Protein misfolding is linked to a wide array of human disorders, including Alzheimer's disease, Parkinson's disease and type II diabetes(1,2). Protective cellular protein quality control (PQC) mechanisms have evolved to selectively recognize misfolded proteins and limit their toxic effects(3-9), thus contributing to the maintenance of the proteome (proteostasis). Here we examine how molecular chaperones and the ubiquitin-proteasome system cooperate to recognize and promote the clearance of soluble misfolded proteins. Using a panel of PQC substrates with distinct characteristics and localizations, we define distinct chaperone and ubiquitination circuitries that execute quality control in the cytoplasm and nucleus. In the cytoplasm, proteasomal degradation of misfolded proteins requires tagging with mixed lysine 48 (K48)and lysine 11 (K11)-linked ubiquitin chains. A distinct combination of E3 ubiquitin ligases and specific chaperones is required to achieve each type of linkage-specific ubiquitination. In the nucleus, however, proteasomal degradation of misfolded proteins requires only K48-linked ubiquitin chains, and is thus independent of K11 specific ligases and chaperones. The distinct ubiquitin codes for nuclear and cytoplasmic PQC appear to be linked to the function of the ubiquilin protein Dsk2, which is specifically required to clear nuclear misfolded proteins. Our work defines the principles of cytoplasmic and nuclear PQC as distinct, involving combinatorial recognition by defined sets of cooperating chaperones and E3 ligases. A better understanding of how these organelle-specific PQC requirements implement proteome integrity has implications for our understanding of diseases linked to impaired protein clearance and proteostasis dysfunction.

Optical frequency combs, which emit pulses of light at discrete, equally spaced frequencies, are cornerstones of modern-day frequency metrology, precision spectroscopy, astronomical observations, ultrafast optics and quantum information(1-7). Chip scale frequency combs, based on the Kerr and Raman nonlinearities in monolithic microresonators with ultrahigh quality factors(8-10), have recently led to progress in optical clockwork and observations of temporal cavity solitons(11-14). But the chromatic dispersion within a laser cavity, which determines the comb formation(15-16), is usually difficult to tune with an electric field, whether in microcavities or fibre cavities. Such electrically dynamic control could bridge optical frequency combs and optoelectronics, enabling diverse comb outputs in one resonator with fast and convenient tunability. Arising from its exceptional Fermi-Dirac tunability and ultrafast carrier mobility(17-19), graphene has a complex optical dispersion determined by its optical conductivity, which can be tuned through a gate voltage(20,21). This has brought about optoelectronic advances such as modulators(22,23), photodetectors' and controllable plasmonics(25,26). Here we demonstrate the gated intracavity tunability of graphene-based optical frequency combs, by coupling the gate-tunable optical conductivity to a silicon nitride photonic microresonator, thus modulating its second-and higher-order chromatic dispersions by altering the Fermi level. Preserving cavity quality factors up to 10(6) in the graphene-based comb, we implement a dual-layer ion gel-gated transistor to tune the Fermi level of graphene across the range 0.45-0.65 electronvolts, under single-volt-level control. We use this to produce charge-tunable primary comb lines from 2.3 terahertz to 7.2 terahertz, coherent Kerr frequency combs, controllable Cherenkov radiation and controllable soliton states, all in a single microcavity. We further demonstrate voltage-tunable transitions from periodic soliton crystals to crystals with defects, mapped by our ultrafast second-harmonic optical autocorrelation. This heterogeneous graphene microcavity, which combines single atomic-layer nanoscience and ultrafast optoelectronics, will help to improve our understanding of dynamical frequency combs and ultrafast optics.

With the rapid development of artificial intelligence have come concerns about how machines will make moral decisions, and the major challenge of quantifying societal expectations about the ethical principles that should guide machine behaviour. To address this challenge, we deployed the Moral Machine, an online experimental platform designed to explore the moral dilemmas faced by autonomous vehicles. This platform gathered 40 million decisions in ten languages from millions of people in 233 countries and territories. Here we describe the results of this experiment. First, we summarize global moral preferences. Second, we document individual variations in preferences, based on respondents' demographics. Third, we report cross-cultural ethical variation, and uncover three major clusters of countries. Fourth, we show that these differences correlate with modern institutions and deep cultural traits. We discuss how these preferences can contribute to developing global, socially acceptable principles for machine ethics. All data used in this article are publicly available.

