Editorials
イタリア政府当局は、科学的検証が十分でない幹細胞治療の臨床試験の実施を認めるべきではない。
Trial and error p.125
Italian officials should not go ahead with expensive clinical tests of an unproven stem-cell therapy that has no good scientific basis.
doi: 10.1038/499125a
ドイツの研究助成機関DFGは、不正行為の内部告発に関する指針を改訂したが、誤った告発の扱いや秘密保持の規定をもっと明確化すべきだ。
In the dark p.125
Germany’s main funding agency must specify how it will deal with false charges of misconduct.
doi: 10.1038/499125b
科学分野の情報伝達の在り方は激しく様変わりしているが、事実の究明や調査を重視する報道は今でも重要だ。
Headline message p.126
Science communication is changing, but investigative reporting is still important.
doi: 10.1038/499126a
News
米アリゾナ州に設置された大型双眼望遠鏡（LBT）に、初動トラブルの悩みが。
Teething troubles at huge telescope p.133
The Large Binocular Telescope gets off to a sluggish start.
doi: 10.1038/499133a
著作権に関する新たな国際条約が制定され、視覚障害者の出版物へのアクセスが容易に。
Deal boosts blind’s access to texts p.134
Global copyright agreement will increase availability of scientific texts in accessible formats.
doi: 10.1038/499134a
電子顕微鏡の分解能アップは、ノイズの問題でそろそろ限界に。
Imaging hits noise barrier p.135
Physical limits mean that electron microscopy may be nearing highest possible resolution.
doi: 10.1038/499135a
安倍政権の「日本版NIH」構想に、研究者たちから、基礎科学がないがしろにされるとの強い懸念が。
Outcry over plans for ‘Japanese NIH’ p.136
Researchers fear reforms will bring cuts to basic science.
doi: 10.1038/499136a
米国の中小企業技術革新研究プログラム（SBIR）が商品化推進の姿勢を強め、研究重視の企業が苦境に。
US research firms put under pressure to sell p.137
Commercialization rules threaten to curtail SBIR grants.
doi: 10.1038/499137a
News Features
気候変動：あいまいなまま、ますます熱を帯びる近未来予報
Climate change: The forecast for 2018 is cloudy with record heat p.139
5年、10年先の気候変動予測が試みられているが、これまでのところ精度は上がっていない。
doi: 10.1038/499139a
科学メディア：注目の的
Science media: Centre of attention p.142
科学報道をより良いものにしようとするFiona Foxとサイエンス・メディア・センターの試みが、世界に広まりつつある。
doi: 10.1038/499142a
News & Views
フォーラム：マラリア：寄生虫分子の秘密
Malaria: Molecular secrets of a parasite p.156
マラリア原虫（ Plasmodium falciparum ）が自身のvar遺伝子の発現を操作して宿主免疫系による監視を回避する仕組みが明らかにされた。4人の専門家が、この結果が一般的な遺伝子調節の解明、また抗マラリアワクチンの開発にどのように関係してくるかを論じている。
doi: 10.1038/nature12407
地球物理学：大陸を裂く第三の方法
Geophysics: A third way to rift continents p.157
大陸の地溝形成は、普通は地溝形成が起きている地域から遠く離れた場所で生じた作用に基づく2つの機構のどちらかによって説明される。実験によって、この地球力学過程は局地的な作用によっても生じ得ることが示された。
doi: 10.1038/499157a
光物性：光の奇想天外な捕捉法
Optical physics: Trapping the light fantastic p.159
フォトニック結晶と呼ばれる材料を使って、ある意味で完全な鏡が設計された。原理的には、光はこの鏡を通過することも、鏡によって吸収されることもないのである。
doi: 10.1038/499159a
地球科学：気候目標に対する全体論的な迫り方
Earth science: A holistic approach to climate targets p.160
複数の気候目標を計算に入れて許容炭素排出量を計算すると、気温変化だけに注目した研究から推定された値よりも少ない許容排出量が得られることが分かった。
doi: 10.1038/nature12406
細胞生物学：脂質スイッチと輸送制御
Cell biology: Lipid switches and traffic control p.161
細胞の1つの膜から出芽する輸送小胞は、他の小胞と融合する前に性質を変えなければならない。クラスリンが仲介するエンドサイトーシスの過程では、さまざまなリン酸化脂質がこの性質変換を仲介している。
doi: 10.1038/nature12408
Analysis
量子物理学：量子因数分解の過剰な単純化
Oversimplifying quantum factoring p.163
Shor’s quantum factoring algorithm exponentially outperforms known classical methods. Previous experimental implementations have used simplifications dependent on knowing the factors in advance. However, as we show here, all composite numbers admit simplification of the algorithm to a circuit equivalent to flipping coins. The difficulty of a particular experiment therefore depends on the level of simplification chosen, not the size of the number factored. Valid implementations should not make use of the answer sought.
