目次

Editorials

H7N9鳥インフルエンザウイルス流行に対する中国の対応は、これまでに比べ、高く評価できる。

The fight against bird flu p.397

China’s well-handled response to outbreaks of H7N9 avian influenza belies the country’s bad reputation from its past dealings with disease. But there are still improvements to be made.

doi: 10.1038/496397a

精神疾患を診断する際の人為的な分類が、効果的な治療の妨げになっている。

Across the divide p.397

Diagnostic boundaries separating mental disorders hamper effective treatments.

doi: 10.1038/496397b

Natureでは、生命科学系の掲載論文の再現性を改善するための対策を導入する。

Announcement: Reducing our irreproducibility p.398

doi: 10.1038/496398a

News

アマゾンの熱帯雨林で、二酸化炭素による肥沃化効果を調べるための実験が。

Experiment aims to steep rainforest in carbon dioxide p.405

Sensor-studded plots in the Amazon forest will measure the fertilizing effect of the gas.

doi: 10.1038/496405a

国際天文学連合(IAU)による天体の命名の慣例をめぐり、企業から異論が。

Moon and planet names spark battle p.407

Company clashes with International Astronomical Union over popular labels for exoplanets.

doi: 10.1038/496407a

ヨーロッパで、ミツバチを保護するために、殺虫剤の禁止が議論に。

Europe debates risk to bees p.408

Proposed pesticide ban gathers scientific support as some experts call for more field studies.

doi: 10.1038/496408a

日本が海底のメタンハイドレートからのガスの回収に初めて成功し、期待が。

Japanese test coaxes fire from ice p.409

First attempt to extract methane from frozen hydrates far beneath the ocean shows promise.

doi: 10.1038/496409a

地表の岩石が地球内部を経て再び火山から噴出する、長い循環過程の存在が明らかに。

Ancient crust rises from the deep p.410

Remnants of surface rocks take long tour of planet’s interior.

doi: 10.1038/496410a

米保健社会福祉省(DHHS)が、インターネットを利用して個人データを収集する研究のための手引きを。

Guidance issued for US Internet research p.411

Institutional review boards may need to take a closer look at some types of online research.

doi: 10.1038/496411a

News Features

銃器研究:ガン・ファイター

Firearms research: The gun fighter p.412

国民とほぼ同数の銃が出回る米国で、銃所有が何をもたらすかを研究している医師がいる。

doi: 10.1038/496412a

心の健康:スペクトルの中で

Mental health: On the spectrum p.416

精神疾患は、色のスペクトルのように少しずつ違いながら連続して並ぶものだが、最新の診断マニュアルでも、いまだにそれらを別々の分離した病気と捉えている。

doi: 10.1038/496416a

News & Views

フォーラム:量子物理学:誤ったふるまいを掌握する

Quantum physics: A grip on misbehaviour p.436

信頼できない量子系の特性を明らかにし、その系を統制する方法が考案された。このような知見が基礎科学、実際の量子計算や量子暗号に持つ意味について、2人の専門家が論じている。

doi: 10.1038/496436a

自己免疫:塩で追い打ちをかける

Autoimmunity: Rubbing salt in the wound p.437

塩化ナトリウムが、病原性のTH17免疫細胞の産生を引き起こす酵素の活性化を誘導できることがわかった。これは、塩が自己免疫疾患を悪化させかねない因子である可能性を示している。

doi: 10.1038/nature11959

素粒子物理学:最小限主義の勝利

Particle physics: Minimalism triumphant p.439

ヒッグスボソンと思われる粒子の発見は、物理学における画期的な出来事であった。この発見以後に報告された実験結果は、素粒子物理学の最小標準模型におけるヒッグス粒子についての予想と非常によく一致している。

doi: 10.1038/496439a

HIV:ワクチンへのロードマップ

HIV: Roadmaps to a vaccine p.441

エイズの全世界的流行が始まってから30年以上たったが、有効なワクチンはいまだに見つかっていない。だが、単一細胞から得られた、広範囲に作用する強力なヒト抗体の解析から、ワクチン開発の合理的手法が考えられるようになった。

doi: 10.1038/nature12091

画像化法:ダイヤモンドの皿に載った磁性細菌

Imaging: Magnetic bacteria on a diamond plate p.442

磁気走性を示す細菌の生細胞中の磁場が新規な手法を使って画像化された。この手法は他の生物系における磁気動態の研究に使えそうである。

doi: 10.1038/496442a

ゲノミクス:注目度上昇中のゼブラフィッシュゲノム

Genomics: Zebrafish earns its stripes p.443

ゼブラフィッシュのゲノム塩基配列が解読された。このことは、その全タンパク質コード領域の3分の1以上をカバーする数の変異体系統が作出されたことと相まって、ヒト遺伝子の特徴解明を加速すると思われる。

doi: 10.1038/nature12094

Review

免疫:発生、恒常性維持および疾患におけるマクロファージの生物学的な役割

Macrophage biology in development, homeostasis and disease p.445

Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the ‘hallmarks’ of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.

