Volume 499 Issue 7459


Plastic fantastic p.379

A resurgence in organic technology is set to transform the world of electronic devices, offering a way to give the very fabric of life enhanced functionality.

doi: 10.1038/499379a

Antibiotic threat p.379

In the fight to combat antibiotic resistance, researchers should strengthen their advocacy.

doi: 10.1038/499379b


News Features

The last resort p.394

Health officials are watching in horror as bacteria become resistant to powerful carbapenem antibiotics — one of the last drugs on the shelf.

doi: 10.1038/499394a

Farming up trouble p.398

Microbiologists are trying to work out whether use of antibiotics on farms is fuelling the human epidemic of drug-resistant bacteria.

doi: 10.1038/499398a

News & Views

Pathways to human adaptation p.412

An outbreak of avian H7N9 influenza in humans was reported in early 2013. Structural and infection studies are helping to reveal how these viruses can adapt to infect, and potentially transmit in, new species. See Letters p.496 & p.500

doi: 10.1038/nature12455

Dark and heavy p.413

Whenever a medium's dispersion and nonlinear properties appear hand in hand, particle-like entities known as solitons can form. These have now been observed in a gas of strongly interacting fermionic atoms. See Article p.426

doi: 10.1038/nature12454

Tumour stem cells in bone p.414

Activation of the signalling molecule SHP2 is implicated in driving several cancers. In a newly described class of bone-progenitor cells, however, it seems that the protein acts as a tumour suppressor. See Letter p.491

doi: 10.1038/nature12412

How to catch a galactic wind p.416

Observations obtained by the Atacama Large Millimeter Array in Chile's Atacama Desert have revealed properties of the cold molecular phase of the wind that is being blown out of a nearby starburst galaxy. See Letter p.450

doi: 10.1038/499416a

Meet the B family p.417

The first crystal structures of class B G-protein-coupled receptors have been solved. They reveal features that might inform drug-development strategies for diseases ranging from osteoporosis to diabetes. See Articles p.438 & p.444

doi: 10.1038/nature12413


Van der Waals heterostructures p.419

Research on graphene and other two-dimensional atomic crystals is intense and is likely to remain one of the leading topics in condensed matter physics and materials science for many years. Looking beyond this field, isolated atomic planes can also be reassembled into designer heterostructures made layer by layer in a precisely chosen sequence. The first, already remarkably complex, such heterostructures (often referred to as ‘van der Waals’) have recently been fabricated and investigated, revealing unusual properties and new phenomena. Here we review this emerging research area and identify possible future directions. With steady improvement in fabrication techniques and using graphene’s springboard, van der Waals heterostructures should develop into a large field of their own.

doi: 10.1038/nature12385


Heavy solitons in a fermionic superfluid p.426

Solitons — solitary waves that maintain their shape as they propagate — in a strongly interacting superfluid of fermionic lithium atoms are found to have an effective mass more than 50 times larger than the theoretically predicted value, a sign of strong quantum fluctuations.

doi: 10.1038/nature12338

Insights into the phylogeny and coding potential of microbial dark matter OPEN p.431

Uncultivated archaeal and bacterial cells of major uncharted branches of the tree of life are targeted and sequenced using single-cell genomics; this enables resolution of many intra- and inter-phylum-level relationships, uncovers unexpected metabolic features that challenge established boundaries between the three domains of life, and leads to the proposal of two new superphyla.

doi: 10.1038/nature12352

Structure of class B GPCR corticotropin-releasing factor receptor 1 p.438

Approximately 30% of known drugs target G protein-coupled receptors (GPCRs), but all the published structures of GPCRs to date are from the class A family of GPCRs; here the first X-ray crystal structure of a member of the class B family of GPCRs, the human corticotropin-releasing factor receptor 1, is determined.

doi: 10.1038/nature12357


Suppression of star formation in the galaxy NGC 253 by a starburst-driven molecular wind p.450

