Editorials
予算の効果の評価や削減の決定を、エビデンスに基づいて行うという米オバマ政権の方針は、賢いやり方だ。
Look after the pennies p.269
Government decisions about where to spend and where to cut should be based on evidence, not ideology.
doi: 10.1038/496269a
イタリア議会の幹細胞治療の規制緩和の動きは、誤った誘導による危険なものであり、まず専門家の意見を求めるべきだ。
Smoke and mirrors p.269
Italy’s parliament must listen to expert advice before deregulating stem-cell therapies.
doi: 10.1038/496269b
Natureポッドキャストでは、科学史を彩る12の画期的発見をシリーズで取り上げる。
Due credit p.270
Nature’s podcast charts 12 landmark discoveries in the history of science.
doi: 10.1038/496270a
News
米オバマ政権の予算案は、基礎研究よりもトランスレーショナル研究を重視。
A back seat for basic science p.277
Translational research wins in Obama’s budget, but its economic value remains uncertain.
doi: 10.1038/496277a
合成生物学界に、環境保護への貢献を模索する動きが。
Synthetic biologists and conservationists open talks p.281
But worries persist about unintended consequences of tinkering with nature.
doi: 10.1038/496281a
コンテクスチュアリティ定理によって、安全なコミュニケーションが改善される可能性が。
Photons test quantum paradox p.282
Contextuality theorem could improve secure communication.
doi: 10.1038/496282a
「生きた化石」シーラカンスゲノムが解読され、進化の解明の手がかりに。
‘Living fossil’ genome unlocked p.283
The genes of an ancient fish, the coelacanth, have much to reveal about our distant past.
doi: 10.1038/496283a
気候変動モデルでは米国の過去の干ばつは正しく「予測」できないことが明らかに。
Climate models fail to ‘predict’ US droughts p.284
Simulations identify past megadroughts, but at wrong times.
doi: 10.1038/496284a
News Features
生態学：アマゾンの断片
Forest ecology: Splinters of the Amazon p.286
ブラジルの熱帯雨林を分割して調査研究するThomas Lovejoyの方法論が、世界各地に引き継がれている。
doi: 10.1038/496286a
公衆衛生：ポリオの動く標的
Public health: Polio’s moving target p.290
ナイジェリアの遊牧民の居場所を探してワクチン接種を実施できれば、ポリオの根絶につながる可能性がある。
doi: 10.1038/496290a
News & Views
考古学：日本における土器使用の歴史
Archaeology: A potted history of Japan p.302
日本の縄文時代の遺跡から見つかった土器の断片に脂質が付着していたことがわかった。これは土器を調理に使用したことを示す最古の例であり、このことはまた、ヒトの技術革新についての見方の一部について再考を促すものでもある。
doi: 10.1038/nature12093
天文学：若い銀河に見られる宇宙の急成長
Astronomy: A cosmic growth spurt in an infant galaxy p.303
初期宇宙での最も激しいスターバースト銀河の1つが見つかり、その特徴が調べられた。この銀河は、宇宙の年齢が現在のたった6％という若さだった頃に起こった大質量銀河の急速な形成を示している。
doi: 10.1038/496303a
感覚生物学：ゲノムの匂い
Sensory biology: A whiff of genome p.304
動物の血縁関係はその行動に影響を与えるが、動物は親戚であることをどうやって感知するのだろうか。鼻腔にある感覚ニューロンが、遺伝的な変動を反映している尿ペプチドの微小な構造的差異を識別しているようだ。
doi: 10.1038/496304a
物理化学：分子の動きを観察する
Physical chemistry: Molecular motion watched p.306
レーザーパルスを使えば、ある種の結晶を絶縁相から高伝導相へと切り替えることができる。この転移を駆動する超高速の分子運動が、電子回折法を使って直接観察された。
doi: 10.1038/496306a
生物地球化学：窒素の蓄積と森林中の炭素
Biogeochemistry: Nitrogen deposition and forest carbon p.307
農業用肥料の使用などの人間活動は、大気から森林中への窒素の蓄積量を増やしている。こうした蓄積に対する常緑針葉樹林での光合成応答が全球レベルで定量された。
doi: 10.1038/496307a
複雑系：復元力の空間的特徴
Complex systems: Spatial signatures of resilience p.308
複雑系の動態がどの時点で急激な変化を起こすかを予測することは難しい。新たに行われた実験で、そのような転換点が近づく時点を、生物の空間的分布が示す場合があることが明らかになった。
doi: 10.1038/nature12092
Articles
ゲノミクス：アフリカシーラカンスのゲノムは四肢類の進化を解明するための手がかりとなる
The African coelacanth genome provides insights into tetrapod evolution OPEN p.311
Genome sequencing and phylogenomic analysis show that the lungfish, not the coelacanth, is the closest living relative of tetrapods, that coelacanth protein-coding genes are more slowly evolving than those of tetrapods and lungfish, and that the genes and regulatory elements that underwent changes during the vertebrate transition to land reflect adaptation to a new environment.