doi: 10.1038/nature12034

Articles

量子物理学:量子系の古典的命令

Classical command of quantum systems p.456

A scheme is described that enables characterization and classical command of large quantum systems; it provides a test of whether a claimed quantum computer is truly quantum, and also advances towards a goal of quantum cryptography, namely the use of untrusted devices to establish a shared random key, with security based on the validity of quantum physics.

doi: 10.1038/nature12035

システム生物学:TH17細胞の分化を制御する動的な調節ネットワーク

Dynamic regulatory network controlling TH17 cell differentiation p.461

A global view of the genetic networks regulating the differentiation of TH17 cells is presented, based on temporal expression profiling, computational network reconstruction and validation of predicted interactions by nanowire-mediated siRNA perturbation.

doi: 10.1038/nature11981

免疫:HIV-1広範囲中和抗体とファウンダーウイルスの共進化

Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus p.469

Longitudinal sampling is used to map the evolution of an HIV-1 virus from the time of infection, and the co-evolution of a broadly neutralizing antibody in the same infected patient; the findings have important implications for HIV vaccine development.

doi: 10.1038/nature12053

構造生物学:小角散乱法によって得られた質量、モデルおよび分解能の正確な評価

Accurate assessment of mass, models and resolution by small-angle scattering p.477

Small-angle scattering of X-rays or neutrons is more readily applied to macromolecular complexes than is X-ray crystallography, and is particularly useful for protein complexes with high flexibility; here new quantitative metrics are presented that will allow solution-derived structures to be validated and assessed for mass, resolution and accuracy.

doi: 10.1038/nature12070

Letters

量子物理学:非アーベル型非断熱幾何学的ゲートの実験による実現

Experimental realization of non-Abelian non-adiabatic geometric gates p.482

Microwave stimulation of a superconducting artificial three-level atom is used to demonstrate high-fidelity, non-Abelian geometric transformations, the results of which depend on the order in which they are performed.

doi: 10.1038/nature12010

計測:生細胞の光磁気画像化

Optical magnetic imaging of living cells p.486

Magnetic imaging is a powerful tool for probing biological and physical systems. However, existing techniques either have poor spatial resolution compared to optical microscopy and are hence not generally applicable to imaging of sub-cellular structure (for example, magnetic resonance imaging), or entail operating conditions that preclude application to living biological samples while providing submicrometre resolution (for example, scanning superconducting quantum interference device microscopy, electron holography and magnetic resonance force microscopy). Here we demonstrate magnetic imaging of living cells (magnetotactic bacteria) under ambient laboratory conditions and with sub-cellular spatial resolution (400 nanometres), using an optically detected magnetic field imaging array consisting of a nanometre-scale layer of nitrogen–vacancy colour centres implanted at the surface of a diamond chip. With the bacteria placed on the diamond surface, we optically probe the nitrogen–vacancy quantum spin states and rapidly reconstruct images of the vector components of the magnetic field created by chains of magnetic nanoparticles (magnetosomes) produced in the bacteria. We also spatially correlate these magnetic field maps with optical images acquired in the same apparatus. Wide-field microscopy allows parallel optical and magnetic imaging of multiple cells in a population with submicrometre resolution and a field of view in excess of 100 micrometres. Scanning electron microscope images of the bacteria confirm that the correlated optical and magnetic images can be used to locate and characterize the magnetosomes in each bacterium. Our results provide a new capability for imaging bio-magnetic structures in living cells under ambient conditions with high spatial resolution, and will enable the mapping of a wide range of magnetic signals within cells and cellular networks.

doi: 10.1038/nature12072

地球:プリューム溶岩の異常な硫黄同位体が明らかにしたマントル深部の始生代地殻貯蔵庫

Anomalous sulphur isotopes in plume lavas reveal deep mantle storage of Archaean crust p.490

