During the twentieth century, inflammatory bowel disease (IBD) was considered a disease of early industrialized regions in North America, Europe and Oceania1. At the turn of the twenty-first century, IBD incidence increased in newly industrialized and emerging regions in Africa, Asia and Latin America, while the prevalence in early industrialized regions continued to grow steadily2-4. Changes in the incidence and prevalence denote the evolution of IBD across four epidemiologic stages: stage 1 (emergence), characterized by low incidence and prevalence; stage 2 (acceleration in incidence), marked by rapidly rising incidence and low prevalence; and stage 3 (compounding prevalence), where the incidence decelerates, plateaus or declines while the prevalence steadily increases. A fourth stage (prevalence equilibrium) has been proposed in which the prevalence slope plateaus due to demographic shifts in an ageing IBD population, but it has not yet been evidenced. To date, these stages have remained theoretical, lacking specific numerical indicators to define transition points. Here, using real-world data from 522 population-based studies encompassing 82 global regions and spanning more than a century (1920-2024), we show spatiotemporal transitions across stages 1-3 and model stage 4 progression. Understanding the evolution of IBD across epidemiologic stages enables healthcare systems to better anticipate the future worldwide burden of IBD.

Neuronal activity must be regulated in a narrow permissive band for the proper operation of neural networks. Changes in synaptic connectivity and network activity-for example, during learning-might disturb this balance, eliciting compensatory mechanisms to maintain network function1-3. In the neocortex, excitatory pyramidal cells and inhibitory interneurons exhibit robust forms of stabilizing plasticity. However, although neuronal plasticity has been thoroughly studied in pyramidal cells4-8, little is known about how interneurons adapt to persistent changes in their activity. Here we describe a critical cellular process through which cortical parvalbumin-expressing (PV+) interneurons adapt to changes in their activity levels. We found that changes in the activity of individual PV+ interneurons drive bidirectional compensatory adjustments of the number and strength of inhibitory synapses received by these cells, specifically from other PV+ interneurons. High-throughput profiling of ribosome-associated mRNA revealed that increasing the activity of a PV+ interneuron leads to upregulation of two genes encoding multiple secreted neuropeptides: Vgf and Scg2. Functional experiments demonstrated that VGF is critically required for the activity-dependent scaling of inhibitory PV+ synapses onto PV+ interneurons. Our findings reveal an instructive role for neuropeptide-encoding genes in regulating synaptic connections among PV+ interneurons in the adult mouse neocortex.

Indigenous groups often encounter significant challenges when asserting ancestral claims and cultural affiliations based on oral histories, particularly in the USA where such narratives have historically been undervalued. Although ancient DNA offers a tool to complement traditional knowledge and address gaps in oral history, longstanding disregard for Indigenous sovereignty and beliefs has understandably led many Indigenous communities to distrust DNA studies1-4. Earlier research often focused on repatriation claims5-7, whereas more recent work has increasingly moved towards enhancing Tribal histories8,9. Here we present a collaborative study initiated by a federally recognized Native American tribe, the sovereign nation of Picuris Pueblo in the Northern Rio Grande region of New Mexico, USA, to address gaps in traditional knowledge and further their understanding of their population history and ancestry. We generated genomes from 16 ancient Picuris individuals and 13 present-day members of Picuris Pueblo, providing genomic data spanning the last millennium. We show genetic continuity between ancient and present-day Picuris, and more broadly with Ancestral Puebloans from Pueblo Bonito in Chaco Canyon10, 275 km to the west. This suggests a firm spatiotemporal link among these Puebloan populations of the North American Southwest. Furthermore, we see no evidence of population decline before European arrival11-13, and no Athabascan ancestry in individuals predating 1500 CE, challenging earlier migration hypotheses14-16. This work prioritizes Indigenous control of genetic data and brings together oral tradition, archaeology, ethnography and genetics.

Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts1-6, but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system7-10. Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates-in concert with soluble regulators of the TGFβ pathway-a robust transcriptomic, morphological and metabolic shift towards quiescence. By conducting a meta-analysis of public human and mouse single-cell sequencing datasets, we identify the focal-adhesion-associated tyrosine kinase SRC as a fibroblast-enriched mechanosensor that can be targeted selectively in stromal cells to mimic the effects of matrix softening in vivo. Pharmacological inhibition of SRC by saracatinib, coupled with TGFβ suppression, induces synergistic repression of key profibrotic gene programs in fibroblasts, characterized by a marked inhibition of the MRTF-SRF pathway, which is not seen after treatment with either drug alone. Importantly, the dual treatment alleviates contractile dysfunction in fibrotic engineered heart tissues and in a mouse model of heart failure. Our findings point to joint inhibition of SRC-mediated stromal mechanosensing and TGFβ signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.

Marine plastic pollution is a global issue, with microplastics (1 µm-5 mm) dominating the measured plastic count1,2. Although microplastics can be found throughout the oceanic water column3,4, most studies collect microplastics from surface waters (less than about 50-cm depth) using net tows5. Consequently, our understanding of the microplastics distribution across ocean depths is more limited. Here we synthesize depth-profile data from 1,885 stations collected between 2014 and 2024 to provide insights into the distribution and potential transport mechanisms of subsurface (below about 50-cm depth, which is not usually sampled by traditional practices3,6) microplastics throughout the oceanic water column. We find that the abundances of microplastics range from 10-4 to 104 particles per cubic metre. Microplastic size affects their distribution; the abundance of small microplastics (1 µm to 100 µm) decreases gradually with depth, indicating a more even distribution and longer lifespan in the water column compared with larger microplastics (100 µm to 5,000 µm) that tend to concentrate at the stratified layers. Mid-gyre accumulation zones extend into the subsurface ocean but are concentrated in the top 100 m and predominantly consist of larger microplastics. Our analysis suggests that microplastics constitute a measurable fraction of the total particulate organic carbon, increasing from 0.1% at 30 m to 5% at 2,000 m. Although our study establishes a global benchmark, our findings underscore that the lack of standardization creates substantial uncertainties, making it challenging to advance our comprehension of the distribution of microplastics and its impact on the oceanic environment.

The maritime Phoenician civilization from the Levant transformed the entire Mediterranean during the first millennium BCE1-3. However, the extent of human movement between the Levantine Phoenician homeland and Phoenician-Punic settlements in the central and western Mediterranean has been unclear in the absence of comprehensive ancient DNA studies. Here, we generated genome-wide data for 210 individuals, including 196 from 14 sites traditionally identified as Phoenician and Punic in the Levant, North Africa, Iberia, Sicily, Sardinia and Ibiza, and an early Iron Age individual from Algeria. Levantine Phoenicians made little genetic contribution to Punic settlements in the central and western Mediterranean between the sixth and second centuries BCE, despite abundant archaeological evidence of cultural, historical, linguistic and religious links4. Instead, these inheritors of Levantine Phoenician culture derived most of their ancestry from a genetic profile similar to that of Sicily and the Aegean. Much of the remaining ancestry originated from North Africa, reflecting the growing influence of Carthage5. However, this was a minority contributor of ancestry in all of the sampled sites, including in Carthage itself. Different Punic sites across the central and western Mediterranean show similar patterns of high genetic diversity. We also detect genetic relationships across the Mediterranean, reflecting shared demographic processes that shaped the Punic world.

Acute myocardial infarction is a leading cause of morbidity and mortality worldwide1. Clinical studies have shown that the severity of cardiac injury after myocardial infarction exhibits a circadian pattern, with larger infarcts and poorer outcomes in patients experiencing morning-onset events2-7. However, the molecular mechanisms underlying these diurnal variations remain unclear. Here we show that the core circadian transcription factor BMAL17-11 regulates circadian-dependent myocardial injury by forming a transcriptionally active heterodimer with a non-canonical partner-hypoxia-inducible factor 2 alpha (HIF2A)12-16-in a diurnal manner. To substantiate this finding, we determined the cryo-EM structure of the BMAL1-HIF2A-DNA complex, revealing structural rearrangements within BMAL1 that enable cross-talk between circadian rhythms and hypoxia signalling. BMAL1 modulates the circadian hypoxic response by enhancing the transcriptional activity of HIF2A and stabilizing the HIF2A protein. We further identified amphiregulin (AREG)16,17 as a rhythmic target of the BMAL1-HIF2A complex, critical for regulating daytime variations of myocardial injury. Pharmacologically targeting the BMAL1-HIF2A-AREG pathway provides cardioprotection, with maximum efficacy when aligned with the pathway's circadian phase. These findings identify a mechanism governing circadian variations of myocardial injury and highlight the therapeutic potential of clock-based pharmacological interventions for treating ischaemic heart disease.

