in metamaterials—artificially engineered media with exotic properties, including negative refractive index—the once fanciful invisibility cloak has now assumed a prominent place in scientific research. By extending these concepts to the temporal domain, investigators have recently described a cloak which hides events in time by creating a temporal gap in a probe beam that is subsequently closed up; any interaction which takes place during this hole in time is not detected. However, these results are limited to isolated events that fill a tiny portion of the temporal period, giving a fractional cloaking window of only about 10−4 per cent at a repetition rate of 41 kilohertz (ref. 15)—which is much too low for applications such as optical communications. Here we demonstrate another technique for temporal cloaking, which operates at telecommunication data rates and, by exploiting temporal self-imaging through the Talbot effect, hides optical data from a receiver. We succeed in cloaking 46 per cent of the entire time axis and conceal pseudorandom digital data at a rate of 12.7 gigabits per second. This potential to cloak real-world messages introduces temporal cloaking into the sphere of practical application, with immediate ramifications in secure communications.
Heat dissipation in atomic-scale junctions p.209
Atomic and single-molecule junctions represent the ultimate limit to the miniaturization of electrical circuits. They are also ideal platforms for testing quantum transport theories that are required to describe charge and energy transfer in novel functional nanometre-scale devices. Recent work has successfully probed electric and thermoelectric phenomena in atomic-scale junctions. However, heat dissipation and transport in atomic-scale devices remain poorly characterized owing to experimental challenges. Here we use custom-fabricated scanning probes with integrated nanoscale thermocouples to investigate heat dissipation in the electrodes of single-molecule (‘molecular’) junctions. We find that if the junctions have transmission characteristics that are strongly energy dependent, this heat dissipation is asymmetric—that is, unequal between the electrodes—and also dependent on both the bias polarity and the identity of the majority charge carriers (electrons versus holes). In contrast, junctions consisting of only a few gold atoms (‘atomic junctions’) whose transmission characteristics show weak energy dependence do not exhibit appreciable asymmetry. Our results unambiguously relate the electronic transmission characteristics of atomic-scale junctions to their heat dissipation properties, establishing a framework for understanding heat dissipation in a range of mesoscopic systems where transport is elastic—that is, without exchange of energy in the contact region. We anticipate that the techniques established here will enable the study of Peltier effects at the atomic scale, a field that has been barely explored experimentally despite interesting theoretical predictions. Furthermore, the experimental advances described here are also expected to enable the study of heat transport in atomic and molecular junctions—an important and challenging scientific and technological goal that has remained elusive.
Small effect of water on upper-mantle rheology based on silicon self-diffusion coefficients p.213
Water has been thought to affect the dynamical processes in the Earth’s interior to a great extent. In particular, experimental deformation results suggest that even only a few tens of parts per million of water by weight enhances the creep rates in olivine by orders of magnitude. However, those deformation studies have limitations, such as considering only a limited range of water concentrations and very high stresses, which might affect the results. Rock deformation can also be understood as an effect of silicon self-diffusion, because the creep rates of minerals at temperatures as high as those in the Earth’s interior are limited by self-diffusion of the slowest species. Here we experimentally determine the silicon self-diffusion coefficient DSi in forsterite at 8 GPa and 1,600 K to 1,800 K as a function of water content CH2O from less than 1 to about 800 parts per million of water by weight, yielding the relationship, DSi ≈ (CH2O)1/3. This exponent is strikingly lower than that obtained by deformation experiments (1.2; ref. 7). The high nominal creep rates in the deformation studies under wet conditions may be caused by excess grain boundary water. We conclude that the effect of water on upper-mantle rheology is very small. Hence, the smooth motion of the Earth’s tectonic plates cannot be caused by mineral hydration in the asthenosphere. Also, water cannot cause the viscosity minimum zone in the upper mantle. And finally, the dominant mechanism responsible for hotspot immobility cannot be water content differences between their source and surrounding regions.
Barium distributions in teeth reveal early-life dietary transitions in primates p.216
Early-life dietary transitions reflect fundamental aspects of primate evolution and are important determinants of health in contemporary human populations. Weaning is critical to developmental and reproductive rates; early weaning can have detrimental health effects but enables shorter inter-birth intervals, which influences population growth. Uncovering early-life dietary history in fossils is hampered by the absence of prospectively validated biomarkers that are not modified during fossilization. Here we show that large dietary shifts in early life manifest as compositional variations in dental tissues. Teeth from human children and captive macaques, with prospectively recorded diet histories, demonstrate that barium (Ba) distributions accurately reflect dietary transitions from the introduction of mother’s milk through the weaning process. We also document dietary transitions in a Middle Palaeolithic juvenile Neanderthal, which shows a pattern of exclusive breastfeeding for seven months, followed by seven months of supplementation. After this point, Ba levels in enamel returned to baseline prenatal levels, indicating an abrupt cessation of breastfeeding at 1.2 years of age. Integration of Ba spatial distributions and histological mapping of tooth formation enables novel studies of the evolution of human life history, dietary ontogeny in wild primates, and human health investigations through accurate reconstructions of breastfeeding history.
De novo mutations in histone-modifying genes in congenital heart disease p.220
Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent–offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left–right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes ‘poised’ promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.
