Immune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity1-9. Although personalized mRNA cancer vaccines sensitize tumours to ICIs by directing immune attacks against preselected antigens, personalized vaccines are limited by complex and time-intensive manufacturing processes10-14. Here we show that mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to ICIs. In preclinical models, SARS-CoV-2 mRNA vaccines led to a substantial increase in type I interferon, enabling innate immune cells to prime CD8+ T cells that target tumour-associated antigens. Concomitant ICI treatment is required for maximal efficacy in immunologically cold tumours, which respond by increasing PD-L1 expression. Similar correlates of vaccination response are found in humans, including increases in type I interferon, myeloid-lymphoid activation in healthy volunteers and PD-L1 expression on tumours. Moreover, receipt of SARS-CoV-2 mRNA vaccines within 100 days of initiating ICI is associated with significantly improved median and three-year overall survival in multiple large retrospective cohorts. This benefit is similar among patients with immunologically cold tumours. Together, these results demonstrate that clinically available mRNA vaccines targeting non-tumour-related antigens are potent immune modulators capable of sensitizing tumours to ICIs.

Artificial superlattices, constructed from atomic layers such as graphene using layer-by-layer periodic stacking or sequential epitaxial growth, have emerged as a versatile platform for developing new materials with properties surpassing the existing materials1-3. However, the explored superlattices are predominantly van der Waals (vdW) superlattices, constrained by weak interface coupling4,5. Here we present an efficient synthetic protocol that achieves a family of non-vdW superlattices of carbides and carbonitrides, featuring hydrogen bonding between layers through a stiffness-mediated rolling-up strategy. The crucial step involves customizing the bending stiffness of the atomic layers derived from MAX phases by creating metal vacancies in MX slabs, triggering their ordered rolling-up under rapid flexural deformation. Unlike vdW superlattices, our non-vdW superlattices with hydrogen bonding afford robust interlayer electronic coupling with highly concentrated charge carriers (1022 cm-3). Consequently, our superlattices exhibit a notable electrical conductivity of about 30,000 S cm-1, which is around 22 times that of the counterparts. When used in electromagnetic interference shielding, the optimal non-vdW superlattice film demonstrates a remarkable shielding effectiveness of 124 dB, surpassing that of any known synthetic materials with comparable thickness. The non-vdW superlattices are anticipated to markedly broaden the material platform, offering variable compositions and crystal structures for new developments in artificially stacked systems.

G-protein-coupled receptors (GPCRs) convert extracellular signals into intracellular responses by signalling through 16 subtypes of Gα proteins and two β-arrestin proteins. Biased compounds-molecules that preferentially activate a subset of these proteins-engage therapy-relevant pathways more selectively1 and promise to be safer, more effective medications than compounds that uniformly activate all pathways2. However, the determinants of bias are poorly understood, and we lack rationally designed molecules that select for specific G proteins. Here, using the prototypical class A GPCR neurotensin receptor 1 (NTSR1), we show that small molecules that bind to the intracellular GPCR-transducer interface change G protein coupling by subtype-specific and predictable mechanisms, enabling structure-guided drug design. We find that the intracellular, core-binding compound SBI-553 switches the G protein preference of NTSR1 through direct intermolecular interactions3-5, promoting or preventing association with specific G protein subtypes. Modifications to the SBI-553 scaffold produce allosteric modulators with distinct G protein selectivity profiles. Selectivity profiles are probe independent, conserved across species and translate to differences in activity in vivo. Our studies show that G protein selectivity can be tailored with small changes to a single chemical scaffold targeting the receptor-transducer interface. Moreover, given that this pocket is broadly conserved, our findings could provide a strategy for pathway-selective drug discovery that is applicable to the diverse GPCR superfamily.

