The James Webb Space Telescope (JWST) has uncovered many compact galaxies at high redshift with broad hydrogen and helium lines, including the enigmatic population of little red dots (LRDs)1,2. The nature of these galaxies is debated and is attributed to supermassive black holes (SMBHs)3,4 or intense star formation5. They exhibit unusual properties for SMBHs, such as black holes that are overmassive for their host galaxies4 and extremely weak X-ray6-10 and radio6,11-13 emission. Here we show that in most objects studied with the highest-quality JWST spectra, the lines are broadened by electron scattering with a narrow intrinsic core. The data require very high electron column densities and compact sizes (light days), which, when coupled with their high luminosities, can be explained only by SMBH accretion. The narrow intrinsic line cores imply black hole masses of 105-7M⊙, two orders of magnitude lower than previous estimates. These are the lowest mass black holes known at high redshift, to our knowledge, and suggest a population of young SMBHs. They are enshrouded in a dense cocoon of ionized gas producing broad lines from which they are accreting close to the Eddington limit, with very mild neutral outflows. Reprocessed nebular emission from this cocoon dominates the optical spectrum, explaining most LRD spectral characteristics, including the weak radio and X-ray emission14,15.

The multifaceted dysfunction of tumour-infiltrating T cells, including exhaustion and mitochondrial dysfunction, remains a major obstacle in cancer immunotherapy1-6. Transcriptomic and epigenomic regulation of T cell dysfunction have been extensively studied7-9, but the role of proteostasis in regulating these obstacles remains less defined. Here we combined computational analyses of atlases of T cell exhaustion and mitochondrial fitness with performed targeted in vivo CRISPR screens, which identified the E3 ubiquitin ligase KLHL6 as a dual-negative regulator of both T cell exhaustion and mitochondrial dysfunction. Mechanistically, KLHL6 expression promoted TOX poly-ubiquitination and subsequent proteasomal degradation, thereby attenuating the transition of progenitor exhausted T cells towards terminal exhaustion. Simultaneously, KLHL6 maintained mitochondrial fitness by constraining the excessive mitochondrial fission that occurs during chronic T cell receptor stimulation by means of post-translational regulation of the PGAM5-Drp1 axis. However, KLHL6 is naturally downregulated by T cell receptor ligation, mitigating its potentially beneficial ubiquitin ligase activities during exposure to chronic stimulation. Enforcing KLHL6 expression in T cells markedly improved efficacy and long-term persistence against tumours and during viral infections in vivo. These findings uncover KLHL6 as a multifunctional, clinically actionable target for cancer immunotherapy, and highlight the potential of modulating proteostasis and ubiquitin modification to improve immunotherapy.

River deltas sustain dense human populations, major economic centres and vital ecosystems worldwide1,2. Rising sea levels and subsiding land threaten the sustainability of these valuable landscapes with relative sea-level rise and associated flood, land loss and salinization hazards1-3. Despite these risks, vulnerability assessments are impeded by the lack of contemporary, high-resolution, delta-wide subsidence observations4. Here we present spatially variable surface-elevation changes across 40 global deltas using interferometric synthetic aperture radar. Using this dataset, we quantify delta surface-elevation loss and show the prevalence and severity of subsidence in river deltas worldwide. Our analysis of three key anthropogenic drivers of delta elevation changes shows that groundwater storage has the strongest relative influence on vertical land motion in 10 of the 40 deltas. The other deltas are either influenced by multiple drivers or dominated by sediment flux or urban expansion. Furthermore, we find that contemporary subsidence surpasses absolute (geocentric) sea-level rise as the dominant driver of relative sea-level rise for most deltas over the twenty-first century. These findings suggest the need for targeted interventions addressing subsidence as an immediate and localized challenge, in parallel with broader efforts to mitigate and adapt to climate change-driven global sea-level rise.

