네이처 컨텐츠

Editorials

Turning point p.295

The result of next week’s crucial UK referendum on whether or not to remain in the European Union will have worldwide repercussions.

doi: 10.1038/534295a

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Nature distilled p.296

We need your views on an experiment to convey the latest research in digestible form.

doi: 10.1038/534296b

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Under the sea p.296

If life in the oceans is to be preserved, people must get to know the wonders of the deep.

doi: 10.1038/534296a

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News

Boon or burden: what has the EU ever done for science? p.307

More than 500 million people and 28 nations make up the European Union. It will lose one of its richest, most populous members, if the United Kingdom votes to leave on 23 June. Ahead of a possible ‘Brexit’, Nature examines five core ways that the EU shapes the course of research.

Alison Abbott, Declan Butler, Elizabeth Gibney, Quirin Schiermeier & Richard Van Noorden

doi: 10.1038/534307a

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News Features

How iPS cells changed the world p.310

Induced pluripotent stem cells were supposed to herald a medical revolution. But ten years after their discovery, they are transforming biological research instead.

Megan Scudellari

doi: 10.1038/534310a

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Can you teach old drugs new tricks? p.314

Faced with skyrocketing costs for developing new drugs, researchers are looking at ways to repurpose older ones — and even some that failed in initial trials.

Nicola Nosengo

doi: 10.1038/534314a

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News & Views

The language of flowers p.328

The complete DNA sequences of the two wild parents of the garden petunia provide valuable genetic insights into this model plant, and will improve the optimization of other crop plants for agriculture.

Sandra Knapp & Dani Zamir

doi: 10.1038/nature18445

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Cancer vaccine triggers antiviral-type defences p.329

An immunotherapy approach targets nanoparticles to dendritic cells of the immune system, leading to an antitumour immune response with antiviral-like features. Initial clinical tests of this approach show promise. See Letter p.396

Jolanda De Vries & Carl Figdor

doi: 10.1038/nature18443

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Predictions of pinning p.331

A multiscale model has been implemented that provides accurate predictions of the behaviour of ferroelectric materials in electric fields, and might aid efforts to design devices such as sensors and digital memory. See Letter p.360

Patrycja Paruch & Philippe Ghosez

doi: 10.1038/534331a

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Brain versus brawn p.332

The mechanisms that underlie enforced transitions between mature cell lineages are poorly understood. Profiling single skin cells that are induced to become neurons reveals that, unexpectedly, they often become muscle. See Letter p.391

Bruno Di Stefano & Konrad Hochedlinger

doi: 10.1038/nature18444

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Articles

Stem cell function and stress response are controlled by protein synthesis p.335

The protein translation rate is low in tissue stem cells and tumour-initiating cells, and genetically preventing cytosine-5 methylation on transfer RNA in skin tumours is shown to favour the maintenance of a state of translational inhibition in mice, with tumour-initiating cells in this state becoming more sensitive to cytotoxic stress.

Sandra Blanco, Roberto Bandiera, Martyna Popis, Shobbir Hussain, Patrick Lombard, Jelena Aleksic, Abdulrahim Sajini, Hinal Tanna, Rosana Cortés-Garrido, Nikoletta Gkatza + et al.

doi: 10.1038/nature18282

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Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells p.341

Leukaemic stem cells (LSCs) are responsible for BCR–ABL-driven chronic myeloid leukaemia relapse; here, p53 and MYC signalling networks are shown to regulate LSCs concurrently, and targeting both these pathways has a synergistic effect in managing the disease.

Sheela A. Abraham, Lisa E. M. Hopcroft, Emma Carrick, Mark E. Drotar, Karen Dunn, Andrew J. K. Williamson, Koorosh Korfi, Pablo Baquero, Laura E. Park, Mary T. Scott + et al.

doi: 10.1038/nature18288

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TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action p.347

Cryo-electron microscopy has undergone a resolution revolution—here, this method has been combined with lipid nanodisc technology to solve structures of TRPV1, the receptor for capsaicin, in a membrane bilayer, revealing mechanisms of lipid and ligand regulation.

