Perovskite solar cells (PSCs) with power-conversion efficiencies comparable to established technologies hold huge promise for becoming the future photovoltaic technology, also given their versatility, low-cost and energy-efficient fabrication processes1. However, PSCs are not stable under moderate reverse bias2-4, an unavoidable situation under real-world operation, for instance, caused by partial shading of a module or installation with PSCs connected in series. Approaches to address this issue have focused on engineering the device architecture to enhance the breakdown voltage and mitigate the detrimental effects of reverse bias2,5,6. Here we present a completely different approach that fully solves the reverse-bias issue. With our Memsol, we developed a new concept of a solar cell with an integrated memristor, which protects the solar cell and simultaneously works as a bypass element. The memristor is realized by area-selective deposition of an additional metal-insulator stack and shares the perovskite and electrodes with the solar-cell part. Reverse-bias and shading tests show that the Memsol remains stable and automatically toggles between a low-resistance bypass state and full-efficiency solar-cell operation, dependent on the illumination and bias conditions. We anticipate that our Memsol concept, which we demonstrated on a nine-cell string in the lab, will be implemented in large-scale modules, accelerating their commercialization and potentially making external bypass diodes unnecessary.

Mammals have evolved a more complex brain, exemplified by the transformation of the single-layer dorsal cortex of excitatory projection neurons (ExNs) in ancestors into a multilayered cerebral neocortex1-4 enriched with diverse intratelencephalic and extratelencephalic ExN subtypes5-7, thereby establishing specialized projection systems that enhance brain connectivity and functionality5-8. This is in contrast to modern reptiles and birds with single-layered or pseudolayered columnar organization of ExNs4,9-12. However, the mechanisms underlying these mammalian-specific adaptations remain elusive. By comparing the landscape of gene expression and putative cis-regulatory elements (CREs) in mouse ExN subtypes and through cross-species examination, we identified mammalian-specific CREs, including a subset bound by the transcription factor ZBTB18 (also RP58, ZFP238 or ZNF238) and associated with genes defining intratelencephalic and extratelencephalic subtypes and connectivity, which have been implicated in intellectual disability and autism. Deletion of Zbtb18 in mouse ExNs dysregulated target gene expression, reduced molecular diversity, diminished cortico-spinal and callosal projections and increased intrahemispheric cortico-cortical association projections to the prefrontal cortex, thereby resembling non-mammalian brain. ZBTB18 binding motifs are highly enriched in callosally projecting intratelencephalic-biased putative CREs and show higher conservation specifically in mammals. This study uncovers critical components and mammalian-specific evolutionary adaptations within a regulatory node essential for neocortical ExN identity and connectivity.

Although immunotherapy has revolutionized cancer treatment, many patients still experience limited benefit, highlighting the urgent need for improved biomarkers1. Although immunotherapy is founded on unleashing T cells2, most existing biomarkers remain tumour-centric and mainly overlook host immune competence. The thymus is a key immune organ that is crucial for T cell maturation, and we hypothesized that thymic functionality is associated with immunotherapy outcomes3. Here we show that thymic health, a radiographic measure of thymic functionality, is strongly associated with immunotherapy outcomes across several cancer types. Using a deep-learning framework applied to routine computed tomography images, we quantified thymic health in a pan-cancer cohort of 3,476 patients receiving immune checkpoint inhibitors. In patients with non-small cell lung cancer, higher thymic health was associated with reduced risks of progression and all-cause mortality. These associations remained significant across clinically relevant levels of programmed death ligand 1 (PD-L1) and tumour mutation burden. In the prospective TRACERx lung cancer study, thymic health was positively associated with T cell receptor diversity and T cell receptor excision circles, and correlated with immune-system signalling pathways, supporting radiographic thymic health as a proxy for thymic activity and adaptive immune competence. Analysis across patients with melanoma, breast cancer or renal cancer demonstrated pan-cancer relevance. Together, these findings identify thymic health as a previously unrecognized, tumour-agnostic determinant of immunotherapy efficacy, with potential implications for patient stratification, treatment timing and the development of immune-rejuvenating strategies in precision immuno-oncology.

