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.

Paternal care is rare among mammals and the neural mechanisms governing its emergence are poorly understood1. We leveraged the natural paternal behaviour of African striped mice (Rhabdomys pumilio)2,3, and integrated brain-wide cFos mapping, single-nucleus RNA sequencing, virally mediated gene perturbation and environmental manipulation to dissect the neural basis of natural variation in male parenting. Here we find that socio-environmental conditions drive individual variation in male alloparenting such that postweaning social isolation increases paternal care whereas social living in higher density groups increases infanticide. This natural variation in care corresponds to neural activity in the medial preoptic area and changes in correlated activity across brain regions. Within the medial preoptic area, expression of agouti signalling protein (Agouti) in neurons is increased by group housing and is negatively associated with care, and overexpression of Agouti reduces care and enhances infanticide in previously tolerant mice. Naturalistic manipulations further reveal that Agouti integrates long-term housing conditions rather than food availability or hunger. Our findings reveal that variation in male paternal care reflects context-dependent regulation of conserved hypothalamic and melanocortin signalling mechanisms rather than the presence or absence of paternal capacity.

Organic batteries using abundant and recyclable organic electrode materials provide a sustainable and environmentally friendly alternative to commercial lithium-ion batteries1-5, which rely on resource-limited mineral-derived inorganic electrode materials6-8. However, the practical use of organic batteries has been severely hindered by the intrinsic insulation and dissolution of organic electrode materials9,10. Here we report practical organic batteries using an n-type conducting polymer cathode, poly(benzodifurandione) (PBFDO), which exhibits excellent mixed ionic and electronic transport and low solubility. The PBFDO cathode maintains its n-doped state throughout the electrochemical processes and exhibits stable and reversible redox characteristics, high electrical conductivities and significant lithium-ion diffusion coefficients, without the need for additional conductive additives. Consequently, ultrahigh-mass-loading polymer cathodes, with mass loadings up to 206 mg cm-2, are realized, delivering a high areal capacity of 42 mAh cm-2 and demonstrating robust cycling stability. Furthermore, practical 2.5 Ah lithium-organic pouch cells were fabricated, achieving an impressive energy density of 255 Wh kg-1. Notably, the conducting polymer cathode operates efficiently over a wide temperature range from -70 °C to 80 °C and demonstrates excellent flexibility and safety, marking considerable potential for applications in extreme conditions and wearable electronics.

Cytoplasmic dynein-1, a microtubule (MT)-based motor protein, requires dynactin and a coiled-coil adaptor to form the processive dynein-dynactin-adaptor (DDA) complex1,2. The roles of MTs and dynein regulator lissencephaly-1 (LIS1) in DDA assembly have remained elusive. Here we use cryo-electron microscopy to determine the structural basis of MT- and LIS1-mediated DDA assembly. We show that an adaptor-independent dynein-dynactin complex spontaneously forms on MTs with an intrinsic 2:1 stoichiometry in a highly efficient manner, driven by parallel alignment of dynein tails upon MT binding. Adaptors can wedge into and exchange within the assembled MT-bound dynein-dynactin complex; these processes are enabled by relative rotations between dynein and dynactin and facilitated by the dynein light-intermediate chains that assist the adaptor 'search' mechanism. Although LIS1 is dispensable for efficient DD(A)-MT assembly, its presence expands the conformational landscape of DD(A) assemblies on MTs. Cryo-electron microscopy reveals that LIS1 bridges dynactin p150glued and dynein in both the closed Phi-like and open prepowerstroke states, stabilizing low-MT-affinity intermediates that tether dynein molecules in proximity to MTs and prime them for subsequent DD(A) assembly through alternative pathways. These findings demonstrate the dynamic adaptability of the dynein transport machinery and the coordinated roles of MTs and LIS1 in DDA assembly.