doi: 10.1038/nature12027
構造生物学：TrkHイオンチャネルの、会合RCKタンパク質TrkAによるゲート開閉
Gating of the TrkH ion channel by its associated RCK protein TrkA p.317
Here it is shown that ion flux through the TrkH–TrkA complex is upregulated by ATP and downregulated by ADP; solving the X-ray crystal structures of the tetrameric TrkA ring in the absence and presence of TrkH suggests a mechanism by which ATP-induced conformational changes in TrkA augment the activity of TrkH.
doi: 10.1038/nature12056
構造生物学：KtrABカリウム輸送体の構造
The structure of the KtrAB potassium transporter p.323
This study reports the X-ray crystal structure of a Ktr K+ transporter; the structure of this KtrAB complex reveals how the dimeric membrane protein KtrB interacts with the cytosolic octameric KtrA regulatory protein.
doi: 10.1038/nature12055
Letters
宇宙：赤方偏移6.34にある塵に隠された大質量で最高形成率のスターバースト銀河
A dust-obscured massive maximum-starburst galaxy at a redshift of 6.34 p.329
Massive present-day early-type (elliptical and lenticular) galaxies probably gained the bulk of their stellar mass and heavy elements through intense, dust-enshrouded starbursts—that is, increased rates of star formation—in the most massive dark-matter haloes at early epochs. However, it remains unknown how soon after the Big Bang massive starburst progenitors exist. The measured redshift (z) distribution of dusty, massive starbursts has long been suspected to be biased low in z owing to selection effects, as confirmed by recent findings of systems with redshifts as high as ∼5 (refs 2–4). Here we report the identification of a massive starburst galaxy at z = 6.34 through a submillimetre colour-selection technique. We unambiguously determined the redshift from a suite of molecular and atomic fine-structure cooling lines. These measurements reveal a hundred billion solar masses of highly excited, chemically evolved interstellar medium in this galaxy, which constitutes at least 40 per cent of the baryonic mass. A ‘maximum starburst’ converts the gas into stars at a rate more than 2,000 times that of the Milky Way, a rate among the highest observed at any epoch. Despite the overall downturn in cosmic star formation towards the highest redshifts, it seems that environments mature enough to form the most massive, intense starbursts existed at least as early as 880 million years after the Big Bang.
doi: 10.1038/nature12050
量子情報科学：シリコン中の核スピンキュービットの高忠実度読み出しと制御
High-fidelity readout and control of a nuclear spin qubit in silicon p.334
Electrical detection and coherent manipulation of a single 31P nuclear spin qubit is reported; the high fidelities are promising for fault-tolerant nuclear-spin-based quantum computing using silicon.