The thymus is essential for establishing T cell diversity early in life, but undergoes profound involution with age and has therefore traditionally been regarded as largely nonfunctional in adults1,2. Here we propose that preserving thymic functionality is integral to adult health and longevity. We developed a deep learning framework to quantify thymic health from routine radiographic images and evaluated its association with longevity and risk of major age-associated diseases in two large prospective cohorts of asymptomatic adults: the National Lung Screening Trial (n = 25,031) and the Framingham Heart Study (n = 2,581). In both cohorts, thymic health varied markedly across the population. In the National Lung Screening Trial, higher thymic health was consistently associated with lower all-cause mortality, reduced lung cancer incidence and lower cardiovascular mortality over 12 years of follow-up after adjustment for age, sex, smoking and comorbidities. In the independent Framingham Heart Study cohort, higher thymic health was significantly associated with reduced cardiovascular mortality, independent of age, sex and smoking. Thymic health was further linked to systemic inflammation and metabolic dysregulation, and associated with modifiable lifestyle factors including smoking, obesity and physical activity. Together, these findings reposition the thymus as a central regulator of immune-mediated ageing and disease susceptibility in adulthood, highlighting its potential as a target for preventive and regenerative strategies to promote healthy ageing and longevity.

Radiative forcing from well-mixed greenhouse gases (WMGHGs) is a main driver of Earth's energy imbalance and global surface climate change1,2. It remains difficult to constrain, largely because its longwave (LW) instantaneous radiative forcing (IRF) component depends on atmospheric state and is subject to radiative parameterization error3-7. The IRF measures the immediate change in radiative fluxes at the tropopause8-10 caused by perturbations in WMGHG concentrations. Here we show that increasing WMGHG concentrations have enhanced LW IRF by 3.69 ± 0.07 W m-2 (95% confidence interval) since 1850. We first use global line-by-line radiative transfer simulations to provide a global benchmark of LW IRF for the main WMGHGs under realistic, all-sky conditions. We then identify a robust linear relationship between LW IRF and outgoing longwave radiation (OLR), enabling state-dependent LW IRF to be directly inferred from regressions against satellite-observed OLR. Furthermore, LW IRF explains 91% of the inter-model spread in effective radiative forcing (ERF, which includes rapid atmospheric adjustments beyond the IRF) for CO2 (ref. 11) across Earth system models. Benchmarking model-simulated IRF using the regression technique reveals that most discrepancies originate from radiation parameterizations and correcting LW IRF biases would reduce uncertainty in CO2 ERF by 50%. Our results establish a simple and robust framework for quantifying state-dependent radiative forcing of WMGHGs, providing an observation-informed pathway for future climate assessments.

MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to form complexes that down-regulate target RNAs, including messenger RNAs from most human genes1-3. Within each complex, the miRNA pairs to target RNAs, and AGO provides effector function while also protecting the miRNA from cellular nucleases2-5. Although much is known about miRNA-directed gene regulation, less is known about how miRNAs themselves are regulated. One pathway that regulates miRNAs involves unusual targets called 'trigger' RNAs, which reverse the canonical regulatory logic and instead down-regulate miRNAs6-9. This target-directed miRNA degradation (TDMD) is thought to require a cullin-RING E3 ligase because it depends on the cullin protein CUL3 and other ubiquitylation components, including the BC-box protein ZSWIM8 (refs. 10,11). ZSWIM8 is required for murine perinatal viability and for destabilization of most short-lived miRNAs, which suggests biological importance of TDMD11-13. Here, biochemical and cellular assays establish AGO binding and polyubiquitylation by the ZSWIM8-CUL3 E3 ligase as the key regulatory steps of TDMD, and thereby define a unique cullin-RING E3 ligase class. Cryogenic electron microscopy analyses show ZSWIM8 recognizing distinct AGO and RNA conformations shaped by pairing of the miRNA to the trigger. Specificity of AGO ubiquitylation is established through generalizable RNA-RNA, RNA-protein and protein-protein interactions. The substrate features recognized by the E3 ligase do not conform to a conventional degron14,15 but instead establish a two-RNA-factor authentication mechanism for specifying a protein ubiquitylation substrate.

Bistable switching typically arises from ferroic orders, such as ferroelectricity and ferromagnetism, in which the bistable states are encoded in charge or spin degrees of freedom1,2. Here we report the observation of bistable superlattice switching in monolayer TaIrTe4, a dual quantum spin Hall insulator3-5. Switching occurs between two lattice configurations with sharply contrasting periodicities. In particular, in a pristine monolayer, we observe the spontaneous emergence of a long-period superlattice that can be programmed on and off in a non-volatile manner by electrostatic tuning of low-energy electronic states. This switching toggles the system between two structural configurations with unit cell areas differing by two orders of magnitude. Mechanistically, our results reveal two independent and distinct instabilities, one in the lattice and the other in the quantum spin Hall electrons. These instabilities are coupled, leading to electrostatic control of lattice configurations with non-volatile memory. This finding is enabled by combining linear and nonlinear transport measurements6-13, Raman spectroscopy and scanning tunnelling microscopy, which probe complementary aspects of the underlying orders. Notably, this non-volatile memory stabilizes a spontaneous superlattice with a periodicity on the few-nanometre scale that remains robust across a wide doping range, persists over days and survives above 70 K. Our preliminary data also show the emergence of new insulating states at fractional superlattice fillings, which can be switched on and off together with the superlattice.

