Quantum simulations of electronic structure and strongly correlated quantum phases are among the most promising applications of quantum computing. These computations benefit from native fermionic encodings1,2, enforcing fermionic statistics and conservation laws such as particle number and magnetization3 independent of gate errors. While ultracold atoms in optical lattices have become established as powerful analogue simulators of strongly correlated fermionic matter4-7, neutral-atom platforms have concurrently emerged as versatile, scalable architectures for spin-based digital quantum computation8. Unifying these capabilities requires high-fidelity motionally coherent gates for fermionic atoms9-11, similar to collisional gates in bosonic systems12,13, paving the way for programmable fermionic quantum processors. Here we demonstrate collisional entangling gates with fidelities up to 99.75(6)% and Bell-state lifetimes exceeding 10 s, realized by means of controlled interactions of fermionic atoms in an optical superlattice. Using quantum gas microscopy14, we microscopically characterize spin-exchange and pair-tunnelling gates and realize a robust composite pair-exchange gate, a key building block for quantum chemistry simulations3,15. Our results establish controlled collisions in optical lattices as a competitive and complementary route to high entangling gate fidelities in neutral-atom quantum computers. Operating intrinsically with fermions, this capability naturally extends to many-qubit architectures, in which fermionic statistics become relevant, enabling complex state preparation and advanced readout16-19 in scalable analogue-digital hybrid quantum simulators. Combined with local addressing20,21, these gates mark a crucial step towards a fully digital fermionic quantum computer based on controlled motion and entanglement of neutral atoms.

Ruddlesden-Popper nickelates have emerged as a crucial platform for exploring the mechanisms of high-temperature superconductivity1-7. However, the Fermi surface topology required for superconductivity remains unknown. Here, beyond the superconducting pure bilayer (2222) phase, we report the thin film growth and ambient-pressure superconductivity of monolayer-bilayer (1212) and bilayer-trilayer (2323) superstructures, together with the absence of superconductivity in monolayer-trilayer (1313) superstructure, under identical compressive epitaxial strain. The onset superconducting transition temperatures range from 46 K to 50 K, exceeding the McMillan limit. Angle-resolved photoemission spectroscopy shows key Fermi surface differences in these atomically engineered structures. In superconducting 1212 and 2222 films, a dispersive hole-like band (γΙΙ) forms an underlying Fermi pocket, surrounding the Brillouin zone corner. By contrast, the top of the flat band (γΙΙΙ) is observed at about 70 meV below EF in the non-superconducting 1313 films. Particularly, the superconducting 2323 films host both γΙΙ and γΙΙΙ bands. The polarization dependence of the γ bands reveals their Ni dz2 origin. Our findings expand the family of ambient-pressure nickelate superconductors and establish a connection between structural configuration, electronic structure and the emergence of superconductivity in nickelates.

Cell-type-specific promoters are used in gene therapy to restrict expression of the therapeutic payload. However, these promoters often have suboptimal strength, selectivity and size. Here, leveraging recent insights into the function of enhancers, we developed synthetic super-enhancers (SSEs) by assembling functionally validated enhancer fragments into multipart arrays. Focusing on the core SOX2-driven and SOX9-driven transcriptional regulatory network in glioblastoma stem cells (GSCs)1, we engineered SSEs with robust activity and high selectivity. Single-cell profiling, biochemical analyses and genome-binding data indicated that SSEs integrate neurodevelopmental and signalling-state transcription factors to trigger the formation of large multimeric complexes of transcription factors. Moreover, GSC-selective expression of a combination of cytotoxic (HSV-TK and ganciclovir) and immunomodulatory (IL-12) payloads, delivered using adeno-associated virus vectors, as a single treatment led to curative outcomes in a mouse model of aggressive glioblastoma. Notably, IL-12 induced an immunological memory that prevented tumour recurrence. The activity and selectivity of the adeno-associated virus and SSE were validated using primary human glioblastoma tissue and normal cortex samples. In summary, SSEs harness the unique core transcriptional programs that define the GSC phenotype and enable precision immune activation. This approach may have broader applications in other contexts when precise control of transgene expression in specific cell states is necessary.

