Volume 495 Issue 7440


Form and function p.141

Although debate over scientific definitions is important, it risks obscuring the real issues.

doi: 10.1038/495141b

The antibiotic alarm p.141

There is a growing recognition that action must be taken to deal with the alarming rise in the incidence of bacteria resistant to today’s antibiotics, and its implications for global health.

doi: 10.1038/495141a

Cancer costs p.142

Educating patients is key, but the US National Cancer Institute must keep spending in check.

doi: 10.1038/495142a


News Features

The patchwork array p.156

After years of delays and cost overruns, an international collaboration is finally inaugurating the world's highest-altitude radio telescope.

doi: 10.1038/495156a

Campus 2.0 p.160

Massive open online courses are transforming higher education — and providing fodder for scientific research.

doi: 10.1038/495160a

News & Views

Broad reception for coronavirus p.176

The discovery that a new coronavirus associated with lethal respiratory infections binds to an evolutionarily conserved receptor on airway cells suggests that direct transmission from bats to humans may occur. See Letter p.251

doi: 10.1038/495176a

Core composition revealed p.177

The composition of Earth's core may be easier to resolve than previously thought. Laboratory experiments strengthen the hypothesis that oxygen and silicon are the prime candidates for the light elements present in the outer core.

doi: 10.1038/495177a

Alternative energy for neuronal motors p.178

Neurons use molecular motors to power the transport of cargoes along their axonal extensions. Fresh evidence challenges the view that cellular organelles called mitochondria are the main energy providers for this process.

doi: 10.1038/495178a

Porosity in a single crystal p.180

A low-temperature synthesis has been developed to make single crystals of titanium dioxide that contain pores tens to hundreds of nanometres in size. This opens the way to cheap, highly efficient optoelectronic devices. See Letter p.215

doi: 10.1038/nature11961

Methylation's mark on inheritance p.181

Epigenetic changes to the genome can have heritable effects. An epigenome-wide study of wild plants identifies shared patterns of such modifications and their associations with genetic information. See Article p.193

doi: 10.1038/nature11960

Anatomy of an ovarian cancer p.183

Whether ovarian cancer originates in the ovary or the surrounding tissues is a focus of debate. Work in mice now shows that stem cells that replenish the ovarian surface epithelium can be the initiators of this cancer. See Letter p.241

doi: 10.1038/nature11962

Sleuthing tissue fingerprints p.184

A type of data-acquisition sequence in magnetic resonance imaging has been developed that rapidly and robustly quantifies properties of imaged tissue by elucidating a characteristic signal fingerprint. See Article p.187

doi: 10.1038/495184a


Magnetic resonance fingerprinting p.187

A new approach to magnetic resonance, ‘magnetic resonance fingerprinting', is reported, which combines a data acquisition scheme with a pattern-recognition algorithm that looks for the ‘fingerprints’ of interest within the data.

doi: 10.1038/nature11971

Patterns of population epigenomic diversity p.193

A population epigenomic analysis of wild Arabidopsis thaliana accessions is presented, obtained by sequencing their whole genomes, methylomes and transcriptomes; thousands of DNA methylation variants are identified, some of which are associated with methylation quantitative trait loci.

doi: 10.1038/nature11968

Membrane potential dynamics of grid cells p.199

Intracellular membrane potential changes are measured directly in mouse grid cells during navigation along linear tracks in virtual reality; the recordings reveal that slow ramps of depolarization are the sub-threshold signatures of firing fields, as in attractor network models of grid cells, whereas theta oscillations pace action potential timing.

doi: 10.1038/nature11973


Observation of quantum state collapse and revival due to the single-photon Kerr effect p.205

