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.

Magnetic fields can influence reactions involving spin-correlated radical pairs (SCRPs)1,2. This provides a mechanism by which both static and time-varying magnetic fields can affect living systems at the biomolecular level3. However, an engineered SCRP system conferring magnetic sensitivity to a non-native biochemical process in a multicellular organism has not yet been demonstrated. Here we demonstrate control of SCRP dynamics using magnetic resonance in a live transgenic animal. We show that the emission of various red fluorescent proteins (RFPs), in the presence of a flavin cofactor, can be modified by a combination of static and radiofrequency magnetic fields applied near the electron spin resonance frequency. This effect was measured at room temperature both in vitro and in the nematode Caenorhabditis elegans, genetically modified to express the RFP mScarlet4. These observations suggest that the magnetic field effects measured in RFP-flavin systems5 are due to quantum-correlated radical pairs with a coherence time larger than 4 ns. Our experiments demonstrate that radiofrequency magnetic fields can influence dynamics of reactions involving SCRPs in vivo, potentially enabling new methods for remotely controlling biomolecular processes, such as gene expression, and suggest broader potential for quantum tools in biology.

Restricting amino acids from tumours is an emerging therapeutic strategy with substantial promise1. Although typically considered an intracellular antioxidant with tumour-promoting capabilities2, glutathione (GSH), as a tripeptide of cysteine, glutamate and glycine, can be catabolized to release amino acids. The extent to which GSH-derived amino acids are essential to cancers is unclear. Here we show that depletion of intracellular GSH does not alter tumour growth and extracellular GSH is highly abundant in the tumour microenvironment, highlighting the potential importance of GSH outside tumours. Supplementation with GSH rescues cancer cell survival and growth in cystine-deficient conditions, and this rescue depends on the catabolic activity of γ-glutamyltransferases. Finally, pharmacological targeting of the activity of γ-glutamyltransferases prevents the breakdown of circulating GSH, reduces tumour cysteine levels and slows tumour growth. Our findings indicate a non-canonical role for GSH in supporting tumours by acting as a reservoir of amino acids. Depriving tumours of extracellular GSH or inhibiting its breakdown is potentially a therapeutically tractable approach for patients with cancer. Furthermore, these findings change our view of GSH and how amino acids, including cysteine, are supplied to cells.

Recent advances in genetic engineering have provided diverse tools for artificially diversifying both prokaryotic and eukaryotic cell populations1-6. However, achieving precise control over the ratios of multiple cell types within a population derived from a single founder remains a major challenge. Here we introduce a suite of recombinase-mediated genetic devices designed to accurately control population ratios, enabling the distribution of distinct functionalities across multiple cell types. We systematically evaluated key parameters that influence recombination efficiency and developed data-driven models to reliably predict binary differentiation outcomes. Using these devices, we constructed parallel and series circuit topologies to implement user-defined, multistep cell-fate branching programs. The branching devices facilitated the autonomous differentiation of precision fermentation consortia from a single founder yeast strain, optimizing cell-type ratios for applications such as pigmentation and cellulose degradation. Similar effects were obtained with mammalian cells. We also engineered multicellular aggregates with genetically encoded morphologies by coordinating self-organization through cell adhesion molecules. Our work provides a comprehensive characterization of recombinase-based cell-fate branching mechanisms and introduces an approach for constructing synthetic consortia and multicellular assemblies.

The transition to agriculture was a transformative process in human history with wide-ranging demographic and social consequences1. Across South America, agriculture was adopted at different times and through diverse pathways, resulting in a mosaic of regionally distinct farming histories2,3. The Uspallata Valley, at the southern frontier of Andean farming, offers a unique opportunity to examine a case of late adoption of agriculture. Here we show that agriculture in the Uspallata Valley was adopted by local hunter-gatherers, as evidenced by genetic continuity between pre-farming and farming populations inferred from 46 newly sequenced ancient human genomes. These groups carried a distinct genetic component in Indigenous American diversity, indicating a unique population history in the region. Palaeodietary isotopes (δ13C/δ15N) reveal fluctuating maize intake consistent with flexible farming. Strontium isotopes (87Sr/86Sr) indicate the arrival of migrants from nearby regions between around 810-700 cal years BP, shortly before the Inka expansion. Genomic and isotopic analyses show that these migrants belonged to the same regional metapopulation as local groups, relied heavily on maize, probably moved in matrilineally organized family groups, exhibited stress markers (including malnutrition and diseases, such as tuberculosis, as confirmed by pathogen genomics) and experienced a long-term demographic decline. Our results suggest that these groups used social organization and migration as resilience strategies in the face of a multidimensional crisis.