doi: 10.1038/nature12011
材料：結晶固体における予想外のひずみ剛化
Unexpected strain-stiffening in crystalline solids p.339
Strain-stiffening—an increase in material stiffness at large strains—is a vital mechanism by which many soft biological materials thwart excessive deformation to protect tissue integrity. Understanding the fundamental science of strain-stiffening and incorporating this concept into the design of metals and ceramics for advanced applications is an attractive prospect. Using cementite (Fe3C) and aluminium borocarbide (Al3BC3) as prototypes, here we show via quantum-mechanical calculations that strain-stiffening also occurs, surprisingly, in simple inorganic crystalline solids and confers exceptionally high strengths to these two solids, which have anomalously low resistance to deformation near equilibrium. For Fe3C and Al3BC3, their ideal shear strength to shear modulus ratios attain remarkably high values of 1.14 and 1.34 along the (010)[001] and slip systems, respectively. These values are more than seven times larger than the original Frenkel value of 1/2π (refs 4, 5) and are the highest yet reported for crystalline solids. The extraordinary stiffening of Fe3C arises from the strain-induced reversible ‘cross-linking’ between weakly coupled edge- and corner-sharing Fe6C slabs. This new bond formation creates a strong, three-dimensional covalent bond network that resists large shear deformation. Unlike Fe3C, no new bond forms in Al3BC3 but stiffening still occurs because strong repulsion between Al and B in a compressed Al–B bond unsettles the existing covalent bond network. These discoveries challenge the conventional wisdom that large shear modulus is a reliable predictor of hardness and strength of materials, and provide new lessons for materials selection and design.
doi: 10.1038/nature12008
物理化学：電荷非局在化をもたらす分子運動を超高輝度電子線でマッピングする
Mapping molecular motions leading to charge delocalization with ultrabright electrons p.343
Ultrafast processes can now be studied with the combined atomic spatial resolution of diffraction methods and the temporal resolution of femtosecond optical spectroscopy by using femtosecond pulses of electrons or hard X-rays as structural probes. However, it is challenging to apply these methods to organic materials, which have weak scattering centres, thermal lability, and poor heat conduction. These characteristics mean that the source needs to be extremely bright to enable us to obtain high-quality diffraction data before cumulative heating effects from the laser excitation either degrade the sample or mask the structural dynamics. Here we show that a recently developed, ultrabright femtosecond electron source makes it possible to monitor the molecular motions in the organic salt (EDO-TTF)2PF6 as it undergoes its photo-induced insulator-to-metal phase transition. After the ultrafast laser excitation, we record time-delayed diffraction patterns that allow us to identify hundreds of Bragg reflections with which to map the structural evolution of the system. The data and supporting model calculations indicate the formation of a transient intermediate structure in the early stage of charge delocalization (less than five picoseconds), and reveal that the molecular motions driving its formation are distinct from those that, assisted by thermal relaxation, convert the system into a metallic state on the hundred-picosecond timescale. These findings establish the potential of ultrabright femtosecond electron sources for probing the primary processes governing structural dynamics with atomic resolution in labile systems relevant to chemistry and biology.
doi: 10.1038/nature12044
環境科学：蒸散が大半を占める地球の水フラックス
Terrestrial water fluxes dominated by transpiration p.347
Renewable fresh water over continents has input from precipitation and losses to the atmosphere through evaporation and transpiration. Global-scale estimates of transpiration from climate models are poorly constrained owing to large uncertainties in stomatal conductance and the lack of catchment-scale measurements required for model calibration, resulting in a range of predictions spanning 20 to 65 per cent of total terrestrial evapotranspiration (14,000 to 41,000 km3 per year) (refs 1, 2, 3, 4, 5). Here we use the distinct isotope effects of transpiration and evaporation to show that transpiration is by far the largest water flux from Earth’s continents, representing 80 to 90 per cent of terrestrial evapotranspiration. On the basis of our analysis of a global data set of large lakes and rivers, we conclude that transpiration recycles 62,000 ± 8,000 km3 of water per year to the atmosphere, using half of all solar energy absorbed by land surfaces in the process. We also calculate CO2 uptake by terrestrial vegetation by connecting transpiration losses to carbon assimilation using water-use efficiency ratios of plants, and show the global gross primary productivity to be 129 ± 32 gigatonnes of carbon per year, which agrees, within the uncertainty, with previous estimates. The dominance of transpiration water fluxes in continental evapotranspiration suggests that, from the point of view of water resource forecasting, climate model development should prioritize improvements in simulations of biological fluxes rather than physical (evaporation) fluxes.