Quantum computing represents a central challenge in modern science. Neutral atoms in optical lattices have emerged as a leading computing platform, with collisional gates offering a stable mechanism for quantum logic1-10. However, previous experiments have treated ultracold collisions as a dynamically fine-tuned process11-22, which obscures the underlying quantum geometry and quantum statistics crucial for realizing intrinsically robust operations. Here we propose and experimentally demonstrate a purely geometric two-qubit SWAP gate by transiently populating qubit doublon states of fermionic atoms in a dynamical optical lattice. The presence of these doublon states, together with fermionic exchange anti-symmetry, enables a two-particle quantum holonomy-a geometric evolution in which dynamical phases are absent23. This yields a gate mechanism that is intrinsically protected against fluctuations and inhomogeneities of the confining potentials. The resilience of the gate is further reinforced by time-reversal and chiral symmetries of the Hamiltonian. We experimentally validate this exceptional protection, achieving a loss-corrected amplitude fidelity of 99.91(7)% measured across the entire system consisting of more than 17,000 atom pairs. When combined with recently developed topological pumping methods for atom transport16, our results pave the way for large-scale, highly connected quantum processors. This work introduces a new model for quantum logic that transforms fundamental symmetries, including quantum statistics, into a powerful resource for fault-tolerant computation.

Heart failure remains a leading cause of morbidity and mortality, yet no approved therapies effectively prevent or reverse pathological cardiac fibrosis and the associated decline in cardiac function1-4. Chronic inflammation is a central driver of pathological fibrosis after ischaemic or haemodynamic stress, but strategies that locally rebalance injurious and reparative immune responses without systemic immunosuppression are lacking5,6. Dendritic cells (DCs) are key regulators of immune activation and tolerance, providing an opportunity for therapeutic immune reprogramming in cardiac diseases7,8. Here we show that engineered immunosuppressive and fibrosis-targeted DCs (iCDCs) effectively protect against pathological cardiac remodelling. In mouse models of ischaemia-reperfusion injury, myocardial infarction and pressure overload, iCDC therapy reduced inflammatory cardiac fibrosis, improved cardiac perfusion and preserved contractility. Mechanistically, iCDCs conferred sustained cardioprotection directly by suppressing immune and stromal cell activation or indirectly through promoting clonal expansion of regulatory T cells. Importantly, in a non-human primate model of myocardial infarction, iCDC therapy also reduced cardiac fibrosis, improved cardiac perfusion and contractile function without inducing systemic toxicity. These findings establish lesion-targeted immune modulation as a feasible strategy to control cardiac fibrosis and identify engineered dendritic cells as a promising therapeutic platform for treating cardiac remodelling and heart failure.

Artificial selection has greatly shaped crop agronomic traits1-3; however, the mechanistic basis of how immunity is selected remains unclear. Here we identify the Oryza sativa nucleotide-binding site and leucine-rich repeat (NLR) receptor XA48 and downstream transcription factors OsVOZ1 and OsVOZ2 (OsVOZ1/2), which confer resistance to bacterial blight. XA48 perceives the ancient pathogen effector XopG, activating effector-triggered immunity by degrading the negative regulator OsVOZ1/2. The XA48-OsVOZ1 module has undergone subspecies-specific selection: Xa48 is retained only in Oryza sativa indica and was lost in Oryza sativa japonica. By contrast, OsVOZ1 has diverged into two haplotypes-O. s. indica retains both OsVOZ1A/S alleles compatible with Xa48, whereas O. s. japonica has only OsVOZ1A. Reintroducing Xa48 into O. s. japonica severely compromises yield owing to the XA48-OsVOZ1A-mediated immune incompatibility. Stacking XA48-mediated effector-triggered immunity with XA21-mediated pattern-triggered immunity reconstitutes the broad-spectrum resistance from wild rice. Our study therefore reveals how asymmetric selection of an NLR-transcription factor module shapes disease resistance and reproductive development, providing a strategy for breeding crops by harnessing the relative immunity of wild rice.

