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Influenza A viruses have caused more documented global pandemics in human history than any other pathogen1,2. High pathogenicity avian influenza viruses belonging to the H5N1 subtype are a leading pandemic risk. Two decades after H5N1 ‘bird flu’ became established in poultry in Southeast Asia, its descendants have resurged3, setting off a H5N1 panzootic in wild birds that is fuelled by: (1) rapid intercontinental spread, reaching South America and Antarctica for the first time4,5; (2) fast evolution via genomic reassortment6; and (3) frequent spillover into terrestrial7,8and marine mammals9. The virus has sustained mammal-to-mammal transmission in multiple settings, including European fur farms10,11, South American marine mammals12, 13, 14–15and US dairy cattle16, 17, 18–19, raising questions about whether humans are next. Historically, swine are considered optimal intermediary hosts that help avian influenza viruses adapt to mammals before jumping to humans20. However, the altered ecology of H5N1 has opened the door to new evolutionary pathways. Dairy cattle, farmed mink or South American sea lions may have the potential to serve as new mammalian gateways for transmission of avian influenza viruses to humans. In this Perspective, we explore the molecular and ecological factors driving the sudden expansion in H5N1 host range and assess the likelihood of different zoonotic pathways leading to an H5N1 pandemic.

Controlling the functional properties of quantum materials with light has emerged as a frontier of condensed-matter physics, leading to the discovery of various light-induced phases of matter, such as superconductivity1, ferroelectricity2,3, magnetism4, 5–6and charge density waves7. However, in most cases, the photoinduced phases return to equilibrium on ultrafast timescales after the light is turned off, limiting their practical applications. Here we use intense terahertz pulses to induce a metastable magnetization with a remarkably long lifetime of more than 2.5 milliseconds in the van der Waals antiferromagnet FePS3. The metastable state becomes increasingly robust as the temperature approaches the antiferromagnetic transition point, suggesting that critical order parameter fluctuations play an important part in facilitating the extended lifetime. By combining first-principles calculations with classical Monte Carlo and spin dynamics simulations, we find that the displacement of a specific phonon mode modulates the exchange couplings in a manner that favours a ground state with finite magnetization near the Néel temperature. This analysis also clarifies how the critical fluctuations of the dominant antiferromagnetic order can amplify both the magnitude and the lifetime of the new magnetic state. Our discovery demonstrates the efficient manipulation of the magnetic ground state in layered magnets through non-thermal pathways using terahertz light and establishes regions near critical points with enhanced order parameter fluctuations as promising areas to search for metastable hidden quantum states.

Brain-wide association studies (BWAS) are a fundamental tool in discovering brain–behaviour associations1,2. Several recent studies have shown that thousands of study participants are required for good replicability of BWAS1, 2–3. Here we performed analyses and meta-analyses of a robust effect size index using 63 longitudinal and cross-sectional MRI studies from the Lifespan Brain Chart Consortium4(77,695 total scans) to demonstrate that optimizing study design is critical for increasing standardized effect sizes and replicability in BWAS. A meta-analysis of brain volume associations with age indicates that BWAS with larger variability of the covariate and longitudinal studies have larger reported standardized effect size. Analysing age effects on global and regional brain measures from the UK Biobank and the Alzheimer’s Disease Neuroimaging Initiative, we showed that modifying study design through sampling schemes improves standardized effect sizes and replicability. To ensure that our results are generalizable, we further evaluated the longitudinal sampling schemes on cognitive, psychopathology and demographic associations with structural and functional brain outcome measures in the Adolescent Brain and Cognitive Development dataset. We demonstrated that commonly used longitudinal models, which assume equal between-subject and within-subject changes can, counterintuitively, reduce standardized effect sizes and replicability. Explicitly modelling the between-subject and within-subject effects avoids conflating them and enables optimizing the standardized effect sizes for each separately. Together, these results provide guidance for study designs that improve the replicability of BWAS.

