To orchestrate ribosomal peptide synthesis, transfer RNAs (tRNAs) must be aminoacylated, with activated amino acids, at their 2',3'-diol moiety1,2, and so the selective aminoacylation of RNA in water is a key challenge that must be resolved to explain the origin of protein biosynthesis. So far, there have been no chemical methods to effectively and selectively aminoacylate RNA-2',3'-diols with the breadth of proteinogenic amino acids in water3-5. Here we demonstrate that (biological) aminoacyl-thiols (1) react selectively with RNA diols over amine nucleophiles, promoting aminoacylation over adventitious (non-coded) peptide bond formation. Broad side-chain scope is demonstrated, including Ala, Arg, Asp, Glu, Gln, Gly, His, Leu, Lys, Met, Phe, Pro, Ser and Val, and Arg aminoacylation is enhanced by unprecedented side-chain nucleophilic catalysis. Duplex formation directs chemoselective 2',3'-aminoacylation of RNA. We demonstrate that prebiotic nitriles, N-carboxyanhydrides and amino acid anhydrides, as well as biological aminoacyl-adenylates, all react with thiols (including coenzymes A and M) to selectively yield aminoacyl-thiols (1) in water. Finally, we demonstrate that the switch from thioester to thioacid activation inverts diol/amine selectivity, promoting peptide synthesis in excellent yield. Two-step, one-pot, chemically controlled formation of peptidyl-RNA is observed in water at neutral pH. Our results indicate an important role for thiol cofactors in RNA aminoacylation before the evolution of proteinaceous synthetase enzymes.

Generative models cover various application areas, including image and video synthesis, natural language processing and molecular design, among many others1-11. As digital generative models become larger, scalable inference in a fast and energy-efficient manner becomes a challenge12-14. Here we present optical generative models inspired by diffusion models4, where a shallow and fast digital encoder first maps random noise into phase patterns that serve as optical generative seeds for a desired data distribution; a jointly trained free-space-based reconfigurable decoder all-optically processes these generative seeds to create images never seen before following the target data distribution. Except for the illumination power and the random seed generation through a shallow encoder, these optical generative models do not consume computing power during the synthesis of the images. We report the optical generation of monochrome and multicolour images of handwritten digits, fashion products, butterflies, human faces and artworks, following the data distributions of MNIST15, Fashion-MNIST16, Butterflies-10017, Celeb-A datasets18, and Van Gogh's paintings and drawings19, respectively, achieving an overall performance comparable to digital neural-network-based generative models. To experimentally demonstrate optical generative models, we used visible light to generate images of handwritten digits and fashion products. In addition, we generated Van Gogh-style artworks using both monochrome and multiwavelength illumination. These optical generative models might pave the way for energy-efficient and scalable inference tasks, further exploiting the potentials of optics and photonics for artificial-intelligence-generated content.

Brain cortical morphology, indexed by its surface area and thickness, is known to be highly heritable. Previous research has suggested a relationship of cortical morphology with several neuropsychiatric phenotypes. However, the multitude of potential confounders makes it difficult to establish causal relationships. Here, we employ Generalized Summary-data-based Mendelian Randomization and a series of sensitivity analyses to investigate causal links between 70 cortical morphology measures and 199 neuropsychiatric, behavioral, and metabolic phenotypes. We show that total brain cortical surface area (TSA) has significant positive causal effects on 18 phenotypes. The strongest effects include TSA positively influencing cognitive performance, while reverse analyses reveal small effects of cognitive performance on TSA. Global mean cortical thickness (MTH) exhibits significant causal effects on five phenotypes, including schizophrenia. MTH reduces schizophrenia risk and bidirectional causality is found between MTH and smoking initiation. Finally, in regional analyses we detect positive influences of the transverse temporal surface area on cognitive performance and negative influences of transverse temporal thickness on schizophrenia risk. Overall, our results highlight bidirectional associations between TSA, MTH, and neuropsychiatric traits. These insights offer potential avenues for intervention studies aimed at improving brain health.

Chemical feedback is ubiquitous in physiology but is challenging to study without perturbing basal functions. One example is addictive drugs, which elicit a positive-feedback cycle of drug-seeking and ingestion by acting on the brain to increase dopamine signalling1-3. However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness4. Here, inspired by physiological control systems, we developed a highly selective synthetic physiology approach to interfere with the positive-feedback cycle of addiction by installing a cocaine-dependent opposing signalling process into this body-brain signalling loop. We used protein engineering to create cocaine-gated ion channels that are selective for cocaine over other drugs and endogenous molecules. Expression of an excitatory cocaine-gated channel in the rat lateral habenula, a brain region that is normally inhibited by cocaine, suppressed cocaine self-administration without affecting food motivation. This artificial cocaine-activated chemogenetic process reduced the cocaine-induced extracellular dopamine rise in the nucleus accumbens. Our results show that cocaine chemogenetics is a selective approach for countering drug reinforcement by clamping dopamine release in the presence of cocaine. In the future, chemogenetic receptors could be developed for additional addictive drugs or hormones and metabolites, which would facilitate efforts to probe their neural circuit mechanisms using a synthetic physiology approach. As these chemogenetic ion channels are specific for cocaine over natural rewards, they may also offer a route towards gene therapies for cocaine addiction.