The human maternal-fetal interface is characterized by mosaic intermingling of maternal and fetal cells1. Yet the underlying cellular, molecular and spatial programmes remain incompletely defined. Here we generate a comprehensive atlas of the human maternal-fetal interface across normal pregnancies from early gestation to term by integrating large-scale paired single-nucleus transcriptomic and chromatin accessibility profiling with submicrometre-resolution spatial transcriptomics and CODEX multiplex protein imaging2, substantially boosting the spatiotemporal resolution of prior research3. This framework delineates common and transient cell types, states and spatial niches across the fetal and maternal compartments, reconstructs transcriptional programmes that guide cytotrophoblast and decidual stromal cell differentiation, and resolves recurrent architecture structural units that build this interface. We identify previously unrecognized arterial endothelial state transitions during cytotrophoblast-mediated spiral artery remodelling and develop a machine learning model that predicts cytotrophoblast invasiveness from transcriptomic signatures. We further discover a decidual stromal cell subtype that suppresses cytotrophoblast invasion via endocannabinoid signalling at the human maternal-fetal interface. By integrating the atlas with genome-wide association data, we pinpoint maternal and fetal cells that are most vulnerable to pre-eclampsia, preterm birth or miscarriage. This resource provides a comprehensive spatially resolved single-cell multiomic reference of the human placenta and decidua and offers a framework for decoding their normal and disordered development.

The UN Decade on Ecosystem Restoration aims to stop biodiversity losses1. Approximately 60% of tropical forests have already been lost or severely degraded2, making restoration essential to achieve conservation goals. Recovery trajectories of trees have been studied intensively3,4, but a comprehensive understanding of biodiversity recovery is lacking. Here we analyse recovery trajectories across trophic levels including 16 taxonomic groups from three kingdoms in a lowland tropical forest by investigating resistance to perturbation, recovery times and return rates to old-growth forest conditions. Abundance and diversity regained more than 90% and composition approximately 75% similarity to old-growth forests within 30 years, but full recovery takes several decades. Mobile animal communities acting as seed dispersers or pollinators had high resistance levels and recovered faster than trees or tree seedlings. Return rates contributed 1-2.5 times more than resistance to the recovery times of species composition. Taxon-specific recovery times could not be explained by simple mechanisms (life-history strategies, trophic level or mobility). We show the enormous potential of protecting naturally recovering secondary forests to stop and reverse biodiversity losses.

Although competition and facilitation both influence tree diversity1-5, their relative importance and variation with latitude remain poorly understood. Using data from 17 large forest plots, including around 2.7 million trees and over 5,400 species spanning 5° S to 47° N, we quantified the latitudinal trends of the relative importance of negative (competitive) and positive (facilitative) interactions among neighbouring tree species, accounting for three biotic and eight environmental factors. We examined whether the average neighbourhood species diversity around individuals of each focal species was larger or smaller than expected under null models. The results show that negative interspecific interactions prevailed across most plots. Near the equator, the relative proportions of species surrounded by a lower or higher than expected number of neighbours were roughly equal, but at higher latitudes, the proportions of species with a relatively higher number of neighbours declined, and those with fewer neighbours increased significantly. This latitudinal pattern can be attributed in part to reduced abundance of legumes, non-arbuscular mycorrhizal associations, and the weaker canopy nursing effect towards higher latitudes, but it was mediated by mean annual temperature. These findings reveal a previously unrecognized relative decline in facilitative interactions and increase in competitive interactions with latitude and suggest that rising temperatures could enhance facilitative effects and promote tree community diversity at higher latitudes.