Congenital heart defects (CHDs) are the most common developmental abnormalities, affecting around 1% of live births1. Aneuploidy causes around 15% of CHDs, with trisomy 21 (also known as Down syndrome) being the most frequent form2. CHDs occur in around 50% of cases of Down syndrome, with an approximately 1,000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the junction between the atria and ventricles3,4. The AVC contains unique myocardial cells that are essential for valvuloseptal development; however, the specific combination of dosage-sensitive genes on chromosome 21 that are responsible for Down syndrome-associated CHDs have remained unknown. Here, using human pluripotent stem cell and mouse models of Down syndrome, we identify HMGN1, a nucleosome-binding epigenetic regulator encoded on chromosome 21, as a key contributor to these defects. Single-cell transcriptomics showed that trisomy 21 shifts human AVC cardiomyocytes towards a ventricular cardiomyocyte state. A CRISPR-activation single-cell RNA droplet sequencing (CROP-seq) screen of chromosome 21 genes expressed during heart development revealed that HMGN1 upregulation mimics this shift, whereas deletion of one HMGN1 allele in trisomic cells restored normal gene expression. In a mouse model of trisomy 21, a similar transcriptional shift of AVC cardiomyocytes was restored by a reduction in Hmgn1 dosage, leading to rescue of valvuloseptal defects. These findings identify HMGN1 as a dosage-sensitive modulator of AVC development and cardiac septation in Down syndrome. This study offers a paradigm for dissecting aneuploidy-associated pathogenesis using isogenic systems to map causal genes in complex genetic syndromes.

Diverse pathogen-encoded virulence factors disable apoptosis, pyroptosis or necroptosis, the host cell death programs that remove infected cells1. In the intestine, the extrusion of infected cells into the lumen for elimination provides an additional layer of host defence, but no virulence mechanisms that target the cytoskeletal changes required are known2. Here we show that the Escherichia coli ubiquitin ligase NleL is an inhibitor of intestinal epithelial cell (IEC) extrusion, targeting caspase-4, ROCK1 and ROCK2 for proteasomal degradation. Genetic deletion of Rock1 and Rock2 from cultured IECs diminished inflammasome-induced IEC extrusion. Moreover, mice with Rock1- and Rock2-deficient IECs were less effective than wild-type mice at constraining the numbers of Citrobacter rodentium in the colon. Notably, NleL-deficient C. rodentium triggered more IEC extrusion than did wild-type C. rodentium, resulting in diminished colonization of the colon in infected mice. Our work highlights a host-pathogen arms race focused on dynamic regulation of the host epithelial barrier.

Calcium (Ca2+) is an essential mineral that must be strictly regulated to support numerous physiological activities1,2. Extracellular fluid Ca2+ is regulated in vertebrates through endocrine systems that manage the vast Ca2+ reservoir in the bones3-6, but the Ca2+ regulatory mechanisms used by invertebrates, which lack bones, remain largely unclear. Here we identified a potent peptide hormone, Capa, which is responsible for regulating extracellular fluid Ca2+ levels in the fruit fly Drosophila melanogaster. Capa-deficient larvae exhibit low haemolymph Ca2+ levels, resulting in reduced locomotion and induced elongated pupae that mimic those of animals reared on a Ca2+-free diet. Capa secreted from specific neurosecretory cells acts on specialized Ca2+ storage compartments in the anterior Malpighian tubules, elevating haemolymph Ca2+. This endocrine mechanism governing Ca2+ regulation in terrestrial invertebrates resembles the parathyroid hormone system in vertebrates.

Atmospheric particulate matter (PM), a public health concern worldwide, is at present regulated according to its mass concentration1. However, it is increasingly thought that mass concentration may not fully capture the physicochemical properties of PM linked to its health impact2. Consequently, it has been suggested to further investigate the adequacy of this metric as an unequivocal indicator of PM health effects3-5. The new European regulation on air quality introduced oxidative potential (OP) as a recommended parameter to be monitored at supersites1, to explore further deciphering information about PM reactivity and health impacts6,7. Here we use a database of almost 11,500 OP measurements from 43 locations across parts of Europe that were analysed with the two most commonly used OP assays8, OPAA and OPDTT, with a standardized protocol9,10. We find high spatial variability of OP across Europe, strongly influenced by site type, such as urban or rural. Accounting for OP alongside PM mass suggests that further improvements in urban air quality may require consideration, particularly near roads, where volumetric OP of PM10 exceeds background levels by a factor of 2.4 to 3.1, depending on the assay used. Analysis of mitigation strategies shows that traffic is a key source to target for effectively reducing OP in cities, whereas comprehensive reductions in PM from both traffic and biomass burning are required to also meet World Health Organization mass guidelines. Although the epidemiological evidence for OP health impacts is still evolving2,8, our findings may help inform the interpretation of future work.