Mendel1 studied in detail seven pairs of contrasting traits in pea (Pisum sativum), establishing the foundational principles of genetic inheritance. Here we investigate the genetic architecture that underlies these traits and uncover previously undescribed alleles for the four characterized Mendelian genes2-7, including a rare revertant of Mendel's white-flowered a allele. Primarily, we focus on the three remaining uncharacterized traits and find that (1) an approximately 100-kb genomic deletion upstream of the Chlorophyll synthase (ChlG) gene disrupts chlorophyll biosynthesis through the generation of intergenic transcriptional fusion products, conferring the yellow pod phenotype of gp mutants; (2) a MYB gene with an upstream Ogre element insertion and a CLE peptide-encoding gene with an in-frame premature stop codon explain the v and p alleles, which disrupt secondary cell wall thickening and lignification, resulting in the parchmentless, edible-pod phenotype; and (3) a 5-bp exonic deletion in a CIK-like co-receptor kinase gene, in combination with a genetic modifier locus, is associated with the fasciated stem (fa) phenotype. Furthermore, we characterize genes and alleles associated with diverse agronomic traits, such as axil ring anthocyanin pigmentation, seed size and the 'semi-leafless' form. This study establishes a foundation for fundamental research, education in biology and genetics, and pea breeding practices.

Understanding the relationship between antibiotic use and the evolution of antimicrobial resistance is vital for effective antibiotic stewardship. Yet, animal models and in vitro experiments poorly replicate real-world conditions1. To explain how resistance evolves in vivo, we exposed 60 human participants to ciprofloxacin and used longitudinal stool samples and a new computational method to assemble the genomes of 5,665 populations of commensal bacterial species within participants. Analysis of 2.3 million polymorphic sequence variants revealed 513 populations that underwent selective sweeps. We found convergent evolution focused on DNA gyrase and evidence of dispersed selective pressure at other genomic loci. Roughly 10% of susceptible bacterial populations evolved towards resistance through sweeps that involved substitutions at a specific amino acid in gyrase. The evolution of gyrase was associated with large populations that decreased in relative abundance during exposure. Sweeps persisted for more than 10 weeks in most cases and were not projected to revert within a year. Targeted amplification showed that gyrase mutations arose de novo within the participants and exhibited no measurable fitness cost. These findings revealed that brief ciprofloxacin exposure drives the evolution of resistance in gut commensals, with mutations persisting long after exposure. This study underscores the capacity of the human gut to promote the evolution of resistance and identifies key genomic and ecological factors that shape bacterial adaptation in vivo.

Environmental thermal challenges trigger the brain to coordinate both autonomic and behavioural responses to maintain optimal body temperature1-4. It is unknown how temperature information is precisely stored and retrieved in the brain and how it is converted into a physiological response. Here we investigated whether memories could control whole-body metabolism by training mice to remember a thermal challenge. Mice were conditioned to associate a context with a specific temperature by combining thermoregulatory Pavlovian conditioning with engram-labelling technology, optogenetics and chemogenetics. We report that if mice are returned to an environment in which they previously experienced a 4 °C cold challenge, they increase their metabolic rates regardless of the actual environmental temperature. Furthermore, we show that mice have increased hypothalamic activity when they are exposed to the cold, and that a specific network emerges between the hippocampus and the hypothalamus during the recall of a cold memory. Both natural retrieval and artificial reactivation of cold-sensitive memory engrams in the hippocampus mimic the physiological responses that are seen during a cold challenge. These ensembles are necessary for cold-memory retrieval. These findings show that retrieval of a cold memory causes whole-body autonomic and behavioural responses that enable mice to maintain thermal homeostasis.