Yuan Gao, Erhu Cao, David Julius & Yifan Cheng

doi: 10.1038/nature17964

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Letters

Fission and reconfiguration of bilobate comets as revealed by 67P/Churyumov–Gerasimenko p.352

A modelling study of the bilobate nucleus of comet 67P/Churyumov–Gerasimenko reveals that it has spun much faster in the past, but that its chaotically changing spin rate has so far prevented it from splitting; eventually the two lobes will separate, but they will be unable to escape each other and will ultimately merge again—a situation that seems to be common among cometary nuclei.

Masatoshi Hirabayashi, Daniel J. Scheeres, Steven R. Chesley, Simone Marchi, Jay W. McMahon, Jordan Steckloff, Stefano Mottola, Shantanu P. Naidu & Timothy Bowling

doi: 10.1038/nature17670

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Mean first-passage times of non-Markovian random walkers in confinement p.356

An analytical method of determining the mean first-passage time (the time taken by a random walker in confinement to reach a target point) is presented for a Gaussian non-Markovian random walker, thus revealing the importance of memory effects in first-passage statistics.

T. Guérin, N. Levernier, O. Bénichou & R. Voituriez

doi: 10.1038/nature18272

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Intrinsic ferroelectric switching from first principles p.360

Molecular dynamics simulations of 90° domain walls in PbTiO3 are used to construct a nucleation-and-growth-based analytical model that quantifies the dynamics of many types of domain walls in various ferroelectrics, suggesting intrinsic domain-wall motion as a universal mechanism for ferroelectric switching.

Shi Liu, Ilya Grinberg & Andrew M. Rappe

doi: 10.1038/nature18286

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Self-assembly of microcapsules via colloidal bond hybridization and anisotropy p.364

The self-assembly of colloidal particles into hollow micrometre-scale capsules is achieved through the combination of anisotropic particle morphology, deformable surface ligands that re-distribute on binding and the mutual attraction between particles, suggesting a design strategy for colloidal self-assembly

Chris H. J. Evers, Jurriaan A. Luiken, Peter G. Bolhuis & Willem K. Kegel

doi: 10.1038/nature17956

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Concerted nucleophilic aromatic substitution with 19F and 18F p.369

Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain 18F for use in positron-emission tomography (PET) imaging. A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. During SNAr, attack of a nucleophile at a carbon atom bearing a ‘leaving group’ leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s). Here we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant 18F-deoxyfluorination reaction of phenols, which can be used to synthesize 18F-PET probes. Selective 18F introduction, without the need for the common, but cumbersome, azeotropic drying of 18F, can now be accomplished from phenols as starting materials, and provides access to 18F-labelled compounds not accessible through conventional chemistry.

Constanze N. Neumann, Jacob M. Hooker & Tobias Ritter

doi: 10.1038/nature17667

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Seafloor geodetic constraints on interplate coupling of the Nankai Trough megathrust zone p.374

Seafloor geodetic data from the Nankai Trough, off southwestern Japan, show that most offshore sites in this earthquake-prone region have high slip-deficit rates, revealing previously unknown locations that could be important for the mitigation of future earthquake- and tsunami-associated disasters.

Yusuke Yokota, Tadashi Ishikawa, Shun-ichi Watanabe, Toshiharu Tashiro & Akira Asada

doi: 10.1038/nature17632

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Neural correlates of single-vessel haemodynamic responses in vivo p.378

Functional imaging techniques use changes in blood flow to infer neural activity, but how strongly the two are correlated is a subject of debate; here, vascular and neural responses to a range of visual stimuli are imaged in cat and rat primary visual cortex, revealing that vascular signals are partially decoupled from local neural signals.