To ensure specificity, sensory neurons must select and express a single receptor from often vast gene families, adhering to the rule of 'one receptor per neuron'. For example, each olfactory sensory neuron in mammals expresses only one odorant receptor (Or) gene1,2. In Drosophila, which has about 60 Or genes, this selection is deterministic3. By contrast, mice face the challenge of choosing one Or gene from over 1,000 options4. They solve this through a complex system of stochastic choices5-9. Ants also possess many Or genes, most of which are organized into tandem arrays similar to those in mammals, but their regulatory mechanisms have evolved independently. Here we show that, in the ant Harpegnathos saltator, each olfactory sensory neuron activates a single promoter within an Or gene array, producing a mature capped and polyadenylated mRNA. While the promoters of downstream genes in the array are inactive, all downstream genes are nonetheless transcribed due to transcriptional readthrough from the active promoter, probably caused by inefficient RNA polymerase II termination. This readthrough appears to suppress downstream promoters through transcriptional interference, resulting in aberrant non-capped transcripts that are not translated, ensuring that only the active gene is expressed. Simultaneously, long antisense transcription originating from the chosen Or promoter covers upstream genes, presumably silencing them. Ants therefore appear to have evolved a unique transcriptional-interference-based mechanism to express a single OR protein from an array of Or genes with functionally similar promoters.

The human malaria parasite, Plasmodium falciparum, relies exclusively on Anopheles mosquitoes for transmission. Once ingested during blood feeding, most parasites die in the mosquito midgut lumen or during epithelium traversal1. How surviving ookinetes interact with midgut cells and form oocysts remains poorly understood, yet these steps are essential to initiate a remarkable growth process culminating in the production of thousands of infectious sporozoites2. Here, using single-cell RNA sequencing of both parasites and mosquito cells across different developmental stages and metabolic conditions, we unveil key transitions and mosquito-parasite interactions that occur in the midgut. Functional analyses uncover processes that regulate oocyst growth and identify the Plasmodium transcription factor PfSIP2 as essential for sporozoite infection of human hepatocytes. Combining shared mosquito-parasite barcode analysis with confocal microscopy, we reveal that parasites preferentially interact with midgut progenitor cells during epithelial crossing, potentially using their basal location as an exit landmark. Additionally, we show tight connections between extracellular late oocysts and surrounding muscle cells that may ensure parasite adherence to the midgut. We confirm our major findings in several mosquito-parasite combinations, including field-derived parasites. Our study provides fundamental insight into the molecular events that characterize previously inaccessible biological transitions and mosquito-parasite interactions, and identifies candidates for transmission-blocking strategies.

Native ion channels play key roles in biological systems, and engineered versions are widely used as chemogenetic tools and in sensing devices1,2. Protein design has been harnessed to generate pore-containing transmembrane proteins, but the design of selectivity filters with precise arrangements of amino acid side chains specific for a target ion, a crucial feature of native ion channels3, has been constrained by the lack of methods for placing the metal-coordinating residues with atomic-level precision. Here we describe a bottom-up RFdiffusion-based approach to construct Ca2+ channels from defined selectivity filter residue geometries, and use this approach to design symmetric oligomeric channels with Ca2+ selectivity filters having different coordination numbers and different geometries at the entrance of a wider pore buttressed by multiple transmembrane helices. The designed channel proteins assemble into homogeneous pore-containing particles and, for both tetrameric and hexameric ion-coordinating configurations, patch-clamp experiments show that the designed channels have higher conductances for Ca2+ than for Na+ and other divalent ions (Sr2+ and Mg2+) that are eliminated after mutation of selectivity filter residues. Cryogenic electron microscopy indicates that the design method has high accuracy: the structure of the hexameric Ca2+ channel is nearly identical to that of the design model. Our bottom-up design approach now enables the testing of hypotheses relating filter geometry to ion selectivity by direct construction, and provides a roadmap for creating selective ion channels for a wide range of applications.