doi: 10.1038/nature11983
考古学：土器の使用法を裏付ける最古の証拠
Earliest evidence for the use of pottery p.351
Pottery was a hunter-gatherer innovation that first emerged in East Asia between 20,000 and 12,000 calibrated years before present (cal bp), towards the end of the Late Pleistocene epoch, a period of time when humans were adjusting to changing climates and new environments. Ceramic container technologies were one of a range of late glacial adaptations that were pivotal to structuring subsequent cultural trajectories in different regions of the world, but the reasons for their emergence and widespread uptake are poorly understood. The first ceramic containers must have provided prehistoric hunter-gatherers with attractive new strategies for processing and consuming foodstuffs, but virtually nothing is known of how early pots were used. Here we report the chemical analysis of food residues associated with Late Pleistocene pottery, focusing on one of the best-studied prehistoric ceramic sequences in the world, the Japanese Jōmon. We demonstrate that lipids can be recovered reliably from charred surface deposits adhering to pottery dating from about 15,000 to 11,800 cal bp (the Incipient Jōmon period), the oldest pottery so far investigated, and that in most cases these organic compounds are unequivocally derived from processing freshwater and marine organisms. Stable isotope data support the lipid evidence and suggest that most of the 101 charred deposits analysed, from across the major islands of Japan, were derived from high-trophic-level aquatic food. Productive aquatic ecotones were heavily exploited by late glacial foragers, perhaps providing an initial impetus for investment in ceramic container technology, and paving the way for further intensification of pottery use by hunter-gatherers in the early Holocene epoch. Now that we have shown that it is possible to analyse organic residues from some of the world’s earliest ceramic vessels, the subsequent development of this critical technology can be clarified through further widespread testing of hunter-gatherer pottery from later periods.
doi: 10.1038/nature12109
生態：連結された集団の崩壊の前には空間的回復が遅くなる
Slower recovery in space before collapse of connected populations p.355
Slower recovery from perturbations near a tipping point and its indirect signatures in fluctuation patterns have been suggested to foreshadow catastrophes in a wide variety of systems. Recent studies of populations in the field and in the laboratory have used time-series data to confirm some of the theoretically predicted early warning indicators, such as an increase in recovery time or in the size and timescale of fluctuations. However, the predictive power of temporal warning signals is limited by the demand for long-term observations. Large-scale spatial data are more accessible, but the performance of warning signals in spatially extended systems needs to be examined empirically. Here we use spatially extended yeast populations, an experimental system with a fold bifurcation (tipping point), to evaluate early warning signals based on spatio-temporal fluctuations and to identify a novel spatial warning indicator. We found that two leading indicators based on fluctuations increased before collapse of connected populations; however, the magnitudes of the increases were smaller than those observed in isolated populations, possibly because local variation is reduced by dispersal. Furthermore, we propose a generic indicator based on deterministic spatial patterns, which we call ‘recovery length’. As the spatial counterpart of recovery time, recovery length is the distance necessary for connected populations to recover from spatial perturbations. In our experiments, recovery length increased substantially before population collapse, suggesting that the spatial scale of recovery can provide a superior warning signal before tipping points in spatially extended systems.