Recent James Webb Space Telescope (JWST) observations have revealed an unexpected abundance of massive-galaxy candidates in the early Universe, extending further in redshift and to lower luminosity than what had previously been found by submillimetre surveys1–6. These JWST candidates have been interpreted as challenging the Λcold dark-matter cosmology (where Λis the cosmological constant)7–9, but, so far, these studies have mostly relied on only rest-frame ultraviolet data and have lacked spectroscopic confirmation of their redshifts10–16. Here we report a systematic study of 36 massive dust-obscured galaxies with spectroscopic redshifts between 5 and 9 from the JWST FRESCO survey. We find no tension with the Λcold dark-matter model in our sample. However, three ultra-massive galaxies (logM★/M⊙≳ 11.0, where M★is the stellar mass and M⊙is the mass of the Sun) require an exceptional fraction of 50 per cent of baryons converted into stars—two to three times higher than the most efficient galaxies at later epochs. The contribution from an active galactic nucleus is unlikely because of their extended emission. Ultra-massive galaxies account for as much as 17 per cent of the total cosmic star-formation-rate density17at redshifts between about five and six.

Many-particle entanglement is a key resource for achieving the fundamental precision limits of a quantum sensor1. Optical atomic clocks2, the current state of the art in frequency precision, are a rapidly emerging area of focus for entanglement-enhanced metrology3–6. Augmenting tweezer-based clocks featuring microscopic control and detection7–10with the high-fidelity entangling gates developed for atom-array information processing11,12offers a promising route towards making use of highly entangled quantum states for improved optical clocks. Here we develop and use a family of multi-qubit Rydberg gates to generate Schrödinger cat states of the Greenberger–Horne–Zeilinger (GHZ) type with up to nine optical clock qubits in a programmable atom array. In an atom-laser comparison at sufficiently short dark times, we demonstrate a fractional frequency instability below the standard quantum limit (SQL) using GHZ states of up to four qubits. However, because of their reduced dynamic range, GHZ states of a single size fail to improve the achievable clock precision at the optimal dark time compared with unentangled atoms13. Towards overcoming this hurdle, we simultaneously prepare a cascade of varying-size GHZ states to perform unambiguous phase estimation over an extended interval14–17. These results demonstrate key building blocks for approaching Heisenberg-limited scaling of optical atomic clock precision.

Semiconductors have already had a very profound effect on society, accelerating scientific research and driving greater connectivity. Future semiconductor hardware will open up new possibilities in quantum computing, artificial intelligence and edge computing, for applications such as cybersecurity and personalized healthcare. By nature of its ethos, open hardware provides opportunities for even greater collaboration and innovations across education, academic research and industry. Here we present Flex-RV, a 32-bit microprocessor based on an open RISC-V (ref. 1) instruction set fabricated with indium gallium zinc oxide thin-film transistors2on a flexible polyimide substrate, enabling an ultralow-cost bendable microprocessor. Flex-RV also integrates a programmable machine learning (ML) hardware accelerator inside the microprocessor and demonstrates new instructions to extend the RISC-V instruction set to run ML workloads. It is implemented, fabricated and demonstrated to operate at 60 kHz consuming less than 6 mW power. Its functionality when assembled onto a flexible printed circuit board is validated while executing programs under flat and tight bending conditions, achieving no worse than 4.3% performance variation on average. Flex-RV pioneers an era of sub-dollar open standard non-silicon 32-bit microprocessors and will democratize access to computing and unlock emerging applications in wearables, healthcare devices and smart packaging.

Amazonia contains the most extensive tropical forests on Earth, but Amazon carbon sinks of atmospheric CO2are declining, as deforestation and climate-change-associated droughts1–4threaten to push these forests past a tipping point towards collapse5–8. Forests exhibit complex drought responses, indicating both resilience (photosynthetic greening) and vulnerability (browning and tree mortality), that are difficult to explain by climate variation alone9–17. Here we combine remotely sensed photosynthetic indices with ground-measured tree demography to identify mechanisms underlying drought resilience/vulnerability in different intact forest ecotopes18,19(defined by water-table depth, soil fertility and texture, and vegetation characteristics). In higher-fertility southern Amazonia, drought response was structured by water-table depth, with resilient greening in shallow-water-table forests (where greater water availability heightened response to excess sunlight), contrasting with vulnerability (browning and excess tree mortality) over deeper water tables. Notably, the resilience of shallow-water-table forest weakened as drought lengthened. By contrast, lower-fertility northern Amazonia, with slower-growing but hardier trees (or, alternatively, tall forests, with deep-rooted water access), supported more-drought-resilient forests independent of water-table depth. This functional biogeography of drought response provides a framework for conservation decisions and improved predictions of heterogeneous forest responses to future climate changes, warning that Amazonia’s most productive forests are also at greatest risk, and that longer/more frequent droughts are undermining multiple ecohydrological strategies and capacities for Amazon forest resilience.

