目次

Editorials

最新の宇宙望遠鏡から得られるスペクトルデータが急増しており、それを生かすには実験室での実証研究がどうしても必要だ。

Nailing fingerprints in the stars p.437

Laboratory-based experiments are sorely needed to complement the rapidly proliferating spectral data originating from observations by the latest space telescopes.

doi: 10.1038/503437a

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「DIYバイオ」の可能性を広げるために、規制をめぐる誤解を一掃すべき時にきている。

The DIY dilemma p.437

Misconceptions about do-it-yourself biology mean that opportunities are being missed.

doi: 10.1038/503437b

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大学は、研究者育成の努力を無駄にしないように、若手研究者への圧力に対抗すべきだ。

Enemy of the good p.438

Universities need to counter pressures that undermine support for younger researchers.

doi: 10.1038/503438a

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News

月面探査計画の順調な進展で、中国が宇宙大国の仲間入りへ。

China aims for the Moon p.445

Planned launch of lunar rover follows a string of triumphs for the country’s space programme.

doi: 10.1038/503445a

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LHC(大型ハドロン衝突型加速器)が、データを将来もずっと利用できる形で公開するための計画を。

LHC plans for open data future p.447

Researchers share results to keep them accessible.

doi: 10.1038/503447a

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医薬品開発の促進を目指し、薬剤分子やタンパク質の情報から相互作用を予測できるウェブサイトが。

Project ranks billions of drug interactions p.449

Drugable.com predicts mechanisms through computation.

doi: 10.1038/503449a

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中国が、侵入生物種の増加を食い止めるため、さまざまな対策を。

China battles army of invaders p.450

Raft of control measures slows the march of alien species.

doi: 10.1038/503450a

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象牙の密猟が急増しており、各国が話し合い、対策を強化。

Nations fight back on ivory p.452

Politicians take action on poaching in Africa as tusk seizures approach record numbers.

doi: 10.1038/503452a

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News Features

研究倫理:内部告発のための3つの方法

Research ethics: 3 ways to blow the whistle p.454

科学的不正行為を告発するのは容易ではないが、疑いを抱いたときにどうするのが効果的か、経験者が語る。

doi: 10.1038/503454a

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免疫学:幸福の追求

Immunology: The pursuit of happiness p.458

ある種の精神状態が体の健康に影響するのは、どのような仕組みによるのだろうか。

doi: 10.1038/503458a

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News & Views

生態学:ループのほころび

Ecology: A leak in the loop p.472

外来種のイネ科草本の侵入を受けている森林地域では、正および負のフィードバックの性質が変動することが分かった。これは、自然系の管理の複雑性を明らかにしている。

doi: 10.1038/nature12838

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惑星科学:古代火星のひとかけら

Planetary science: A chunk of ancient Mars p.473

北西アフリカで見つかり、NWA 7533という平凡な名前が付けられた隕石について解析が行われ、これが火星のレゴリス、つまり土壌の初めて得られた試料であることが示された。この隕石は、これまで見つかった中で最古の火成岩地殻に由来するものだ。

doi: 10.1038/nature12836

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創薬:好機が潜むポケット

Drug discovery: Pocket of opportunity p.475

がんを引き起こすRasタンパク質を中和する小分子の開発は、30年間にわたって失敗が続いてきたが、抗がん剤研究への新しい道を開く手法が今回見つかった。

doi: 10.1038/nature12835

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システム生物学:細菌のライフスタイル選択法

Systems biology: How bacteria choose a lifestyle p.476

ある種の細菌集団では、一部の細胞は単独で存在して運動性を持ち続けるが、他の細胞はどこかに落ち着いて連鎖状の形態をとる。細胞がどちらの状態をとるかを決定する機序が今回調べられた。

doi: 10.1038/nature12837

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宇宙物理学:例外が規則を検証する

Astrophysics: Exception tests the rules p.477

間欠的に非常に明るくなるX線源の詳しい観測から、その放射が、以前に考えられていたように中間質量ブラックホールへの質量降着からエネルギーを得ているのではないらしいことが示された。

