Vision enables many animals to perform spatial reasoning from remote locations1. By viewing distant landmarks, animals recall spatial memories and plan future trajectories. Although these spatial functions depend on hippocampal place cells2,3, the relationship between place cells and active visual behaviour is unknown. Here we studied a highly visual animal, the chickadee, in a behaviour that required alternating between remote visual search and spatial navigation. We leveraged the head-directed nature of avian vision to track gaze in freely moving animals. We discovered a profound link between place coding and gaze. Place cells activated not only when the chickadee was in a specific location, but also when it simply gazed at that location from a distance. Gaze coding was precisely timed by fast ballistic head movements called 'head saccades'4,5. On each saccadic cycle, the hippocampus switched between encoding a prediction of what the bird was about to see and a reaction to what it actually saw. The temporal structure of these responses was coordinated by subclasses of interneurons that fired at different phases of the saccade. We suggest that place and gaze coding are components of a unified process by which the hippocampus represents the location that is relevant to the animal in each moment. This process allows the hippocampus to implement both local and remote spatial functions.

Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1-3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4-6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.

Developing bioelectronics capable of stably tracking brain-wide, single-cell, millisecond-resolved neural activity in the developing brain is critical for advancing neuroscience and understanding neurodevelopmental disorders. During development, the three-dimensional structure of the vertebrate brain arises from a two-dimensional neural plate1,2. These large morphological changes have previously posed a challenge for implantable bioelectronics to reliably track neural activity throughout brain development3-9. Here we introduce a tissue-level-soft, submicrometre-thick mesh microelectrode array that integrates into the embryonic neural plate by leveraging the tissue's natural two-dimensional-to-three-dimensional reconfiguration. As organogenesis progresses, the mesh deforms, stretches and distributes throughout the brain, seamlessly integrating with neural tissue. Immunostaining, gene expression analysis and behavioural testing confirm no adverse effects on brain development or function. This embedded electrode array enables long-term, stable mapping of how single-neuron activity and population dynamics emerge and evolve during brain development. In axolotl models, it not only records neural electrical activity during regeneration but also modulates the process through electrical stimulation.

The James Webb Space Telescope (JWST) has revealed unexpectedly rapid galaxy assembly in the early Universe, in tension with galaxy-formation models1-3. At the low abundances of heavy elements (metals) and dust typical in early galaxies, the formation of molecular hydrogen and its connection to star formation remain poorly understood. Some models predict that stars form in predominantly atomic gas at low metallicity4,5, in contrast to molecular gas at higher metallicities6. Despite repeated searches7, cold molecular gas has not yet been observed in any galaxy below 7% solar metallicity8. Here we report the detection of rotational emission from molecular hydrogen near the only O-type star in the 3% solar metallicity galaxy Leo P (refs. 9,10) with JWST's Mid-Infrared Instrument/Medium Resolution Spectroscopy (MIRI-MRS) observing mode. These observations place a lower limit on Leo P's molecular gas content, and modelling of the photodissociation region illuminated by the O star suggests a compact (≤2.6 pc radius), approximately 104 M⊙ cloud. We also report a stringent upper limit on carbon monoxide (CO) emission from a deep search with the Atacama Large Millimeter/submillimeter Array (ALMA). Our results highlight the power of MIRI-MRS to characterize even small ultraviolet-illuminated molecular clouds in the low-metallicity regime, in which the traditional observational tracer CO is uninformative. This discovery pushes the limiting metallicity at which molecular gas is present in detectable quantities more than a factor of two lower, providing crucial empirical guidance for models of the interstellar medium in early galaxies.

Sex inequalities in cancer are well documented, but the current limited understanding is hindering advances in precision medicine and therapies1. Consideration of ethnicity, age and sex is essential for the management of cancer patients because they underlie important differences in both incidence and response to treatment2,3. Age-related hormone production, which is a consistent divergence between the sexes, is underestimated in cancers that are not recognized as being hormone dependent4-6. Here, we show that premenopausal women have increased vulnerability to cancers, and we identify the cell-cell adhesion molecule E-cadherin as a crucial component in the oestrogen response in various cancers, including melanoma. In a mouse model of melanoma, we discovered an oestrogen-sensitizing pathway connecting E-cadherin, β-catenin, oestrogen receptor-α and GRPR that promotes melanoma aggressiveness in women. Inhibiting this pathway by targeting GRPR or oestrogen receptor-α reduces metastasis in mice, indicating its therapeutic potential. Our study introduces a concept linking hormone sensitivity and tumour phenotype in which hormones affect cell phenotype and aggressiveness. We have identified an integrated pro-tumour pathway in women and propose that targeting a G-protein-coupled receptor with drugs not commonly used for cancer treatment could be more effective in treating E-cadherin-dependent cancers in women. This study emphasizes the importance of sex-specific factors in cancer management and offers hope of improving outcomes in various cancers.