Cinchona alkaloids, which have been studied for more than 250 years, are plant-derived natural products that have collectively had a substantial impact in medicine and basic science1-5. Examples of cinchona alkaloids include quinine, a historically important antimalarial drug, and cinchonidine, a chiral catalyst widely used in process chemistry. However, it is still largely unknown how plants synthesize these well-known compounds. Here we report the discovery of genes responsible for the biosynthesis of the distinctive quinoline-quinuclidine scaffold of cinchona alkaloids. A combination of isotopic labelling, gene silencing, single-nucleus RNA sequencing and comparative transcriptomics revealed the involvement of several unexpected biosynthetic transformations. We also describe a previously unreported quaternary amine intermediate that is generated through an unusual enzymatic cyclization. We show that dihydroquini(di)none, dihydrocinchoni(di)none and cinchoni(di)none can be produced when these genes are heterologously expressed in Nicotiana benthamiana. Furthermore, we demonstrate that this N. benthamiana expression platform can convert non-native fluorinated and chlorinated tryptamine substrates into dihydrocinchoni(di)none analogues, which suggests that these biosynthetic enzymes can be leveraged to produce halogenated cinchona alkaloid derivatives. These discoveries uncover the long-standing mystery of how the cinchona alkaloid scaffold is biosynthesized and highlight prospects for access to these compounds through metabolic engineering approaches.

The robust and repeatable performance of scalable integrated photonic neural networks (PNNs)1-3 strongly depends on the quality of their training. Gradient-based backpropagation is the mainstream algorithm for training digital neural networks thanks to its scalability, versatility and implementation efficiency4. Consequently, there is an interest in implementing it within a photonic platform in an all-optical manner. At present, owing to the lack of a scalable on-chip activation gradient5, training PNNs has relied on digital computers to run backpropagation, whose performance is reduced in the presence of inevitable device-to-device and environmental variations, or on gradient-free algorithms that do not fully benefit from the versatility of backpropagation training. Here we report the demonstration of an integrated photonic deep neural network, trained end-to-end with on-chip gradient-descent backpropagation. All linear and nonlinear computations are performed on a single photonic chip, leading to scalable and robust training, despite the considerable yet typical fabrication-induced device variations. In two nonlinear data classification tasks, chip performance matches that of the reference digital model in accuracy (over 90%) and robustness without using a digital computer. Integrating the advantages of backpropagation training with PNNs allows for generalization to various PNN architectures for future scalable and reliable photonic computing systems.

Climbing fibre (CF) inputs to Purkinje cells (PCs) instruct plasticity and learning in the cerebellum1-3. Paradoxically, CFs also excite molecular layer interneurons (MLIs)4,5, a cell type that inhibits PCs and can restrict plasticity and learning6,7. However, two types of MLI with opposing influences have recently been identified: MLI1s inhibit PCs, reduce dendritic calcium signals and suppress plasticity of granule cell to PC synapses2,6-9, whereas MLI2s inhibit MLI1s and disinhibit PCs8. To determine how CFs can activate MLIs without also suppressing the PC calcium signals necessary for plasticity and learning, we investigated the specificity of CF inputs onto MLIs. Serial electron microscopy reconstructions indicate that CFs contact both MLI subtypes without making conventional synapses, but more CFs contact each MLI2 through more sites with larger contact areas. Slice experiments indicate that CFs preferentially excite MLI2s through glutamate spillover4,5. In agreement with these anatomical and slice experiments, in vivo Neuropixels recordings show that spontaneous CF activity excites MLI2s, inhibits MLI1s and disinhibits PCs. By contrast, learning-related sensory stimulation produces more complex responses, driving convergent CF and granule cell inputs that could either activate or suppress MLI1s. This balance was robustly shifted towards MLI1 suppression when CFs were synchronously active, in turn elevating the PC dendritic calcium signals necessary for long-term depression. These data provide mechanistic insight into why CF synchrony can be highly effective at inducing cerebellar learning2,3 by revealing a critical disinhibitory circuit that allows CFs to act through MLIs to enhance PC dendritic calcium signals necessary for plasticity.