doi: 10.1038/nature12071
神経科学：コカインで誘発された前前頭皮質の活動低下を回復させることにより強迫的コカイン探索行動は防がれる
Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking p.359
Loss of control over harmful drug seeking is one of the most intractable aspects of addiction, as human substance abusers continue to pursue drugs despite incurring significant negative consequences. Human studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control could be crucial in promoting compulsive drug use. However, it remains unknown whether chronic drug use compromises cortical activity and, equally important, whether this deficit promotes compulsive cocaine seeking. Here we use a rat model of compulsive drug seeking in which cocaine seeking persists in a subgroup of rats despite delivery of noxious foot shocks. We show that prolonged cocaine self-administration decreases ex vivo intrinsic excitability of deep-layer pyramidal neurons in the prelimbic cortex, which was significantly more pronounced in compulsive drug-seeking animals. Furthermore, compensating for hypoactive prelimbic cortex neurons with in vivo optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking. Our results show a marked reduction in prelimbic cortex excitability in compulsive cocaine-seeking rats, and that in vivo optogenetic prelimbic cortex stimulation decreased compulsive drug-seeking behaviours. Thus, targeted stimulation of the prefrontal cortex could serve as a promising therapy for treating compulsive drug use.
doi: 10.1038/nature12024
発生：胚発生における内在性のレチノイン酸勾配の可視化
Visualization of an endogenous retinoic acid gradient across embryonic development p.363
In vertebrate development, the body plan is determined by primordial morphogen gradients that suffuse the embryo. Retinoic acid (RA) is an important morphogen involved in patterning the anterior–posterior axis of structures, including the hindbrain and paraxial mesoderm. RA diffuses over long distances, and its activity is spatially restricted by synthesizing and degrading enzymes. However, gradients of endogenous morphogens in live embryos have not been directly observed; indeed, their existence, distribution and requirement for correct patterning remain controversial. Here we report a family of genetically encoded indicators for RA that we have termed GEPRAs (genetically encoded probes for RA). Using the principle of fluorescence resonance energy transfer we engineered the ligand-binding domains of RA receptors to incorporate cyan-emitting and yellow-emitting fluorescent proteins as fluorescence resonance energy transfer donor and acceptor, respectively, for the reliable detection of ambient free RA. We created three GEPRAs with different affinities for RA, enabling the quantitative measurement of physiological RA concentrations. Live imaging of zebrafish embryos at the gastrula and somitogenesis stages revealed a linear concentration gradient of endogenous RA in a two-tailed source–sink arrangement across the embryo. Modelling of the observed linear RA gradient suggests that the rate of RA diffusion exceeds the spatiotemporal dynamics of embryogenesis, resulting in stability to perturbation. Furthermore, we used GEPRAs in combination with genetic and pharmacological perturbations to resolve competing hypotheses on the structure of the RA gradient during hindbrain formation and somitogenesis. Live imaging of endogenous concentration gradients across embryonic development will allow the precise assignment of molecular mechanisms to developmental dynamics and will accelerate the application of approaches based on morphogen gradients to tissue engineering and regenerative medicine.
doi: 10.1038/nature12037
医学：病原性ピコルナウイルスは、細胞膜を乗っ取って、エンベロープを獲得する
A pathogenic picornavirus acquires an envelope by hijacking cellular membranes p.367
Animal viruses are broadly categorized structurally by the presence or absence of an envelope composed of a lipid-bilayer membrane, attributes that profoundly affect stability, transmission and immune recognition. Among those lacking an envelope, the Picornaviridae are a large and diverse family of positive-strand RNA viruses that includes hepatitis A virus (HAV), an ancient human pathogen that remains a common cause of enterically transmitted hepatitis. HAV infects in a stealth-like manner and replicates efficiently in the liver. Virus-specific antibodies appear only after 3–4 weeks of infection, and typically herald its resolution. Although unexplained mechanistically, both anti-HAV antibody and inactivated whole-virus vaccines prevent disease when administered as late as 2 weeks after exposure, when virus replication is well established in the liver. Here we show that HAV released from cells is cloaked in host-derived membranes, thereby protecting the virion from antibody-mediated neutralization. These enveloped viruses (‘eHAV’) resemble exosomes, small vesicles that are increasingly recognized to be important in intercellular communications. They are fully infectious, sensitive to extraction with chloroform, and circulate in the blood of infected humans. Their biogenesis is dependent on host proteins associated with endosomal-sorting complexes required for transport (ESCRT), namely VPS4B and ALIX. Whereas the hijacking of membranes by HAV facilitates escape from neutralizing antibodies and probably promotes virus spread within the liver, anti-capsid antibodies restrict replication after infection with eHAV, suggesting a possible explanation for prophylaxis after exposure. Membrane hijacking by HAV blurs the classic distinction between ‘enveloped’ and ‘non-enveloped’ viruses and has broad implications for mechanisms of viral egress from infected cells as well as host immune responses.