Our knowledge of the brain processes that govern vision is largely derived from studying primates, whose hierarchically organized visual system1 inspired the architecture of deep neural networks2. This raises questions about the universality of such hierarchical structures. Here we examined the large-scale functional organization for vision in one of the closest living relatives to primates, the tree shrew. We performed Neuropixels recordings3,4 across many cortical and thalamic areas spanning the tree shrew ventral visual system while presenting a large battery of visual stimuli in awake tree shrews. We found that receptive field size, response latency and selectivity for naturalistic textures, compared with spectrally matched noise5, all increased moving anteriorly along the tree shrew visual pathway, consistent with a primate-like hierarchical organization6,7. However, tree shrew area V2 already harboured a high-level representation of complex objects. First, V2 encoded a complete representation of a high-level object space8. Second, V2 activity supported the most accurate object decoding and reconstruction among all tree shrew visual areas. In fact, object decoding accuracy from tree shrew V2 was comparable to that in macaque posterior IT and substantially higher than that in macaque V2. Finally, starting in V2, we found strongly face-selective cells resembling those reported in macaque inferotemporal cortex9. Overall, these findings show how core computational principles of visual form processing found in primates are conserved, yet hierarchically compressed, in a small but highly visual mammal.

To cope in uncertain environments, animals must balance their actions between using current resources and searching for new ones1. This exploration-exploitation dilemma has been studied extensively in paradigms involving positive outcomes, and neural correlates have been identified in frontal cortices and subcortical structures2-11, including the amygdala12. Importantly, exploration is just as essential for survival or well-being when trying to avoid negative outcomes, yet we do not know whether the single-neuron mechanisms that drive exploration are shared across positive and negative environments. Here we examined the dynamics of exploration when human participants engaged in a probabilistic learning task with intermixed loss and gain trials, while simultaneously recording single-neuron activity. We show that neurons of the amygdala and temporal cortex modulate their activity before a decision to explore in both loss and gain. Moreover, we find that humans exhibit more exploration when trying to avoid losses, and that an increase in the levels of noise in amygdala neurons contributes to this behaviour. Overall, we report that human exploration is driven by two distinct neural mechanisms, a valence-independent rate signal and a valence-dependent global noise signal. The results suggest a link between the heightened amygdala activity observed in mood disorders13,14 and higher exploration rates15-17 that underlie maladaptive and even pathological behaviours.

Symmetry-protected topological phases1-4 cannot be described by any local order parameter and are beyond the conventional symmetry-breaking model5. They are characterized by topological boundary modes that remain stable under symmetry respecting perturbations1-4,6-8. In clean, gapped systems without disorder, the stability of these edge modes is restricted to the zero-temperature manifold; at finite temperatures, interactions with mobile thermal excitations lead to their decay9-11. Here we report the observation of a distinct type of topological edge mode12-14, which is protected by emergent symmetries and persists across the entire spectrum, in an array of 100 programmable superconducting qubits. Through digital quantum simulation of a one-dimensional disorder-free stabilizer Hamiltonian, we observe robust long-lived topological edge modes over up to 30 cycles for a wide range of initial states. We show that the interaction between these edge modes and bulk excitations can be suppressed by dimerizing the stabilizer strength, leading to an emergent U(1) × U(1) symmetry in the prethermal regime of the system. Furthermore, we exploit these topological edge modes as logical qubits and prepare a logical Bell state, which exhibits persistent coherence, despite the system being disorder-free and at finite temperature. Our results establish a viable digital simulation approach15-18 to experimentally study topological matter at finite temperature and demonstrate a potential route to construct long-lived, robust boundary qubits in disorder-free systems.