Basaltic lavas erupted at some oceanic intraplate hotspot volcanoes are thought to sample ancient subducted crustal materials. However, the residence time of these subducted materials in the mantle is uncertain and model-dependent, and compelling evidence for their return to the surface in regions of mantle upwelling beneath hotspots is lacking. Here we report anomalous sulphur isotope signatures indicating mass-independent fractionation (MIF) in olivine-hosted sulphides from 20-million-year-old ocean island basalts from Mangaia, Cook Islands (Polynesia), which have been suggested to sample recycled oceanic crust. Terrestrial MIF sulphur isotope signatures (in which the amount of fractionation does not scale in proportion with the difference in the masses of the isotopes) were generated exclusively through atmospheric photochemical reactions until about 2.45 billion years ago. Therefore, the discovery of MIF sulphur in these young plume lavas suggests that sulphur—probably derived from hydrothermally altered oceanic crust—was subducted into the mantle before 2.45 billion years ago and recycled into the mantle source of Mangaia lavas. These new data provide evidence for ancient materials, with negative Δ33S values, in the mantle source for Mangaia lavas. Our data also complement evidence for recycling of the sulphur content of ancient sedimentary materials to the subcontinental lithospheric mantle that has been identified in diamond-hosted sulphide inclusions. This Archaean age for recycled oceanic crust also provides key constraints on the length of time that subducted crustal material can survive in the mantle, and on the timescales of mantle convection from subduction to upwelling beneath hotspots.

doi: 10.1038/nature12020

遺伝:ゼブラフィッシュのタンパク質コード遺伝子の機能に関するゲノム全域での系統的解析

A systematic genome-wide analysis of zebrafish protein-coding gene function p.494

Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes, this number falls considerably short of the more than 22,000 mouse protein-coding genes. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning, insertional mutagenesis, antisense morpholino oligonucleotides, targeted re-sequencing, and zinc finger and TAL endonucleases have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis.

doi: 10.1038/nature11992

遺伝:ゼブラフィッシュのゲノム参照配列とヒトゲノムとのその類縁性

The zebrafish reference genome sequence and its relationship to the human genome OPEN p.498

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

doi: 10.1038/nature12111

医学:デング熱の世界的分布と疾病負荷

The global distribution and burden of dengue p.504

Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. For some patients, dengue is a life-threatening illness. There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread. The contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known. Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284–528) dengue infections per year, of which 96 million (67–136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization. Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.

doi: 10.1038/nature12060

生化学:多様なVI型分泌ホスホリパーゼは機能的可塑性を持つ抗菌エフェクターである

Diverse type VI secretion phospholipases are functionally plastic antibacterial effectors p.508

Membranes allow the compartmentalization of biochemical processes and are therefore fundamental to life. The conservation of the cellular membrane, combined with its accessibility to secreted proteins, has made it a common target of factors mediating antagonistic interactions between diverse organisms. Here we report the discovery of a diverse superfamily of bacterial phospholipase enzymes. Within this superfamily, we defined enzymes with phospholipase A1 and A2 activity, which are common in host-cell-targeting bacterial toxins and the venoms of certain insects and reptiles. However, we find that the fundamental role of the superfamily is to mediate antagonistic bacterial interactions as effectors of the type VI secretion system (T6SS) translocation apparatus; accordingly, we name these proteins type VI lipase effectors. Our analyses indicate that PldA of Pseudomonas aeruginosa, a eukaryotic-like phospholipase D, is a member of the type VI lipase effector superfamily and the founding substrate of the haemolysin co-regulated protein secretion island II T6SS (H2-T6SS). Although previous studies have specifically implicated PldA and the H2-T6SS in pathogenesis, we uncovered a specific role for the effector and its secretory machinery in intra- and interspecies bacterial interactions. Furthermore, we find that this effector achieves its antibacterial activity by degrading phosphatidylethanolamine, the major component of bacterial membranes. The surprising finding that virulence-associated phospholipases can serve as specific antibacterial effectors suggests that interbacterial interactions are a relevant factor driving the continuing evolution of pathogenesis.

