Chiral superconductors are unconventional superconducting states that break time reversal symmetry spontaneously and typically feature Cooper pairing at non-zero angular momentum. Such states may host Majorana fermions and provide an important platform for topological physics research and fault-tolerant quantum computing1-7. Despite intensive search and prolonged studies of several candidate systems8-26, chiral superconductivity has remained elusive so far. Here we report the discovery of robust unconventional superconductivity in rhombohedral tetra- and penta-layer graphene without moiré superlattice effects. We observed two superconducting states in the gate-induced flat conduction bands with Tc up to 300 mK and charge density ne down to 2.4*1011 cm-2 in five devices. Spontaneous time-reversal-symmetry-breaking due to electron's orbital motion is found, and several observations indicate the chiral nature of these superconducting states, including: 1. In the superconducting state, Rxx shows magnetic hysteresis in varying out-of-plane magnetic field B⊥-absent from all other superconductors; 2. the superconducting states are robust against in-plane magnetic field and are developed within a spin- and valley-polarized quarter-metal phase; 3. the normal states show anomalous Hall signals at zero magnetic field and magnetic hysteresis. We also observed a critical B⊥ of 1.4 Tesla, higher than any graphene superconductivity and indicates a strong-coupling superconductivity close to the BCS-BEC crossover27. Our observations establish a pure carbon material for the study of topological superconductivity, with the promise to explore Majorana modes and topological quantum computing.

Every generation, the human genome is shuffled during meiosis and a single fertilized egg gives rise to all of the cells of the body1. Meiotic errors leading to chromosomal abnormalities are known causes of pregnancy loss2,3, but genetic aetiologies of euploid pregnancy loss remain largely unexplained4. Here we characterize sequence diversity in early pregnancy loss through whole-genome sequencing of 1,007 fetal samples and 934 parental samples from 467 trios affected by pregnancy loss (fetus, mother and father). Sequenced parental genomes enabled us to determine both the parental and meiotic origins of chromosomal abnormalities, detected in half of our set. It further enabled us to assess de novo mutations on both homologous chromosomes from parents transmitting extra chromosomes, and date them, revealing that 6.6% of maternal mutations occurred before sister chromatid formation in fetal oocytes. We find a similar number of de novo mutations in the trios affected by pregnancy loss as in 9,651 adult trios, but three times the number of pathogenic small (<50 bp) sequence variant genotypes in the loss cases compared with adults. Overall, our findings indicate that around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus. Our results highlight the vast sequence diversity that is lost in early pregnancy.

Reliable forecasting of the Earth system is essential for mitigating natural disasters and supporting human progress. Traditional numerical models, although powerful, are extremely computationally expensive1. Recent advances in artificial intelligence (AI) have shown promise in improving both predictive performance and efficiency2,3, yet their potential remains underexplored in many Earth system domains. Here we introduce Aurora, a large-scale foundation model trained on more than one million hours of diverse geophysical data. Aurora outperforms operational forecasts in predicting air quality, ocean waves, tropical cyclone tracks and high-resolution weather, all at orders of magnitude lower computational cost. With the ability to be fine-tuned for diverse applications at modest expense, Aurora represents a notable step towards democratizing accurate and efficient Earth system predictions. These results highlight the transformative potential of AI in environmental forecasting and pave the way for broader accessibility to high-quality climate and weather information.

To grow at distant sites, metastatic cells must overcome major challenges posed by the unique cellular and metabolic composition of secondary organs1. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that metastasizes to the liver and lungs. Despite evidence of metabolic reprogramming away from the primary site, the key drivers that dictate the ability of PDAC cells to colonize the liver or lungs and survive there remain undefined. Here we identified PCSK9 as predictive of liver versus lung colonization by integrating metastatic tropism data of human PDAC cell lines2, in vivo metastasis modelling in mice and gene expression correlation analysis. PCSK9 negatively regulates low density lipoprotein (LDL)-cholesterol import and, accordingly, PCSK9-low PDAC cells preferentially colonize LDL-rich liver tissue. LDL-cholesterol taken up by liver-avid PCSK9-low cells supports activation of pro-growth mTORC1 activation at the lysosome, and through conversion into the signalling oxysterol, 24(S)-hydroxycholesterol, reprogrammes the microenvironment to release nutrients from neighbouring hepatocytes. Conversely, PCSK9-high, lung-avid PDAC cells rely on transcriptional upregulation of the distal cholesterol synthesis pathway to generate intermediates-7-dehydrocholesterol and 7-dehydrodesmosterol-with protective action against ferroptosis, a vulnerability in the oxygen-rich microenvironment of the lung. Increasing the amount of PCSK9 redirected liver-avid cells to the lung whereas ablating PCSK9 drove lung-avid cells to the liver, thereby establishing PCSK9 as necessary and sufficient for secondary organ site preference. Our studies reveal PCSK9-driven differential utilization of the distal cholesterol synthesis pathway as a key and potentially actionable driver of metastatic growth in PDAC.