doi: 10.1038/nature12029
細胞：ミトコンドリア脱分極に応答したPARKIN依存性ユビキチロームの全体像
Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization p.372
The PARKIN ubiquitin ligase (also known as PARK2) and its regulatory kinase PINK1 (also known as PARK6), often mutated in familial early-onset Parkinson’s disease, have central roles in mitochondrial homeostasis and mitophagy. Whereas PARKIN is recruited to the mitochondrial outer membrane (MOM) upon depolarization via PINK1 action and can ubiquitylate porin, mitofusin and Miro proteins on the MOM, the full repertoire of PARKIN substrates—the PARKIN-dependent ubiquitylome—remains poorly defined. Here we use quantitative diGly capture proteomics (diGly) to elucidate the ubiquitylation site specificity and topology of PARKIN-dependent target modification in response to mitochondrial depolarization. Hundreds of dynamically regulated ubiquitylation sites in dozens of proteins were identified, with strong enrichment for MOM proteins, indicating that PARKIN dramatically alters the ubiquitylation status of the mitochondrial proteome. Using complementary interaction proteomics, we found depolarization-dependent PARKIN association with numerous MOM targets, autophagy receptors, and the proteasome. Mutation of the PARKIN active site residue C431, which has been found mutated in Parkinson’s disease patients, largely disrupts these associations. Structural and topological analysis revealed extensive conservation of PARKIN-dependent ubiquitylation sites on cytoplasmic domains in vertebrate and Drosophila melanogaster MOM proteins. These studies provide a resource for understanding how the PINK1–PARKIN pathway re-sculpts the proteome to support mitochondrial homeostasis.
doi: 10.1038/nature12043
生化学：HP1のコンホメーション切り替えは自己阻害を解除してヘテロクロマチン構築を進行させる
A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly p.377
A hallmark of histone H3 lysine 9 (H3K9)-methylated heterochromatin, conserved from the fission yeast Schizosaccharomyces pombe to humans, is its ability to spread to adjacent genomic regions. Central to heterochromatin spread is heterochromatin protein 1 (HP1), which recognizes H3K9-methylated chromatin, oligomerizes and forms a versatile platform that participates in diverse nuclear functions, ranging from gene silencing to chromosome segregation. How HP1 proteins assemble on methylated nucleosomal templates and how the HP1–nucleosome complex achieves functional versatility remain poorly understood. Here we show that binding of the key S. pombe HP1 protein, Swi6, to methylated nucleosomes drives a switch from an auto-inhibited state to a spreading-competent state. In the auto-inhibited state, a histone-mimic sequence in one Swi6 monomer blocks methyl-mark recognition by the chromodomain of another monomer. Auto-inhibition is relieved by recognition of two template features, the H3K9 methyl mark and nucleosomal DNA. Cryo-electron-microscopy-based reconstruction of the Swi6–nucleosome complex provides the overall architecture of the spreading-competent state in which two unbound chromodomain sticky ends appear exposed. Disruption of the switch between the auto-inhibited and spreading-competent states disrupts heterochromatin assembly and gene silencing in vivo. These findings are reminiscent of other conditionally activated polymerization processes, such as actin nucleation, and open up a new class of regulatory mechanisms that operate on chromatin in vivo.
doi: 10.1038/nature12032
構造生物学：キヌレニン 3-モノオキシゲナーゼ阻害の構造基盤
Structural basis of kynurenine 3-monooxygenase inhibition p.382
Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington’s-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer’s disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO–UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood–brain barrier in targeted therapies against neurodegenerative diseases such as Huntington’s, Alzheimer’s and Parkinson’s diseases.
doi: 10.1038/nature12039