doi: 10.1038/nature12290
Articles
細胞生物学：足場タンパク質Shc1によるEGFシグナル伝達ネットワークの経時的な調節
Temporal regulation of EGF signalling networks by the scaffold protein Shc1 p.166
The Shc1 scaffold mediates a switch in the signaling output of the epidermal growth factor receptor tyrosine kinase over time through recruitment of successive waves of proteins with distinct biological functions.
doi: 10.1038/nature12308
生化学：遺伝子調節を解読するためのRNA結合モチーフの概要
A compendium of RNA-binding motifs for decoding gene regulation p.172
This study reports a global analysis of binding sites for over 200 RNA-binding proteins (RBPs) from 24 species; conserved RNA-binding motifs are identified, and their analysis allows prediction of interaction sites based on the sequence of the RNA-binding domain alone.
doi: 10.1038/nature12311
医学：結核菌の調節ネットワークと低酸素
The Mycobacterium tuberculosis regulatory network and hypoxia p.178
Mycobacterium tuberculosis has the ability to survive within the host for months to decades in an asymptomatic state, and adaptations to hypoxia are thought to have an important role in pathogenesis; here a systems-wide reconstruction of the regulatory network provides a framework for understanding mycobacterial persistence in the host.
doi: 10.1038/nature12337
Letters
宇宙：デブリ円盤における、惑星ではなくガスによる鮮明な離心環の形成
Formation of sharp eccentric rings in debris disks with gas but without planets p.184
‘Debris disks’ around young stars (analogues of the Kuiper Belt in our Solar System) show a variety of non-trivial structures attributed to planetary perturbations and used to constrain the properties of those planets. However, these analyses have largely ignored the fact that some debris disks are found to contain small quantities of gas, a component that all such disks should contain at some level. Several debris disks have been measured with a dust-to-gas ratio of about unity, at which the effect of hydrodynamics on the structure of the disk cannot be ignored. Here we report linear and nonlinear modelling that shows that dust–gas interactions can produce some of the key patterns attributed to planets. We find a robust clumping instability that organizes the dust into narrow, eccentric rings, similar to the Fomalhaut debris disk. The conclusion that such disks might contain planets is not necessarily required to explain these systems.
doi: 10.1038/nature12281
光学：連続スペクトル放射における捕捉された光の観測
Observation of trapped light within the radiation continuum p.188
The ability to confine light is important both scientifically and technologically. Many light confinement methods exist, but they all achieve confinement with materials or systems that forbid outgoing waves. These systems can be implemented by metallic mirrors, by photonic band-gap materials, by highly disordered media (Anderson localization) and, for a subset of outgoing waves, by translational symmetry (total internal reflection) or by rotational or reflection symmetry. Exceptions to these examples exist only in theoretical proposals. Here we predict and show experimentally that light can be perfectly confined in a patterned dielectric slab, even though outgoing waves are allowed in the surrounding medium. Technically, this is an observation of an ‘embedded eigenvalue’—namely, a bound state in a continuum of radiation modes—that is not due to symmetry incompatibility. Such a bound state can exist stably in a general class of geometries in which all of its radiation amplitudes vanish simultaneously as a result of destructive interference. This method to trap electromagnetic waves is also applicable to electronic and mechanical waves.