To create and manipulate non-classical states of light for quantum information protocols, a strong, nonlinear interaction at the single-photon level is required. One approach to the generation of suitable interactions is to couple photons to atoms, as in the strong coupling regime of cavity quantum electrodynamic systems. In these systems, however, the quantum state of the light is only indirectly controlled by manipulating the atoms. A direct photon–photon interaction occurs in so-called Kerr media, which typically induce only weak nonlinearity at the cost of significant loss. So far, it has not been possible to reach the single-photon Kerr regime, in which the interaction strength between individual photons exceeds the loss rate. Here, using a three-dimensional circuit quantum electrodynamic architecture, we engineer an artificial Kerr medium that enters this regime and allows the observation of new quantum effects. We realize a gedanken experiment in which the collapse and revival of a coherent state can be observed. This time evolution is a consequence of the quantization of the light field in the cavity and the nonlinear interaction between individual photons. During the evolution, non-classical superpositions of coherent states (that is, multi-component ‘Schrödinger cat’ states) are formed. We visualize this evolution by measuring the Husimi Q function and confirm the non-classical properties of these transient states by cavity state tomography. The ability to create and manipulate superpositions of coherent states in such a high-quality-factor photon mode opens perspectives for combining the physics of continuous variables with superconducting circuits. The single-photon Kerr effect could be used in quantum non-demolition measurement of photons, single-photon generation, autonomous quantum feedback schemes and quantum logic operations.

doi: 10.1038/nature11902

Coherent state transfer between itinerant microwave fields and a mechanical oscillator p.210

Macroscopic mechanical oscillators have been coaxed into a regime of quantum behaviour by direct refrigeration or a combination of refrigeration and laser-like cooling. This result supports the idea that mechanical oscillators may perform useful functions in the processing of quantum information with superconducting circuits, either by serving as a quantum memory for the ephemeral state of a microwave field or by providing a quantum interface between otherwise incompatible systems. As yet, the transfer of an itinerant state or a propagating mode of a microwave field to and from a storage medium has not been demonstrated, owing to the inability to turn on and off the interaction between the microwave field and the medium sufficiently quickly. Here we demonstrate that the state of an itinerant microwave field can be coherently transferred into, stored in and retrieved from a mechanical oscillator with amplitudes at the single-quantum level. Crucially, the time to capture and to retrieve the microwave state is shorter than the quantum state lifetime of the mechanical oscillator. In this quantum regime, the mechanical oscillator can both store quantum information and enable its transfer between otherwise incompatible systems.

doi: 10.1038/nature11915

Mesoporous TiO2 single crystals delivering enhanced mobility and optoelectronic device performance p.215

Mesoporous ceramics and semiconductors enable low-cost solar power, solar fuel, (photo)catalyst and electrical energy storage technologies. State-of-the-art, printable high-surface-area electrodes are fabricated from thermally sintered pre-formed nanocrystals. Mesoporosity provides the desired highly accessible surfaces but many applications also demand long-range electronic connectivity and structural coherence. A mesoporous single-crystal (MSC) semiconductor can meet both criteria. Here we demonstrate a general synthetic method of growing semiconductor MSCs of anatase TiO2 based on seeded nucleation and growth inside a mesoporous template immersed in a dilute reaction solution. We show that both isolated MSCs and ensembles incorporated into films have substantially higher conductivities and electron mobilities than does nanocrystalline TiO2. Conventional nanocrystals, unlike MSCs, require in-film thermal sintering to reinforce electronic contact between particles, thus increasing fabrication cost, limiting the use of flexible substrates and precluding, for instance, multijunction solar cell processing. Using MSC films processed entirely below 150 °C, we have fabricated all-solid-state, low-temperature sensitized solar cells that have 7.3 per cent efficiency, the highest efficiency yet reported. These high-surface-area anatase single crystals will find application in many different technologies, and this generic synthetic strategy extends the possibility of mesoporous single-crystal growth to a range of functional ceramics and semiconductors.