Recently, de novo variants in an 18-nucleotide region in the centre of RNU4-2 were shown to cause ReNU syndrome, a syndromic neurodevelopmental disorder that is predicted to affect tens of thousands of individuals worldwide1,2. RNU4-2 is a non-protein-coding gene that is transcribed into the U4 small nuclear RNA component of the major spliceosome3. ReNU syndrome variants disrupt spliceosome function and alter 5' splice site selection1,4. Here we performed saturation genome editing (SGE) of RNU4-2 to identify the functional and clinical impact of variants across the entire gene. The resulting SGE function scores, derived from variants' effects on cell fitness, discriminate ReNU syndrome variants from those observed in the population and markedly outperform in silico variant effect prediction. Using these data, we redefine the ReNU syndrome critical region at single-nucleotide resolution, resolve variant pathogenicity for variants of uncertain significance and show that SGE function scores delineate variants by phenotypic severity and the extent of observed splicing disruption. Furthermore, we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome. Together, this work defines the landscape of variant function across RNU4-2, providing critical insights for both diagnosis and therapeutic development.

β-Thalassaemia is caused by reduced or absent production of β-haemoglobin1-4. Previously, we performed laboratory-scale electroporation of CD34+ haematopoietic stem and progenitor cells from patients with β-thalassaemia using a transformer base editor5,6. The aim was to target the binding motif of the transcription repressor BCL11A in the HBG1 and HBG2 promoters7 to reactivate fetal haemoglobin (HbF) production. Here we present results of a phase 1 clinical trial (ClinicalTrials.gov identifier: NCT06024876) of five patients who received autologous CD34+ cells modified using a transformer base editor at clinical scale (CS-101). With a median follow-up of 23.0 months after CS-101 infusion, the median times to neutrophil and platelet engraftment were 16 days and 25 days, respectively. Moreover, all patients had stopped red blood cell transfusions, with a median time to the last transfusion of 18 days after CS-101 infusion. The mean total haemoglobin and HbF concentrations were 12.4 ± 1.0 and 11.5 ± 0.9 g dl-1, respectively, at month 3 after infusion. These levels remained at similar or higher levels throughout the follow-up period, which indicated rapid haematopoietic reconstitution. The adverse events of CS-101 were generally consistent with those of busulfan myeloablative conditioning and autologous haematopoietic stem and progenitor cell transplantation. No deaths or cancer occurrences were reported. In summary, CS-101 can lead to rapid and sustained increases in both total haemoglobin and HbF levels, which resulted in early and enduring transfusion independence.

Transcription factors establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility and regulating gene expression1. Mapping accessible chromatin offers critical insights into transcriptional control, but available datasets for human development are restricted to bulk tissue, single organs or single modalities2. Here we present the Human Development Multiomic Atlas, a single-cell atlas of chromatin accessibility and gene expression from 817,740 fetal cells across 12 organs, spanning 203 cell types and more than 1 million candidate cis-regulatory elements, many of which exhibit organ-specific in vivo enhancer activity. Deep learning models trained to predict accessibility from local DNA sequence unravel a comprehensive lexicon of motifs that influence accessibility, including composite motifs exhibiting distinct syntactic constraints that are predicted to mediate transcription factor cooperativity. We identify 'hard' syntactic rules requiring precise motif spacing and orientation, 'soft' rules allowing flexible motif arrangements, and ubiquitous motifs inhibiting accessibility. Model-based interpretation of genetic variants reveals that disruption of motifs with positive and negative effects is associated with concordant effects on gene expression. Our work delineates how motif syntax governs cell-type-specific chromatin accessibility and provides a foundational resource for decoding cis-regulatory logic and interpreting genetic variation during human development.

The development of glucagon-like peptide 1 (GLP1) receptor agonists, including semaglutide and tirzepatide, has transformed the clinical management of overweight and obesity. However, substantial inter-person variability exists in both weight loss efficacy and the incidence of side effects1. To investigate the genetic basis of this variability, here we conduct a genome-wide association study of self-reported weight loss and treatment-related side effects in 27,885 people following GLP1 receptor agonist therapy. We identify a missense variant in GLP1R that is associated significantly with increased efficacy of GLP1 medications (P = 2.9 × 10-10), with an additional -0.76 kg of weight loss expected per copy of the effect allele. Furthermore, we identify associations linking variation in both GLP1R and GIPR to GLP1 medication-related nausea or vomiting, with the GIPR association being restricted to people using tirzepatide. We incorporate these findings into a broader model of GLP1 medication response, and demonstrate the ability to stratify patients by efficacy and side effect risk. These findings provide direct genetic evidence that variation in the drug target genes contributes to inter-person variability in response and lay the foundation for precision medicine approaches in the treatment of obesity.

