Challenge anti-Semitism p.407

doi: 10.1038/d41586-018-04926-3

Climate talks are not enough p.407

doi: 10.1038/d41586-018-04925-4

The science photos worth seeing p.408

doi: 10.1038/d41586-018-04924-5

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

doi: 10.1038/d41586-018-04854-2

Scientists’ early grant success fuels further funding p.416

doi: 10.1038/d41586-018-04958-9

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

doi: 10.1038/d41586-018-04874-y

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

doi: 10.1038/d41586-018-04917-4

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

doi: 10.1038/d41586-018-04948-x

Flu virus finally sequenced in its native form p.420

doi: 10.1038/d41586-018-04908-5

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

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

doi: 10.1038/d41586-018-04684-2

A broader look at adolescents with perinatal HIV p.439

doi: 10.1038/d41586-018-04476-8

Shrimp cause a stir p.440

doi: 10.1038/d41586-018-04673-5

Organoids reveal cancer dynamics p.441

doi: 10.1038/d41586-018-03841-x

Transition states that allow cancer to spread p.442

doi: 10.1038/d41586-018-04403-x

Entangled vibrations in mechanical oscillators p.444

doi: 10.1038/d41586-018-04827-5

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

doi: 10.1038/s41586-018-0043-0

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

doi: 10.1038/s41586-018-0024-3

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

doi: 10.1038/s41586-018-0040-3

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

doi: 10.1038/s41586-018-0025-2

Remote quantum entanglement between two micromechanical oscillators p.473

doi: 10.1038/s41586-018-0036-z

Stabilized entanglement of massive mechanical oscillators p.478

doi: 10.1038/s41586-018-0038-x

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

doi: 10.1038/s41586-018-0031-4

Earthquake-induced transformation of the lower crust p.487

doi: 10.1038/s41586-018-0045-y

Global warming transforms coral reef assemblages p.492

doi: 10.1038/s41586-018-0041-2

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

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 dehydrogenase^2,3, 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

doi: 10.1038/s41586-018-0049-7

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

doi: 10.1038/s41586-018-0048-8

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

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 biology^1,2. 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