doi: 10.1038/nature11936

Water and hydrogen are immiscible in Earth’s mantle p.220

In the deep, chemically reducing parts of Earth’s mantle, hydrous fluids contain significant amounts of molecular hydrogen (H2). Thermodynamic models of fluids in Earth’s mantle so far have always assumed that molecular hydrogen and water are completely miscible. Here we show experimental evidence that water and hydrogen can coexist as two separate, immiscible phases. Immiscibility between water and hydrogen may be the cause of the formation of enigmatic, ultra-reducing domains in the mantle that contain moissanite (SiC) and other phases indicative of extremely reducing conditions. Moreover, the immiscibility between water and hydrogen may provide a mechanism for the rapid oxidation of Earth’s upper mantle immediately following core formation.

doi: 10.1038/nature11908

CALHM1 ion channel mediates purinergic neurotransmission of sweet, bitter and umami tastes p.223

Recognition of sweet, bitter and umami tastes requires the non-vesicular release from taste bud cells of ATP, which acts as a neurotransmitter to activate afferent neural gustatory pathways. However, how ATP is released to fulfil this function is not fully understood. Here we show that calcium homeostasis modulator 1 (CALHM1), a voltage-gated ion channel, is indispensable for taste-stimuli-evoked ATP release from sweet-, bitter- and umami-sensing taste bud cells. Calhm1 knockout mice have severely impaired perceptions of sweet, bitter and umami compounds, whereas their recognition of sour and salty tastes remains mostly normal. Calhm1 deficiency affects taste perception without interfering with taste cell development or integrity. CALHM1 is expressed specifically in sweet/bitter/umami-sensing type II taste bud cells. Its heterologous expression induces a novel ATP permeability that releases ATP from cells in response to manipulations that activate the CALHM1 ion channel. Knockout of Calhm1 strongly reduces voltage-gated currents in type II cells and taste-evoked ATP release from taste buds without affecting the excitability of taste cells by taste stimuli. Thus, CALHM1 is a voltage-gated ATP-release channel required for sweet, bitter and umami taste perception.

doi: 10.1038/nature11906

CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance p.227

Haematopoietic stem cells (HSCs) primarily reside in the bone marrow where signals generated by stromal cells regulate their self-renewal, proliferation and trafficking. Endosteal osteoblasts and perivascular stromal cells including endothelial cells, CXCL12-abundant reticular cells, leptin-receptor-positive stromal cells, and nestin–green fluorescent protein (GFP)-positive mesenchymal progenitors have all been implicated in HSC maintenance. However, it is unclear whether specific haematopoietic progenitor cell (HPC) subsets reside in distinct niches defined by the surrounding stromal cells and the regulatory molecules they produce. CXCL12 (chemokine (C–X–C motif) ligand 12) regulates both HSCs and lymphoid progenitors and is expressed by all of these stromal cell populations. Here we selectively deleted Cxcl12 from candidate niche stromal cell populations and characterized the effect on HPCs. Deletion of Cxcl12 from mineralizing osteoblasts has no effect on HSCs or lymphoid progenitors. Deletion of Cxcl12 from osterix-expressing stromal cells, which include CXCL12-abundant reticular cells and osteoblasts, results in constitutive HPC mobilization and a loss of B-lymphoid progenitors, but HSC function is normal. Cxcl12 deletion from endothelial cells results in a modest loss of long-term repopulating activity. Strikingly, deletion of Cxcl12 from nestin-negative mesenchymal progenitors using Prx1–cre (Prx1 also known as Prrx1) is associated with a marked loss of HSCs, long-term repopulating activity, HSC quiescence and common lymphoid progenitors. These data suggest that osterix-expressing stromal cells comprise a distinct niche that supports B-lymphoid progenitors and retains HPCs in the bone marrow, and that expression of CXCL12 from stromal cells in the perivascular region, including endothelial cells and mesenchymal progenitors, supports HSCs.