G-protein-coupled receptors (GPCRs) are key mediators of cell communication and represent the most important class of drug targets1,2. Biophysical studies with purified GPCRs in vitro have suggested that they exist in an equilibrium of distinct inactive and active states, which is modulated by ligands in an efficacy-dependent manner3-11. However, how efficacy is encoded and whether multiple receptor states occur in living cells remain unclear. Here we use genetic code expansion12 and bioorthogonal labelling13-16 to generate a panel of fluorescence-based biosensors for a prototypical GPCR, the M2 muscarinic acetylcholine receptor (M2R). These biosensors enable real-time monitoring of agonist-promoted conformational changes across the receptor's extracellular surface in intact cells. We demonstrate that different agonists produce equilibria of at least four distinct active states of the G-protein-bound M2R, each with a different ability to activate G proteins. The formation of these M2R-G-protein complexes occurs over 0.2-5 s along trajectories that involve both common and ligand-specific conformational changes and appear to determine G-protein selectivity. These observations reveal the molecular nature of ligand efficacy in intact cells. Selectively exploiting such different GPCR activation trajectories and conformational equilibria may open new avenues for GPCR drug discovery.

Metabolites are central to cellular homeostasis. Although much emphasis has been placed on their relevance to meet energetic and biosynthetic demands, metabolic intermediates also function as signalling molecules. Here we show that polyamines, small polycations that are critical to cellular homeostasis1-3, regulate the process of alternative pre-mRNA splicing. We find that inhibition of polyamine synthesis increases phosphorylation of spliceosomal proteins, concomitant with perturbation of alternative splicing in cells and tissues. Mechanistically, molecular modelling combined with biochemical assays revealed that polyamines bind to acidic phosphorylatable motifs in splicing factors of the U2 small nuclear ribonucleoprotein SF3 subcomplex, thus preventing the action of upstream kinases. We refer to this molecular process by which polyamines regulate protein phosphorylation as metabolic shielding.

Disease tolerance is a defence strategy essential for survival of infections, limiting physiological damage without killing the pathogen1,2. The disease course and pathology an infection may cause can change over the lifespan of a host due to the structural and functional physiological changes that accumulate with age. Because successful disease tolerance responses require the host to engage mechanisms that are compatible with the disease course and pathology caused by an infection, we predicted that this defence strategy would change with age. Animals infected with a 50% lethal dose  (LD50) of a pathogen often show distinct health and sickness trajectories due to differences in disease tolerance1,3 and can be used to define tolerance mechanisms. Here, using a polymicrobial sepsis model, we found that, despite having the same LD50, aged and young susceptible mice showed distinct disease courses. In young survivors, cardiac Foxo1 and its downstream effector Trim63 (MuRF1) protected from sepsis-induced cardiac remodelling, multi-organ injury and mortality. Conversely, in aged hosts, Foxo1 and Trim63 acted as drivers of sepsis pathogenesis and death. Our findings have implications for the tailoring of therapy to the age of an infected individual and indicate that disease tolerance genes show antagonistic pleiotropy.

Despite decades of study, large parts of the mammalian metabolome remain unexplored1. Mass spectrometry-based metabolomics routinely detects thousands of small molecule-associated peaks in human tissues and biofluids, but typically only a small fraction of these can be identified, and structure elucidation of novel metabolites remains challenging2-4. Biochemical language models have transformed the interpretation of DNA, RNA and protein sequences, but have not yet had a comparable impact on understanding small molecule metabolism. Here we present an approach that leverages chemical language models5-7 to anticipate the existence of previously uncharacterized metabolites. We introduce DeepMet, a chemical language model that learns from the structures of known metabolites to anticipate the existence of previously unrecognized metabolites. Integration of DeepMet with mass spectrometry-based metabolomics data facilitates metabolite discovery. We harness DeepMet to reveal several dozen structurally diverse mammalian metabolites. Our work demonstrates the potential for language models to advance the mapping of the mammalian metabolome.