RIP1-driven autoinflammation targets IL-1α independently of inflammasomes and RIP3 p.224
The protein-tyrosine phosphatase SHP-1 has critical roles in immune signalling, but how mutations in SHP-1 cause inflammatory disease in humans remains poorly defined. Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of SHP-1 (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory syndrome that resembles neutrophilic dermatosis in humans and is characterized by persistent footpad swelling and suppurative inflammation. Here we report that receptor-interacting protein 1 (RIP1)-regulated interleukin (IL)-1α production by haematopoietic cells critically mediates chronic inflammatory disease in Ptpn6spin mice, whereas inflammasome signalling and IL-1β-mediated events are dispensable. IL-1α was also crucial for exacerbated inflammatory responses and unremitting tissue damage upon footpad microabrasion of Ptpn6spin mice. Notably, pharmacological and genetic blockade of the kinase RIP1 protected against wound-induced inflammation and tissue damage in Ptpn6spin mice, whereas RIP3 deletion failed to do so. Moreover, RIP1-mediated inflammatory cytokine production was attenuated by NF-κB and ERK inhibition. Together, our results indicate that wound-induced tissue damage and chronic inflammation in Ptpn6spin mice are critically dependent on RIP1-mediated IL-1α production, whereas inflammasome signalling and RIP3-mediated necroptosis are dispensable. Thus, we have unravelled a novel inflammatory circuit in which RIP1-mediated IL-1α secretion in response to deregulated SHP-1 activity triggers an inflammatory destructive disease that proceeds independently of inflammasomes and programmed necrosis.
Vector transmission regulates immune control of Plasmodium virulence p.228
Defining mechanisms by which Plasmodium virulence is regulated is central to understanding the pathogenesis of human malaria. Serial blood passage of Plasmodium through rodents, primates or humans increases parasite virulence, suggesting that vector transmission regulates Plasmodium virulence within the mammalian host. In agreement, disease severity can be modified by vector transmission, which is assumed to ‘reset’ Plasmodium to its original character. However, direct evidence that vector transmission regulates Plasmodium virulence is lacking. Here we use mosquito transmission of serially blood passaged (SBP) Plasmodium chabaudi chabaudi to interrogate regulation of parasite virulence. Analysis of SBP P. c. chabaudi before and after mosquito transmission demonstrates that vector transmission intrinsically modifies the asexual blood-stage parasite, which in turn modifies the elicited mammalian immune response, which in turn attenuates parasite growth and associated pathology. Attenuated parasite virulence associates with modified expression of the pir multi-gene family. Vector transmission of Plasmodium therefore regulates gene expression of probable variant antigens in the erythrocytic cycle, modifies the elicited mammalian immune response, and thus regulates parasite virulence. These results place the mosquito at the centre of our efforts to dissect mechanisms of protective immunity to malaria for the development of an effective vaccine.
Negligible impact of rare autoimmune-locus coding-region variants on missing heritability p.232
Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect.
Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells p.236
Recent molecular studies have shown that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels and phenotypic output, with important functional consequences. Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs or proteins simultaneously, because genomic profiling methods could not be applied to single cells until very recently. Here we use single-cell RNA sequencing to investigate heterogeneity in the response of mouse bone-marrow-derived dendritic cells (BMDCs) to lipopolysaccharide. We find extensive, and previously unobserved, bimodal variation in messenger RNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit, involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits.
MBNL proteins repress ES-cell-specific alternative splicing and reprogramming p.241
Previous investigations of the core gene regulatory circuitry that controls the pluripotency of embryonic stem (ES) cells have largely focused on the roles of transcription, chromatin and non-coding RNA regulators. Alternative splicing represents a widely acting mode of gene regulation, yet its role in regulating ES-cell pluripotency and differentiation is poorly understood. Here we identify the muscleblind-like RNA binding proteins, MBNL1 and MBNL2, as conserved and direct negative regulators of a large program of cassette exon alternative splicing events that are differentially regulated between ES cells and other cell types. Knockdown of MBNL proteins in differentiated cells causes switching to an ES-cell-like alternative splicing pattern for approximately half of these events, whereas overexpression of MBNL proteins in ES cells promotes differentiated-cell-like alternative splicing patterns. Among the MBNL-regulated events is an ES-cell-specific alternative splicing switch in the forkhead family transcription factor FOXP1 that controls pluripotency. Consistent with a central and negative regulatory role for MBNL proteins in pluripotency, their knockdown significantly enhances the expression of key pluripotency genes and the formation of induced pluripotent stem cells during somatic cell reprogramming.
The bromodomain protein Brd4 insulates chromatin from DNA damage signalling p.246
DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.
Chromosome-specific nonrandom sister chromatid segregation during stem-cell division p.251
Adult stem cells undergo asymmetric cell division to self-renew and give rise to differentiated cells that comprise mature tissue. Sister chromatids may be distinguished and segregated nonrandomly in asymmetrically dividing stem cells, although the underlying mechanism and the purpose it may serve remain elusive. Here we develop the CO-FISH (chromosome orientation fluorescence in situ hybridization) technique with single-chromosome resolution and show that sister chromatids of X and Y chromosomes, but not autosomes, are segregated nonrandomly during asymmetric divisions of Drosophila male germline stem cells. This provides the first direct evidence, to our knowledge, that two sister chromatids containing identical genetic information can be distinguished and segregated nonrandomly during asymmetric stem-cell divisions. We further show that the centrosome, SUN–KASH nuclear envelope proteins and Dnmt2 (also known as Mt2) are required for nonrandom sister chromatid segregation. Our data indicate that the information on X and Y chromosomes that enables nonrandom segregation is primed during gametogenesis in the parents. Moreover, we show that sister chromatid segregation is randomized in germline stem cell overproliferation and dedifferentiated germline stem cells. We propose that nonrandom sister chromatid segregation may serve to transmit distinct information carried on two sister chromatids to the daughters of asymmetrically dividing stem cells.