Many chirality-sensitive light-matter interactions are governed by chiral electron dynamics. Therefore, the development of advanced technologies making use of chiral phenomena would critically benefit from measuring and controlling chiral electron dynamics on their natural attosecond timescales. Such endeavours have so far been hampered by the lack of characterized circularly polarized attosecond pulses, an obstacle that has recently been overcome1,2. Here we introduce chiroptical spectroscopy with attosecond pulses and demonstrate attosecond coherent control over photoelectron circular dichroism (PECD)3,4, as well as the measurement of chiral asymmetries in the forward-backward and angle-resolved photoionization delays of chiral molecules. We show that co-rotating attosecond and near-infrared (IR) pulses can nearly double the PECD and even change its sign compared with single-photon ionization. We demonstrate that chiral photoionization delays depend on both polar and azimuthal angles of photoemission in the light-propagation frame, requiring 3D momentum resolution. We measure forward-backward chiral-sensitive delays of up to 60 as and polar-angle-resolved photoionization delays of up to 240 as, which include an asymmetry of about 60 as originating from chirality in the continuum-continuum transitions. Attosecond chiroptical spectroscopy opens the door to quantitatively understanding and controlling the dynamics of chiral molecules on the electronic timescale.

Bipedalism is a human-defining trait1-3. It is made possible by the familiar, bowl-shaped pelvis, whose short, wide iliac blades curve along the sides of the body to stabilize walking and support internal organs and a large-brained, broad-shouldered baby4-6. The ilium changes compared with living primates are an evolutionary novelty7. However, how this evolution came about remains unknown. Here, using a multifaceted histological, comparative genomic and functional genomic approach, we identified the developmental bases of the morphogenetic shifts in the human pelvis that made bipedalism possible. First, we observe that the human ilium cartilage growth plate underwent a heterotopic shift, residing perpendicular to the orientation present in other primate (and mouse) ilia. Second, we observe heterochronic and heterotopic shifts in ossification that are unlike those in non-human primate ilia or human long bones. Ossification initiates posteriorly, resides externally with fibroblast (and perichondral) cells contributing to osteoblasts, and is delayed compared with other bones in humans and with primate ilia. Underlying these two shifts are regulatory changes in an integrated chondrocyte-perichondral-osteoblast pathway, involving complex hierarchical interactions between SOX9-ZNF521-PTH1R and RUNX2-FOXP1/2. These innovations facilitated further growth of the human pelvis and the unique formation of the ilium among primates.

Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.

Terrestrial plant communities show great variation in their annual rhythms of growth, or seasonal phenology1,2. The geographical patterns resulting from this variation, known as land surface phenology (LSP)3, contain valuable information for the study of ecosystem function4,5, plant ecophysiology6-8, landscape ecology9,10 and evolutionary biogeography11-13. Yet globally consistent LSP mapping has been hampered by methods that struggle to represent the full range of seasonal phenologies occurring across terrestrial biomes14, especially the subtle and complex phenologies of many arid and tropical ecosystems1,15,16. Here, using a data-driven analysis of satellite imagery to map LSP worldwide, we provide insights into Earth's phenological diversity, documenting both intercontinental convergence between similar climates and regional heterogeneity associated with topoclimate, ecohydrology and vegetation structure. We then map spatial phenological asynchrony and the modes of asynchronous seasonality that control it, identifying hotspots of asynchrony in tropical mountains and Mediterranean climate regions and reporting evidence for the hypothesis that climatically similar sites exhibit greater phenological asynchrony within the tropics. Finally, we find that our global LSP map predicts complex geographical discontinuities in flowering phenology, genetic divergence and even harvest seasonality across a range of taxa, establishing remote sensing as a crucial tool for understanding the ecological and evolutionary consequences of allochrony by allopatry.

Cannabinoid receptor 1 (CB1) is the primary target of the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive constituent of marijuana1. Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841). The two CB1-agonist complexes reveal important conformational changes in the overall structure relative to the antagonist-bound state2, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G protein-binding region. Furthermore, a twin toggle switch of Phe2003.36 and Trp3566.48 (where the superscripts denote Ballesteros-Weinstein numbering3) is experimentally observed and seems to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

Protein-protein interactions are at the core of all key biological processes. However, the complexity of the structural features that determine protein-protein interactions makes their design challenging. Here we present BindCraft, an open-source and automated pipeline for de novo protein binder design with experimental success rates of 10-100%. BindCraft leverages the weights of AlphaFold2 (ref. 1) to generate binders with nanomolar affinity without the need for high-throughput screening or experimental optimization, even in the absence of known binding sites. We successfully designed binders against a diverse set of challenging targets, including cell-surface receptors, common allergens, de novo designed proteins and multi-domain nucleases, such as CRISPR-Cas9. We showcase the functional and therapeutic potential of designed binders by reducing IgE binding to birch allergen in patient-derived samples, modulating Cas9 gene editing activity and reducing the cytotoxicity of a foodborne bacterial enterotoxin. Last, we use cell-surface-receptor-specific binders to redirect adeno-associated virus capsids for targeted gene delivery. This work represents a significant advancement towards a 'one design-one binder' approach in computational design, with immense potential in therapeutics, diagnostics and biotechnology.