Volume 556 Number 7702



Challenge anti-Semitism p.407

A wave of anti-Jewish prejudice is once again washing over schools and universities. There is no excuse not to call out this vile behaviour.

doi: 10.1038/d41586-018-04926-3


Climate talks are not enough p.407

As officials meet in Bonn to swap stories on progress towards the Paris goals, only emissions cuts will guarantee a happy ending.

doi: 10.1038/d41586-018-04925-4


The science photos worth seeing p.408

Results from a Nature photo competition show the power of images.

doi: 10.1038/d41586-018-04924-5



Clear signs of global warming will hit poorer countries first p.415

New climate-inequality tool quantifies how quickly the weather will veer beyond normal in different regions.

doi: 10.1038/d41586-018-04854-2


Scientists’ early grant success fuels further funding p.416

Young researchers who narrowly miss out on postdoctoral grant struggle to compete with those who just qualify.

doi: 10.1038/d41586-018-04958-9


US government considers charging for popular Earth-observing data p.417

Images from Landsat satellites and agricultural-survey programme are freely available to scientists — but for how long?

doi: 10.1038/d41586-018-04874-y


Rent increase hits Europe’s drug regulator before Brexit move p.418

With a move from London to Amsterdam less than a year away, the European Medicines Agency is facing uncertainty.

doi: 10.1038/d41586-018-04917-4


Mars probe poised to solve red planet’s methane mystery p.419

Researchers hope European–Russian Trace Gas Orbiter will end a long-running debate over source of the gas on Mars.

doi: 10.1038/d41586-018-04948-x


Flu virus finally sequenced in its native form p.420

Direct sequencing of RNA molecules such as virus genomes should help to unpick role of mysterious chemical modifications.

doi: 10.1038/d41586-018-04908-5

News Features


Can the world kick its fossil-fuel addiction fast enough? p.422


doi: 10.1038/d41586-018-04931-6


Is ‘friendly fire’ in the brain provoking Alzheimer’s disease? p.426


doi: 10.1038/d41586-018-04930-7

News & Views


Organic chemistry: Classic reaction re-engineered through molecular face recognition p.438


doi: 10.1038/d41586-018-04684-2


Epidemiology: A broader look at adolescents with perinatal HIV p.439


doi: 10.1038/d41586-018-04476-8


Ocean science: Shrimp cause a stir p.440


doi: 10.1038/d41586-018-04673-5


Biotechnology: Organoids reveal cancer dynamics p.441

がんの単一細胞解析は、個々の細胞の生物量が少ないため限界がある。今回、単一の腫瘍由来細胞から3Dオルガノイド構造体をin vitroで作ることで、詳細に解析するのに十分な生物量が得られた。

doi: 10.1038/d41586-018-03841-x


Tumour biology: Transition states that allow cancer to spread p.442


doi: 10.1038/d41586-018-04403-x


Quantum physics: Entangled vibrations in mechanical oscillators p.444


doi: 10.1038/d41586-018-04827-5


Neuroscience: Hunger is a gatekeeper of pain in the brain p.445


doi: 10.1038/d41586-018-04759-0



Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction p.447

The unimolecular nucleophilic substitution (SN1) mechanism features prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate enables the construction of highly congested carbon centres. However, the intrinsic instability and high reactivity of the carbocationic intermediates make it very difficult to control product distributions and stereoselectivity in reactions that proceed via SN1 pathways. Here we report asymmetric catalysis of an SN1-type reaction mechanism that results in the enantioselective construction of quaternary stereocentres from racemic precursors. The transformation relies on the synergistic action of a chiral hydrogen-bond-donor catalyst with a strong Lewis-acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and to achieve high levels of control over reaction enantioselectivity and product distribution. This work provides a foundation for the enantioconvergent synthesis of other fully substituted carbon stereocentres.

doi: 10.1038/s41586-018-0042-1


Renewing Felsenstein’s phylogenetic bootstrap in the era of big data p.452

A new version of the phylogenetic bootstrap method enables assessment of the robustness of phylogenies that are based on large datasets of hundreds or thousands of taxa.

doi: 10.1038/s41586-018-0043-0


Intra-tumour diversification in colorectal cancer at the single-cell level p.457

Organoids derived from individual cells from colorectal cancers and adjacent normal tissue are used to investigate intra-tumour diversification at the genomic, epigenetic and functional levels.

doi: 10.1038/s41586-018-0024-3


Identification of the tumour transition states occurring during EMT p.463

Epithelial-to-mesenchymal transition in tumour cells occurs through distinct intermediate states, associated with different metastatic potential, cellular properties, gene expression, and chromatin landscape

doi: 10.1038/s41586-018-0040-3



A massive core for a cluster of galaxies at a redshift of 4.3 p.469

Observations of carbon monoxide and ionized carbon lines from the source SPT2349-56 show it to contain a cluster of at least fourteen gas-rich galaxies with redshifts of 4.31, in a highly dense core region.