Cell heterogeneity is a universal feature of life. Although biological processes affected by cell-to-cell variation are manifold, from developmental plasticity to tumour heterogeneity and differential drug responses, the sources of cell heterogeneity remain largely unclear1,2. Mutational and epigenetic signatures from cancer (epi)genomics are powerful for deducing processes that shaped cancer genome evolution3-5. However, retrospective analyses face difficulties in resolving how cellular heterogeneity emerges and is propagated to subsequent cell generations. Here, we used multigenerational single-cell tracking based on endogenously labelled proteins and custom-designed computational tools to elucidate how oncogenic perturbations induce sister cell asymmetry and phenotypic heterogeneity. Dual CRISPR-based genome editing enabled simultaneous tracking of DNA replication patterns and heritable endogenous DNA lesions. Cell lineage trees of up to four generations were tracked in asynchronously growing cells, and time-resolved lineage analyses were combined with end-point measurements of cell cycle and DNA damage markers through iterative staining. Besides revealing replication and repair dynamics, damage inheritance and emergence of sister cell heterogeneity across multiple cell generations, through combination with single-cell transcriptomics, we delineate how common oncogenic events trigger multiple routes towards polyploidization with distinct outcomes for genome integrity. Our study provides a framework to dissect phenotypic plasticity at the single-cell level and sheds light onto cellular processes that may resemble early events during cancer development.

Glioblastoma is the most common and aggressive primary brain cancer and shows minimal response to therapies. The immunosuppressive tumour microenvironment in glioblastoma contributes to the limited therapeutic response. Astrocytes are abundant in the central nervous system and have important immunoregulatory roles. However, little is known about their role in the immune response to glioblastoma1. Here we used single-cell and bulk RNA sequencing of clinical glioblastoma samples and samples from preclinical models, multiplexed immunofluorescence, in vivo CRISPR-based cell-specific genetic perturbations and in vitro mouse and human experimental systems to address this gap in knowledge. We identified an astrocyte subset that limits tumour immunity by inducing T cell apoptosis through the death receptor ligand TRAIL. Moreover, we identified that IL-11 produced by tumour cells is a driver of STAT3-dependent TRAIL expression in astrocytes. Astrocyte signalling through STAT3 and TRAIL expression were associated with a shorter time to recurrence and overall decreased survival in patients with glioblastoma. Genetic inactivation of the IL-11 receptor or TRAIL in astrocytes extended survival in mouse models of glioblastoma and enhanced T cell and macrophage responses. Finally, treatment with an oncolytic HSV-1 virus engineered to express a TRAIL-blocking single-chain antibody in the tumour microenvironment extended survival and enhanced tumour-specific immunity in preclinical models of glioblastoma. In summary, we establish that IL-11-STAT3-driven astrocytes suppress glioblastoma-specific protective immunity by inducing TRAIL-dependent T cell apoptosis, and engineered therapeutic viruses can be used to target this mechanism of astrocyte-driven tumour immunoevasion.