Ultracold fermionic atoms in optical lattices offer pristine realizations of Hubbard models1, which are fundamental to modern condensed-matter physics2,3. Despite notable advancements4-6, the accessible temperatures in these optical lattice material analogues are still too high to address many open problems7-10. Here we demonstrate a several-fold reduction in temperature6,11-13, bringing large-scale quantum simulations of the Hubbard model into an entirely new regime. This is accomplished by transforming a low-entropy product state into strongly correlated states of interest via dynamic control of the model parameters14,15, which is extremely challenging to simulate classically10. At half-filling, the long-range antiferromagnetic order is close to saturation, leading to a temperature of T/t=0.05-0.05+0.06 based on comparisons with numerically exact simulations. Doped away from half-filling, it is exceedingly challenging to realize systematically accurate and predictive numerical simulations9. Importantly, we are able to use quantum simulation to identify a new pathway for achieving similarly low temperatures with doping. This is confirmed by comparing short-range spin correlations to state-of-the-art, but approximate, constrained-path auxiliary-field quantum Monte Carlo simulations16-18. Compared with the cuprates2,19,20, the reported temperatures correspond to a reduction from far above to below room temperature, at which physics such as the pseudogap and stripe phases may be expected3,19,21-24. Our work opens the door to quantum simulations that solve open questions in material science, develop synergies with numerical methods and theoretical studies, and lead to discoveries of new physics8,10.

Type I interferons are essential for antiviral immunity1 but must be tightly regulated2. The conserved transcriptional repressor SP140 inhibits interferon-β (Ifnb1) expression through an unknown mechanism3,4. Here we report that SP140 does not directly repress Ifnb1 transcription. Instead, SP140 negatively regulates Ifnb1 mRNA stability by directly repressing the expression of a previously uncharacterized regulator that we call RESIST (regulated stimulator of interferon via stabilization of transcript; previously annotated as annexin 2 receptor). RESIST promotes Ifnb1 mRNA stability by counteracting Ifnb1 mRNA destabilization mediated by the tristetraprolin (TTP) family of RNA-binding proteins and the CCR4-NOT deadenylase complex. SP140 localizes within punctate structures called nuclear bodies that have important roles in silencing DNA-virus gene expression in the nucleus3. Consistent with this observation, we find that SP140 inhibits replication of the gammaherpesvirus MHV68. The antiviral activity of SP140 is independent of its ability to regulate Ifnb1. Our results establish dual antiviral and interferon regulatory functions for SP140. We propose that SP140 and RESIST participate in antiviral effector-triggered immunity5,6.

Chest radiography frequently serves as baseline imaging for most lung diseases1. Deep learning has great potential for automating the interpretation of chest radiography2. However, existing chest radiographic deep learning models are limited in diagnostic scope, generalizability, adaptability, robustness and extensibility. To overcome these limitations, we have developed Ark+, a foundation model applied to chest radiography and pretrained by cyclically accruing and reusing the knowledge from heterogeneous expert labels in numerous datasets. Ark+ excels in diagnosing thoracic diseases. It expands the diagnostic scope and addresses potential misdiagnosis. It can adapt to evolving diagnostic needs and respond to novel diseases. It can learn rare conditions from a few samples and transfer to new diagnostic settings without training. It tolerates data biases and long-tailed distributions, and it supports federated learning to preserve privacy. All codes and pretrained models have been released, so that Ark+ is open for fine-tuning, local adaptation and improvement. It is extensible to several modalities. Thus, it is a foundation model for medical imaging. The exceptional capabilities of Ark+ stem from our insight: aggregating various datasets diversifies the patient populations and accrues knowledge from many experts to yield unprecedented performance while reducing annotation costs3. The development of Ark+ reveals that open models trained by accruing and reusing knowledge from heterogeneous expert annotations with a multitude of public (big or small) datasets can surpass the performance of proprietary models trained on large data. We hope that our findings will inspire more researchers to share code and datasets or federate privacy-preserving data to create open foundation models with diverse, global expertise and patient populations, thus accelerating open science and democratizing AI for medicine.

