Volume 506 Issue 7489


Fish have feelings too p.407

Our obligation to keep the suffering of laboratory animals to a minimum — both in life and in death — does not apply only to mammals.

doi: 10.1038/506407a

Virgin territory p.408

Putting a private craft into space requires vision, hard work and a big dose of optimism.

doi: 10.1038/506408a


News Features

Strength in numbers p.422

Researchers are finding that online, crowd-sourced collaboration can speed up their work — if they choose the right problem.

doi: 10.1038/506422a

Disease detectives p.424

A powerful method for deducing microbial relationships has been edging its way into civil and criminal investigations. But courts should proceed with caution.

doi: 10.1038/506424a

News & Views

Drug discovery goes au naturel p.436

In a study that showcases the potential of semisynthetic drug design, structural modification of an existing antibiotic with little activity against Mycobacterium tuberculosis has generated a new class of effective antitubercular lead.

doi: 10.1038/506436a

Optical trapping for space mirrors p.437

Might it be possible to create mirrors for space telescopes, using nothing but microscopic particles held in place by light? A study that exploits a technique called optical binding provides a step towards this goal.

doi: 10.1038/506437a

Tumours outside the mutation box p.438

Analyses of ependymoma brain tumours reveal a gene rearrangement in one subtype, but no DNA mutations in two others, suggesting that mechanisms for cancer initiation are broader than is typically thought. See Articles p.445 & p.451

doi: 10.1038/nature13061

The teamwork of precision p.440

A new value for the atomic mass of the electron is a link in a chain of measurements that will enable a test of the standard model of particle physics with better than part-per-trillion precision. See Letter p.467

doi: 10.1038/nature13059

Stressful genetics in Crohn's disease p.441

A common variant of the autophagy protein ATG16L1 is a risk factor for Crohn's disease. But the genetic alteration is revealed only when the protein is cleaved by the enzyme caspase 3 during cellular stress. See Article p.456

doi: 10.1038/nature13060

Involatile particles from rapid oxidation p.442

How tiny aerosol particles form and grow from vapours produced by vegetation has been a mystery. The finding that highly oxygenated products form directly from volatile organic compounds may offer the solution. See Letter p.476

doi: 10.1038/506442a


Epigenomic alterations define lethal CIMP-positive ependymomas of infancy p.445

Although genetically bland, the posterior fossa group A subgroup of ependymomas, found often in infants and associated with poor prognosis, exhibit widespread epigenetic alterations, namely a CpG island methylator phenotype; these tumours are shown to be susceptible both in vitro and in vivo to various compounds that target epigenetic modifications, such as DNA methylation and H3K27 tri-methylation.

doi: 10.1038/nature13108

C11orf95RELA fusions drive oncogenic NF-κB signalling in ependymoma p.451

At least two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of nuclear factor-κB (NF-κB) signalling, and uncharacterized gene C11orf95; C11orf95–RELA fusion proteins translocate spontaneously to the nucleus to activate NF-κB target genes, and rapidly transform neural stem cells to form tumours in mice

doi: 10.1038/nature13109


A single low-energy, iron-poor supernova as the source of metals in the star SMSS J031300.36−670839.3 p.463

The element abundance ratios of four low-mass stars with extremely low metallicities (abundances of elements heavier than helium) indicate that the gas out of which the stars formed was enriched in each case by at most a few—and potentially only one—low-energy supernova. Such supernovae yield large quantities of light elements such as carbon but very little iron. The dominance of low-energy supernovae seems surprising, because it had been expected that the first stars were extremely massive, and that they disintegrated in pair-instability explosions that would rapidly enrich galaxies in iron. What has remained unclear is the yield of iron from the first supernovae, because hitherto no star has been unambiguously interpreted as encapsulating the yield of a single supernova. Here we report the optical spectrum of SMSS J031300.36−670839.3, which shows no evidence of iron (with an upper limit of 10−7.1 times solar abundance). Based on a comparison of its abundance pattern with those of models, we conclude that the star was seeded with material from a single supernova with an original mass about 60 times that of the Sun (and that the supernova left behind a black hole). Taken together with the four previously mentioned low-metallicity stars, we conclude that low-energy supernovae were common in the early Universe, and that such supernovae yielded light-element enrichment with insignificant iron. Reduced stellar feedback both chemically and mechanically from low-energy supernovae would have enabled first-generation stars to form over an extended period. We speculate that such stars may perhaps have had an important role in the epoch of cosmic reionization and the chemical evolution of early galaxies.