Malaria-causing protozoa of the genus Plasmodiumhave exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivaxand P. malariaefrom 16 countries spanning around 5,500 years of human history. We identified P. vivaxand P. falciparumacross geographically disparate regions of Eurasia from as early as the fourth and first millennia bce, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparumand P. vivaxin the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparuminto the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodiumparasites on human history. Finally, our unexpected discovery of P. falciparumin the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.

Asteroids with diameters less than about 5 km have complex histories because they are small enough for radiative torques (that is, YORP, short for the Yarkovsky–O’Keefe–Radzievskii–Paddack effect)1to be a notable factor in their evolution2. (152830) Dinkinesh is a small asteroid orbiting the Sun near the inner edge of the main asteroid belt with a heliocentric semimajor axis of 2.19 au; its S-type spectrum3,4is typical of bodies in this part of the main belt5. Here we report observations by the Lucy spacecraft6,7as it passed within 431 km of Dinkinesh. Lucy revealed Dinkinesh, which has an effective diameter of only 720 m, to be unexpectedly complex. Of particular note is the presence of a prominent longitudinal trough overlain by a substantial equatorial ridge and the discovery of the first confirmed contact binary satellite, now named (152830) Dinkinesh I Selam. Selam consists of two near-equal-sized lobes with diameters of 210 m and 230 m. It orbits Dinkinesh at a distance of 3.1 km with an orbital period of about 52.7 h and is tidally locked. The dynamical state, angular momentum and geomorphologic observations of the system lead us to infer that the ridge and trough of Dinkinesh are probably the result of mass failure resulting from spin-up by YORP followed by the partial reaccretion of the shed material. Selam probably accreted from material shed by this event.

Early JWST observations have uncovered a population of red sources that might represent a previously overlooked phase of supermassive black hole growth1–3. One of the most intriguing examples is an extremely red, point-like object that was found to be triply imaged by the strong lensing cluster Abell 2744 (ref. 4). Here we present deep JWST/NIRSpec observations of this object, Abell2744-QSO1. The spectroscopy confirms that the three images are of the same object, and that it is a highly reddened (AV≃ 3) broad emission line active galactic nucleus at a redshift of zspec= 7.0451 ± 0.0005. From the width of Hβ (full width at half-maximum = 2,800 ± 250 km s−1), we derive a black hole mass of MBH=4−1+2×107M⊙. We infer a very high ratio of black-hole-to-galaxy mass of at least 3%, an order of magnitude more than that seen in local galaxies5and possibly as high as 100%. The lack of strong metal lines in the spectrum together with the high bolometric luminosity (Lbol= (1.1 ± 0.3) × 1045erg s−1) indicate that we are seeing the black hole in a phase of rapid growth, accreting at 30% of the Eddington limit. The rapid growth and high black-hole-to-galaxy mass ratio of Abell2744-QSO1 suggest that it may represent the missing link between black hole seeds6and one of the first luminous quasars7.

Topological whirls or ‘textures’ of spins such as magnetic skyrmions represent the smallest realizable emergent magnetic entities1–5. They hold considerable promise as robust, nanometre-scale, mobile bits for sustainable computing6–8. A longstanding roadblock to unleashing their potential is the absence of a device enabling deterministic electrical readout of individual spin textures9,10. Here we present the wafer-scale realization of a nanoscale chiral magnetic tunnel junction (MTJ) hosting a single, ambient skyrmion. Using a suite of electrical and multimodal imaging techniques, we show that the MTJ nucleates skyrmions of fixed polarity, whose large readout signal—20–70% relative to uniformly magnetized states—corresponds directly to skyrmion size. The MTJ exploits complementary nucleation mechanisms to stabilize distinctly sized skyrmions at zero field, thereby realizing three non-volatile electrical states. Crucially, it can electrically write and delete skyrmions to both uniform states with switching energies 1,000 times lower than the state of the art. Here, the applied voltage emulates a magnetic field and, in contrast to conventional MTJs, it reshapes both the energetics and kinetics of the switching transition, enabling deterministic bidirectional switching. Our stack platform enables large readout and efficient switching, and is compatible with lateral manipulation of skyrmionic bits, providing the much-anticipated backbone for all-electrical skyrmionic device architectures9,10. Its wafer-scale realizability provides a springboard to harness chiral spin textures for multibit memory and unconventional computing8,11.