Understanding thermal transport mechanisms across material interfaces is crucial for advancing semiconductor technologies, particularly in miniaturized devices operating under extreme power densities1,2. Although the interface phonon-mediated processes are theoretically established3-6 as the dominant mechanism for interfacial thermal transport in semiconductors7, their nanoscale dynamics remain experimentally elusive owing to challenges in measuring the temperature and non-equilibrium phonon distributions across the buried interface8-11. Here we overcome these limitations by using in situ vibrational electron energy-loss spectroscopy (EELS) in an electron microscope to nanoscale profile temperature gradients across the AlN-SiC interface during thermal transport and map its non-equilibrium phonon occupations at sub-nanometre resolution. We observe a sharp temperature drop within about 2 nm across the interface, enabling direct extraction of relative interfacial thermal resistance (ITR). During thermal transport, the mismatch of phonon modes' thermal conductivity at the interface causes substantial non-equilibrium phonons nearby, making the populations of interface modes different under forward and reverse heat flow and also leading to marked changes in the modal temperature of AlN optical phonons within about 3 nm of the interface. These results reveal the phonon transport dynamics at the (sub-)nanoscale and establish the inelastic phonon scattering mechanism involved by interface modes, offering valuable insights into the engineering of thermal interfaces.

Non-homologous end joining (NHEJ) is the main repair pathway of double-strand DNA breaks in higher eukaryotes1,2. Here we report reconstitution of the final steps of NHEJ and structures of DNA polymerase μ and ligase IV (LIG4) engaged in gap filling and end joining. These reactions take place in a flexible ω-shaped framework composed of XRCC4 and XLF. Two broken DNA ends, each encircled by Ku70-Ku80 internally, are docked onto the ω frame, mediated by LIG4. DNA polymerase and ligase attached to each ω arm repair only one broken strand of a defined polarity; the final steps of NHEJ requires coordination and toggling of a pair of such enzymes. The facilitators XLF and PAXX additively stimulate NHEJ reactions. As DNA-end sensor and protector, LIG4 replaces DNA-PKcs for end joining and bridges the two DNA ends for polymerase to fill remaining gaps. These assemblies present new targets for NHEJ inhibition to enhance efficacy of radiotherapy and accuracy of gene editing.

Metal halide perovskites are promising materials for light-emitting diodes (LEDs)1-4. Spatially confining charge carriers using nanocrystal/quantum dots5-9, low-dimensional perovskites10-13 and ultrathin perovskite layers14 have all been used to improve the external quantum efficiency of perovskite LEDs (PeLEDs). However, most strongly space-confined perovskites suffer from severe Auger recombination, ion migration and thermal instability, resulting in limited brightness and operational lifetime6,7,10-12,14-17. Here, we report an alternative strategy based on weakly space-confined, large-grained crystals of all-inorganic perovskite. Sacrificial additives, namely, hypophosphorous acid and ammonium chloride, were used to induce nucleation and crystallization of caesium lead bromide, resulting in monocrystal grains with minimized trap density and a high photoluminescence quantum yield. Benefiting from the high carrier mobility and suppressed Auger recombination, we obtained efficient PeLEDs with an external quantum efficiency reaching 22.0%, which remained above 20% at a high current density near 1,000 mA cm-2 and a brightness of over 1,167,000 cd m-2. Furthermore, benefiting from the suppressed ion migration and better thermal stability, the extrapolated half-lifetime of the weakly space-confined PeLEDs increased to 185,600 h under an initial luminance of 100 cd m-2 at room temperature. Our work is a new approach for designing efficient, bright and stable PeLEDs for real applications.

Preventing gender disparities in mathematics is a worldwide preoccupation1,2. In infancy and early childhood, boys and girls exhibit similar core knowledge of number and space3-8. Gender disparities in maths are, therefore, thought to primarily reflect an internalization of the sociocultural stereotype that 'girls are bad at maths'. However, where, when and how widely this stereotype becomes entrenched remains uncertain. Here, we report the results of a 4-year longitudinal assessment of language and mathematical performance of all French first and second graders (2,653,082 children). Boys and girls exhibited very similar maths scores upon school entry, but a gender gap in favour of boys became highly significant after 4 months of schooling and reached an effect size of about 0.20 after 1 year. These findings were repeated each year and varied only slightly across family, class or school type and socio-economic level. Although schooling correlated with age, exploiting the near-orthogonal variations indicated that the gender gap increased with schooling rather than with age. These findings point to the first year of school as the time and place where a maths gender gap emerges in favour of boys, thus helping focus the search for solutions and interventions.