The under-abundance of very massive galaxies in the Universe is frequently attributed to the effect of galactic winds. Although ionized galactic winds are readily observable, most of the expelled mass (that is, the total mass flowing out from the nuclear region) is likely to be in atomic and molecular phases that are cooler than the ionized phases. Expanding molecular shells observed in starburst systems such as NGC 253 (ref. 12) and M 82 (refs 13, 14) may facilitate the entrainment of molecular gas in the wind. Although shell properties are well constrained, determining the amount of outflowing gas emerging from such shells and the connection between this gas and the ionized wind requires spatial resolution better than 100 parsecs coupled with sensitivity to a wide range of spatial scales, a combination hitherto not available. Here we report observations of NGC 253, a nearby starburst galaxy (distance ∼ 3.4 megaparsecs) known to possess a wind, that trace the cool molecular wind at 50-parsec resolution. At this resolution, the extraplanar molecular gas closely tracks the Hα filaments, and it appears to be connected to expanding molecular shells located in the starburst region. These observations allow us to determine that the molecular outflow rate is greater than 3 solar masses per year and probably about 9 solar masses per year. This implies a ratio of mass-outflow rate to star-formation rate of at least 1, and probably ∼3, indicating that the starburst-driven wind limits the star-formation activity and the final stellar content.

doi: 10.1038/nature12351

Solving the Martian meteorite age conundrum using micro-baddeleyite and launch-generated zircon p.454

Invaluable records of planetary dynamics and evolution can be recovered from the geochemical systematics of single meteorites. However, the interpreted ages of the ejected igneous crust of Mars differ by up to four billion years, a conundrum due in part to the difficulty of using geochemistry alone to distinguish between the ages of formation and the ages of the impact events that launched debris towards Earth. Here we solve the conundrum by combining in situ electron-beam nanostructural analyses and U–Pb (uranium–lead) isotopic measurements of the resistant micromineral baddeleyite (ZrO2) and host igneous minerals in the highly shock-metamorphosed shergottite Northwest Africa 5298 (ref. 8), which is a basaltic Martian meteorite. We establish that the micro-baddeleyite grains pre-date the launch event because they are shocked, cogenetic with host igneous minerals, and preserve primary igneous growth zoning. The grains least affected by shock disturbance, and which are rich in radiogenic Pb, date the basalt crystallization near the Martian surface to 187 ± 33 million years before present. Primitive, non-radiogenic Pb isotope compositions of the host minerals, common to most shergottites, do not help us to date the meteorite, instead indicating a magma source region that was fractionated more than four billion years ago to form a persistent reservoir so far unique to Mars. Local impact melting during ejection from Mars less than 22 ± 2 million years ago caused the growth of unshocked, launch-generated zircon and the partial disturbance of baddeleyite dates. We can thus confirm the presence of ancient, non-convecting mantle beneath young volcanic Mars, place an upper bound on the interplanetary travel time of the ejected Martian crust, and validate a new approach to the geochronology of the inner Solar System.

doi: 10.1038/nature12341

An ultra-lightweight design for imperceptible plastic electronics p.458

Electronic devices have advanced from their heavy, bulky origins to become smart, mobile appliances. Nevertheless, they remain rigid, which precludes their intimate integration into everyday life. Flexible, textile and stretchable electronics are emerging research areas and may yield mainstream technologies. Rollable and unbreakable backplanes with amorphous silicon field-effect transistors on steel substrates only 3 μm thick have been demonstrated. On polymer substrates, bending radii of 0.1 mm have been achieved in flexible electronic devices. Concurrently, the need for compliant electronics that can not only be flexed but also conform to three-dimensional shapes has emerged. Approaches include the transfer of ultrathin polyimide layers encapsulating silicon CMOS circuits onto pre-stretched elastomers, the use of conductive elastomers integrated with organic field-effect transistors (OFETs) on polyimide islands, and fabrication of OFETs and gold interconnects on elastic substrates to realize pressure, temperature and optical sensors. Here we present a platform that makes electronics both virtually unbreakable and imperceptible. Fabricated directly on ultrathin (1 μm) polymer foils, our electronic circuits are light (3 g m−2) and ultraflexible and conform to their ambient, dynamic environment. Organic transistors with an ultra-dense oxide gate dielectric a few nanometres thick formed at room temperature enable sophisticated large-area electronic foils with unprecedented mechanical and environmental stability: they withstand repeated bending to radii of 5 μm and less, can be crumpled like paper, accommodate stretching up to 230% on prestrained elastomers, and can be operated at high temperatures and in aqueous environments. Because manufacturing costs of organic electronics are potentially low, imperceptible electronic foils may be as common in the future as plastic wrap is today. Applications include matrix-addressed tactile sensor foils for health care and monitoring, thin-film heaters, temperature and infrared sensors, displays, and organic solar cells.