The characteristic tides of coastal rivers influence the distribution of estuarine and wetland habitats1, the extent of fresh drinking water2, carbon and nitrogen cycles3,4, and sediment export to the ocean5. Despite the importance of riverine tides, their range is generally unknown over most of the world's rivers because the propagation of tidal waves in channels is complex, gauging stations are scarce and conventional nadir altimetry6 has historically been too sparse for use in rivers. Here we use data from the recently launched Surface Water and Ocean Topography (SWOT) satellite to quantify tidal dynamics across 3,172 coastal rivers. Capitalizing on the wide swath coverage of SWOT, we show that over 165,000 river kilometres are influenced by tides. More than 700 million people live near and depend on these coastal transition zones. River size, slope and tidal range at the river mouth influence the extent to which tides propagate within river systems. Natural and artificial obstacles, such as dams, limit tidal propagation in an estimated 16% of all tidal rivers. The tidal dataset opens new possibilities for monitoring and modelling changes in estuarine habitats, fresh drinking water for coastal cities and riverine carbon budgets7 across annual to decadal timescales in response to sea-level rise8, megadrought9, intensifying water extraction and river regulation10.

Climate warming is shifting biological communities, with warmth-demanding species being favoured at the expense of cold-adapted species in a process referred to as thermophilization1-4. Because biodiversity responses often lag behind climate warming, climatic debts are accumulating in many ecosystems across the world5-7. Although we might expect that thermophilization and climatic debts will vary among habitats, standardized quantification across ecosystems is lacking. Here we analysed multidecadal data from 6,067 resurveyed vegetation plots over 12-78 years in forests, grasslands and on alpine summits across Europe. We demonstrate that forest understory and grassland plant communities experienced positive thermophilization, although not significantly different from zero. By contrast, alpine summit vegetation showed much stronger (up to five times) and significant thermophilization. Thermophilization was driven largely by increases in warmth-demanding species in grasslands, by declines in cold-adapted species on alpine summits and by both processes in forests. Significant climatic debts have accumulated in forests and alpine summits, but less so in grasslands, with debts positively correlated with macroclimate temperature changes. Our findings uncover divergent thermophilization trajectories and increasing climatic debts across ecosystems. Moreover, we highlight the mechanisms that enable some communities to track climate change more closely than others and provide a basis for projecting future shifts in plant communities under accelerating climate warming.

The accumulation of depolarized mitochondria commits T cells to exhaustion1-3, yet the precise mechanism remains unclear. Here we find that exhausted CD8+ T cells increase proteasome activity owing to the accumulation of depolarized mitochondria, which drives the selective degradation of mitochondrial proteins and the release of regulatory haem through haemoprotein breakdown. In turn, increased regulatory haem disrupts BACH2-mediated transcriptional regulation, thereby exacerbating T cell exhaustion and compromising stemness-like properties. Inhibition of nuclear import of regulatory haem prevents BACH2 degradation and enhances the anti-tumour efficacy of antigen-specific T cells. We find that the therapeutic efficacy of human CD19+ chimeric antigen receptor (CAR)-T cells in patients with B cell acute lymphoblastic leukaemia negatively correlates with the proteasome gene signature in their CAR-T cells. Manufacturing CAR-T cells in the presence of bortezomib, an FDA-approved proteasome inhibitor, prevents T cell exhaustion and improves therapeutic efficacy. Our findings identify a proteasome-guided haem signalling axis, governed by mitochondrial integrity, as a regulator of CD8+ T cell exhaustion and propose innovative therapeutic strategies that exploit this pathway to optimize adoptive cellular immunotherapy.

Engineered T cells, reprogrammed to express chimeric antigen receptors (CAR) or T cell receptors (TCR), have transformed cancer treatment and are being explored as therapeutics for autoimmune and infectious diseases. Enhancing T cell function through genome editing, either by disrupting endogenous genes or precisely inserting DNA payloads, has shown considerable promise1. However, the ex vivo manufacturing process is lengthy and costly, limiting accessibility of these therapies. In vivo generation of CAR T cells could overcome these barriers, but current methods rely either on transient expression with limited durability, or on random integration of DNA payloads that lack specificity. Here we demonstrate that stable and cell-specific transgene expression can be achieved through in vivo site-specific integration of large DNA payloads. We developed a two-vector system to deliver CRISPR-Cas9 ribonucleoproteins and a DNA donor template, using enveloped delivery vehicles and adeno-associated viruses, respectively. We optimized both vectors for T cell-specific delivery and gene-targeting efficiency. By integrating a CAR transgene into a T cell-specific locus, we generate therapeutic levels of CAR T cells in vivo in humanized mouse models of B cell aplasia, and haematological and solid malignancies. These findings offer a pathway to more efficient, precise and widely accessible T cell therapies.