doi: 10.1038/503477a

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分子生物学:抗生物質は暗号解読の枠をずらす

Molecular biology: Antibiotic re-frames decoding p.478

ケトライド系の抗生物質は、細菌でリボソームのフレームシフト、つまりRNA翻訳の変更を引き起こすことが分かった。これによって抗生物質耐性に関わる遺伝子の発現が促進されるので、この現象は広い範囲に関わってくると考えられる。

doi: 10.1038/503478a

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Articles

システム生物学:細胞運命決定における記憶とモジュール性

Memory and modularity in cell-fate decision making p.481

This study shows that Bacillus subtilis switches from a solitary, motile lifestyle to a multicellular, sessile state in a random, memoryless fashion, but that the underlying gene network is buffered against its own stochastic variation to tightly time the reverse transition; thus bacteria keep track of time to force their progeny to cooperate during the earliest stage of multicellular growth.

doi: 10.1038/nature12804

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遺伝:天然の遺伝的変動がエンハンサーの選択および機能に与える影響

Effect of natural genetic variation on enhancer selection and function p.487

Naturally occurring genetic variation between inbred mouse strains is used as a mutagenesis strategy to investigate mechanisms responsible for the selection and function of cis-regulatory elements in macrophages; lineage-determining transcription factors are proposed to select enhancer-like regions in the genome in a collaborative fashion and facilitate the binding of signal-dependent factors.

doi: 10.1038/nature12615

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医学:2型糖尿病と肥満による寿命短縮に有効な低分子AdipoRアゴニスト

A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity p.493

An orally active small molecule, AdipRon, that binds to and activates both adiponectin receptors (AdipoR1 and AdipoR2) is identified; it ameliorates diabetes in mice on a high-fat diet and in genetically obese db/db mice, and if this can be extrapolated to humans, orally active agonists such as AdipoRon are a promising new approach to treat obesity-related diseases such as type 2 diabetes.

doi: 10.1038/nature12656

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Letters

宇宙:超高輝度X線源M 101 ULX-1におけるブラックホールへの不可解な降着

Puzzling accretion onto a black hole in the ultraluminous X-ray source M 101 ULX-1 p.500

There are two proposed explanations for ultraluminous X-ray sources (ULXs) with luminosities in excess of 1039 erg s−1. They could be intermediate-mass black holes (more than 100–1,000 solar masses, ) radiating at sub-maximal (sub-Eddington) rates, as in Galactic black-hole X-ray binaries but with larger, cooler accretion disks. Alternatively, they could be stellar-mass black holes radiating at Eddington or super-Eddington rates. On its discovery, M 101 ULX-1 had a luminosity of 3 × 1039 erg s−1 and a supersoft thermal disk spectrum with an exceptionally low temperature—uncomplicated by photons energized by a corona of hot electrons—more consistent with the expected appearance of an accreting intermediate-mass black hole. Here we report optical spectroscopic monitoring of M 101 ULX-1. We confirm the previous suggestion that the system contains a Wolf-Rayet star, and reveal that the orbital period is 8.2 days. The black hole has a minimum mass of 5, and more probably a mass of 20−30, but we argue that it is very unlikely to be an intermediate-mass black hole. Therefore, its exceptionally soft spectra at high Eddington ratios violate the expectations for accretion onto stellar-mass black holes. Accretion must occur from captured stellar wind, which has hitherto been thought to be so inefficient that it could not power an ultraluminous source.

doi: 10.1038/nature12762

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量子情報科学:薄膜分子半導体におけるスピンを利用した情報処理の可能性

Potential for spin-based information processing in a thin-film molecular semiconductor p.504

Organic semiconductors are studied intensively for applications in electronics and optics, and even spin-based information technology, or spintronics. Fundamental quantities in spintronics are the population relaxation time (T1) and the phase memory time (T2): T1 measures the lifetime of a classical bit, in this case embodied by a spin oriented either parallel or antiparallel to an external magnetic field, and T2 measures the corresponding lifetime of a quantum bit, encoded in the phase of the quantum state. Here we establish that these times are surprisingly long for a common, low-cost and chemically modifiable organic semiconductor, the blue pigment copper phthalocyanine, in easily processed thin-film form of the type used for device fabrication. At 5 K, a temperature reachable using inexpensive closed-cycle refrigerators, T1 and T2 are respectively 59 ms and 2.6 μs, and at 80 K, which is just above the boiling point of liquid nitrogen, they are respectively 10 μs and 1 μs, demonstrating that the performance of thin-film copper phthalocyanine is superior to that of single-molecule magnets over the same temperature range. T2 is more than two orders of magnitude greater than the duration of the spin manipulation pulses, which suggests that copper phthalocyanine holds promise for quantum information processing, and the long T1 indicates possibilities for medium-term storage of classical bits in all-organic devices on plastic substrates.