Social behaviour is substantially shaped by internal physiological states. Although progress has been made in understanding how individual states such as hunger, stress or arousal modulate behaviour1-9, animals experience multiple states at any given time10. The neural mechanisms that integrate such orthogonal states-and how this integration affects behaviour-remain poorly understood. Here we report how hunger and oestrous state converge on neurons in the medial preoptic area (MPOA) to shape infant-directed behaviour. We find that hunger promotes pup-directed aggression in normally non-aggressive virgin female mice. This behavioural switch occurs through the inhibition of MPOA neurons, driven by the release of neuropeptide Y from Agouti-related peptide-expressing neurons in the arcuate nucleus (ArcAgRP neurons). The propensity for hunger-induced aggression is set by reproductive state, with MPOA neurons detecting changes in the progesterone to oestradiol ratio across the oestrous cycle. Hunger and oestrous state converge on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which sets the baseline activity and excitability of MPOA neurons. Using microendoscopy imaging, we confirm these findings in vivo, revealing that MPOA neurons encode a state for pup-directed aggression. This work provides a mechanistic understanding of how multiple physiological states are integrated to flexibly control social behaviour.

The lithium-ion battery supply chain is critical for global decarbonization1,2, yet its geographically dispersed production stages pose substantial challenges for carbon management3,4. Here we developed a lithium cycle computable general equilibrium (LCCGE) model, integrating life-cycle thinking with global economic dynamics to systematically assess decarbonization pathways. Our analysis reveals a notable 'value-emission paradox' across the supply chain: downstream cathode production generates 42.56% of economic value from 34.82% of emissions, whereas upstream mining accounts for 38.52% of total emissions from only 18.78% of the value. A comprehensive scenario analysis shows that, although consumer-oriented recycling can reduce global emission intensity by 16.30% in 2060, it is far surpassed by integrated strategies. The highest global emission reduction (35.87%) is achieved by combining cross-regional cooperation on technology and trade with regionally tailored domestic circular economy policies. This synergistic approach proves highly effective in key manufacturing economies, yielding potential emission reductions of 39.14% in the USA, 37.28% in the European Union and 42.35% in China. By revealing the synergy of combining environmental, technological and trade levers through both global collaboration and local adaptation, our work provides a blueprint for decarbonizing complex global supply chains and establishes a framework for analysing their sustainability analysis.

As demand for immersive experiences grows, displays with smaller sizes and higher resolutions are being viewed increasingly closer to the human eye1. As the size of emitting pixels shrinks, the intensity and uniformity of their emission are degraded while colour cross-talk and fabrication complexity increase, making ultra-high-resolution imaging challenging2-4. By contrast, electronic paper, which uses ambient light for visibility, can maintain high optical contrast regardless of pixel size, but cannot achieve high resolution5,6. Here we demonstrate electronic paper with electrically tunable metapixels down to ~560 nm in size (>25,000 pixels per inch) consisting of WO3 nanodisks, which undergo a reversible insulator-to-metal transition on electrochemical reduction. This transition enables dynamic modulation of the refractive index and optical absorption, allowing precise control over reflectance and contrast at the nanoscale. By using this effect, the metapixels can achieve pixel densities approaching the visual resolution limit when the display size matches the pupil diameter, which we refer to as retina electronic paper. Our technology also demonstrates full-colour video capability (>25 Hz), high reflectance (~80%), strong optical contrast (~50%), low energy consumption (~0.5-1.7 mW cm-2) and support for anaglyph 3D display, highlighting its potential as a next-generation solution for immersive virtual reality systems.

Global climate change and its consequences for the symbiosis between corals and microalgae are impacting coral reefs worldwide-ecosystems that support more than one-quarter of marine species and sustain nearly one billion people1-3. Understanding how stony corals, the primary architects of both shallow and deep reef ecosystems, responded to past environmental challenges is key to predicting their future4. Here we describe a time-calibrated molecular phylogenetic analysis that includes hundreds of newly sequenced coral taxa, and sheds light on the deep-time evolution of scleractinian corals. We date the emergence of the most recent common ancestor of Scleractinia to about 460 million years ago and infer that it was probably a solitary, heterotrophic and free-living organism-or one that could reproduce through transverse division-thriving in both shallow and deep waters. Our analyses suggest that symbiosis with photosynthetic dinoflagellates was established around 300 million years ago and spurred coral diversification. However, only a few photosymbiotic lineages survived major environmental disruptions in the Mesozoic era. By contrast, solitary, heterotrophic corals with flexible depth and substrate preferences appear to have thrived in the deep sea despite these environmental disturbance events. Even though ongoing environmental changes are expected to severely affect shallow reefs5, our finding that stony corals have shown resilience throughout geological history offers hope for the persistence of some lineages in the face of climate and other environmental changes.