doi: 10.1038/nature11926

Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches p.231

Although haematopoietic stem cells (HSCs) are commonly assumed to reside within a specialized microenvironment, or niche, most published experimental manipulations of the HSC niche have affected the function of diverse restricted progenitors. This raises the fundamental question of whether HSCs and restricted progenitors reside within distinct, specialized niches or whether they share a common niche. Here we assess the physiological sources of the chemokine CXCL12 for HSC and restricted progenitor maintenance. Cxcl12DsRed knock-in mice (DsRed-Express2 recombined into the Cxcl12 locus) showed that Cxcl12 was primarily expressed by perivascular stromal cells and, at lower levels, by endothelial cells, osteoblasts and some haematopoietic cells. Conditional deletion of Cxcl12 from haematopoietic cells or nestin–cre-expressing cells had little or no effect on HSCs or restricted progenitors. Deletion of Cxcl12 from endothelial cells depleted HSCs but not myeloerythroid or lymphoid progenitors. Deletion of Cxcl12 from perivascular stromal cells depleted HSCs and certain restricted progenitors and mobilized these cells into circulation. Deletion of Cxcl12 from osteoblasts depleted certain early lymphoid progenitors but not HSCs or myeloerythroid progenitors, and did not mobilize these cells into circulation. Different stem and progenitor cells thus reside in distinct cellular niches in bone marrow: HSCs occupy a perivascular niche and early lymphoid progenitors occupy an endosteal niche.

doi: 10.1038/nature11885

PRC1 coordinates timing of sexual differentiation of female primordial germ cells p.236

In mammals, sex differentiation of primordial germ cells (PGCs) is determined by extrinsic cues from the environment. In mouse female PGCs, expression of stimulated by retinoic acid gene 8 (Stra8) and meiosis are induced in response to retinoic acid provided from the mesonephroi. Given the widespread role of retinoic acid signalling during development, the molecular mechanisms that enable PGCs to express Stra8 and enter meiosis in a timely manner are unknown. Here we identify gene-dosage-dependent roles in PGC development for Ring1 and Rnf2, two central components of the Polycomb repressive complex 1 (PRC1). Both paralogues are essential for PGC development between days 10.5 and 11.5 of gestation. Rnf2 is subsequently required in female PGCs to maintain high levels of Oct4 (also known as Pou5f1) and Nanog expression, and to prevent premature induction of meiotic gene expression and entry into meiotic prophase. Chemical inhibition of retinoic acid signalling partially suppresses precocious Oct4 downregulation and Stra8 activation in Rnf2-deficient female PGCs. Chromatin immunoprecipitation analyses show that Stra8 is a direct target of PRC1 and PRC2 in PGCs. These data demonstrate the importance of PRC1 gene dosage in PGC development and in coordinating the timing of sex differentiation of female PGCs by antagonizing extrinsic retinoic acid signalling.

doi: 10.1038/nature11918

Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche p.241

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths among women in the United States, but its pathogenesis is poorly understood. Some epithelial cancers are known to occur in transitional zones between two types of epithelium, whereas others have been shown to originate in epithelial tissue stem cells. The stem cell niche of the ovarian surface epithelium (OSE), which is ruptured and regenerates during ovulation, has not yet been defined unequivocally. Here we identify the hilum region of the mouse ovary, the transitional (or junction) area between the OSE, mesothelium and tubal (oviductal) epithelium, as a previously unrecognized stem cell niche of the OSE. We find that cells of the hilum OSE are cycling slowly and express stem and/or progenitor cell markers ALDH1, LGR5, LEF1, CD133 and CK6B. These cells display long-term stem cell properties ex vivo and in vivo, as shown by our serial sphere generation and long-term lineage-tracing assays. Importantly, the hilum cells show increased transformation potential after inactivation of tumour suppressor genes Trp53 and Rb1, whose pathways are altered frequently in the most aggressive and common type of human EOC, high-grade serous adenocarcinoma. Our study supports experimentally the idea that susceptibility of transitional zones to malignant transformation may be explained by the presence of stem cell niches in those areas. Identification of a stem cell niche for the OSE may have important implications for understanding EOC pathogenesis.