doi: 10.1038/nature12597

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材料科学:可視光吸収強誘電体および光起電材料用としてのペロブスカイト型酸化物

Perovskite oxides for visible-light-absorbing ferroelectric and photovoltaic materials p.509

Ferroelectrics have recently attracted attention as a candidate class of materials for use in photovoltaic devices, and for the coupling of light absorption with other functional properties. In these materials, the strong inversion symmetry breaking that is due to spontaneous electric polarization promotes the desirable separation of photo-excited carriers and allows voltages higher than the bandgap, which may enable efficiencies beyond the maximum possible in a conventional p–n junction solar cell. Ferroelectric oxides are also stable in a wide range of mechanical, chemical and thermal conditions and can be fabricated using low-cost methods such as sol–gel thin-film deposition and sputtering. Recent work has shown how a decrease in ferroelectric layer thickness and judicious engineering of domain structures and ferroelectric–electrode interfaces can greatly increase the current harvested from ferroelectric absorber materials, increasing the power conversion efficiency from about 10−4 to about 0.5 per cent. Further improvements in photovoltaic efficiency have been inhibited by the wide bandgaps (2.7–4 electronvolts) of ferroelectric oxides, which allow the use of only 8–20 per cent of the solar spectrum. Here we describe a family of single-phase solid oxide solutions made from low-cost and non-toxic elements using conventional solid-state methods: [KNbO3]1 −x[BaNi1/2Nb1/2O3 −δ]x (KBNNO). These oxides exhibit both ferroelectricity and a wide variation of direct bandgaps in the range 1.1–3.8 electronvolts. In particular, the x = 0.1 composition is polar at room temperature, has a direct bandgap of 1.39 electronvolts and has a photocurrent density approximately 50 times larger than that of the classic ferroelectric (Pb,La)(Zr,Ti)O3 material. The ability of KBNNO to absorb three to six times more solar energy than the current ferroelectric materials suggests a route to viable ferroelectric semiconductor-based cells for solar energy conversion and other applications.

doi: 10.1038/nature12622

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宇宙:NWA 7533隕石から得られた最初期の火星地殻の起源と年代

Origin and age of the earliest Martian crust from meteorite NWA 7533 p.513

The ancient cratered terrain of the southern highlands of Mars is thought to hold clues to the planet’s early differentiation, but until now no meteoritic regolith breccias have been recovered from Mars. Here we show that the meteorite Northwest Africa (NWA) 7533 (paired with meteorite NWA 7034) is a polymict breccia consisting of a fine-grained interclast matrix containing clasts of igneous-textured rocks and fine-grained clast-laden impact melt rocks. High abundances of meteoritic siderophiles (for example nickel and iridium) found throughout the rock reach a level in the fine-grained portions equivalent to 5 per cent CI chondritic input, which is comparable to the highest levels found in lunar breccias. Furthermore, analyses of three leucocratic monzonite clasts show a correlation between nickel, iridium and magnesium consistent with differentiation from impact melts. Compositionally, all the fine-grained material is alkalic basalt, chemically identical (except for sulphur, chlorine and zinc) to soils from Gusev crater. Thus, we propose that NWA 7533 is a Martian regolith breccia. It contains zircons for which we measured an age of 4,428 ± 25 million years, which were later disturbed 1,712 ± 85 million years ago. This evidence for early crustal differentiation implies that the Martian crust, and its volatile inventory, formed in about the first 100 million years of Martian history, coeval with earliest crust formation on the Moon and the Earth. In addition, incompatible element abundances in clast-laden impact melt rocks and interclast matrix provide a geochemical estimate of the average thickness of the Martian crust (50 kilometres) comparable to that estimated geophysically.