The galaxy correlation function serves as a fundamental tool for studying cosmology, galaxy formation and the nature of dark matter. It is well established that more massive, redder and more compact galaxies tend to have stronger clustering in space1,2. These results can be understood in terms of galaxy formation in cold dark matter (CDM) halos of different mass and assembly history. Here we report an unexpectedly strong large-scale clustering for isolated, diffuse and blue dwarf galaxies, comparable to that seen for massive galaxy groups but much stronger than that expected from their halo mass. Our analysis indicates that the strong clustering aligns with the halo assembly bias seen in simulations3 with the standard ΛCDM cosmology only if more diffuse dwarfs formed in low-mass halos of older ages. This pattern is not reproduced by existing models of galaxy evolution in a ΛCDM framework4-6, and our finding provides clues for the search of more viable models. Our results can be explained well by assuming self-interacting dark matter7, suggesting that such a scenario should be considered seriously.

ATP generated in the mitochondria is exported by an ADP/ATP carrier of the SLC25 family1. The endoplasmic reticulum (ER) cannot synthesize ATP but must import cytoplasmic ATP to energize protein folding, quality control and trafficking2,3. It was recently proposed that a member of the nucleotide sugar transporter family, termed SLC35B1 (also known as AXER), is not a nucleotide sugar transporter but a long-sought-after ER importer of ATP4. Here we report that human SLC35B1 does not bind nucleotide sugars but indeed executes strict ATP/ADP exchange with uptake kinetics consistent with the import of ATP into crude ER microsomes. A CRISPR-Cas9 cell-line knockout demonstrated that SLC35B1 clusters with the most essential SLC transporters for cell growth, consistent with its proposed physiological function. We have further determined seven cryogenic electron microscopy structures of human SLC35B1 in complex with an Fv fragment and either bound to an ATP analogue or ADP in all major conformations of the transport cycle. We observed that nucleotides were vertically repositioned up to approximately 6.5 Å during translocation while retaining key interactions with a flexible substrate-binding site. We conclude that SLC35B1 operates by a stepwise ATP translocation mechanism, which is a previously undescribed model for substrate translocation by an SLC transporter.

The earliest record of tooth antecedents and the tissue dentine1,2, an early-vertebrate novelty, has been controversially represented by fragmentary Cambrian fossils identified as Anatolepis heintzi3-5. Anatolepis exoskeletons have the characteristic tubules of dentine that prompted their interpretation as the first precursors of teeth3, known as odontodes. Debates over whether Anatolepis is a legitimate vertebrate6-8 have arisen because of limitations in imaging and the lack of comparative exoskeletal tissues. Here, to resolve this controversy and understand the origin of dental tissues, we synchrotron-scanned diverse extinct and extant vertebrate and invertebrate exoskeletons. We find that the tubules of Anatolepis have been misidentified as dentine tubules and instead represent aglaspidid arthropod sensory sensilla structures9,10. Synchrotron scanning reveals that deep ultrastructural similarities between odontodes and sensory structures also extend to definitive vertebrate tissues. External odontodes of the Ordovician vertebrate Eriptychius11-13 feature large dentine tubules1 that are morphologically convergent with invertebrate sensilla. Immunofluorescence analysis shows that the external odontodes of extant chondrichthyans and teleosts retain extensive innervation suggestive of a sensory function akin to teeth14-16. These patterns of convergence and innervation reveal that dentine evolved as a sensory tissue in the exoskeleton of early vertebrates, a function retained in modern vertebrate teeth16. Middle-Ordovician fossils now represent the oldest known evidence for vertebrate dental tissues.

The amputation of a salamander limb triggers anterior and posterior connective tissue cells to form distinct signalling centres that together fuel regeneration1. Anterior and posterior identities are established during development and are thought to persist for the whole life in the form of positional memory2. However, the molecular basis of positional memory and whether positional memory can be altered remain unknown. Here, we identify a positive-feedback loop that is responsible for posterior identity in the limb of an axolotl (Ambystoma mexicanum). Posterior cells express residual Hand2 transcription factor from development, and this primes them to form a Shh signalling centre after limb amputation. During regeneration, Shh signalling is also upstream of Hand2 expression. After regeneration, Shh is shut down but Hand2 is sustained, safeguarding posterior memory. We used this regeneration circuitry to convert anterior cells to a posterior-cell memory state. Transient exposure of anterior cells to Shh during regeneration kick-started an ectopic Hand2-Shh loop, leading to stable Hand2 expression and lasting competence to express Shh. Our results implicate positive-feedback in the stability of positional memory and reveal that positional memory is reprogrammed more easily in one direction (anterior to posterior) than in the other. Modifying positional memory in regenerative cells changes their signalling outputs, which has implications for tissue engineering.