doi: 10.1038/nature11979

Naturally occurring allele diversity allows potato cultivation in northern latitudes p.246

Potato (Solanum tuberosum L.) originates from the Andes and evolved short-day-dependent tuber formation as a vegetative propagation strategy. Here we describe the identification of a central regulator underlying a major-effect quantitative trait locus for plant maturity and initiation of tuber development. We show that this gene belongs to the family of DOF (DNA-binding with one finger) transcription factors and regulates tuberization and plant life cycle length, by acting as a mediator between the circadian clock and the StSP6A mobile tuberization signal. We also show that natural allelic variants evade post-translational light regulation, allowing cultivation outside the geographical centre of origin of potato. Potato is a member of the Solanaceae family and is one of the world’s most important food crops. This annual plant originates from the Andean regions of South America. Potato develops tubers from underground stems called stolons. Its equatorial origin makes potato essentially short-day dependent for tuberization and potato will not make tubers in the long-day conditions of spring and summer in the northern latitudes. When introduced in temperate zones, wild material will form tubers in the course of the autumnal shortening of day-length. Thus, one of the first selected traits in potato leading to a European potato type is likely to have been long-day acclimation for tuberization. Potato breeders can exploit the naturally occurring variation in tuberization onset and life cycle length, allowing varietal breeding for different latitudes, harvest times and markets.

doi: 10.1038/nature11912

Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC p.251

Most human coronaviruses cause mild upper respiratory tract disease but may be associated with more severe pulmonary disease in immunocompromised individuals. However, SARS coronavirus caused severe lower respiratory disease with nearly 10% mortality and evidence of systemic spread. Recently, another coronavirus (human coronavirus-Erasmus Medical Center (hCoV-EMC)) was identified in patients with severe and sometimes lethal lower respiratory tract infection. Viral genome analysis revealed close relatedness to coronaviruses found in bats. Here we identify dipeptidyl peptidase 4 (DPP4; also known as CD26) as a functional receptor for hCoV-EMC. DPP4 specifically co-purified with the receptor-binding S1 domain of the hCoV-EMC spike protein from lysates of susceptible Huh-7 cells. Antibodies directed against DPP4 inhibited hCoV-EMC infection of primary human bronchial epithelial cells and Huh-7 cells. Expression of human and bat (Pipistrellus pipistrellus) DPP4 in non-susceptible COS-7 cells enabled infection by hCoV-EMC. The use of the evolutionarily conserved DPP4 protein from different species as a functional receptor provides clues about the host range potential of hCoV-EMC. In addition, it will contribute critically to our understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.

doi: 10.1038/nature12005

USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110 p.255

Centrosome duplication is critical for cell division, and genome instability can result if duplication is not restricted to a single round per cell cycle. Centrosome duplication is controlled in part by CP110, a centriolar protein that positively regulates centriole duplication while restricting centriole elongation and ciliogenesis. Maintenance of normal CP110 levels is essential, as excessive CP110 drives centrosome over-duplication and suppresses ciliogenesis, whereas its depletion inhibits centriole amplification and leads to highly elongated centrioles and aberrant assembly of cilia in growing cells. CP110 levels are tightly controlled, partly through ubiquitination by the ubiquitin ligase complex SCFcyclin F during G2 and M phases of the cell cycle. Here, using human cells, we report a new mechanism for the regulation of centrosome duplication that requires USP33, a deubiquitinating enzyme that is able to regulate CP110 levels. USP33 interacts with CP110 and localizes to centrioles primarily in S and G2/M phases, the periods during which centrioles duplicate and elongate. USP33 potently and specifically deubiquitinates CP110, but not other cyclin-F substrates. USP33 activity antagonizes SCFcyclin F-mediated ubiquitination and promotes the generation of supernumerary centriolar foci, whereas ablation of USP33 destabilizes CP110 and thereby inhibits centrosome amplification and mitotic defects. To our knowledge, we have identified the first centriolar deubiquitinating enzyme whose expression regulates centrosome homeostasis by countering cyclin-F-mediated destruction of a key substrate. Our results point towards potential therapeutic strategies for inhibiting tumorigenesis associated with centrosome amplification.