HIV-1 integrase (IN) promotes encapsulation of viral genomic RNA into mature viral cores, and this function is a target for ongoing antiretroviral drug development efforts1-3. Here we determined the cryogenic electron microscopy (cryo-EM) structure of a primate lentiviral IN in a complex with RNA, revealing a linear filament made of IN octamer repeat units, each comprising a pair of asymmetric homotetramers. The assembly is stabilized through IN-RNA interactions involving mainly the IN C-terminal domains and RNA backbone. The spacing and orientation of the IN filament repeat units closely matched those of consecutive capsid (CA) hexamers within the mature CA lattice. Using cryo-EM images of native purified HIV-1 cores, we refined the structure of the IN filament as it propagates along the luminal side of the CA lattice. Each IN tetramer within the filament nestled in a CA hexamer, engaging closely with the major homology regions. Substitutions of residues involved in IN-CA contacts yielded eccentric virions with RNA nucleoids located outside of the cores. Collectively, our results establish the structural basis for the HIV-1 IN-RNA interaction and reveal that IN forms an RNA-binding module on the luminal side of the mature CA lattice.

The central nervous system is surrounded by three interconnected membranes referred to as the meninges, which host a diverse immune network1-3. Within the skull-interfacing dura mater are venous sinuses, large veins that are traditionally viewed as passive blood drains for the brain and skull4,5. However, these structures also constitute an important neuroimmune interface6-8. Here we used intravital microscopy to gain mechanistic insight into this interface and reveal that dural sinuses and their endothelial cells form a highly dynamic surface that continually restructures to regulate blood flow, fluid movement and immune surveillance. We show that sinuses are not passive conduits, but instead undergo RAMP1-dependent constriction and dilation mediated by smooth muscle, resembling arterial behaviour. Moreover, the superior sagittal sinus in mice is bifurcated into upper and lower chambers that contribute to intracranial pressure regulation. Both chambers are lined by specialized, highly fenestrated sinus endothelial cells (SECs) that permit movement of fluids, macromolecules and microorganisms between the sinus lumen and leukocyte-rich perisinus space. To safeguard this permeable interface, SECs dynamically open and close intercellular boundaries in a RAMP2-dependent manner. Transcranial RAMP2 antagonism impaired SEC boundary dynamics and reduced immune cell trafficking along the sinus wall during homeostasis and systemic viral infection. Disruption of SEC dynamics during infection compromised local antiviral immunity and promoted pathogen entry into the meninges. Together, these findings establish dural sinuses as dynamic venous structures that regulate fluid exchange and support immune surveillance and antiviral defence.

The brain displays the richest repertoire of post-transcriptional mechanisms regulating mRNA translation1-11. Among these, alternative splicing has been shown to drive cell-type specificity and, when disrupted, is strongly linked to neurological disorders12-17. However, genome-wide measurements of mRNA translation with isoform sensitivity at single-cell resolution have not been achieved. To address this, we deployed Surveying Ribosomal Targets by APOBEC-Mediated Profiling (Ribo-STAMP) coupled with short-read and long-read single-cell RNA sequencing in the brain18. We generated the first isoform-sensitive single-cell translatomes of the mouse hippocampus at postnatal day 25, discovering cell-type-specific translation of 3,857 alternative transcripts across 1,641 genes and identifying isoforms of the same genes undergoing differential translation within and across 8 different cell types. We defined high and low translational states in CA1 and CA3 neurons, with synaptic and metabolic genes enriched in high states. We found that CA3 exhibited higher basal translation compared with CA1, as confirmed by metabolic labelling of newly synthesized proteins and immunohistochemistry of translational machinery components. This accessible platform will expand our understanding of how cell-type-specific and isoform-specific translation drives brain physiology and disease.