Lipids are essential components of cancer cells due to their structural and signalling roles1. To meet metabolic demands, many cancers take up extracellular lipids2-5; however, how these lipids contribute to cancer growth and progression remains poorly understood. Here, using functional genetic screens, we identify uptake of lipoproteins-the primary mechanism for lipid transport in circulation-as a key determinant of ferroptosis sensitivity in cancer. Lipoprotein supplementation robustly inhibits ferroptosis across diverse cancer types, primarily through the delivery of α-tocopherol (α-toc), the most abundant form of vitamin E in human lipoproteins. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Disrupting GAG biosynthesis or acutely degrading surface GAGs reduces lipoprotein uptake, sensitizes cancer cells to ferroptosis and impairs tumour growth in mice. Notably, human clear cell renal cell carcinomas-a lipid-rich malignancy-exhibit elevated levels of chondroitin sulfate and increased lipoprotein-derived α-toc compared with normal kidney tissue. Together, our study establishes lipoprotein uptake as a critical anti-ferroptotic mechanism in cancer and implicates GAG biosynthesis as a therapeutic target.

Natural killer (NK) cells use inhibitory and activating immune receptors to differentiate between human cells and pathogens. Signalling by these receptors determines whether an NK cell becomes activated and destroys a target cell. In some cases, such as killer immunoglobulin-like receptors, immune receptors are found in pairs, with inhibitory and activating receptors containing nearly identical extracellular ligand-binding domains coupled to different intracellular signalling domains1. Previous studies showed that repetitive interspersed family (RIFIN) proteins, displayed on the surfaces of Plasmodium falciparum-infected erythrocytes, can bind to inhibitory immune receptors and dampen NK cell activation2,3, reducing parasite killing. However, no pathogen-derived ligand has been identified for any human activating receptor. Here we identified a clade of RIFINs that bind to inhibitory immune receptor KIR2DL1 more strongly than KIR2DL1 binds to the human ligand (MHC class I). This interaction mediates inhibitory signalling and suppresses the activation of KIR2DL1-expressing NK cells. We show that KIR2DL1-binding RIFINs are abundant in field-isolated strains from both Africa and Asia and reveal how the two RIFINs bind to KIR2DL1. The RIFIN binding surface of KIR2DL1 is conserved in the cognate activating immune receptor KIR2DS1. We find that KIR2DL1-binding RIFINs can also bind to KIR2DS1, resulting in the activation of KIR2DS1-expressing NK cells. This study demonstrates that activating killer immunoglobulin-like receptors can recruit NK cells to target a pathogen and reveals a potential role for activating immune receptors in controlling malaria infection.

Plants make complex and potent therapeutic molecules1,2, but sourcing these molecules from natural producers or through chemical synthesis is difficult, which limits their use in the clinic. A prominent example is the anti-cancer therapeutic paclitaxel (sold under the brand name Taxol), which is derived from yew trees (Taxus species)3. Identifying the full paclitaxel biosynthetic pathway would enable heterologous production of the drug, but this has yet to be achieved despite half a century of research4. Within Taxus' large, enzyme-rich genome5, we suspected that the paclitaxel pathway would be difficult to resolve using conventional RNA-sequencing and co-expression analyses. Here, to improve the resolution of transcriptional analysis for pathway identification, we developed a strategy we term multiplexed perturbation × single nuclei (mpXsn) to transcriptionally profile cell states spanning tissues, cell types, developmental stages and elicitation conditions. Our data show that paclitaxel biosynthetic genes segregate into distinct expression modules that suggest consecutive subpathways. These modules resolved seven new genes, allowing a de novo 17-gene biosynthesis and isolation of baccatin III, the industrial precursor to Taxol, in Nicotiana benthamiana leaves, at levels comparable with the natural abundance in Taxus needles. Notably, we found that a nuclear transport factor 2 (NTF2)-like protein, FoTO1, is crucial for promoting the formation of the desired product during the first oxidation, resolving a long-standing bottleneck in paclitaxel pathway reconstitution. Together with a new β-phenylalanine-CoA ligase, the eight genes discovered here enable the de novo biosynthesis of 3'-N-debenzoyl-2'-deoxypaclitaxel. More broadly, we establish a generalizable approach to efficiently scale the power of co-expression analysis to match the complexity of large, uncharacterized genomes, facilitating the discovery of high-value gene sets.