doi: 10.1038/nature12990

High-precision measurement of the atomic mass of the electron p.467

The quest for the value of the electron’s atomic mass has been the subject of continuing efforts over the past few decades. Among the seemingly fundamental constants that parameterize the Standard Model of physics and which are thus responsible for its predictive power, the electron mass me is prominent, being responsible for the structure and properties of atoms and molecules. It is closely linked to other fundamental constants, such as the Rydberg constant R and the fine-structure constant α (ref. 6). However, the low mass of the electron considerably complicates its precise determination. Here we combine a very precise measurement of the magnetic moment of a single electron bound to a carbon nucleus with a state-of-the-art calculation in the framework of bound-state quantum electrodynamics. The precision of the resulting value for the atomic mass of the electron surpasses the current literature value of the Committee on Data for Science and Technology (CODATA) by a factor of 13. This result lays the foundation for future fundamental physics experiments and precision tests of the Standard Model.

doi: 10.1038/nature13026

Quantum droplets of electrons and holes p.471

Interacting many-body systems are characterized by stable configurations of objects—ranging from elementary particles to cosmological formations—that also act as building blocks for more complicated structures. It is often possible to incorporate interactions in theoretical treatments of crystalline solids by introducing suitable quasiparticles that have an effective mass, spin or charge which in turn affects the material’s conductivity, optical response or phase transitions. Additional quasiparticle interactions may also create strongly correlated configurations yielding new macroscopic phenomena, such as the emergence of a Mott insulator, superconductivity or the pseudogap phase of high-temperature superconductors. In semiconductors, a conduction-band electron attracts a valence-band hole (electronic vacancy) to create a bound pair, known as an exciton, which is yet another quasiparticle. Two excitons may also bind together to give molecules, often referred to as biexcitons, and even polyexcitons may exist. In indirect-gap semiconductors such as germanium or silicon, a thermodynamic phase transition may produce electron–hole droplets whose diameter can approach the micrometre range. In direct-gap semiconductors such as gallium arsenide, the exciton lifetime is too short for such a thermodynamic process. Instead, different quasiparticle configurations are stabilized dominantly by many-body interactions, not by thermalization. The resulting non-equilibrium quantum kinetics is so complicated that stable aggregates containing three or more Coulomb-correlated electron–hole pairs remain mostly unexplored. Here we study such complex aggregates and identify a new stable configuration of charged particles that we call a quantum droplet. This configuration exists in a plasma and exhibits quantization owing to its small size. It is charge neutral and contains a small number of particles with a pair-correlation function that is characteristic of a liquid. We present experimental and theoretical evidence for the existence of quantum droplets in an electron–hole plasma created in a gallium arsenide quantum well by ultrashort optical pulses.

doi: 10.1038/nature12994

A large source of low-volatility secondary organic aerosol p.476

The link between biogenic volatile organic compounds in the atmosphere and their conversion to aerosol particles is unclear, but a direct reaction pathway is now described by which volatile organic compounds lead to low-volatility vapours that can then condense onto aerosol surfaces, producing secondary organic aerosol.

doi: 10.1038/nature13032

Rapid remobilization of magmatic crystals kept in cold storage p.480

The processes involved in the formation and storage of magma within the Earth’s upper crust are of fundamental importance to volcanology. Many volcanic eruptions, including some of the largest, result from the eruption of components stored for tens to hundreds of thousands of years before eruption. Although the physical conditions of magma storage and remobilization are of paramount importance for understanding volcanic processes, they remain relatively poorly known. Eruptions of crystal-rich magma are often suggested to require the mobilization of magma stored at near-solidus conditions; however, accumulation of significant eruptible magma volumes has also been argued to require extended storage of magma at higher temperatures. What has been lacking in this debate is clear observational evidence linking the thermal (and therefore physical) conditions within a magma reservoir to timescales of storage—that is, thermal histories. Here we present a method of constraining such thermal histories by combining timescales derived from uranium-series disequilibria, crystal sizes and trace-element zoning in crystals. At Mount Hood (Oregon, USA), only a small fraction of the total magma storage duration (at most 12 per cent and probably much less than 1 per cent) has been spent at temperatures above the critical crystallinity (40–50 per cent) at which magma is easily mobilized. Partial data sets for other volcanoes also suggest that similar conditions of magma storage are widespread and therefore that rapid mobilization of magmas stored at near-solidus temperatures is common. Magma storage at low temperatures indicates that, although thermobarometry calculations based on mineral compositions may record the conditions of crystallization, they are unlikely to reflect the conditions of most of the time that the magma is stored. Our results also suggest that largely liquid magma bodies that can be imaged geophysically will be ephemeral features and therefore their detection could indicate imminent eruption.

