Epstein-Barr virus (EBV) infects approximately 90-95% of the global population1,2 and persists in B cells as a lifelong infection3. Previous EBV infection is associated with autoimmune and neoplastic disease4. Still, the biological basis of host control during EBV persistence remains unclear. Here we report the identification of non-genetic and genetic factors that are associated with EBV control during persistent infection. Using blood-based genome sequence data from 486,315 UK Biobank and 336,123 All of Us participants, we identified short-read pairs mapping to the EBV genome in 16.2% and 21.8% of individuals, respectively. EBV read detection (EBVread+) reflects increased viral load in blood cells, as shown by orthogonal measurements, and was associated with HIV infection, immunosuppressive drug intake and current smoking. Genome-wide analyses of EBVread+ identified strong associations at the major histocompatibility complex (MHC), including 54 independent human leukocyte antigen (HLA) alleles of MHC classes I and II, and at 27 genomic regions outside MHC. Epistasis with distinct HLA alleles of MHC class I was observed at the ERAP2 locus. Analysis of individuals with EBV-associated diseases4 revealed a higher polygenic burden of EBVread+ for HLA alleles at MHC class I in multiple sclerosis (driven by HLA-A*02:01) and at MHC class II in rheumatoid arthritis. Phenome-wide analyses identified a polygenic overlap of EBVread+ with inflammatory bowel disease, hypothyroidism and type 1 diabetes. Our study establishes by-products of human genome sequencing as a surrogate marker of EBV viral load. This will facilitate investigation and treatment for EBV and other persistent viral infections.

Anthropogenic nitrogen (N) pollution is a cause of eutrophication globally1. However, recent datasets indicate that some ecosystems may be experiencing widespread oligotrophication-declining N availability-which is suggested to be a response to elevated atmospheric carbon dioxide (CO2)2. Plant N isotope (δ15N) chronologies have served as primary evidence for oligotrophication, but there is wide disagreement whether rising CO2 or temporal changes in N deposition explain these patterns3-6. Here we construct δ15N tree-ring chronologies using archived samples from Sweden's 23.5-million-hectare forest area from 1961 to 2018. The study area spans a 1,500-km latitudinal distance where N deposition varies fourfold, but where rising CO2 is spatially uniform. Our data show declining δ15N chronologies throughout Sweden, including forests in the far north where atmospheric N deposition rates are very low. Linear mixed-effects models showed that rising CO2 is the strongest predictor of δ15N values, whereas N deposition variables, temperature and forest basal area had lower explanatory power. Our findings suggest that elevated atmospheric CO2 is causing oligotrophication in boreal forests, which has implications for predicting their future role as sinks in the global carbon cycle7-9.

The question of whether large language models (LLMs) can exhibit moral capabilities is of growing interest and urgency, as these systems are deployed in sensitive roles such as companionship and medical advising, and will increasingly be tasked with making decisions and taking actions on behalf of humans. These trends require moving beyond evaluating for mere moral performance, the ability to produce morally appropriate outputs, to evaluating for moral competence, the ability to produce morally appropriate outputs based on morally relevant considerations. Assessing moral competence is critical for predicting future model behaviour, establishing appropriate public trust and justifying moral attributions. However, both the unique architectures of LLMs and the complexity of morality itself introduce fundamental challenges. Here we identify three such challenges: the facsimile problem, whereby models may imitate reasoning without genuine understanding; moral multidimensionality, whereby moral decisions are influenced by a range of context-sensitive relevant moral and non-moral considerations; and moral pluralism, which demands a new standard for globally deployed artificial intelligence. We provide a roadmap for tackling these challenges, advocating for a suite of adversarial and confirmatory evaluations that will enable us to work towards a more scientifically grounded understanding and, in turn, a more responsible attribution of moral competence to LLMs.