doi: 10.1038/nature11941

Crystal structures of the calcium pump and sarcolipin in the Mg2+-bound E1 state p.260

P-type ATPases are ATP-powered ion pumps that establish ion concentration gradients across biological membranes, and are distinct from other ATPases in that the reaction cycle includes an autophosphorylation step. The best studied is Ca2+-ATPase from muscle sarcoplasmic reticulum (SERCA1a), a Ca2+ pump that relaxes muscle cells after contraction, and crystal structures have been determined for most of the reaction intermediates. An important outstanding structure is that of the E1 intermediate, which has empty high-affinity Ca2+-binding sites ready to accept new cytosolic Ca2+. In the absence of Ca2+ and at pH 7 or higher, the ATPase is predominantly in E1, not in E2 (low affinity for Ca2+), and if millimolar Mg2+ is present, one Mg2+ is expected to occupy one of the Ca2+-binding sites with a millimolar dissociation constant. This Mg2+ accelerates the reaction cycle, not permitting phosphorylation without Ca2+ binding. Here we describe the crystal structure of native SERCA1a (from rabbit) in this E1·Mg2+ state at 3.0 Å resolution in addition to crystal structures of SERCA1a in E2 free from exogenous inhibitors, and address the structural basis of the activation signal for phosphoryl transfer. Unexpectedly, sarcolipin, a small regulatory membrane protein of Ca2+-ATPase, is bound, stabilizing the E1·Mg2+ state. Sarcolipin is a close homologue of phospholamban, which is a critical mediator of β-adrenergic signal in Ca2+ regulation in heart (for reviews, see, for example, refs 8–10), and seems to play an important role in muscle-based thermogenesis. We also determined the crystal structure of recombinant SERCA1a devoid of sarcolipin, and describe the structural basis of inhibition by sarcolipin/phospholamban. Thus, the crystal structures reported here fill a gap in the structural elucidation of the reaction cycle and provide a solid basis for understanding the physiological regulation of the calcium pump.

doi: 10.1038/nature11899

The sarcolipin-bound calcium pump stabilizes calcium sites exposed to the cytoplasm p.265

The contraction and relaxation of muscle cells is controlled by the successive rise and fall of cytosolic Ca2+, initiated by the release of Ca2+ from the sarcoplasmic reticulum and terminated by re-sequestration of Ca2+ into the sarcoplasmic reticulum as the main mechanism of Ca2+ removal. Re-sequestration requires active transport and is catalysed by the sarcoplasmic reticulum Ca2+-ATPase (SERCA), which has a key role in defining the contractile properties of skeletal and heart muscle tissue. The activity of SERCA is regulated by two small, homologous membrane proteins called phospholamban (PLB, also known as PLN) and sarcolipin (SLN). Detailed structural information explaining this regulatory mechanism has been lacking, and the structural features defining the pathway through which cytoplasmic Ca2+ enters the intramembranous binding sites of SERCA have remained unknown. Here we report the crystal structure of rabbit SERCA1a (also known as ATP2A1) in complex with SLN at 3.1 Å resolution. The regulatory SLN traps the Ca2+-ATPase in a previously undescribed E1 state, with exposure of the Ca2+ sites through an open cytoplasmic pathway stabilized by Mg2+. The structure suggests a mechanism for selective Ca2+ loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca2+. These findings may prove useful in studying how autoinhibitory domains of other ion pumps modulate transport across biological membranes.

doi: 10.1038/nature11900