Volume 534 Issue 7607



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


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

doi: 10.1038/534296a


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

doi: 10.1038/534296b



Firms chase a new breed of advanced veterinary care, from antibodies to cell therapies.

doi: 10.1038/534303a


Tracking space rocks that reach Earth will give insight into the early Solar System.

doi: 10.1038/nature.2016.20070


Economists, investors and medical insurers can’t figure out how to pay for cutting-edge drugs.

doi: 10.1038/534305a


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.

doi: 10.1038/534307a

News Features


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

doi: 10.1038/534310a


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.

doi: 10.1038/534314a

News & Views


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.

doi: 10.1038/nature18445


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

doi: 10.1038/nature18443


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

doi: 10.1038/534331a


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

doi: 10.1038/nature18444



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.

doi: 10.1038/nature18282


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.

doi: 10.1038/nature18288


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.

doi: 10.1038/nature17964



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.

doi: 10.1038/nature17670


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.

doi: 10.1038/nature18272


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.

doi: 10.1038/nature18286


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

doi: 10.1038/nature17956


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.

doi: 10.1038/nature17667


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.

doi: 10.1038/nature17632


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.

doi: 10.1038/nature17965


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.

doi: 10.1038/nature18303


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.

doi: 10.1038/nature18004


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.

doi: 10.1038/nature18323


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.

doi: 10.1038/nature18300


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.

doi: 10.1038/nature18294


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

doi: 10.1038/nature17988


The bacterial chromosome replication origin contains an indispensable element composed of a repeating trinucleotide motif, termed the DnaA-trio, that stabilizes DnaA binding on single-stranded DNA.

doi: 10.1038/nature17962


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.

doi: 10.1038/nature17991