Unique phosphorylation 'barcodes' installed in different regions of an active seven-transmembrane receptor by different G-protein-coupled receptor (GPCR) kinases (GRKs) have been proposed to promote distinct cellular outcomes1, but it is unclear whether or how arrestins differentially engage these barcodes. Here, to address this, we developed an antigen-binding fragment (Fab7) that recognizes both active arrestin2 (β-arrestin1) and arrestin3 (β-arrestin2) without interacting with bound receptor polypeptides. We used Fab7 to determine the structures of both arrestins in complex with atypical chemokine receptor 3 (ACKR3) phosphorylated in different regions of its C-terminal tail by either GRK2 or GRK5 (ref. 2). The GRK2-phosphorylated ACKR3 resulted in more heterogeneous 'tail-mode' assemblies, whereas phosphorylation by GRK5 resulted in more rigid 'ACKR3-adjacent' assemblies. Unexpectedly, the finger loops of both arrestins engaged the micelle surface rather than the receptor intracellular pocket, with arrestin3 being more dynamic, partly because of its lack of a membrane-anchoring motif. Thus, both the region of the barcode and the arrestin isoform involved can alter the structure and dynamics of GPCR-arrestin complexes, providing a possible mechanistic basis for unique downstream cellular effects, such as the efficiency of chemokine scavenging and the robustness of arrestin binding in ACKR3.

Spatial RNA organization has a pivotal role in diverse cellular processes and diseases1-4. However, functional implications of the spatial transcriptome remain largely unexplored due to limited technologies for perturbing endogenous RNA within specific subcellular regions1,5. Here we present CRISPR-mediated transcriptome organization (CRISPR-TO), a system that harnesses RNA-guided, nuclease-dead dCas13 for programmable control of endogenous RNA localization in live cells. CRISPR-TO enables targeted localization of endogenous RNAs to diverse subcellular compartments, including the outer mitochondrial membrane, p-bodies, stress granules, telomeres and nuclear stress bodies, across various cell types. It allows for inducible and reversible bidirectional RNA transport along microtubules via motor proteins, facilitating real-time manipulation and monitoring of RNA localization dynamics in living cells. In primary cortical neurons, we demonstrate that repositioned mRNAs undergo local translation along neurites and at neurite tips, and co-transport with ribosomes, with β-actin mRNA localization enhancing the formation of dynamic filopodial protrusions and inhibiting axonal regeneration. CRISPR-TO-enabled screening in primary neurons identifies Stmn2 mRNA localization as a driver of neurite outgrowth. By enabling large-scale perturbation of the spatial transcriptome, CRISPR-TO bridges a critical gap left by sequencing and imaging technologies, offering a versatile platform for high-throughput functional interrogation of RNA localization in living cells and organisms.

Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

Skeletal editing comprises the structural reorganization of compounds. Such editing can be achieved through atom swapping, atom insertion, atom deletion or reorganization of the compound's backbone structure1,2. Conducted at a late stage in drug development campaigns, skeletal editing enables diversification of an existing pharmacophore, enhancing the efficiency of drug development. Instead of constructing a heteroarene classically from basic building blocks, structural variants are readily accessible directly starting from a lead compound or approved pharmacophore. Here we present C to N atom swapping in indoles at the C2 position to give indazoles through oxidative cleavage of the indole heteroarene core and subsequent ring closure. Reactions proceed through ring-opened oximes as intermediates. These ring deconstructed intermediates can also be diverted into benzimidazoles resulting in an overall C to N atom swapping with concomitant skeletal reorganization. The same structural diverting strategies are equally well applicable to benzofurans leading to either benzisoxazoles or benzoxazoles. The compound classes obtained through these methods-indazoles3,4, benzisoxazoles5, benzimidazoles6,7 and benzoxazoles8-are biologically relevant moieties found as substructures in natural products and pharmaceuticals. The procedures introduced substantially enlarge the methods portfolio in the emerging field of skeletal editing.