doi: 10.1038/nature12289
化学：逆リバウンド機構による金属を用いない芳香族炭素–水素結合の酸化
Metal-free oxidation of aromatic carbon–hydrogen bonds through a reverse-rebound mechanism p.192
Methods for carbon–hydrogen (C–H) bond oxidation have a fundamental role in synthetic organic chemistry, providing functionality that is required in the final target molecule or facilitating subsequent chemical transformations. Several approaches to oxidizing aliphatic C–H bonds have been described, drastically simplifying the synthesis of complex molecules. However, the selective oxidation of aromatic C–H bonds under mild conditions, especially in the context of substituted arenes with diverse functional groups, remains a challenge. The direct hydroxylation of arenes was initially achieved through the use of strong Brønsted or Lewis acids to mediate electrophilic aromatic substitution reactions with super-stoichiometric equivalents of oxidants, significantly limiting the scope of the reaction. Because the products of these reactions are more reactive than the starting materials, over-oxidation is frequently a competitive process. Transition-metal-catalysed C–H oxidation of arenes with or without directing groups has been developed, improving on the acid-mediated process; however, precious metals are required. Here we demonstrate that phthaloyl peroxide functions as a selective oxidant for the transformation of arenes to phenols under mild conditions. Although the reaction proceeds through a radical mechanism, aromatic C–H bonds are selectively oxidized in preference to activated –H bonds. Notably, a wide array of functional groups are compatible with this reaction, and this method is therefore well suited for late-stage transformations of advanced synthetic intermediates. Quantum mechanical calculations indicate that this transformation proceeds through a novel addition–abstraction mechanism, a kind of ‘reverse-rebound’ mechanism as distinct from the common oxygen-rebound mechanism observed for metal–oxo oxidants. These calculations also identify the origins of the experimentally observed aryl selectivity.
doi: 10.1038/nature12284
気候：複数の気候目標によって減少する許容炭素排出量
Allowable carbon emissions lowered by multiple climate targets p.197
Climate targets are designed to inform policies that would limit the magnitude and impacts of climate change caused by anthropogenic emissions of greenhouse gases and other substances. The target that is currently recognized by most world governments places a limit of two degrees Celsius on the global mean warming since preindustrial times. This would require large sustained reductions in carbon dioxide emissions during the twenty-first century and beyond. Such a global temperature target, however, is not sufficient to control many other quantities, such as transient sea level rise, ocean acidification and net primary production on land. Here, using an Earth system model of intermediate complexity (EMIC) in an observation-informed Bayesian approach, we show that allowable carbon emissions are substantially reduced when multiple climate targets are set. We take into account uncertainties in physical and carbon cycle model parameters, radiative efficiencies, climate sensitivity and carbon cycle feedbacks along with a large set of observational constraints. Within this framework, we explore a broad range of economically feasible greenhouse gas scenarios from the integrated assessment community to determine the likelihood of meeting a combination of specific global and regional targets under various assumptions. For any given likelihood of meeting a set of such targets, the allowable cumulative emissions are greatly reduced from those inferred from the temperature target alone. Therefore, temperature targets alone are unable to comprehensively limit the risks from anthropogenic emissions.
doi: 10.1038/nature12269
地球：1日の長さの10年以下の変動に見られる特性とその影響
Characterization and implications of intradecadal variations in length of day p.202
Variations in Earth's rotation (defined in terms of length of day) arise from external tidal torques, or from an exchange of angular momentum between the solid Earth and its fluid components. On short timescales (annual or shorter) the non-tidal component is dominated by the atmosphere, with small contributions from the ocean and hydrological system. On decadal timescales, the dominant contribution is from angular momentum exchange between the solid mantle and fluid outer core. Intradecadal periods have been less clear and have been characterized by signals with a wide range of periods and varying amplitudes, including a peak at about 6 years (refs 2, 3, 4). Here, by working in the time domain rather than the frequency domain, we show a clear partition of the non-atmospheric component into only three components: a decadally varying trend, a 5.9-year period oscillation, and jumps at times contemporaneous with geomagnetic jerks. The nature of the jumps in length of day leads to a fundamental change in what class of phenomena may give rise to the jerks, and provides a strong constraint on electrical conductivity of the lower mantle, which can in turn constrain its structure and composition.
doi: 10.1038/nature12282
生態：地下生物圏における遺伝子発現
Gene expression in the deep biosphere p.205
Scientific ocean drilling has revealed a deep biosphere of widespread microbial life in sub-seafloor sediment. Microbial metabolism in the marine subsurface probably has an important role in global biogeochemical cycles, but deep biosphere activities are not well understood. Here we describe and analyse the first sub-seafloor metatranscriptomes from anaerobic Peru Margin sediment up to 159 metres below the sea floor, represented by over 1 billion complementary DNA (cDNA) sequence reads. Anaerobic metabolism of amino acids, carbohydrates and lipids seem to be the dominant metabolic processes, and profiles of dissimilatory sulfite reductase (dsr) transcripts are consistent with pore-water sulphate concentration profiles. Moreover, transcripts involved in cell division increase as a function of microbial cell concentration, indicating that increases in sub-seafloor microbial abundance are a function of cell division across all three domains of life. These data support calculations and models of sub-seafloor microbial metabolism and represent the first holistic picture of deep biosphere activities.