Understanding strongly correlated phases of matter, such as the quark-gluon plasma and neutron stars, and in particular the dynamics of such systems, for example, following a Hamiltonian quench (a sudden change in some Hamiltonian parameter, such as the strength of interparticle interactions) is a fundamental challenge in modern physics. Ultracold atomic gases are excellent quantum simulators for these problems, owing to their tunable interparticle interactions and experimentally resolvable intrinsic timescales. In particular, they provide access to the unitary regime, in which the interactions are as strong as allowed by quantum mechanics. This regime has been extensively studied in Fermi gases(1,2). The less-explored unitary Bose gases(3-11) offer possibilities(12) such as universal physics controlled solely by the gas density(13,14) and new forms of superfluidity(15-17). Here, through momentum- and time-resolved studies, we explore degenerate and thermal homogeneous Bose gases quenched to unitarity. In degenerate samples, we observe universal post-quench dynamics in agreement with the emergence of a prethermal state(18-24)( )with a universal non-zero condensed fraction(22,24). In thermal gases, the dynamic and thermodynamic properties generally depend on the gas density and the temperature, but we find that they can still be expressed in terms of universal dimensionless functions. Surprisingly, we find that the total quench-induced correlation energy is independent of the gas temperature. These measurements provide quantitative benchmarks and challenges for the theory of unitary Bose gases.

The Suzuki-Miyaura cross-coupling of organoboron nucleophiles with aryl halide electrophiles is one of the most widely used carbon-carbon bond-forming reactions in organic and medicinal chemistry(1,2). A key challenge associated with these transformations is that they generally require the addition of an exogenous base, the role of which is to enable transmetallation between the organoboron nucleophile and the metal catalyst(3). This requirement limits the substrate scope of the reaction because the added base promotes competitive decomposition of many organoboron substrates(3-5). As such, considerable research has focused on strategies for mitigating base-mediated side reactions(6-12). Previous efforts have primarily focused either on designing strategically masked organoboron reagents (to slow base-mediated decomposition)(6-8) or on developing highly active palladium precatalysts (to accelerate cross-coupling relative to base-mediated decomposition pathways)(10-12). An attractive alternative approach involves identifying combinations of catalyst and electrophile that enable Suzuki-Miyaura-type reactions to proceed without an exogenous base(12-14). Here we use this approach to develop a nickel-catalysed coupling of aryl boronic acids with acid fluorides(15-17), which are formed in situ from readily available carboxylic acids(18-22). This combination of catalyst and electrophile enables a mechanistic manifold in which a 'transmetallation-active' aryl nickel fluoride intermediate is generated directly in the catalytic cycle(13,16). As such, this transformation does not require an exogenous base and is applicable to a wide range of base-sensitive boronic acids and biologically active carboxylic acids.

In 1906, Theodore Lyman discovered his eponymous series of transitions in the extreme-ultraviolet region of the atomic hydrogen spectrum(1,2). The patterns in the hydrogen spectrum helped to establish the emerging theory of quantum mechanics, which we now know governs the world at the atomic scale. Since then, studies involving the Lyman-alpha line-the 1S-2P transition at a wavelength of 121.6 nanometres-have played an important part in physics and astronomy, as one of the most fundamental atomic transitions in the Universe. For example, this transition has long been used by astronomers studying the intergalactic medium and testing cosmological models via the so-called 'Lyman-alpha forest('3) of absorption lines at different redshifts. Here we report the observation of the Lyman-alpha transition in the antihydrogen atom, the antimatter counterpart of hydrogen. Using narrow-line-width, nanosecond-pulsed laser radiation, the 1S-2P transition was excited in magnetically trapped antihydrogen. The transition frequency at a field of 1.033 tesla was determined to be 2,466,051.7 +/- 0.12 gigahertz (1 sigma uncertainty) and agrees with the prediction for hydrogen to a precision of 5 x 10(-8). Comparisons of the properties of antihydrogen with those of its well-studied matter equivalent allow precision tests of fundamental symmetries between matter ;and antimatter. Alongside the ground-state hyperfine(4,5) and 1S-2S transitions(6,7) recently observed in antihydrogen, the Lyman-alpha transition will permit laser cooling of antihydrogen(8,9), thus providing a cold and dense sample of anti-atoms for precision spectroscopy and gravity measurements(10). In addition to the observation of this fundamental transition, this work represents both a decisive technological step towards laser cooling of antihydrogen, and the extension of antimatter spectroscopy to quantum states possessing orbital angular momentum.