Philip O’Herron, Pratik Y. Chhatbar, Manuel Levy, Zhiming Shen, Adrien E. Schramm, Zhongyang Lu & Prakash Kara

doi: 10.1038/nature17965

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Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease p.383

Preclinical evaluation and optimization of mitochondrial replacement therapy reveals that a modified form of pronuclear transfer is likely to give rise to normal pregnancies with a reduced risk of mitochondrial DNA disease, but may need further modification to eradicate the disease in all cases.

Louise A. Hyslop, Paul Blakeley, Lyndsey Craven, Jessica Richardson, Norah M. E. Fogarty, Elpida Fragouli, Mahdi Lamb, Sissy E. Wamaitha, Nilendran Prathalingam, Qi Zhang + et al.

doi: 10.1038/nature18303

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Co-repressor CBFA2T2 regulates pluripotency and germline development p.387

A co-repressor protein, CBFA2T2, oligomerizes to stabilize its binding partner PRDM14 and the pluripotency factor OCT4 on chromatin, thus facilitating the transcriptional landscape underpinning the germline and pluripotent fate.

Shengjiang Tu, Varun Narendra, Masashi Yamaji, Simon E. Vidal, Luis Alejandro Rojas, Xiaoshi Wang, Sang Yong Kim, Benjamin A. Garcia, Thomas Tuschl, Matthias Stadtfeld + et al.

doi: 10.1038/nature18004

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Dissecting direct reprogramming from fibroblast to neuron using single-cell RNA-seq p.391

The transcriptome changes driving the conversion of fibroblasts to neurons at the single-cell level are reported, revealing that early neuronal reprogramming steps are homogenous, driven by the proneural pioneer factor Ascl1; the expression of myogenic genes then has a dampening effect on efficiency, which needs to be counteracted by the neuronal factors Myt1l and Brn2 for more efficient reprogramming.

Barbara Treutlein, Qian Yi Lee, J. Gray Camp, Moritz Mall, Winston Koh, Seyed Ali Mohammad Shariati, Sopheak Sim, Norma F. Neff, Jan M. Skotheim, Marius Wernig + et al.

doi: 10.1038/nature18323

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Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy p.396

The development of a nanoparticle RNA vaccine is reported that preferentially targets dendritic cells after systemic administration, and is shown to provide durable interferon-α-dependent antigen-specific immunity in mouse tumour models; initial results in advanced melanoma patients indicate potential efficacy in humans.

Lena M. Kranz, Mustafa Diken, Heinrich Haas, Sebastian Kreiter, Carmen Loquai, Kerstin C. Reuter, Martin Meng, Daniel Fritz, Fulvia Vascotto, Hossam Hefesha + et al.

doi: 10.1038/nature18300

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Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers p.402

Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development. However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma. Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3′ region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3′-untranslated region (UTR). Disruption of the Pd-l1 3′-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3′-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.

Keisuke Kataoka, Yuichi Shiraishi, Yohei Takeda, Seiji Sakata, Misako Matsumoto, Seiji Nagano, Takuya Maeda, Yasunobu Nagata, Akira Kitanaka, Seiya Mizuno + et al.

doi: 10.1038/nature18294

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Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma p.407

The stem cell determinant Musashi (Msi) is a key mediator of pancreatic cancer progression and therapy resistance.

Raymond G. Fox, Nikki K. Lytle, Dawn V. Jaquish, Frederick D. Park, Takahiro Ito, Jeevisha Bajaj, Claire S. Koechlein, Bryan Zimdahl, Masato Yano, Janel L. Kopp + et al.

doi: 10.1038/nature17988

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Structural basis for amino acid export by DMT superfamily transporter YddG p.417

The X-ray structure of the drug/metabolite transporter (DMT) protein YddG from Starkeya novella reveals a new membrane transport topology, with ten transmembrane segments in an outward-facing state and two pseudo-symmetric inverted structural repeats.

Hirotoshi Tsuchiya, Shintaro Doki, Mizuki Takemoto, Tatsuya Ikuta, Takashi Higuchi, Keita Fukui, Yoshihiro Usuda, Eri Tabuchi, Satoru Nagatoishi, Kouhei Tsumoto + et al.

doi: 10.1038/nature17991

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