The generation of ultra-low-noise microwave and mmWave in miniaturized, chip-based platforms can transform communication, radar and sensing systems1–3. Optical frequency division that leverages optical references and optical frequency combs has emerged as a powerful technique to generate microwaves with superior spectral purity than any other approaches4–7. Here we demonstrate a miniaturized optical frequency division system that can potentially transfer the approach to a complementary metal-oxide-semiconductor-compatible integrated photonic platform. Phase stability is provided by a large mode volume, planar-waveguide-based optical reference coil cavity8,9and is divided down from optical to mmWave frequency by using soliton microcombs generated in a waveguide-coupled microresonator10–12. Besides achieving record-low phase noise for integrated photonic mmWave oscillators, these devices can be heterogeneously integrated with semiconductor lasers, amplifiers and photodiodes, holding the potential of large-volume, low-cost manufacturing for fundamental and mass-market applications13.

The identification of sources driving cosmic reionization, a major phase transition from neutral hydrogen to ionized plasma around 600–800 Myr after the Big Bang1–3, has been a matter of debate4. Some models suggest that high ionizing emissivity and escape fractions (fesc) from quasars support their role in driving cosmic reionization5,6. Others propose that the high fescvalues from bright galaxies generate sufficient ionizing radiation to drive this process7. Finally, a few studies suggest that the number density of faint galaxies, when combined with a stellar-mass-dependent model of ionizing efficiency and fesc, can effectively dominate cosmic reionization8,9. However, so far, comprehensive spectroscopic studies of low-mass galaxies have not been done because of their extreme faintness. Here we report an analysis of eight ultra-faint galaxies (in a very small field) during the epoch of reionization with absolute magnitudes between MUV≈ −17 mag and −15 mag (down to 0.005L⋆(refs. 10,11)). We find that faint galaxies during the first thousand million years of the Universe produce ionizing photons with log[ξion(Hz erg−1)] = 25.80 ± 0.14, a factor of 4 higher than commonly assumed values12. If this field is representative of the large-scale distribution of faint galaxies, the rate of ionizing photons exceeds that needed for reionization, even for escape fractions of the order of 5%.

Myeloid cells are known to suppress antitumour immunity1. However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab2–5given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. The rapid development of highly effective vaccines2,3against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics4have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity5. Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant (Kd) of 61 pM and a half-maximal effective concentration (EC50) of 11 nM, inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in primary small airway epithelial cells and in a transgenic mouse model of SARS CoV-2 infection with an efficacy comparable with the FDA-approved reversible covalent protease inhibitor nirmatrelvir6. The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.

Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1–6. Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10–12, Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions.

The cost of drug discovery and development is driven primarily by failure1, with only about 10% of clinical programmes eventually receiving approval2–4. We previously estimated that human genetic evidence doubles the success rate from clinical development to approval5. In this study we leverage the growth in genetic evidence over the past decade to better understand the characteristics that distinguish clinical success and failure. We estimate the probability of success for drug mechanisms with genetic support is 2.6 times greater than those without. This relative success varies among therapy areas and development phases, and improves with increasing confidence in the causal gene, but is largely unaffected by genetic effect size, minor allele frequency or year of discovery. These results indicate we are far from reaching peak genetic insights to aid the discovery of targets for more effective drugs.

Large-scale outflows driven by supermassive black holes are thought to have a fundamental role in suppressing star formation in massive galaxies. However, direct observational evidence for this hypothesis is still lacking, particularly in the young universe where star-formation quenching is remarkably rapid1–3, thus requiring effective removal of gas4as opposed to slow gas heating5,6. Although outflows of ionized gas are frequently detected in massive distant galaxies7, the amount of ejected mass is too small to be able to suppress star formation8,9. Gas ejection is expected to be more efficient in the neutral and molecular phases10, but at high redshift these have only been observed in starbursts and quasars11,12. Here we report JWST spectroscopy of a massive galaxy experiencing rapid quenching at a redshift of 2.445. We detect a weak outflow of ionized gas and a powerful outflow of neutral gas, with a mass outflow rate that is sufficient to quench the star formation. Neither X-ray nor radio activity is detected; however, the presence of a supermassive black hole is suggested by the properties of the ionized gas emission lines. We thus conclude that supermassive black holes are able to rapidly suppress star formation in massive galaxies by efficiently ejecting neutral gas.