Micrometre-sized, densely packed natural cilia that perform non-reciprocal 3D motions with dynamically tunable collective patterns are crucial for biological processes such as microscale locomotion1, nutrient acquisition2, cell trafficking3-5 and embryonic and neurological development6-8. However, replicating these motions in artificial systems remains challenging given the limits of scalable, locally controllable soft-bodied actuation at the micrometre scale. Overcoming this challenge would enhance our understanding of ciliary dynamics, clarify their biological importance and enable new microscale devices and bioinspired technologies. Here we show a previously unrecognized fast electrical response of micrometre-scale hydrogels, induced by voltages down to 1.5 V without hydrolysis, with bending motions driven by ion migration across a nanometre-scale hydrogel network 3D-printed by two-photon polymerization, occurring within milliseconds. On the basis of these findings, we print gel microcilia arrays composed of a soft acrylic acid-co-acrylamide (AAc-co-AAm) hydrogel (modulus of approximately 1,000 Pa) that respond to electrical stimuli within milliseconds. Each microcilium measures 2-10 µm in diameter and 18-90 µm in height, achieving 3D rotational bending motion at up to 40 Hz, mirroring the geometry and dynamics of natural cilia. These gel microcilia maintain functionality after 330,000 continuous actuation cycles with less than 30% performance degradation. The gel microcilia arrays can be integrated on flexible polyimide substrates and fabricated at large scale using conventional lithography techniques. They also offer individual dynamic control by means of microelectrode arrays and enable fluid manipulation and particle transport at the micrometre scale.

The origin of eukaryotes is one of the key problems in evolutionary biology1,2. The demonstration that the last eukaryotic common ancestor (LECA) already contained the mitochondrion-an endosymbiotic organelle derived from an alphaproteobacterium-and the discovery of Asgard archaea-the closest archaeal relatives of eukaryotes3-7-inform and constrain evolutionary scenarios of eukaryogenesis8. We conducted a comprehensive analysis of the origins of core eukaryotic genes tracing to the LECA within a rigorous statistical framework centred around evolutionary hypothesis testing using constrained phylogenetic trees. The results show dominant contributions of Asgard archaea to the origin of most of the conserved eukaryotic functional systems and pathways. A limited contribution from Alphaproteobacteria was identified, relating primarily to energy transformation systems and Fe-S cluster biogenesis, whereas ancestry from other bacterial phyla was scattered across the eukaryotic functional landscape, without clear, consistent trends. These findings imply a model of eukaryogenesis in which key features of eukaryotic cell organization evolved in the Asgard lineage leading to the LECA, followed by the capture of the alphaproteobacterial endosymbiont and augmented by numerous but sporadic horizontal acquisitions of genes from other bacteria both before and after endosymbiosis.

Fine-tuning DNA replication and transcription is crucial to prevent collisions between their machineries1. This is particularly important near promoters, where RNA polymerase II (RNAPII) initiates transcription and frequently arrests, forming R-loops2-4. Arrested RNAPII can obstruct DNA replication, which often initiates near promoters5,6. The mechanisms that rescue arrested RNAPII during elongation to avoid conflicts with co-directional replisomes remain unclear. Here, using genome-wide approaches and genetic screens, we identify CFAP20 as part of a protective pathway that salvages arrested RNAPII in promoter-proximal regions, diverting it from the path of co-directional replisomes. CFAP20-deficient cells accumulate R-loops near promoters, which leads to defects in replication timing and dynamics. These defects stem from accelerated replication-fork speeds that cause a secondary reduction in origin activity. Co-depletion of the Mediator complex or removal of R-loop-engaged RNAPII restores normal replication. Our findings suggest that transcription-dependent fork stalling in cis induces accelerated fork progression in trans, generating single-stranded DNA gaps. We propose that CFAP20 facilitates RNAPII elongation under high levels of Mediator-driven transcription, thereby preventing replisome collisions. This study provides a transcription-centred view of transcription-replication encounters, revealing how locally arrested transcription complexes propagate genome-wide replication phenotypes and defining CFAP20 as a key factor that safeguards genome stability.