Long-term preservation of digital information is vital for safeguarding the knowledge of humanity for future generations. Existing archival storage solutions, such as magnetic tapes and hard disk drives, suffer from limited media lifespans that render them unsuitable for long-term data retention1-3. Optical storage approaches, particularly laser writing in robust media such as glass, have emerged as promising alternatives with the potential for increased longevity. Previous work4-16 has predominantly optimized individual aspects such as data density but has not demonstrated an end-to-end system, including writing, storing and retrieving information. Here we report an optical archival storage technology based on femtosecond laser direct writing in glass that addresses the practical demands of archival storage, which we call Silica. We achieve a data density of 1.59 Gbit mm-3 in 301 layers for a capacity of 4.8 TB in a 120 mm square, 2 mm thick piece of glass. The demonstrated write regimes enable a write throughput of 25.6 Mbit s-1 per beam, limited by the laser repetition rate, with an energy efficiency of 10.1 nJ per bit. Moreover, we extend the storage ability to borosilicate glass, offering a lower-cost medium and reduced writing and reading complexity. Accelerated ageing tests on written voxels in borosilicate suggest data lifetimes exceeding 10,000 years.

In the past decade, moiré materials have revolutionized how we engineer and control quantum phases of matter1,2. They are versatile platforms for strongly correlated electronic phenomena3,4 and support new ferroelectric5,6, magnetic7 and superconducting states8. Among incommensurate materials9, moiré materials are aperiodic composite crystals10,11 whose long-wavelength superlattices enable tunable properties without chemically modifying their layers. So far, nearly all reports of moiré materials have investigated van der Waals heterostructures assembled far from thermodynamic equilibrium (T < 150 °C)1,2. Here we introduce a conceptually new approach to synthesizing high-mobility moiré materials in thermodynamic equilibrium. We report a new family of foliated superlattice materials (Sr6TaS8)1+δ(TaS2)8 that are exfoliatable, incommensurate-lattice, van der Waals crystals. Lattice mismatches between alternating layers generate moiré superlattices, analogous to 2D moiré heterobilayer superlattices, which are coherent throughout these crystals and tunable through synthesis conditions without altering their chemical composition. Quantum oscillation measurements map the complex Fermiology of these moiré metals12-14, showing that the Fermi surface of the structurally simplest moiré metal comprises more than 40 distinct cross-sectional areas. This is naturally understood by proposing that these bulk moiré metals encode electronic properties of higher-dimensional superspace crystals in ways paralleling well-established crystallographic methods for incommensurate lattices15,16. More broadly, our work demonstrates a scalable synthesis approach potentially capable of producing large-area moiré materials for electronics applications and evidences a new material design concept for accessing phenomena proposed in higher dimensions17-21.

Cross-coupling of aryl boronic esters forms a cornerstone of how chemists make molecules. More recently, enantiomerically enriched boronic esters have shown great promise in modular synthesis as versatile building blocks for the rapid construction of diverse molecules. A significant challenge in this area is to use boronic esters for the catalytic construction of C(sp3)-C(sp3) bonds, especially those in which the reaction site is a stereogenic carbon centre. Addressing this challenge would not only expand the utility of boronic esters in the modular synthesis of organic frameworks, but also prove more broadly beneficial in the synthesis of natural products and bioactive molecules1. In this connection, we have developed a stereospecific C(sp3)-C(sp3) coupling reaction catalysed by a copper acetylide complex. This reaction operates with four-coordinate boron-'ate' complexes while remaining inert to simple functional groups, including boronic esters, and thereby enables efficient strategies for modular synthesis of complex molecules. Applications to the synthesis of (-)-spongidepsin and the carbon skeleton of fluvirucinine A1 are described.

Acral melanoma, which is not ultraviolet-associated, is the type of melanoma reported most commonly in several non-European-descent populations1-3, including in Mexican people4. Latin American samples are substantially under-represented in global cancer genomics studies5, which directly affects patients in these regions as it is known that cancer risk and incidence may be influenced by ancestry and environmental exposures6-8. To address this, we characterized the genome and transcriptome of 123 acral melanoma tumours from 92 Mexican patients-a population notable because of its genetic admixture9. Compared with other studies of melanoma, we found fewer mutations in classical driver genes such as BRAF, NRAS or NF1. Although most patients had predominantly Amerindian genetic ancestry, those with higher European ancestry had increased frequency of BRAF mutations. The tumours with activating BRAF mutations had a transcriptional profile more similar to cutaneous non-volar melanocytes, indicating that acral melanomas in these patients may arise from a distinct cell of origin compared with other tumours arising in these locations. Transcriptional profiling defined three expression clusters; these characteristics were associated with recurrence-free and overall survival. Our study enhances knowledge of this understudied disease and underscores the importance of including samples from diverse ancestries in cancer genomics studies.