doi: 10.1038/nature12314

North Atlantic Ocean control on surface heat flux on multidecadal timescales p.464

Nearly 50 years ago Bjerknes suggested that the character of large-scale air–sea interaction over the mid-latitude North Atlantic Ocean differs with timescales: the atmosphere was thought to drive directly most short-term—interannual—sea surface temperature (SST) variability, and the ocean to contribute significantly to long-term—multidecadal—SST and potentially atmospheric variability. Although the conjecture for short timescales is well accepted, understanding Atlantic multidecadal variability (AMV) of SST remains a challenge as a result of limited ocean observations. AMV is nonetheless of major socio-economic importance because it is linked to important climate phenomena such as Atlantic hurricane activity and Sahel rainfall, and it hinders the detection of anthropogenic signals in the North Atlantic sector. Direct evidence of the oceanic influence of AMV can only be provided by surface heat fluxes, the language of ocean–atmosphere communication. Here we provide observational evidence that in the mid-latitude North Atlantic and on timescales longer than 10 years, surface turbulent heat fluxes are indeed driven by the ocean and may force the atmosphere, whereas on shorter timescales the converse is true, thereby confirming the Bjerknes conjecture. This result, although strongest in boreal winter, is found in all seasons. Our findings suggest that the predictability of mid-latitude North Atlantic air–sea interaction could extend beyond the ocean to the climate of surrounding continents.

doi: 10.1038/nature12268

High frequency of functional extinctions in ecological networks p.468

Intensified exploitation of natural populations and habitats has led to increased mortality rates and decreased abundances of many species. There is a growing concern that this might cause critical abundance thresholds of species to be crossed, with extinction cascades and state shifts in ecosystems as a consequence. When increased mortality rate and decreased abundance of a given species lead to extinction of other species, this species can be characterized as functionally extinct even though it still exists. Although such functional extinctions have been observed in some ecosystems, their frequency is largely unknown. Here we use a new modelling approach to explore the frequency and pattern of functional extinctions in ecological networks. Specifically, we analytically derive critical abundance thresholds of species by increasing their mortality rates until an extinction occurs in the network. Applying this approach on natural and theoretical food webs, we show that the species most likely to go extinct first is not the one whose mortality rate is increased but instead another species. Indeed, up to 80% of all first extinctions are of another species, suggesting that a species’ ecological functionality is often lost before its own existence is threatened. Furthermore, we find that large-bodied species at the top of the food chains can only be exposed to small increases in mortality rate and small decreases in abundance before going functionally extinct compared to small-bodied species lower in the food chains. These results illustrate the potential importance of functional extinctions in ecological networks and lend strong support to arguments advocating a more community-oriented approach in conservation biology, with target levels for populations based on ecological functionality rather than on mere persistence.

doi: 10.1038/nature12277

Great ape genetic diversity and population history OPEN p.471

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria–Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

doi: 10.1038/nature12228

Attention enhances synaptic efficacy and the signal-to-noise ratio in neural circuits p.476