Pancreatic ductal adenocarcinoma (PDAC) shows pronounced epithelial and mesenchymal cancer cell populations1–4. Cellular heterogeneity in PDAC is an important feature in disease subtype specification3–5, but how distinct PDAC subpopulations interact, and the molecular mechanisms that underlie PDAC cell fate decisions, are incompletely understood. Here we identify the BMP inhibitor GREM16,7as a key regulator of cellular heterogeneity in pancreatic cancer in human and mouse. Grem1inactivation in established PDAC in mice resulted in a direct conversion of epithelial into mesenchymal PDAC cells within days, suggesting that persistent GREM1 activity is required to maintain the epithelial PDAC subpopulations. By contrast, Grem1overexpression caused an almost complete ‘epithelialization’ of highly mesenchymal PDAC, indicating that high GREM1 activity is sufficient to revert the mesenchymal fate of PDAC cells. Mechanistically, Grem1was highly expressed in mesenchymal PDAC cells and inhibited the expression of the epithelial–mesenchymal transition transcription factors Snai1(also known as Snail) and Snai2(also known as Slug) in the epithelial cell compartment, therefore restricting epithelial–mesenchymal plasticity. Thus, constant suppression of BMP activity is essential to maintain epithelial PDAC cells, indicating that the maintenance of the cellular heterogeneity of pancreatic cancer requires continuous paracrine signalling elicited by a single soluble factor.

Human spaceflight has historically been managed by government agencies, such as in the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first all-civilian crew to low Earth orbit, which included the youngest American astronaut (aged 29), new in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables and immune profiling), ocular alignment measurements and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match those of long-term spaceflight2, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiological and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts3, which can inform countermeasure development for both private and government-sponsored space missions.

Local and low-redshift (z< 3) galaxies are known to broadly follow a bimodal distribution: actively star-forming galaxies with relatively stable star-formation rates and passive systems. These two populations are connected by galaxies in relatively slow transition. By contrast, theory predicts that star formation was stochastic at early cosmic times and in low-mass systems1–4. These galaxies transitioned rapidly between starburst episodes and phases of suppressed star formation, potentially even causing temporary quiescence—so-called mini-quenching events5,6. However, the regime of star-formation burstiness is observationally highly unconstrained. Directly observing mini-quenched galaxies in the primordial Universe is therefore of utmost importance to constrain models of galaxy formation and transformation7,8. Early quenched galaxies have been identified out to redshift z< 5 (refs. 9–12) and these are all found to be massive (M⋆> 1010M⊙) and relatively old. Here we report a (mini-)quenched galaxy at z= 7.3, when the Universe was only 700 Myr old. The JWST/NIRSpec spectrum is very blue (U–V= 0.16 ± 0.03 mag) but exhibits a Balmer break and no nebular emission lines. The galaxy experienced a short starburst followed by rapid quenching; its stellar mass (4–6 × 108M⊙) falls in a range that is sensitive to various feedback mechanisms, which can result in perhaps only temporary quenching.

Hybridization allows adaptations to be shared among lineages and may trigger the evolution of new species1,2. However, convincing examples of homoploid hybrid speciation remain rare because it is challenging to demonstrate that hybridization was crucial in generating reproductive isolation3. Here we combine population genomic analysis with quantitative trait locus mapping of species-specific traits to examine a case of hybrid speciation in Heliconiusbutterflies. We show that Heliconius elevatusis a hybrid species that is sympatric with both parents and has persisted as an independently evolving lineage for at least 180,000 years. This is despite pervasive and ongoing gene flow with one parent, Heliconius pardalinus, which homogenizes 99% of their genomes. The remaining 1% introgressed from the other parent, Heliconius melpomene, and is scattered widely across the H. elevatusgenome in islands of divergence from H. pardalinus. These islands contain multiple traits that are under disruptive selection, including colour pattern, wing shape, host plant preference, sex pheromones and mate choice. Collectively, these traits place H. elevatuson its own adaptive peak and permit coexistence with both parents. Our results show that speciation was driven by introgression of ecological traits, and that speciation with gene flow is possible with a multilocus genetic architecture.