doi: 10.1038/nature12764

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生態:植物侵入の自己増強的な影響は経時的に変化する

Self-reinforcing impacts of plant invasions change over time p.517

Returning native species to habitats degraded by biological invasions is a critical conservation goal. A leading hypothesis poses that exotic plant dominance is self-reinforced by impacts on ecosystem processes, leading to persistent stable states. Invaders have been documented to modify fire regimes, alter soil nutrients or shift microbial communities in ways that feed back to benefit themselves over competitors. However, few studies have followed invasions through time to ask whether ecosystem impacts and feedbacks persist. Here we return to woodland sites in Hawai′i Volcanoes National Park that were invaded by exotic C4 grasses in the 1960s, the ecosystem impacts of which were studied intensively in the 1990s. We show that positive feedbacks between exotic grasses and soil nitrogen cycling have broken down, but rather than facilitating native vegetation, the weakening feedbacks facilitate new exotic species. Data from the 1990s showed that exotic grasses increased nitrogen-mineralization rates by two- to fourfold, but were nitrogen-limited. Thus, the impacts of the invader created a positive feedback early in the invasion. We now show that annual net soil nitrogen mineralization has since dropped to pre-invasion levels. In addition, a seedling outplanting experiment that varied soil nitrogen and grass competition demonstrates that the changing impacts of grasses do not favour native species re-establishment. Instead, decreased nitrogen availability most benefits another aggressive invader, the nitrogen-fixing tree Morella faya. Long-term studies of invasions may reveal that ecosystem impacts and feedbacks shift over time, but that this may not benefit native species recovery.

doi: 10.1038/nature12798

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神経科学:脱抑制性制御に特化した皮質介在ニューロン

Cortical interneurons that specialize in disinhibitory control p.521

In the mammalian cerebral cortex the diversity of interneuronal subtypes underlies a division of labour subserving distinct modes of inhibitory control. A unique mode of inhibitory control may be provided by inhibitory neurons that specifically suppress the firing of other inhibitory neurons. Such disinhibition could lead to the selective amplification of local processing and serve the important computational functions of gating and gain modulation. Although several interneuron populations are known to target other interneurons to varying degrees, little is known about interneurons specializing in disinhibition and their in vivo function. Here we show that a class of interneurons that express vasoactive intestinal polypeptide (VIP) mediates disinhibitory control in multiple areas of neocortex and is recruited by reinforcement signals. By combining optogenetic activation with single-cell recordings, we examined the functional role of VIP interneurons in awake mice, and investigated the underlying circuit mechanisms in vitro in auditory and medial prefrontal cortices. We identified a basic disinhibitory circuit module in which activation of VIP interneurons transiently suppresses primarily somatostatin- and a fraction of parvalbumin-expressing inhibitory interneurons that specialize in the control of the input and output of principal cells, respectively. During the performance of an auditory discrimination task, reinforcement signals (reward and punishment) strongly and uniformly activated VIP neurons in auditory cortex, and in turn VIP recruitment increased the gain of a functional subpopulation of principal neurons. These results reveal a specific cell type and microcircuit underlying disinhibitory control in cortex and demonstrate that it is activated under specific behavioural conditions.

doi: 10.1038/nature12676

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進化遺伝学:ヒトおよび類人猿の多能性幹細胞で見られる差異のあるL1調節

Differential L1 regulation in pluripotent stem cells of humans and apes p.525

Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic understanding of the evolution and diversity of our own species. Until now, preserved tissues have been the main source for most comparative studies between humans, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). However, these tissue samples do not fairly represent the distinctive traits of live cell behaviour and are not amenable to genetic manipulation. We propose that induced pluripotent stem (iPS) cells could be a unique biological resource to determine relevant phenotypical differences between human and NHPs, and that those differences could have potential adaptation and speciation value. Here we describe the generation and initial characterization of iPS cells from chimpanzees and bonobos as new tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and NHP iPS cells revealed differences in the regulation of long interspersed element-1 (L1, also known as LINE-1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B (also known as A3B) and PIWIL2 (ref. 7) in NHP iPS cells correlated with increased L1 mobility and endogenous L1 messenger RNA levels. Moreover, results from the manipulation of A3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPS cells in culture and may have also occurred in the germ line or embryonic cells developmentally upstream to germline specification during primate evolution. We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have continuing adaptive significance.