doi: 10.1038/s41586-018-0025-2


Remote quantum entanglement between two micromechanical oscillators p.473

Remote quantum entanglement is demonstrated in a micromachined solid-state system comprising two optomechanical oscillators across two chips physically separated by 20 cm and with an optical separation of around 70 m.

doi: 10.1038/s41586-018-0036-z


Stabilized entanglement of massive mechanical oscillators p.478

Quantum entanglement is demonstrated in a system of massive micromechanical oscillators coupled to a microwave-frequency electromagnetic cavity by driving the devices into a steady state that is entangled.

doi: 10.1038/s41586-018-0038-x


Low-loss plasmon-assisted electro-optic modulator p.483

Ohmic losses in plasmonic devices can be reduced by exploiting ‘resonant switching’, in which light couples to surface plasmon polaritons only when in resonance and bypasses them otherwise.

doi: 10.1038/s41586-018-0031-4


Earthquake-induced transformation of the lower crust p.487

During continent collision and associated mountain building, a surprisingly large volume of the lower crust is shown to be affected by earthquake aftershocks, producing a top-down effect on crustal geodynamics.

doi: 10.1038/s41586-018-0045-y


Global warming transforms coral reef assemblages p.492

Acute heat stress from the extended marine heatwave of 2016 is a potent driver of the transformation of coral assemblages, which affects even the most remote and well-protected reefs of the Great Barrier Reef.

doi: 10.1038/s41586-018-0041-2


Vertically migrating swimmers generate aggregation-scale eddies in a stratified column p.497

Laboratory experiments with the brine shrimp Artemia salina illustrate the potential for turbulence generated by the diurnal vertical migrations of aggregations of centimetre-scale zooplankton to affect the physical and biogeochemical structure of oceanic water columns.

doi: 10.1038/s41586-018-0044-z


Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis p.501

Metabolic regulation has been recognized as a powerful principle guiding immune responses. Inflammatory macrophages undergo extensive metabolic rewiring1 marked by the production of substantial amounts of itaconate, which has recently been described as an immunoregulatory metabolite2. Itaconate and its membranepermeable derivative dimethyl itaconate (DI) selectively inhibit a subset of cytokines2, including IL-6 and IL-12 but not TNF. The major effects of itaconate on cellular metabolism during macrophage activation have been attributed to the inhibition of succinate dehydrogenase2,3, yet this inhibition alone is not sufficient to account for the pronounced immunoregulatory effects observed in the case of DI. Furthermore, the regulatory pathway responsible for such selective effects of itaconate and DI on the inflammatory program has not been defined. Here we show that itaconate and DI induce electrophilic stress, react with glutathione and subsequently induce both Nrf2 (also known as NFitalicL2)-dependent and -independent responses. We find that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to toll-like receptor stimulation via inhibition of IκBζ protein induction. The regulation of IκBζ is independent of Nrf2, and we identify ATF3 as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of DI can ameliorate IL-17–IκBζ- driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway. Our results demonstrate that targeting the DI–IκBζ regulatory axis could be an important new strategy for the treatment of IL-17–IκBζ-mediated autoimmune diseases.

doi: 10.1038/s41586-018-0052-z


Genetic identification of leptin neural circuits in energy and glucose homeostases p.505

A subset of neurons in the hypothalamus is identified as the primary site of action for regulating energy balance and glucose homeostasis by leptin.

doi: 10.1038/s41586-018-0049-7


Pluripotency factors functionally premark cell-type-restricted enhancers in ES cells p.510

Binding of an ES cell-specific transcription factor pre-marks cell-type-restricted enhancers in ES cells, and this premarking is required for the robustness of enhancer activation in differentiated cells.

doi: 10.1038/s41586-018-0048-8


Mechanism of NMDA receptor channel block by MK-801 and memantine p.515

A high-resolution X-ray structure and molecular dynamics simulations of the N-methyl-d-aspartate receptor in complexes with channel-blocking ligands reveals the molecular basis of the ligand binding and channel block.

doi: 10.1038/s41586-018-0039-9


Structural basis of ligand binding modes at the neuropeptide Y Y1 receptor p.520

Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology1,2. The NPY–Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y1, Y2, Y4 and Y5 receptors, with different affinity and selectivity3. NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y1 receptor (Y1R)4. A number of peptides and small-molecule compounds have been characterized as Y1R antagonists and have shown clinical potential in the treatment of obesity4, tumour1 and bone loss5. However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability6. Here we report crystal structures of the human Y1R bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of Y1R to several structurally diverse antagonists and the determinants of ligand selectivity. The Y1R structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into Y1R can enable structure-based drug discovery that targets NPY receptors.

doi: 10.1038/s41586-018-0046-x

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