Attention is a critical component of perception. However, the mechanisms by which attention modulates neuronal communication to guide behaviour are poorly understood. To elucidate the synaptic mechanisms of attention, we developed a sensitive assay of attentional modulation of neuronal communication. In alert monkeys performing a visual spatial attention task, we probed thalamocortical communication by electrically stimulating neurons in the lateral geniculate nucleus of the thalamus while simultaneously recording shock-evoked responses from monosynaptically connected neurons in primary visual cortex. We found that attention enhances neuronal communication by increasing the efficacy of presynaptic input in driving postsynaptic responses, by increasing synchronous responses among ensembles of postsynaptic neurons receiving independent input, and by decreasing redundant signals between postsynaptic neurons receiving common input. The results demonstrate that attention finely tunes neuronal communication at the synaptic level by selectively altering synaptic weights, enabling enhanced detection of salient events in the noisy sensory environment.

doi: 10.1038/nature12276

Vascularized and functional human liver from an iPSC-derived organ bud transplant p.481

A critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from human induced pluripotent stem cells (iPSCs). Despite many reports describing functional cell differentiation, no studies have succeeded in generating a three-dimensional vascularized organ such as liver. Here we show the generation of vascularized and functional human liver from human iPSCs by transplantation of liver buds created in vitro (iPSC-LBs). Specified hepatic cells (immature endodermal cells destined to track the hepatic cell fate) self-organized into three-dimensional iPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells. Immunostaining and gene-expression analyses revealed a resemblance between in vitro grown iPSC-LBs and in vivo liver buds. Human vasculatures in iPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of iPSC-LBs into tissue resembling the adult liver. Highly metabolic iPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement. Furthermore, mesenteric transplantation of iPSC-LBs rescued the drug-induced lethal liver failure model. To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells. Although efforts must ensue to translate these techniques to treatments for patients, this proof-of-concept demonstration of organ-bud transplantation provides a promising new approach to study regenerative medicine.

doi: 10.1038/nature12271

mTORC1 couples immune signals and metabolic programming to establish Treg-cell function p.485

The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T-cell fate decisions. The activation of mTOR, which is the catalytic subunit of the mTORC1 and mTORC2 complexes, delivers an obligatory signal for the proper activation and differentiation of effector CD4+ T cells, whereas in the regulatory T-cell (Treg) compartment, the Akt–mTOR axis is widely acknowledged as a crucial negative regulator of Treg-cell de novo differentiation and population expansion. However, whether mTOR signalling affects the homeostasis and function of Treg cells remains largely unexplored. Here we show that mTORC1 signalling is a pivotal positive determinant of Treg-cell function in mice. Treg cells have elevated steady-state mTORC1 activity compared to naive T cells. Signals through the T-cell antigen receptor (TCR) and interleukin-2 (IL-2) provide major inputs for mTORC1 activation, which in turn programs the suppressive function of Treg cells. Disruption of mTORC1 through Treg-specific deletion of the essential component raptor leads to a profound loss of Treg-cell suppressive activity in vivo and the development of a fatal early onset inflammatory disorder. Mechanistically, raptor/mTORC1 signalling in Treg cells promotes cholesterol and lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg-cell proliferation and upregulation of the suppressive molecules CTLA4 and ICOS to establish Treg-cell functional competency. By contrast, mTORC1 does not directly affect the expression of Foxp3 or anti- and pro-inflammatory cytokines in Treg cells, suggesting a non-conventional mechanism for Treg-cell functional regulation. Finally, we provide evidence that mTORC1 maintains Treg-cell function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Treg cells to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg-cell suppressive activity in immune homeostasis and tolerance.