doi: 10.1038/nature12991

Skin pigmentation provides evidence of convergent melanism in extinct marine reptiles p.484

Throughout the animal kingdom, adaptive colouration serves critical functions ranging from inconspicuous camouflage to ostentatious sexual display, and can provide important information about the environment and biology of a particular organism. The most ubiquitous and abundant pigment, melanin, also has a diverse range of non-visual roles, including thermoregulation in ectotherms. However, little is known about the functional evolution of this important biochrome through deep time, owing to our limited ability to unambiguously identify traces of it in the fossil record. Here we present direct chemical evidence of pigmentation in fossilized skin, from three distantly related marine reptiles: a leatherback turtle, a mosasaur and an ichthyosaur. We demonstrate that dark traces of soft tissue in these fossils are dominated by molecularly preserved eumelanin, in intimate association with fossilized melanosomes. In addition, we suggest that contrary to the countershading of many pelagic animals, at least some ichthyosaurs were uniformly dark-coloured in life. Our analyses expand current knowledge of pigmentation in fossil integument beyond that of feathers, allowing for the reconstruction of colour over much greater ranges of extinct taxa and anatomy. In turn, our results provide evidence of convergent melanism in three disparate lineages of secondarily aquatic tetrapods. Based on extant marine analogues, we propose that the benefits of thermoregulation and/or crypsis are likely to have contributed to this melanisation, with the former having implications for the ability of each group to exploit cold environments.

doi: 10.1038/nature12899

Sequential evolution of bacterial morphology by co-option of a developmental regulator p.489

What mechanisms underlie the transitions responsible for the diverse shapes observed in the living world? Although bacteria exhibit a myriad of morphologies, the mechanisms responsible for the evolution of bacterial cell shape are not understood. We investigated morphological diversity in a group of bacteria that synthesize an appendage-like extension of the cell envelope called the stalk. The location and number of stalks varies among species, as exemplified by three distinct subcellular positions of stalks within a rod-shaped cell body: polar in the genus Caulobacter and subpolar or bilateral in the genus Asticcacaulis. Here we show that a developmental regulator of Caulobacter crescentus, SpmX, is co-opted in the genus Asticcacaulis to specify stalk synthesis either at the subpolar or bilateral positions. We also show that stepwise evolution of a specific region of SpmX led to the gain of a new function and localization of this protein, which drove the sequential transition in stalk positioning. Our results indicate that changes in protein function, co-option and modularity are key elements in the evolution of bacterial morphology. Therefore, similar evolutionary principles of morphological transitions apply to both single-celled prokaryotes and multicellular eukaryotes.

doi: 10.1038/nature12900

Genetics of single-cell protein abundance variation in large yeast populations p.494

Variation among individuals arises in part from differences in DNA sequences, but the genetic basis for variation in most traits, including common diseases, remains only partly understood. Many DNA variants influence phenotypes by altering the expression level of one or several genes. The effects of such variants can be detected as expression quantitative trait loci (eQTL). Traditional eQTL mapping requires large-scale genotype and gene expression data for each individual in the study sample, which limits sample sizes to hundreds of individuals in both humans and model organisms and reduces statistical power. Consequently, many eQTL are probably missed, especially those with smaller effects. Furthermore, most studies use messenger RNA rather than protein abundance as the measure of gene expression. Studies that have used mass-spectrometry proteomics reported unexpected differences between eQTL and protein QTL (pQTL) for the same genes, but these studies have been even more limited in scope. Here we introduce a powerful method for identifying genetic loci that influence protein expression in the yeast Saccharomyces cerevisiae. We measure single-cell protein abundance through the use of green fluorescent protein tags in very large populations of genetically variable cells, and use pooled sequencing to compare allele frequencies across the genome in thousands of individuals with high versus low protein abundance. We applied this method to 160 genes and detected many more loci per gene than previous studies. We also observed closer correspondence between loci that influence protein abundance and loci that influence mRNA abundance of a given gene. Most loci that we detected were clustered in ‘hotspots’ that influence multiple proteins, and some hotspots were found to influence more than half of the proteins that we examined. The variants that underlie these hotspots have profound effects on the gene regulatory network and provide insights into genetic variation in cell physiology between yeast strains.