Therapies that harness the immune system to target and eliminate tumour cells have revolutionized cancer care. Immune checkpoint blockade (ICB), which boosts the anti-tumour immune response by inhibiting negative regulators of T cell activation1-3, is remarkably successful in a subset of cancer patients. Yet a significant proportion do not respond to treatment, emphasizing the need to understand factors influencing the therapeutic efficacy of ICB4-9. The gut microbiota, consisting of trillions of microorganisms residing in the gastrointestinal tract, has emerged as a critical determinant of immune function and response to cancer immunotherapy, with several studies demonstrating association of microbiota composition with clinical response10-16. However, a mechanistic understanding of how gut commensal bacteria influence the efficacy of ICB remains elusive. Here we use a gut commensal microorganism, segmented filamentous bacteria (SFB), which induces an antigen-specific T helper 17 (TH17) cell effector program in the small intestine lamina propria (SILP)17, to investigate how colonization with this microbe affects the efficacy of ICB in restraining distal growth of tumours sharing antigen with SFB. We find that anti-programmed cell death protein 1 (PD-1) treatment effectively inhibits the growth of implanted SFB antigen-expressing melanoma only if mice are colonized with SFB. Through T cell receptor (TCR) clonal lineage tracing, fate mapping and peptide-major histocompatability complex (MHC) tetramer staining, we identify tumour-associated SFB-specific T helper 1 (TH1)-like cells derived from the homeostatic TH17 cells induced by SFB colonization in the SILP. These gut-educated ex-TH17 cells produce high levels of the pro-inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF) within the tumour microenvironment (TME), enhancing antigen presentation and promoting recruitment, expansion and effector functions of CD8+ tumour-infiltrating cytotoxic lymphocytes and thereby enabling anti-PD-1-mediated tumour control. Conditional ablation of SFB-induced IL-17A+CD4+ T cells, precursors of tumour-associated TH1-like cells, abolishes anti-PD-1-mediated tumour control and markedly impairs tumour-specific CD8+ T cell recruitment and effector function within the TME. Our data, as a proof of principle, define a cellular pathway by which a single, defined intestinal commensal imprints T cell plasticity that potentiates PD-1 blockade, and indicate targeted modulation of the microbiota as a strategy to broaden ICB efficacy.

The mouse PIWI-interacting RNA (piRNA) pathway provides sustained anti-transposon immunity to the developing male germline by directing transposon DNA methylation1-3. The first step in this process is the recruitment of SPOCD1 to young LINE1 loci4. Thereafter, piRNA-mediated tethering of the PIWI protein MIWI2 (also known as PIWIL4) to the nascent transposon transcript recruits the DNA methylation machinery5,6. The piRNA pathway needs to methylate all active transposon copies but how this is achieved remains unknown. Here we show that nuclear piRNA and de novo methylation factors are all euchromatic, exposing constitutive heterochromatin as a genomic blind spot for the piRNA pathway. We discover a 'nowhere-to-hide' mechanism that enables piRNA pathway-mediated LINE1 surveillance of the entire genome. We find that SPOCD1 directly interacts with the nuclear pore component TPR, which forms heterochromatin exclusion zones adjacent to nuclear pores7. In fetal gonocytes undergoing piRNA-directed DNA methylation, TPR is found both at the nuclear periphery and throughout the nucleoplasm. We find that the SPOCD1-TPR interaction is required for complete non-stochastic piRNA-directed LINE1 methylation. The loss of the SPOCD1-TPR interaction results in a fraction of SPOCD1 and other chromatin-bound piRNA factors relocalizing to constitutive heterochromatin where they are no longer accessible to MIWI2 and the de novo methylation machinery. In summary, the piRNA pathway has co-opted TPR to guarantee that LINE1s are accessible to the piRNA and de novo methylation machineries.