Pathogenic expansions of short tandem repeats (STRs) cause over 70 neurological diseases1-3. Here we performed a population-scale survey of pathogenic repeat expansions by analysing repeat length in 37 disease-associated STR loci in a diverse set of 1,020,833 samples using short-read sequencing whole-exome and whole-genome data. Consistent with previous findings, we found that the frequency of pathogenic repeats is higher than the prevalence of corresponding diseases for most loci4,5. Associations of repeat length with 7,671 binary traits captured known locus-trait associations, including HTT and Huntington's disease, DMPK and myotonic disorders and C9orf72 and motor neuron disease, among others. Finally, we found that, even before disease diagnosis, repeat expansions in several loci strongly associate with increased levels of neurofilament light chain (NfL) and a loss of brain volume in specific disease-associated regions. For example, carriers of HTT expansions exhibited a 22.1% loss of putamen volume, and carriers of CACNA1A expansions showed a 24.6% loss of cerebellar volume. These observations suggest that both decreased brain volumes and increased NfL levels occur earlier than disease diagnosis. This study demonstrates the use of characterizing repeat expansions from short-read sequencing data in diverse population-scale cohorts and its application to epidemiology and clinical biomarker development.

Costal aspiration breathing was an evolutionary innovation that was fundamental to the conquest of the terrestrial realm by amniotes (mammals, reptiles, birds and their common ancestor)1-5. Extant amniotes use an integrated thoracic skeleton for costal-muscle-generated inhalation and exhalation, differing substantially from their anamniote relatives, which possess more passive cutaneous and buccal pumping forms of ventilation. This difference extends into the Palaeozoic era, but the evolutionary transformation between these modes of breathing is undocumented and largely unclear6-10 in the absence of soft tissue fossils. Here we present the mummified early Permian reptile Captorhinus, which includes a covering of three-dimensional skin, native protein remnants and a complete shoulder girdle and ribcage with preserved cartilages. These are the oldest-known preserved cartilages and protein remnants in a terrestrial vertebrate. High-resolution neutron computed tomography and histology data reveal previously undescribed structures, including the cartilaginous sternum, sternal ribs, rib extensions and epicoracoids. Our skeletal reconstruction of this ancient reptile reveals the precise relationships between the ribcage and the shoulder girdle, and their pivotal role in the evolution of terrestrial breathing and locomotor regimes11,12. This finding substantially changes expectations of soft tissue preservation in deep time to reveal the potential ancestral amniote breathing mechanism and its impact on terrestrial vertebrate evolution.

Antigenic variation, using large genomic repertoires of antigen-encoding genes, allows pathogens to evade host antibody. Many pathogens, including the African trypanosome Trypanosoma brucei, extend their antigenic repertoire through genomic diversification. Although evidence suggests that T. brucei depends on the generation of new variant surface glycoprotein (VSG) genes to maintain a chronic infection1-4, a lack of experimentally tractable tools for studying this process has obscured its underlying mechanisms. Here we present a highly sensitive targeted sequencing approach for measuring VSG diversification. Using this method, we demonstrate that a Cas9-induced DNA double-strand break within the VSG coding sequence can induce RAD51- and BRCA2-dependent VSG recombination with patterns identical to those observed during infection. These newly generated VSGs are antigenically distinct from parental clones and thus capable of facilitating immune evasion. Together, these results provide insight into the mechanisms of VSG diversification and an experimental framework for studying the evolution of antigen repertoires in pathogenic microorganisms.