Since the invention of the laser, nonlinear effects such as filamentation1, Rabi cycling2,3 and collective emission4 have been explored in the optical regime, leading to a wide range of scientific and industrial applications5-8. X-ray free-electron lasers (XFELs) have extended many optical techniques to X-rays for their advantages of ångström-scale spatial resolution and elemental specificity9. An example is XFEL-driven inner-shell Kα1 (2p3/2 → 1s1/2) X-ray lasing in elements ranging from neon to copper, which has been used for nonlinear spectroscopy and development of new X-ray laser sources10-16. Here we show that strong lasing effects similar to those in the optical regime can occur at 1.5-2.1 Å wavelengths during high-intensity (>1019 W cm-2) XFEL-driven Kα1 lasing of copper and manganese. Depending on the temporal XFEL pump pulse substructure, the resulting X-ray pulses (about 106-108 photons) can exhibit strong spatial inhomogeneities and spectral splitting, inhomogeneities and broadening. Three-dimensional Maxwell-Bloch calculations17 show that the observed spatial inhomogeneities result from X-ray filamentation and that the broad spectral features are driven by sub-femtosecond Rabi cycling. Our simulations indicate that these X-ray pulses can have pulse lengths of less than 100 attoseconds and coherence properties that provide opportunities for quantum X-ray optics applications.

Trace elements and isotopes (TEIs) are important to marine life and are essential tools for studying ocean processes1. Two different frameworks have arisen regarding marine TEI cycling: reversible scavenging favours water-column control on TEI distributions2-5, and seafloor boundary exchange emphasizes sedimentary imprints on water-column biogeochemistry6,7. These two views lead to disparate interpretations of TEI behaviours8-10. Here we use rare earth elements and neodymium isotopes as exemplar tracers of particle scavenging11 and boundary exchange6,7,12. We integrate these data with models of particle cycling and sediment diagenesis to propose a general framework for marine TEI cycling. We show that, for elements with greater affinity for manganese oxide than biogenic particles, scavenging is a net sink throughout the water column, contrary to a common assumption for reversible scavenging3,13. In this case, a benthic flux supports increasing elemental concentrations with water depth. This sedimentary source consists of two components: one recycled from elements scavenged by water-column particles, and another newly introduced to the water column through marine silicate weathering inside sediment8,14,15. Abyssal oxic diagenesis drives this benthic source, and exerts a strong influence on water-column biogeochemistry through seafloor geometry and bottom-intensified turbulent mixing16,17. Our findings affirm the role of authigenic minerals, often overshadowed by biogenic particles, in water-column cycling18, and suggest that the abyssal seafloor, often regarded as inactive, is a focus of biogeochemical transformation19,20.

The generation of self-tolerant repertoires of T cells depends on the expression of peripheral self antigens in the thymic epithelium1 and the presence of small populations of cells that mimic the diverse phenotypes of peripheral tissues2-7. Whereas the molecular underpinnings of self-antigen expression have been extensively studied8, the developmental origins and differentiation pathways of thymic mimetic cells remain to be identified. Moreover, the histological identification of myoid and other peripheral cell types as components of the thymic microenvironment of many vertebrate species9 raises questions regarding the evolutionary origin of this unique tolerance mechanism. Here we show that during mouse development, mimetic cells appear in the microenvironment in two successive waves. Cells that exhibit transcriptional signatures characteristic of muscle, ionocyte, goblet and ciliated cells emerge before birth, whereas others, such as those that mimic enterohepatic cells and skin keratinocytes, appear postnatally. These two groups also respond differently to modulations of thymic epithelial cell progenitor pools caused by deletions of Foxn1 and Ascl1, expression of a hypomorphic variant of the transcription factor FOXN1, and overexpression of the signalling molecules BMP4 and FGF7. Differences in mimetic cell populations were also observed in thymic microenvironments reconstructed by replacement of mouse Foxn1 with evolutionarily ancient Foxn1/4 gene family members, including the Foxn4 gene of the cephalochordate amphioxus and the Foxn4 and Foxn1 genes of a cartilaginous fish. Whereas some cell types, such as ciliated cells, develop in the thymus in the absence of FOXN1, mimetic cells that appear postnatally, such as enterohepatic cells, require the activity of the vertebrate-specific transcription factor FOXN1. The thymus of cartilaginous fishes and the thymoid of lampreys, a representative of jawless vertebrates, which exhibit an alternative adaptive immune system10, also harbour cells that express genes encoding peripheral tissue components such as the liver-specific protein transthyretin. Our findings suggest an evolutionary model of successive changes of thymic epithelial genetic networks enabling the coordinated contribution of peripheral antigen expression and mimetic cell formation to achieve central tolerance for vertebrate-specific innovations of tissues such as the liver11,12.