Ultracold gases of dipolar molecules have long been envisioned as a platform for the realization of novel quantum phases1-8. Recent advances in collisional shielding9-12, protecting molecules from inelastic losses, have enabled the creation of degenerate Fermi gases13-15 and, more recently, Bose-Einstein condensation of dipolar molecules16. However, the observation of quantum phases in ultracold molecular gases that are driven by dipole-dipole interactions has so far remained elusive. Here we report the formation of self-bound droplets and droplet arrays in an ultracold gas of strongly dipolar sodium-caesium molecules. Starting from a molecular Bose-Einstein condensate, microwave dressing fields are used to induce dipole-dipole interactions with controllable strength and anisotropy. By varying the speed at which interactions are induced, covering a dynamic range of four orders of magnitude, we prepare droplets under equilibrium and non-equilibrium conditions, observing a transition from robust one-dimensional arrays to fluctuating two-dimensional structures. The droplets show densities up to 100 times higher than the initial Bose-Einstein condensate, reaching the strongly interacting regime and suggesting the possibility of a quantum-liquid or crystalline state9,17. This work establishes ultracold molecules as a system for the exploration of strongly dipolar quantum matter and opens the door to the realization of self-organized crystal phases3,9,18 and dipolar spin liquids in optical lattices19.

Ice core records from Antarctica document continuous variations in atmospheric greenhouse gases over the past 800,000 years, delineating the glacial-interglacial cycles that characterize the late Pleistocene epoch1-3. Studies of blue ice areas4 have extended these records back to 2 million years (Myr)5,6. The evolution of atmospheric greenhouse gases before this time thus remains uncertain. Here we use discontinuous ice core snapshots spanning 3.1-0.5 Myr ago (Ma) to show no marked change in mean methane (CH4) and a small decline of about 20 ppm in carbon dioxide (CO2) between 2.9 Ma and 1.2 Ma, followed by stable concentrations (±10 ppm) across the mid-Pleistocene Transition. Our findings are based on the shallow ice cores drilled in the Allan Hills Blue Ice Area (BIA), Antarctica7. The records are complicated by postdepositional processes and probably represent averages over glacial cycles weighted by climate-dependent differences in accumulation rates (which we assume to be constant). Samples aged 2.8-3.1 Myr, affected by respiration and corrected using stable carbon isotopes in CO2 (δ13C), yield mean atmospheric CO2 levels indistinguishable from the early Pleistocene (250 ± 10 ppm). Although palaeoclimate archives from Antarctic blue ice areas are complex, our records show that measurements of greenhouse gases in ice cores can be extended to the late Pliocene epoch, providing snapshots of Earth's climate system over a time of global cooling7,8 and falling sea level9.

The Pleistocene epoch was characterized by global cooling and an increase in the intensity and duration of glacial cycles. Regional surface and subsurface ocean temperature records follow distinct trends over this interval, suggesting dynamic changes in zonal and meridional heat transport and ocean circulation. These differing trends also complicate efforts to determine the evolution of total ocean heat content. Here we provide a record of mean ocean temperature over the past 3 million years from noble gas (Xe/Kr) measurements in shallow ice cores recovered in the Allan Hills blue ice area, Antarctica1. The stratigraphically complex records preclude reconstruction of individual glacial cycles and probably represent a weighted averaging of glacial and interglacial conditions2. Nonetheless, we find pronounced cooling roughly coincident with the Plio-Pleistocene Transition (around 2.7 million years ago), and steady temperatures across the Mid-Pleistocene Transition (1.2 to 0.8 million years ago). Comparisons with a recent global sea surface temperature compilation3 show broad consistency in long-term cooling but important differences at the Plio-Pleistocene and Mid-Pleistocene transitions. We suggest that the different trends in surface temperature and mean ocean temperature during these intervals are related to a redistribution of heat between the surface and subsurface via changes in deep water formation and upwelling. Our temperature record also permits an estimate of global ice volume changes between 3 and 0.5 million years ago through a deconvolution of the benthic foraminiferal δ18O record and points to a period of enhanced ice sheet growth around the time of the Mid-Pleistocene Transition.

Insulating oxides are among the most abundant solid materials in the universe1-3. Of the many ways in which they influence natural phenomena, perhaps the most consequential is their capacity to transfer electrical charge during contact4-10-which occurs even between samples of the same oxide-yet the symmetry-breaking parameter that causes this remains unidentified11,12. Here we show that adventitious carbonaceous molecules adsorbed from the environment are the symmetry-breaking factor in same-material oxide contact electrification (CE). We use acoustic levitation to measure charge exchange between a sphere and a plate composed of identical amorphous silicon dioxide (SiO2). Although charging polarity is random for co-prepared samples, we control it with baking or plasma treatment. Observing the charge-exchange relaxation afterwards, we see dynamics over a timescale of hours and connect this directly to the presence of adventitious carbon with time-of-flight mass spectrometry, low-energy ion scattering and infrared spectroscopy. Going further, we confirm that adventitious carbon can even determine charge exchange among different oxides. Our results identify the symmetry-breaking parameter that causes insulating oxides to exchange charge in settings ranging from desert sands4 to volcanic plumes5,6, while simultaneously highlighting an overlooked factor in CE more broadly.