doi: 10.1038/nature12904

A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes p.498

A well-balanced human diet includes a significant intake of non-starch polysaccharides, collectively termed ‘dietary fibre’, from the cell walls of diverse fruits and vegetables. Owing to the paucity of alimentary enzymes encoded by the human genome, our ability to derive energy from dietary fibre depends on the saccharification and fermentation of complex carbohydrates by the massive microbial community residing in our distal gut. The xyloglucans (XyGs) are a ubiquitous family of highly branched plant cell wall polysaccharides whose mechanism(s) of degradation in the human gut and consequent importance in nutrition have been unclear. Here we demonstrate that a single, complex gene locus in Bacteroides ovatus confers XyG catabolism in this common colonic symbiont. Through targeted gene disruption, biochemical analysis of all predicted glycoside hydrolases and carbohydrate-binding proteins, and three-dimensional structural determination of the vanguard endo-xyloglucanase, we reveal the molecular mechanisms through which XyGs are hydrolysed to component monosaccharides for further metabolism. We also observe that orthologous XyG utilization loci (XyGULs) serve as genetic markers of XyG catabolism in Bacteroidetes, that XyGULs are restricted to a limited number of phylogenetically diverse strains, and that XyGULs are ubiquitous in surveyed human metagenomes. Our findings reveal that the metabolism of even highly abundant components of dietary fibre may be mediated by niche species, which has immediate fundamental and practical implications for gut symbiont population ecology in the context of human diet, nutrition and health.

doi: 10.1038/nature12907

Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity p.503

The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs, causing AMs to secrete proinflammatory cytokines that activate alveolar epithelial receptors, leading to recruitment of neutrophils that engulf pathogens. Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca2+ waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca2+-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.

doi: 10.1038/nature12902

A new metabolic cell-wall labelling method reveals peptidoglycan in Chlamydia trachomatis p.507

Peptidoglycan (PG), an essential structure in the cell walls of the vast majority of bacteria, is critical for division and maintaining cell shape and hydrostatic pressure. Bacteria comprising the Chlamydiales were thought to be one of the few exceptions. Chlamydia harbour genes for PG biosynthesis and exhibit susceptibility to ‘anti-PG’ antibiotics, yet attempts to detect PG in any chlamydial species have proven unsuccessful (the ‘chlamydial anomaly’). We used a novel approach to metabolically label chlamydial PG using d-amino acid dipeptide probes and click chemistry. Replicating Chlamydia trachomatis were labelled with these probes throughout their biphasic developmental life cycle, and the results of differential probe incorporation experiments conducted in the presence of ampicillin are consistent with the presence of chlamydial PG-modifying enzymes. These findings culminate 50 years of speculation and debate concerning the chlamydial anomaly and are the strongest evidence so far that chlamydial species possess functional PG.

doi: 10.1038/nature12892

Broadly permissive intestinal chromatin underlies lateral inhibition and cell plasticity p.511

Cells differentiate when transcription factors bind accessible cis-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem cells, chromatin at lineage-restricted genes becomes sequentially accessible, probably by means of ‘pioneer’ transcription factor activity, but tissues may use other strategies in vivo. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbours, and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where notch signalling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages. Transcript profiles in isolated LGR5+ intestinal stem cells and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNase I hypersensitivity—signifying accessible, permissive chromatin—at most of the same cis-elements. Enhancers acting uniquely in progenitors were well demarcated in LGR5+ intestinal stem cells, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific transcription factor, controls lateral inhibition through delta-like notch ligand genes and also drives the expression of numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to the presence or absence of a key transcription factor. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted transcription factor with broadly permissive chromatin established in multipotent stem cells.

doi: 10.1038/nature12903