Pain is a global health issue with substantial individual, societal and economic impacts. Given the risks of pharmacological treatments, complementary approaches to pain management are essential. Nature exposure has emerged as a promising nonpharmacological strategy, but evidence of its effectiveness is inconclusive. Here in this systematic review and meta-analysis we examined 62 studies (96 effects) across 21 countries, including 4,439 participants, to assess the impact of nature exposure on self-reported pain. The results indicate a significant small-to-moderate reduction in pain associated with nature exposure (standardized mean difference of 0.53), but studies exhibited moderate-to-high risk of bias and substantial heterogeneity. Studies evaluating nature against matched comparators reported effects roughly half the size of those using nonmatched controls and multisensory stimuli tended to show stronger effects. These findings support nature as a promising complementary pain management strategy. However, high heterogeneity and risk of bias warrant caution and highlight the need for more rigorous research.

Mental health conditions are associated with an increased risk of chronic physical diseases, but their implications for other physical health outcomes, including injuries, are less established. In this prospective cohort study, we tested whether mental health conditions antedate unintentional as well as self-harm and assault injuries, using administrative data from Norway (N = 2,753,646) and New Zealand (N = 2,238,813). In Norway, after accounting for pre-existing injuries, individuals with a primary care encounter for a mental health condition had an elevated risk of subsequent primary care-recorded injury. In New Zealand, as expected, individuals with a mental health-related inpatient hospital admission had an elevated risk of subsequent inpatient hospital-recorded self-harm injury, as well as assault injury. However, they also had an elevated risk of unintentional injuries. Associations extended to injury insurance claims. Associations were evident across mental health conditions, sex, age and after accounting for indicators of socioeconomic status. Risk was particularly increased for brain and head injuries. Patients with mental health conditions are an important group for injury prevention.

Lipid transfer proteins (LTPs) maintain the specialized lipid compositions of organellar membranes1,2. In humans, many LTPs are implicated in diseases3, but the cargo and auxiliary lipids that facilitate the transfer of the majority of LTPs remain unknown. Here we combined biochemical, lipidomic and computational methods to systematically characterize LTP-lipid complexes4 and measure how LTP gains of function affect cellular lipidomes. We identified bound lipids for around half of the hundreds of LTPs that we analysed, confirming known ligands and identifying new ones across most LTP families. Gains in LTP function affected the cellular abundance of both their known and newly identified lipid ligands, indicating comparable functional relevance of the two ligand sets. Using structural bioinformatics, we characterized mechanisms that contribute to lipid selectivity and identified preferences based on headgroup or acyl chain. We demonstrate some basic principles of how LTPs mobilize their ligands. They commonly interact with several classes of lipids and exhibit broad but selective preference for particular headgroups and for lipid species with shorter acyl chains that contain one or two unsaturated carbons, suggesting that only subsets of lipid species are efficiently mobilized. The datasets represent a resource for further analysis in different cell types and states, such as those associated with pathologies.

The canonical mechanism that drives cell division comprises the formation and constriction of a contractile actin ring1-3. However, this mechanism is not compatible with the early development of many vertebrates4-9. Yolk-anchored embryos typically cannot form a complete ring during early cleavage divisions, but it remains unclear how a partial circular arc with loose ends can divide the cell. Here, by combining laser ablation of the cytokinetic band with rheological measurements in vivo, we show that stiffening of the bulk cytoplasm, mediated by the interphase microtubule network, stabilizes the contractile band by anchoring it along its length during growth. Conversely, as the cell cycle progresses, the cytoplasm fluidizes, diminishing band-cytoplasmic anchoring and facilitating band ingression. This dynamic interplay between stability and growth versus instability and ingression repeats for several cell cycles until division is complete, resulting in a mechanical ratchet that drives cell division. Our study underscores the role of temporal control over cytoplasmic rheology as a key feature that drives unilateral cytokinesis in the absence of a closed actin ring.