doi: 10.1038/nature12230
遺伝：エミリアニア属（Emiliania）の植物プランクトンの世界的分布を支えるパンゲノム
Pan genome of the phytoplankton Emiliania underpins its global distribution OPEN p.209
Coccolithophores have influenced the global climate for over 200 million years. These marine phytoplankton can account for 20 per cent of total carbon fixation in some systems. They form blooms that can occupy hundreds of thousands of square kilometres and are distinguished by their elegantly sculpted calcium carbonate exoskeletons (coccoliths), rendering them visible from space. Although coccolithophores export carbon in the form of organic matter and calcite to the sea floor, they also release CO2 in the calcification process. Hence, they have a complex influence on the carbon cycle, driving either CO2 production or uptake, sequestration and export to the deep ocean. Here we report the first haptophyte reference genome, from the coccolithophore Emiliania huxleyi strain CCMP1516, and sequences from 13 additional isolates. Our analyses reveal a pan genome (core genes plus genes distributed variably between strains) probably supported by an atypical complement of repetitive sequence in the genome. Comparisons across strains demonstrate that E. huxleyi, which has long been considered a single species, harbours extensive genome variability reflected in different metabolic repertoires. Genome variability within this species complex seems to underpin its capacity both to thrive in habitats ranging from the equator to the subarctic and to form large-scale episodic blooms under a wide variety of environmental conditions.
doi: 10.1038/nature12221
医学：がんにおける突然変異の不均一性と新たながん関連遺伝子の探索
Mutational heterogeneity in cancer and the search for new cancer-associated genes p.214
Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour–normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.
doi: 10.1038/nature12213
微生物学：抗生物質投与はファージメタゲノムの耐性リザーバーおよび生態的ネットワークを拡大させる
Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome p.219
The mammalian gut ecosystem has considerable influence on host physiology, but the mechanisms that sustain this complex environment in the face of different stresses remain obscure. Perturbations to the gut ecosystem, such as through antibiotic treatment or diet, are at present interpreted at the level of bacterial phylogeny. Less is known about the contributions of the abundant population of phages to this ecological network. Here we explore the phageome as a potential genetic reservoir for bacterial adaptation by sequencing murine faecal phage populations following antibiotic perturbation. We show that antibiotic treatment leads to the enrichment of phage-encoded genes that confer resistance via disparate mechanisms to the administered drug, as well as genes that confer resistance to antibiotics unrelated to the administered drug, and we demonstrate experimentally that phages from treated mice provide aerobically cultured naive microbiota with increased resistance. Systems-wide analyses uncovered post-treatment phage-encoded processes related to host colonization and growth adaptation, indicating that the phageome becomes broadly enriched for functionally beneficial genes under stress-related conditions. We also show that antibiotic treatment expands the interactions between phage and bacterial species, leading to a more highly connected phage–bacterial network for gene exchange. Our work implicates the phageome in the emergence of multidrug resistance, and indicates that the adaptive capacity of the phageome may represent a community-based mechanism for protecting the gut microflora, preserving its functional robustness during antibiotic stress.
doi: 10.1038/nature12212
分子生物学：PfSETvsによるヒストンH3K36メチル化は熱帯熱マラリア原虫の毒性遺伝子を抑制する
PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum p.223
The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), which is expressed on the surface of P. falciparum-infected red blood cells, is a critical virulence factor for malaria. Each parasite has 60 antigenically distinct var genes that each code for a different PfEMP1 protein. During infection the clonal parasite population expresses only one gene at a time before switching to the expression of a new variant antigen as an immune-evasion mechanism to avoid the host antibody response. The mechanism by which 59 of the 60 var genes are silenced remains largely unknown. Here we show that knocking out the P. falciparum variant-silencing SET gene (here termed PfSETvs), which encodes an orthologue of Drosophila melanogaster ASH1 and controls histone H3 lysine 36 trimethylation (H3K36me3) on var genes, results in the transcription of virtually all var genes in the single parasite nuclei and their expression as proteins on the surface of individual infected red blood cells. PfSETvs-dependent H3K36me3 is present along the entire gene body, including the transcription start site, to silence var genes. With low occupancy of PfSETvs at both the transcription start site of var genes and the intronic promoter, expression of var genes coincides with transcription of their corresponding antisense long noncoding RNA. These results uncover a previously unknown role of PfSETvs-dependent H3K36me3 in silencing var genes in P. falciparum that might provide a general mechanism by which orthologues of PfSETvs repress gene expression in other eukaryotes. PfSETvs knockout parasites expressing all PfEMP1 proteins may also be applied to the development of a malaria vaccine.