doi: 10.1038/nature12074

免疫:誘導性の塩感知キナーゼSGK1による病原性TH17細胞の誘導

Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1 p.513

TH17 cells (interleukin-17 (IL-17)-producing helper T cells) are highly proinflammatory cells that are critical for clearing extracellular pathogens and for inducing multiple autoimmune diseases. IL-23 has a critical role in stabilizing and reinforcing the TH17 phenotype by increasing expression of IL-23 receptor (IL-23R) and endowing TH17 cells with pathogenic effector functions. However, the precise molecular mechanism by which IL-23 sustains the TH17 response and induces pathogenic effector functions has not been elucidated. Here we used transcriptional profiling of developing TH17 cells to construct a model of their signalling network and nominate major nodes that regulate TH17 development. We identified serum glucocorticoid kinase 1 (SGK1), a serine/threonine kinase, as an essential node downstream of IL-23 signalling. SGK1 is critical for regulating IL-23R expression and stabilizing the TH17 cell phenotype by deactivation of mouse Foxo1, a direct repressor of IL-23R expression. SGK1 has been shown to govern Na+ transport and salt (NaCl) homeostasis in other cells. We show here that a modest increase in salt concentration induces SGK1 expression, promotes IL-23R expression and enhances TH17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated Na+-mediated TH17 differentiation in an IL-23-dependent manner. These data demonstrate that SGK1 has a critical role in the induction of pathogenic TH17 cells and provide a molecular insight into a mechanism by which an environmental factor such as a high salt diet triggers TH17 development and promotes tissue inflammation.

doi: 10.1038/nature11984

免疫:塩化ナトリウムは病原性TH17細胞の誘導によって自己免疫疾患を発症させる

Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells p.518

There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4+ helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23–TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.

doi: 10.1038/nature11868

免疫:バイスタンダーB細胞とICOS駆動運動性により支配される濾胞ヘルパーT細胞の動員

Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility p.523

Germinal centres support antibody affinity maturation and memory formation. Follicular T-helper cells promote proliferation and differentiation of antigen-specific B cells inside the follicle. A genetic deficiency in the inducible co-stimulator (ICOS), a classic CD28 family co-stimulatory molecule highly expressed by follicular T-helper cells, causes profound germinal centre defects, leading to the view that ICOS specifically co-stimulates the follicular T-helper cell differentiation program. Here we show that ICOS directly controls follicular recruitment of activated T-helper cells in mice. This effect is independent from ICOS ligand (ICOSL)-mediated co-stimulation provided by antigen-presenting dendritic cells or cognate B cells, and does not rely on Bcl6-mediated programming as an intermediate step. Instead, it requires ICOSL expression by follicular bystander B cells, which do not present cognate antigen to T-helper cells but collectively form an ICOS-engaging field. Dynamic imaging reveals ICOS engagement drives coordinated pseudopod formation and promotes persistent T-cell migration at the border between the T-cell zone and the B-cell follicle in vivo. When follicular bystander B cells cannot express ICOSL, otherwise competent T-helper cells fail to develop into follicular T-helper cells normally, and fail to promote optimal germinal centre responses. These results demonstrate a co-stimulation-independent function of ICOS, uncover a key role for bystander B cells in promoting the development of follicular T-helper cells, and reveal unsuspected sophistication in dynamic T-cell positioning in vivo.

doi: 10.1038/nature12058

生物工学:強力な抗マラリア薬アルテミシニンの高レベルな半合成生産

High-level semi-synthetic production of the potent antimalarial artemisinin p.528

Saccharomyces cerevisiae is engineered to produce high concentrations of artemisinic acid, a precursor of the artemisinin used in combination therapies for malaria treatment; an efficient and practical chemical process to convert artemisinic acid to artemisinin is also developed.

doi: 10.1038/nature12051

構造生物学:真核生物リン酸輸送体の結晶構造

Crystal structure of a eukaryotic phosphate transporter p.533

Phosphate is crucial for structural and metabolic needs, including nucleotide and lipid synthesis, signalling and chemical energy storage. Proton-coupled transporters of the major facilitator superfamily (MFS) are essential for phosphate uptake in plants and fungi, and also have a function in sensing external phosphate levels as transceptors. Here we report the 2.9 Å structure of a fungal (Piriformospora indica) high-affinity phosphate transporter, PiPT, in an inward-facing occluded state, with bound phosphate visible in the membrane-buried binding site. The structure indicates both proton and phosphate exit pathways and suggests a modified asymmetrical ‘rocker-switch’ mechanism of phosphate transport. PiPT is related to several human transporter families, most notably the organic cation and anion transporters of the solute carrier family (SLC22), which are implicated in cancer-drug resistance. We modelled representative cation and anion SLC22 transporters based on the PiPT structure to surmise the structural basis for substrate binding and charge selectivity in this important family. The PiPT structure demonstrates and expands on principles of substrate transport by the MFS transporters and illuminates principles of phosphate uptake in particular.

doi: 10.1038/nature12042

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