Triple-negative breast cancer (TNBC) is frequently associated with metastatic relapse, even at an early stage1. Here we assessed an individualized neoantigen mRNA vaccine in 14 patients with TNBC following surgery and after neoadjuvant or adjuvant therapy. In peripheral blood of nearly all patients, high-magnitude, vaccine-induced, mostly de novo T cell responses to multiple neoantigens were detected that remained functional for several years. Characterization of individual patients revealed that a large proportion of these T cells developed into two subsets: a late-differentiated phenotype with markers indicative of 'ready-to-act' cytotoxic effector T cells, and T cells with a stem cell-like memory phenotype. Eleven patients remained relapse-free for up to six years post-vaccination. Recurrence occurred in three patients: the individual with the weakest vaccine-induced T cell response relapsed, but achieved complete remission on subsequent anti-PD-1 therapy; another patient had a tumour with low major histocompatibility complex (MHC) class I expression with MHC class I-deficient cells growing out under vaccination; and the third patient was BRCA-positive and had a recurrence from a genetically distinct primary tumour. These findings demonstrate the feasibility of individualized RNA vaccines in TNBC, document persistence of vaccine-induced, functional neoantigen-specific T cells and provide insights into possible immune escape mechanisms that will guide future approaches.

Intrinsically disordered proteins and regions (collectively IDRs) are found across all kingdoms of life and have critical roles in virtually every eukaryotic cellular process1. IDRs exist in a broad ensemble of structurally distinct conformations. This structural plasticity facilitates diverse molecular recognition and function2-4. Here we combine advances in physics-based force fields with the power of multi-modal generative deep learning to develop STARLING, a framework for rapid generation of accurate IDR ensembles and ensemble-aware representations from sequence. STARLING supports environmental conditioning across ionic strengths and demonstrates proof of concept for the interpolative ability of generative models beyond their training domain. Moreover, we enable ensemble refinement under experimental constraints using a Bayesian maximum-entropy reweighting scheme. Beyond ensemble characterization, STARLING sequence representations can be used in multiple ways. We showcase two examples: first, STARLING lets us perform ensemble-based search for 'biophysical look-alikes'. Second, we demonstrate how these latent representations can be used to accelerate ensemble-first sequence design from weeks or hours per candidate to seconds, enabling library-scale designs. Together, STARLING dramatically lowers the barrier to the computational interrogation of IDR function through the lens of emergent biophysical properties, complementing bioinformatic protein sequence analysis. We evaluate the accuracy of STARLING against extant experimental data and offer a series of vignettes illustrating how STARLING can enable rapid hypothesis generation for IDR function and aid the interpretation of experimental data.

The cellular nucleotide pool is a major focal point of the host immune response to viral infection. Immune effector proteins that disrupt the nucleotide pool enable animal and bacterial cells to broadly restrict diverse viruses, but reduced nucleotide availability induces cellular toxicity and can limit host fitness1-5. Here we identify Clover, a bacterial anti-phage defence system that overcomes this trade-off by encoding a deoxynucleoside triphosphohydrolase enzyme (CloA) that dynamically responds to both an activating phage cue and an inhibitory nucleotide immune signal produced by a partnering regulatory enzyme (CloB). Analysis of phage restriction by Clover in cells and reconstitution of enzymatic function in vitro demonstrate that CloA is a dGTPase that responds to viral enzymes that increase cellular levels of dTTP. To restrain CloA activation in the absence of infection, we show that CloB synthesizes a dTTP-related inhibitory nucleotide signal, p3diT (5'-triphosphothymidyl-3'5'-thymidine), that binds to CloA and suppresses activation. Cryo-electron microscopy structures of CloA in activated and suppressed states reveal how dTTP and p3diT control distinct allosteric sites and regulate effector function. Our results define how nucleotide signals coordinate both activation and inhibition of antiviral immunity and explain how cells balance defence and immune-mediated toxicity.