doi: 10.1038/nature12361
再生医学：爪上皮におけるWnt活性化が爪の成長と指の再生を結びつける
Wnt activation in nail epithelium couples nail growth to digit regeneration p.228
The tips of mammalian digits can regenerate after amputation, like those of amphibians. It is unknown why this capacity is limited to the area associated with the nail. Here we show that nail stem cells (NSCs) reside in the proximal nail matrix and that the mechanisms governing NSC differentiation are coupled directly with their ability to orchestrate digit regeneration. Early nail progenitors undergo Wnt-dependent differentiation into the nail. After amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to the regeneration of the digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate the nail or digit. Nevertheless, β-catenin stabilization in the NSC region induced their regeneration. These results establish a link between NSC differentiation and digit regeneration, and suggest that NSCs may have the potential to contribute to the development of novel treatments for amputees.
doi: 10.1038/nature12214
細胞生物学：エンドサイトーシスのホスファチジルイノシトール-3,4-ビスリン酸による空間的・時間的制御
Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate p.233
Phosphoinositides serve crucial roles in cell physiology, ranging from cell signalling to membrane traffic. Among the seven eukaryotic phosphoinositides the best studied species is phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), which is concentrated at the plasma membrane where, among other functions, it is required for the nucleation of endocytic clathrin-coated pits. No phosphatidylinositol other than PI(4,5)P2 has been implicated in clathrin-mediated endocytosis, whereas the subsequent endosomal stages of the endocytic pathway are dominated by phosphatidylinositol-3-phosphates(PI(3)P). How phosphatidylinositol conversion from PI(4,5)P2-positive endocytic intermediates to PI(3)P-containing endosomes is achieved is unclear. Here we show that formation of phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) by class II phosphatidylinositol-3-kinase C2α (PI(3)K C2α) spatiotemporally controls clathrin-mediated endocytosis. Depletion of PI(3,4)P2 or PI(3)K C2α impairs the maturation of late-stage clathrin-coated pits before fission. Timed formation of PI(3,4)P2 by PI(3)K C2α is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. These findings provide a mechanistic framework for the role of PI(3,4)P2 in endocytosis and unravel a novel discrete function of PI(3,4)P2 in a central cell physiological process.
doi: 10.1038/nature12360
分子生物学：NFAT活性化に関するsiRNAスクリーニングによって、セプチンがストア作動性Ca2+流入の調節因子であることが明らかになった
An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry p.238
The STIM1–ORAI1 pathway of store-operated Ca2+ entry is an essential component of cellular Ca2+ signalling. STIM1 senses depletion of intracellular Ca2+ stores in response to physiological stimuli, and relocalizes within the endoplasmic reticulum to plasma-membrane-apposed junctions, where it recruits and gates open plasma membrane ORAI1 Ca2+ channels. Here we use a genome-wide RNA interference screen in HeLa cells to identify filamentous septin proteins as crucial regulators of store-operated Ca2+ entry. Septin filaments and phosphatidylinositol-4,5-bisphosphate (also known as PtdIns(4,5)P2) rearrange locally at endoplasmic reticulum–plasma membrane junctions before and during formation of STIM1–ORAI1 clusters, facilitating STIM1 targeting to these junctions and promoting the stable recruitment of ORAI1. Septin rearrangement at junctions is required for PtdIns(4,5)P2 reorganization and efficient STIM1–ORAI1 communication. Septins are known to demarcate specialized membrane regions such as dendritic spines, the yeast bud and the primary cilium, and to serve as membrane diffusion barriers and/or signalling hubs in cellular processes such as vesicle trafficking, cell polarity and cytokinesis. Our data show that septins also organize the highly localized plasma membrane domains that are important in STIM1–ORAI1 signalling, and indicate that septins may organize membrane microdomains relevant to other signalling processes.
doi: 10.1038/nature12229
