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.

Quasars, powered by gas accretion onto supermassive black holes1,2, rank among the most energetic objects in the Universe3,4. Although they are thought to be ignited by galaxy mergers5-11 and affect the surrounding gas12-15, observational constraints on both processes remain scarce16-18. Here we describe a major merging system at redshift z ≈ 2.7 and demonstrate that radiation from the quasar in one galaxy directly alters the gas properties in the other galaxy. Our findings reveal that the galaxies, with centroids separated by only a few kiloparsecs and approaching each other at a speed of approximately 550 km s-1, are massive, are forming stars and contain a substantial molecular mass. Yet, dusty molecular gas seen in absorption against the quasar nucleus is highly excited and confined within cloudlets with densities of approximately 105 to 106 cm-3 and sizes of less than 0.02 pc, several orders of magnitude more compact than those observed in intervening (non-quasar) environments. This is also approximately 105 times smaller than currently resolvable through molecular-line emission at high redshifts. We infer that, wherever it is exposed to the quasar radiation, the molecular gas is disrupted, leaving behind surviving dense clouds too small to give birth to new stars. Our results not only underscore the role of major galaxy mergers in triggering quasar activity but also reveal localized negative feedback as a profound alteration of the internal gas structure, which probably hampers star formation.

Carbon has a central role in biology and organic chemistry, and its solid allotropes provide the basis of much of our modern technology1. However, the liquid form of carbon remains nearly uncharted2, and the structure of liquid carbon and most of its physical properties are essentially unknown3. But liquid carbon is relevant for modelling planetary interiors4,5 and the atmospheres of white dwarfs6, as an intermediate state for the synthesis of advanced carbon materials7,8, inertial confinement fusion implosions9, hypervelocity impact events on carbon materials10 and our general understanding of structured fluids at extreme conditions11. Here we present a precise structure measurement of liquid carbon at pressures of around 1 million atmospheres obtained by in situ X-ray diffraction at an X-ray free-electron laser. Our results show a complex fluid with transient bonding and approximately four nearest neighbours on average, in agreement with quantum molecular dynamics simulations. The obtained data substantiate the understanding of the liquid state of one of the most abundant elements in the universe and can test models of the melting line. The demonstrated experimental abilities open the path to performing similar studies of the structure of liquids composed of light elements at extreme conditions.

The decline in malaria deaths has recently stalled owing to several factors, including the widespread resistance of Anopheles vectors to the insecticides used in long-lasting insecticide-treated nets (LLINs)1,2. One way to mitigate insecticide resistance is to directly kill parasites during their mosquito-stage of development by incorporating antiparasitic compounds into LLINs. This strategy can prevent onward parasite transmission even when insecticides lose efficacy3,4. Here, we performed an in vivo screen of compounds against the mosquito stages of Plasmodium falciparum development. Of the 81 compounds tested, which spanned 28 distinct modes of action, 22 were active against early parasite stages in the mosquito midgut lumen, which in turn prevented establishment of infection. Medicinal chemistry was then used to improve antiparasitic activity of the top hits from the screen. We generated several endochin-like quinolones (ELQs) that inhibited the P. falciparum cytochrome bc1 complex (CytB). Two lead compounds that targeted separate sites in CytB (Qo and Qi) showed potent, long-lasting and stable activity when incorporated and/or extruded into bed net-like polyethylene films. ELQ activity was fully preserved in insecticide-resistant mosquitoes, and parasites resistant to these compounds had impaired development at the mosquito stage. These data demonstrate the promise of incorporating ELQ compounds into LLINs to counteract insecticide resistance and to reduce malaria transmission.

Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.

Decades of research have demonstrated that recovery from serious neurological injury will require synergistic therapeutic approaches. Rewiring spared neural circuits after injury is a long-standing goal of neurorehabilitation1,2. We hypothesized that combining intensive, progressive, task-focused training with real-time closed-loop vagus nerve stimulation (CLV) to enhance synaptic plasticity3 could increase strength, expand range of motion and improve hand function in people with chronic, incomplete cervical spinal cord injury. Here we report the results from a prospective, double-blinded, sham-controlled, randomized study combining gamified physical therapy using force and motion sensors to deliver sham or active CLV (ClinicalTrials.gov identifier NCT04288245). After 12 weeks of therapy composed of a miniaturized implant selectively activating the vagus nerve on successful movements, 19 people exhibited a significant beneficial effect on arm and hand strength and the ability to perform activities of daily living. CLV represents a promising therapeutic avenue for people with chronic, incomplete cervical spinal cord injury.

The isotopic composition of lavas associated with mantle plumes has previously been interpreted in the light of core-mantle interaction, suggesting that mantle plumes may transport core material to Earth's surface1-5. However, a definitive fingerprint of Earth's core in the mantle remains unconfirmed. Precious metals, such as ruthenium (Ru), are highly concentrated in the metallic core but extremely depleted in the silicate mantle. Recently discovered mass-independent Ru isotope variations (ε100Ru) in ancient rocks show that the Ru isotope composition of accreted material changed during later stages of Earth's growth6, indicating that the core and mantle must have different Ru isotope compositions. This illustrates the potential of Ru isotopes as a new tracer for core-mantle interaction. Here we report Ru isotope anomalies for ocean island basalts. Basalts from Hawaii have higher ε100Ru than the ambient mantle. Combined with unradiogenic tungsten (W) isotope ratios, this is diagnostic of a core contribution to their mantle sources. The combined Ru and W isotope systematics of Hawaiian basalts are best explained by simple core entrainment but addition of core-derived oxide minerals at the core-mantle boundary is a possibility.

Close-in companion stars are expected to adversely influence the formation and orbital stability of circumstellar (S-type) planets by tidally truncating protoplanetary discs1-4, impeding mutual accretion of planetesimals5-8 and narrowing dynamically stable regions9. This explains the observed dearth of S-type planets in tight binary star systems10-13. ν Octantis, whose stellar components have a mean separation of 2.6 AU, has long been suspected of hosting a circum-primary planet in a retrograde and exceptionally wide orbit that resides midway between the stars14-20. Strong theoretical grounds against its formation and the absence of observational precedents, however, have challenged the reality of the planet. Here we present new radial velocity measurements that consolidate the planet hypothesis. Stable fits to all radial velocity data require the planetary orbit to be retrograde and practically coplanar. We also report the critical discovery from adaptive optics imaging that the companion star is a white dwarf. Our exploration of credible primordial binary orbital settings shows that the minimum separation between the stars was 1.3 AU initially, which overlaps the current planetary orbit and makes any scenarios in which the circum-primary planetary orbit formed coevally with the young stars hardly conceivable. The retrograde planet must have originated from a circumbinary orbit or a second-generation protoplanetary disc, showing the role of binary stellar evolution in the formation and evolution of planetary systems.