Dielectric polymers used in electrical energy storage require a combination of key metrics, including a high dielectric constant (K), low loss and high breakdown strength (Eb), all while being capable of operating at high temperatures1-6. Decades of research into polymer-inorganic composites have achieved only limited success in reaching these goals5,7,8. Here we introduce high-temperature immiscible blends of two dipolar polymers that, through nanophase separation, self-assemble into three-dimensional all-polymer nanocomposites. The resulting nanostructures induce coiled-chain morphology and large conformation changes, which, combined with relatively low rotational barrier and high dipole moments of both polymers, yield ultrahigh dielectric responses (K > 13) while maintaining a low loss (tanδ approximately 0.002) across a wide temperature range. Simultaneously, the nanostructured interfaces act as barriers for mobile charges, markedly reducing conduction losses at high fields and temperatures. The all-polymer three-dimensional nanocomposites with concurrently high K, high Eb and low loss deliver unprecedented discharged energy densities at elevated temperatures (18.7 J cm-3, 15.1 J cm-3 and 8.6 J cm-3 at 150 °C, 200 °C and 250 °C, respectively). The approach is applicable to other immiscible dipolar blends, demonstrating its universality and tunability. This work addresses the urgent needs in electrical energy storage and provides a new paradigm towards high-energy-density polymer dielectrics over a broad temperature range.

Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.

The prevalence of metabolic-dysfunction-associated steatohepatitis (MASH) is rising globally, yet effective treatments remain limited1. Here we found that systemic or hepatocyte-specific ablation of the gene encoding glycoprotein non-metastatic melanoma protein B (Gpnmb)-a top upregulated gene in MASH-protected mice from diet-induced MASH. Notably, MASH progression was driven specifically by the secreted GPNMB ectodomain (G-ECD), rather than full-length GPNMB. Serum G-ECD levels showed a strong positive correlation with MASH severity in human patients. Using an unbiased screen of a cell-surface-displayed transmembrane protein library, we identified related to receptor tyrosine kinase (RYK) as a functional receptor for G-ECD. Hepatocyte-specific Ryk ablation protected mice against MASH and abolished the pathogenic effects of G-ECD. Mechanistically, G-ECD binding to RYK activated ERK1/2 signaling, resulting in transcriptional activation of PPARγ-CD36 and SREBP1C pathways that promote hepatic lipid uptake and lipogenesis. Multiple therapeutic strategies targeting the GPNMB-RYK axis-including vaccination, short hairpin RNA, neutralizing antibody and N-acetylgalactosamine small interfering RNA-effectively prevented and treated MASH in preclinical models. Our findings identify the GPNMB-RYK axis as a new pathogenic ligand-receptor pathway and a promising therapeutic target for MASH.

Telecommunication systems are evolving towards ultrawide bandwidth and low latency, supporting wired and wireless links and their non-blocking interconnection1. However, a long-standing bandwidth mismatch between fibre communication and its wireless counterpart arises from fundamental disparities in signal architectures and hardware constraints2,3, which prevent high-speed and compatible transmission across the two domains. This challenge further complicates unified system design and hinders the realization of high-throughput-density, congestion-free fibre-wireless links under wideband-access scenarios4. Here we present an ultra-wideband (UWB) integrated photonics scheme that facilitates fibre-wireless communication over a shared-bandwidth infrastructure. Built on electro-optic (EO) and optic-electro (OE) conversions featuring 3-dB operational bandwidths exceeding 250 GHz and cross-architecture adaptability, our system demonstrates unprecedented data transmission capabilities in both wired and wireless links. Using the same set of devices and powered by the proposed complex bidirectional gated recurrent unit (complex-biGRU) algorithm, ultrahigh single-lane data rates of 512 Gbps for short-reach fibre and, for the first time to the authors' knowledge, 400-Gbps high-speed wireless transmission have been achieved. Furthermore, high-density access is enabled by an all-optically assisted ultra-broadband wireless scheme. Real-time multichannel 8K video transmission is successfully demonstrated across 86 channels, seamlessly using a spectral range from 138 to 223 GHz. These findings in unified telecommunication development show the potential for the development of high-speed, densified and low-latency communication networks.