doi: 10.1038/nature12686

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免疫:細胞固有の免疫はcGAMPの細胞間移送を介して近隣の細胞へ広がる

Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP p.530

The innate immune defence of multicellular organisms against microbial pathogens requires cellular collaboration. Information exchange allowing immune cells to collaborate is generally attributed to soluble protein factors secreted by pathogen-sensing cells. Cytokines, such as type I interferons (IFNs), serve to alert non-infected cells to the possibility of pathogen challenge. Moreover, in conjunction with chemokines they can instruct specialized immune cells to contain and eradicate microbial infection. Several receptors and signalling pathways exist that couple pathogen sensing to the induction of cytokines, whereas cytosolic recognition of nucleic acids seems to be exquisitely important for the activation of type I IFNs, master regulators of antiviral immunity. Cytosolic DNA is sensed by the receptor cyclic GMP-AMP (cGAMP) synthase (cGAS), which catalyses the synthesis of the second messenger cGAMP(2′-5′). This molecule in turn activates the endoplasmic reticulum (ER)-resident receptor STING, thereby inducing an antiviral state and the secretion of type I IFNs. Here we find in murine and human cells that cGAS-synthesized cGAMP(2′-5′) is transferred from producing cells to neighbouring cells through gap junctions, where it promotes STING activation and thus antiviral immunity independently of type I IFN signalling. In line with the limited cargo specificity of connexins, the proteins that assemble gap junction channels, most connexins tested were able to confer this bystander immunity, thus indicating a broad physiological relevance of this local immune collaboration. Collectively, these observations identify cGAS-triggered cGAMP(2′-5′) transfer as a novel host strategy that serves to rapidly convey antiviral immunity in a transcription-independent, horizontal manner.

doi: 10.1038/nature12640

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医学:ACE2受容体を利用するコウモリ由来SARS類似コロナウイルスの単離と特性解析

Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor p.535

The 2002–3 pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV) was one of the most significant public health events in recent history. An ongoing outbreak of Middle East respiratory syndrome coronavirus suggests that this group of viruses remains a key threat and that their distribution is wider than previously recognized. Although bats have been suggested to be the natural reservoirs of both viruses, attempts to isolate the progenitor virus of SARS-CoV from bats have been unsuccessful. Diverse SARS-like coronaviruses (SL-CoVs) have now been reported from bats in China, Europe and Africa, but none is considered a direct progenitor of SARS-CoV because of their phylogenetic disparity from this virus and the inability of their spike proteins to use the SARS-CoV cellular receptor molecule, the human angiotensin converting enzyme II (ACE2). Here we report whole-genome sequences of two novel bat coronaviruses from Chinese horseshoe bats (family: Rhinolophidae) in Yunnan, China: RsSHC014 and Rs3367. These viruses are far more closely related to SARS-CoV than any previously identified bat coronaviruses, particularly in the receptor binding domain of the spike protein. Most importantly, we report the first recorded isolation of a live SL-CoV (bat SL-CoV-WIV1) from bat faecal samples in Vero E6 cells, which has typical coronavirus morphology, 99.9% sequence identity to Rs3367 and uses ACE2 from humans, civets and Chinese horseshoe bats for cell entry. Preliminary in vitro testing indicates that WIV1 also has a broad species tropism. Our results provide the strongest evidence to date that Chinese horseshoe bats are natural reservoirs of SARS-CoV, and that intermediate hosts may not be necessary for direct human infection by some bat SL-CoVs. They also highlight the importance of pathogen-discovery programs targeting high-risk wildlife groups in emerging disease hotspots as a strategy for pandemic preparedness.

doi: 10.1038/nature12711

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生化学:C型肝炎ウイルス様リボソーム内部侵入部位は、eIF3を引き離して40Sサブユニットに接触する

Hepatitis-C-virus-like internal ribosome entry sites displace eIF3 to gain access to the 40S subunit p.539