The anterior cingulate cortex is a key brain region involved in the affective and motivational dimensions of pain, but how opioid analgesics modulate this cortical circuit remains unclear1. Uncovering how opioids alter nociceptive neural dynamics to produce pain relief is essential for developing safer and more targeted treatments for chronic pain. Here we show that a population of cingulate neurons encodes spontaneous pain-related behaviours and is selectively modulated by morphine. Using deep learning behavioural analyses combined with longitudinal neural recordings in mice, we identified a persistent shift in cortical activity patterns following nerve injury that reflects the emergence of an unpleasant, affective chronic pain state. Morphine reversed these neuropathic neural dynamics and reduced affective-motivational behaviours without altering sensory detection or reflexive responses, mirroring how opioids alleviate pain unpleasantness in humans. Leveraging these findings, we built a biologically inspired chemogenetic gene therapy that targets opioid-sensitive neurons in the cingulate using a synthetic μ-opioid receptor promoter to drive inhibition2. This opioid-mimetic chemogenetic gene therapy recapitulated the analgesic effects of morphine during chronic neuropathic pain, thereby offering a new strategy for precision pain management that targets a key nociceptive cortical opioid circuit with safe, on-demand analgesia.

The stromal cell compartment plays a central part in the maintenance of tissue homeostasis by coordinating with the immune system throughout inception, amplification and resolution of inflammation1. Chronic inflammation can impede the phased regulation of tissue restitution, resulting in the scarring complication of fibrosis. In inflammatory bowel disease, stromal fibroblasts have been implicated in treatment-refractory disease and fibrosis2,3; however, their mechanisms of activation have remained undefined. Through integrative single-cell and spatial profiling of intestinal tissues from patients with inflammatory bowel disease, we uncovered a pathological cell nexus centred on inflammation-associated fibroblasts. These fibroblasts were induced by proinflammatory macrophages (FCN1+IL1B+) and, in turn, produced profibrotic cytokine IL-11. We investigated the inflammation-associated fibroblast activation program at a mechanistic level using genome-wide CRISPR knockout and activation screens and identified the transcription factor GLIS3 as a key regulator of a gene regulatory network governing expression of inflammatory and fibrotic genes. We further demonstrated that the magnitude of the GLIS3 gene expression program in intestinal biopsies could be used to stratify patients with ulcerative colitis by disease severity, and that fibroblast-specific deletion of Glis3 in mice alleviated pathological features of chronic colitis. Taken together, our findings identify a critical immune-stromal cell circuit that functions as a central node in the inflammation-fibrosis cycle.

Palaeogenetic evidence suggests that the last common ancestor of present-day humans, Neanderthals and Denisovans lived around 765-550 thousand years ago (ka)1. However, both the geographical distribution and the morphology of these ancestral humans remain uncertain. The Homo antecessor fossils from the TD6 layer of Gran Dolina at Atapuerca, Spain, dated between 950 ka and 770 ka (ref. 2), have been proposed as potential candidates for this ancestral population3. However, all securely dated Homo sapiens fossils before 90 ka were found either in Africa or at the gateway to Asia, strongly suggesting an African rather than a Eurasian origin of our species. Here we describe new hominin fossils from the Grotte à Hominidés at Thomas Quarry I (ThI-GH) in Casablanca, Morocco, dated to around 773 ka. These fossils are similar in age to H. antecessor, yet are morphologically distinct, displaying a combination of primitive traits and of derived features reminiscent of later H. sapiens and Eurasian archaic hominins. The ThI-GH hominins provide insights into African populations predating the earliest H. sapiens individuals discovered at Jebel Irhoud in Morocco4 and provide strong evidence for an African lineage ancestral to our species. These fossils offer clues about the last common ancestor shared with Neanderthals and Denisovans.