doi: 10.1038/nature12297

Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling p.491

The tyrosine phosphatase SHP2, encoded by PTPN11, is required for the survival, proliferation and differentiation of various cell types. Germline activating mutations in PTPN11 cause Noonan syndrome, whereas somatic PTPN11 mutations cause childhood myeloproliferative disease and contribute to some solid tumours. Recently, heterozygous inactivating mutations in PTPN11 were found in metachondromatosis, a rare inherited disorder featuring multiple exostoses, enchondromas, joint destruction and bony deformities. The detailed pathogenesis of this disorder has remained unclear. Here we use a conditional knockout (floxed) Ptpn11 allele (Ptpn11fl) and Cre recombinase transgenic mice to delete Ptpn11 specifically in monocytes, macrophages and osteoclasts (lysozyme M-Cre; LysMCre) or in cathepsin K (Ctsk)-expressing cells, previously thought to be osteoclasts. LysMCre;Ptpn11fl/fl mice had mild osteopetrosis. Notably, however, CtskCre;Ptpn11fl/fl mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors. Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh) and parathyroid hormone-related protein (Pthrp, also known as Pthlh) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR) or mitogen-activated protein kinase kinase (MEK) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened inhibitor treatment ameliorated metachondromatosis features in CtskCre;Ptpn11fl/fl mice. Thus, in contrast to its pro-oncogenic role in haematopoietic and epithelial cells, Ptpn11 is a tumour suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.

doi: 10.1038/nature12396

Receptor binding by an H7N9 influenza virus from humans p.496

Of the 132 people known to have been infected with H7N9 influenza viruses in China, 37 died, and many were severely ill. Infection seems to have involved contact with infected poultry. We have examined the receptor-binding properties of this H7N9 virus and compared them with those of an avian H7N3 virus. We find that the human H7 virus has significantly higher affinity for α-2,6-linked sialic acid analogues (‘human receptor’) than avian H7 while retaining the strong binding to α-2,3-linked sialic acid analogues (‘avian receptor’) characteristic of avian viruses. The human H7 virus does not, therefore, have the preference for human versus avian receptors characteristic of pandemic viruses. X-ray crystallography of the receptor-binding protein, haemagglutinin (HA), in complex with receptor analogues indicates that both human and avian receptors adopt different conformations when bound to human H7 HA than they do when bound to avian H7 HA. Human receptor bound to human H7 HA exits the binding site in a different direction to that seen in complexes formed by HAs from pandemic viruses and from an aerosol-transmissible H5 mutant. The human-receptor-binding properties of human H7 probably arise from the introduction of two bulky hydrophobic residues by the substitutions Gln226Leu and Gly186Val. The former is shared with the 1957 H2 and 1968 H3 pandemic viruses and with the aerosol-transmissible H5 mutant. We conclude that the human H7 virus has acquired some of the receptor-binding characteristics that are typical of pandemic viruses, but its retained preference for avian receptor may restrict its further evolution towards a virus that could transmit efficiently between humans, perhaps by binding to avian-receptor-rich mucins in the human respiratory tract rather than to cellular receptors.

doi: 10.1038/nature12372

Biological features of novel avian influenza A (H7N9) virus p.500

Human infection associated with a novel reassortant avian influenza H7N9 virus has recently been identified in China. A total of 132 confirmed cases and 39 deaths have been reported. Most patients presented with severe pneumonia and acute respiratory distress syndrome. Although the first epidemic has subsided, the presence of a natural reservoir and the disease severity highlight the need to evaluate its risk on human public health and to understand the possible pathogenesis mechanism. Here we show that the emerging H7N9 avian influenza virus poses a potentially high risk to humans. We discover that the H7N9 virus can bind to both avian-type (α2,3-linked sialic acid) and human-type (α2,6-linked sialic acid) receptors. It can invade epithelial cells in the human lower respiratory tract and type II pneumonocytes in alveoli, and replicated efficiently in ex vivo lung and trachea explant culture and several mammalian cell lines. In acute serum samples of H7N9-infected patients, increased levels of the chemokines and cytokines IP-10, MIG, MIP-1β, MCP-1, IL-6, IL-8 and IFN-α were detected. We note that the human population is naive to the H7N9 virus, and current seasonal vaccination could not provide protection.

doi: 10.1038/nature12379