Hepatitis C virus (HCV) and classical swine fever virus (CSFV) messenger RNAs contain related (HCV-like) internal ribosome entry sites (IRESs) that promote 5′-end independent initiation of translation, requiring only a subset of the eukaryotic initiation factors (eIFs) needed for canonical initiation on cellular mRNAs. Initiation on HCV-like IRESs relies on their specific interaction with the 40S subunit, which places the initiation codon into the P site, where it directly base-pairs with eIF2-bound initiator methionyl transfer RNA to form a 48S initiation complex. However, all HCV-like IRESs also specifically interact with eIF3 (refs 2, 5, 6, 7, 9, 10, 11, 12), but the role of this interaction in IRES-mediated initiation has remained unknown. During canonical initiation, eIF3 binds to the 40S subunit as a component of the 43S pre-initiation complex, and comparison of the ribosomal positions of eIF3 and the HCV IRES revealed that they overlap, so that their rearrangement would be required for formation of ribosomal complexes containing both components. Here we present a cryo-electron microscopy reconstruction of a 40S ribosomal complex containing eIF3 and the CSFV IRES. Remarkably, although the position and interactions of the CSFV IRES with the 40S subunit in this complex are similar to those of the HCV IRES in the 40S–IRES binary complex, eIF3 is completely displaced from its ribosomal position in the 43S complex, and instead interacts through its ribosome-binding surface exclusively with the apical region of domain III of the IRES. Our results suggest a role for the specific interaction of HCV-like IRESs with eIF3 in preventing ribosomal association of eIF3, which could serve two purposes: relieving the competition between the IRES and eIF3 for a common binding site on the 40S subunit, and reducing formation of 43S complexes, thereby favouring translation of viral mRNAs.

doi: 10.1038/nature12658

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微生物学:DNA複製起点非存在下での増殖の加速

Accelerated growth in the absence of DNA replication origins p.544

DNA replication initiates at defined sites called origins, which serve as binding sites for initiator proteins that recruit the replicative machinery. Origins differ in number and structure across the three domains of life and their properties determine the dynamics of chromosome replication. Bacteria and some archaea replicate from single origins, whereas most archaea and all eukaryotes replicate using multiple origins. Initiation mechanisms that rely on homologous recombination operate in some viruses. Here we show that such mechanisms also operate in archaea. We use deep sequencing to study replication in Haloferax volcanii and identify four chromosomal origins of differing activity. Deletion of individual origins results in perturbed replication dynamics and reduced growth. However, a strain lacking all origins has no apparent defects and grows significantly faster than wild type. Origin-less cells initiate replication at dispersed sites rather than at discrete origins and have an absolute requirement for the recombinase RadA, unlike strains lacking individual origins. Our results demonstrate that homologous recombination alone can efficiently initiate the replication of an entire cellular genome. This raises the question of what purpose replication origins serve and why they have evolved.

doi: 10.1038/nature12650

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創薬:K-Ras (G12C)阻害剤はGTP親和性とエフェクター相互作用をアロステリックに制御する

K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions p.548

Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.

doi: 10.1038/nature12796

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構造生物学:フラビン介在性二重酸化が酵素的ファヴォルスキー型転位を制御する

Flavin-mediated dual oxidation controls an enzymatic Favorskii-type rearrangement p.552

Flavoproteins catalyse a diversity of fundamental redox reactions and are one of the most studied enzyme families. As monooxygenases, they are universally thought to control oxygenation by means of a peroxyflavin species that transfers a single atom of molecular oxygen to an organic substrate. Here we report that the bacterial flavoenzyme EncM catalyses the peroxyflavin-independent oxygenation–dehydrogenation dual oxidation of a highly reactive poly(β-carbonyl). The crystal structure of EncM with bound substrate mimics and isotope labelling studies reveal previously unknown flavin redox biochemistry. We show that EncM maintains an unexpected stable flavin-oxygenating species, proposed to be a flavin-N5-oxide, to promote substrate oxidation and trigger a rare Favorskii-type rearrangement that is central to the biosynthesis of the antibiotic enterocin. This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization.

doi: 10.1038/nature12643

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