Persistent SARS-CoV-2 infections may act as viral reservoirs that could seed future outbreaks1–5, give rise to highly divergent lineages6–8and contribute to cases with post-acute COVID-19 sequelae (long COVID)9,10. However, the population prevalence of persistent infections, their viral load kinetics and evolutionary dynamics over the course of infections remain largely unknown. Here, using viral sequence data collected as part of a national infection survey, we identified 381 individuals with SARS-CoV-2 RNA at high titre persisting for at least 30 days, of which 54 had viral RNA persisting at least 60 days. We refer to these as ‘persistent infections’ as available evidence suggests that they represent ongoing viral replication, although the persistence of non-replicating RNA cannot be ruled out in all. Individuals with persistent infection had more than 50% higher odds of self-reporting long COVID than individuals with non-persistent infection. We estimate that 0.1–0.5% of infections may become persistent with typically rebounding high viral loads and last for at least 60 days. In some individuals, we identified many viral amino acid substitutions, indicating periods of strong positive selection, whereas others had no consensus change in the sequences for prolonged periods, consistent with weak selection. Substitutions included mutations that are lineage defining for SARS-CoV-2 variants, at target sites for monoclonal antibodies and/or are commonly found in immunocompromised people11–14. This work has profound implications for understanding and characterizing SARS-CoV-2 infection, epidemiology and evolution.

During development, inflammation or tissue injury, macrophages may successively engulf and process multiple apoptotic corpses via efferocytosis to achieve tissue homeostasis1. How macrophages may rapidly adapt their transcription to achieve continuous corpse uptake is incompletely understood. Transcriptional pause/release is an evolutionarily conserved mechanism, in which RNA polymerase (Pol) II initiates transcription for 20–60 nucleotides, is paused for minutes to hours and is then released to make full-length mRNA2. Here we show that macrophages, within minutes of corpse encounter, use transcriptional pause/release to unleash a rapid transcriptional response. For human and mouse macrophages, the Pol II pause/release was required for continuous efferocytosis in vitro and in vivo. Interestingly, blocking Pol II pause/release did not impede Fc receptor-mediated phagocytosis, yeast uptake or bacterial phagocytosis. Integration of data from three genomic approaches—precision nuclear run-on sequencing, RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-seq)—on efferocytic macrophages at different time points revealed that Pol II pause/release controls expression of select transcription factors and downstream target genes. Mechanistic studies on transcription factor EGR3, prominently regulated by pause/release, uncovered EGR3-related reprogramming of other macrophage genes involved in cytoskeleton and corpse processing. Using lysosomal probes and a new genetic fluorescent reporter, we identify a role for pause/release in phagosome acidification during efferocytosis. Furthermore, microglia from egr3-deficient zebrafish embryos displayed reduced phagocytosis of apoptotic neurons and fewer maturing phagosomes, supporting defective corpse processing. Collectively, these data indicate that macrophages use Pol II pause/release as a mechanism to rapidly alter their transcriptional programs for efficient processing of the ingested apoptotic corpses and for successive efferocytosis.

Several theories have been proposed to describe the formation of black hole seeds in the early Universe and to explain the emergence of very massive black holes observed in the first thousand million years after the Big Bang1–3. Models consider different seeding and accretion scenarios4–7, which require the detection and characterization of black holes in the first few hundred million years after the Big Bang to be validated. Here we present an extensive analysis of the JWST-NIRSpec spectrum of GN-z11, an exceptionally luminous galaxy at z= 10.6, revealing the detection of the [Neiv]λ2423 and CII*λ1335 transitions (typical of active galactic nuclei), as well as semi-forbidden nebular lines tracing gas densities higher than 109cm−3, typical of the broad line region of active galactic nuclei. These spectral features indicate that GN-z11 hosts an accreting black hole. The spectrum also reveals a deep and blueshifted CIVλ1549 absorption trough, tracing an outflow with velocity 800−1,000 km s−1, probably driven by the active galactic nucleus. Assuming local virial relations, we derive a black hole mass of log(MBH/M⊙)=6.2±0.3, accreting at about five times the Eddington rate. These properties are consistent with both heavy seeds scenarios and scenarios considering intermediate and light seeds experiencing episodic super-Eddington phases. Our finding explains the high luminosity of GN-z11 and can also provide an explanation for its exceptionally high nitrogen abundance.

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity3–6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8+T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.