Volume 556 Issue 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


News Features

News & Views

A broader look at adolescents with perinatal HIV p.439

An epidemiological study of adolescents who had acquired HIV around the time of birth highlights how high-income countries benefit from the ability to begin treating all infected children in the first years of life.

doi: 10.1038/d41586-018-04476-8

Shrimp cause a stir p.440

Migration of brine shrimp causes substantial mixing of the water column.

doi: 10.1038/d41586-018-04673-5

Organoids reveal cancer dynamics p.441

Single-cell analyses in cancer are limited by the small biomass of individual cells. In vitro production of 3D organoid structures from single tumour-derived cells generates sufficient biomass for in-depth analyses.

doi: 10.1038/d41586-018-03841-x

Transition states that allow cancer to spread p.442

Cancers of epithelial-cell origin often contain some tumour cells that have acquired traits of mesenchymal cells. How this leads to cancer spread has now been illuminated in mouse models.

doi: 10.1038/d41586-018-04403-x

Entangled vibrations in mechanical oscillators p.444

Two experiments have demonstrated entanglement — non-classical correlations — between remote mechanical systems comprising billions of atoms. The results could advance our understanding of quantum physics.

doi: 10.1038/d41586-018-04827-5

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

A neuronal population has now been found that regulates two competing needs — hunger and pain. Urgent pain overrides hunger, but appetite-inducing neuronal activity dampens long-term pain responses to enable feeding.

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


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

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

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