Colloidal perovskite nanocrystal (PeNC) has long been synthesized using the hot-injection method and room-temperature ligand-assisted reprecipitation as the prominent techniques1,2. However, both methods have challenges for industrial-scale production3-5: the hot-injection method requires high temperatures, an inert gas environment and rapid cooling, which raise safety concerns, whereas ligand-assisted reprecipitation can exhibit limited productivity on scale-up. Here we present a cold-injection method based on pseudo-emulsion, enabling scalable synthesis of PeNCs with near-unity photoluminescence quantum yield (PLQY, ~100%) and enhanced stability by injecting precursor solution below 4 °C. In the cold-injection method, PeNCs grow through the assembly of fully coordinated plumbates out of the pseudo-emulsion with the assistance of a demulsifier. We discovered that slow assembly of polybromide plumbates, assisted by cold temperature, is essential for defect suppression, resulting in reproducible, stable and pure-green-emitting PeNCs with near-unity PLQY. Furthermore, this method enables efficient large-scale production, achieving 20-l-scale synthesis with remarkable batch weight while maintaining near-unity PLQY. Our findings represent a substantial advancement in synthesis of high-quality PeNCs, offering potential for broad applications in display and lighting industries.

Cytopathology, often abbreviated as cytology, has a central role in the early detection of cancer, such as cervical, lung and bladder cancers, owing to its speed, simplicity and minimally invasive nature1-9. However, its effectiveness is limited by variability in diagnostic accuracy stemming from subjective visual interpretation10-21. Although many artificial intelligence (AI)-powered systems have been proposed to improve consistency22-26, none have achieved fully autonomous, clinical-grade performance. Existing approaches serve as assistive tools and still rely on human oversight for interpretation and decision-making22-26. Here we present a clinical-grade autonomous cytopathology pipeline that combines high-resolution, real-time optical whole-slide tomography with edge computing to deliver end-to-end automation. The system achieves practical performance in imaging speed, quality and data volume, with localized data compression enabling streamlined storage and accelerated AI-driven analysis. In addition to supporting cell-level classification, the platform enables flow cytometry-like, population-wide morphological profiling for comprehensive interpretation of cellular distributions and patterns. A vision transformer achieved area under the receiver operating characteristic (ROC) curve (AUC) values exceeding 0.99 at the single-cell level for detecting low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs) and adenocarcinoma. In a multicentre evaluation of 1,124 cervical liquid-based cytology samples across four centres, the AI model achieved slide-level AUC values of 0.86-0.91 for LSIL+ and 0.89-0.97 for HSIL+, with LSIL counts correlating strongly with human papillomavirus positivity and HSIL counts scaling with diagnostic severity. The system enables autonomous triage cytology, offering a foundation for routine, scalable and objective diagnostics.

The severity of malaria varies substantially between individuals, but the mechanisms that underlie these differences remain unclear. Because erythrocytes have a key role in malaria biology, genetic variants associated with the development of these cells could inform the mechanisms that determine disease severity. Here we investigate the mechanistic basis of the association of the variant rs112233623-T with erythrocyte properties, and examine its role in modulating malaria severity. This variant is associated with increased levels of haemoglobin A2, increased erythrocyte size and reduced erythrocyte number1,2. It is found in an erythroid enhancer of CCND3, which encodes cyclin D3-a cell-division activator that enhances the pentose phosphate pathway and thereby helps to counteract reactive oxygen species (ROS)3. We show that rs112233623-T disrupts a binding site for the transcription factor SMAD3, weakens enhancer activity and, in erythrocyte precursors (erythroblasts), is associated with reduced CCND3 expression and inhibition of the G1-S cell-cycle transition, concomitant with a reduction in the number of erythrocytes and an increase in their size. Using population genetic methods, we observe signatures of positive selection for rs112233623-T in the genetic history of Sardinia, a region in which malaria was once prevalent. Furthermore, we show that parasite growth is impaired in cultured Plasmodium falciparum-infected erythrocytes from rs112233623-T carriers, and that this impairment correlates with ROS levels. This mirrors our observations in erythrocytes from individuals who are deficient in the pentose-phosphate-pathway enzyme G6PD-a trait associated with protection against malaria in some settings-and highlights a common ROS-based mechanism of malaria resistance. Our results suggest that a reduction in CCND3 in erythroblasts constitutes a mechanism of resistance to malaria, and could enable therapeutic interventions.