Volume 534 Number 7607

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

Nature distilled p.296

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

doi: 10.1038/534296b

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

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.

doi: 10.1038/534307a

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.

doi: 10.1038/534310a

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.

doi: 10.1038/534314a

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.

doi: 10.1038/nature18445

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

doi: 10.1038/nature18443

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

doi: 10.1038/534331a

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

doi: 10.1038/nature18444

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.

doi: 10.1038/nature18282

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.

doi: 10.1038/nature17670

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.

doi: 10.1038/nature18286

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.

doi: 10.1038/nature17667

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.

doi: 10.1038/nature17965

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.

doi: 10.1038/nature18323

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.

doi: 10.1038/nature18294