Somatosensory neurons encode detailed information about touch and temperature and are the peripheral drivers of pain1,2. Here by combining functional imaging with multiplexed in situ hybridization3, we determined how heat and mechanical stimuli are encoded across neuronal classes and how inflammation transforms this representation to induce heat hypersensitivity, mechanical allodynia and continuing pain. Our data revealed that trigeminal neurons innervating the cheek exhibited complete segregation of responses to gentle touch and heat. By contrast, heat and noxious mechanical stimuli broadly activated nociceptor classes, including cell types proposed to trigger select percepts and behaviours4-6. Injection of the inflammatory mediator prostaglandin E2 caused long-lasting activity and thermal sensitization in select classes of nociceptors, providing a cellular basis for continuing inflammatory pain and heat hypersensitivity. We showed that the capsaicin receptor TRPV1 (ref. 7) has a central role in heat sensitization but not in spontaneous nociceptor activity. Unexpectedly, the responses to mechanical stimuli were minimally affected by inflammation, suggesting that tactile allodynia results from the continuing firing of nociceptors coincident with touch. Indeed, we have demonstrated that nociceptor activity is both necessary and sufficient for inflammatory tactile allodynia. Together, these findings refine models of sensory coding and discrimination at the cellular and molecular levels, demonstrate that touch and temperature are broadly but differentially encoded across transcriptomically distinct populations of sensory cells and provide insight into how cellular-level responses are reshaped by inflammation to trigger diverse aspects of pain.

The coupling between electrons and phonons is one of the fundamental interactions in solids, underpinning a wide range of phenomena, such as resistivity, heat conductivity and superconductivity. However, direct measurements of this coupling for individual phonon modes remain a substantial challenge. In this work, we introduce a new technique for mapping phonon dispersions and electron-phonon coupling (EPC) in van der Waals (vdW) materials. By generalizing the quantum twisting microscope1 (QTM) to cryogenic temperatures, we demonstrate its capability to map not only electronic dispersions through elastic momentum-conserving tunnelling but also phononic dispersions through inelastic momentum-conserving tunnelling. Crucially, the inelastic tunnelling strength provides a direct and quantitative measure of the momentum and mode-resolved EPC. We use this technique to measure the phonon spectrum and EPC of twisted bilayer graphene (TBG) with twist angles larger than 6°. Notably, we find that, unlike standard acoustic phonons, whose coupling to electrons diminishes as their momentum tends to zero, TBG exhibits a low-energy mode whose coupling increases with decreasing twist angle. We show that this unusual coupling arises from the modulation of the interlayer tunnelling by a layer-antisymmetric 'phason' mode of the moiré system. The technique demonstrated here opens the way for examining a large variety of other neutral collective modes that couple to electronic tunnelling, including plasmons2, magnons3 and spinons4 in quantum materials.

Beneath oceanic spreading centres, the lithosphere-asthenosphere boundary (LAB) acts as a permeability barrier that focuses the delivery of melt from deep within the mantle towards the spreading axis1. At intermediate-spreading to fast-spreading ridge crests, the multichannel seismic reflection technique has imaged a nearly flat, 1-2-km-wide axial magma lens (AML)2 that defines the uppermost section of the LAB3, but the nature of the LAB deeper into the crust has been more elusive, with some clues gained from tomographic images, providing only a diffuse view of a wider halo of lower-velocity material seated just beneath the AML4. Here we present 3D seismic reflection images of the LAB extending deep (5-6 km) into the crust beneath Axial volcano, located at the intersection of the Juan de Fuca Ridge and the Cobb-Eickelberg hotspot. The 3D shape of the LAB, which is coincident with a thermally controlled magma assimilation front, focuses hotspot-related and mid-ocean-spreading-centre-related magmatism towards the centre of the volcano, controlling both eruption and hydrothermal processes and the chemical composition of erupted lavas5. In this context, the LAB can be viewed as the upper surface of a 'magma domain', a volume within which melt bodies reside (replacing the concept of a single 'magma reservoir')6. Our discovery of a funnel-shaped, crustal LAB suggests that thermally controlled magma assimilation could be occurring along this surface at other volcanic systems, such as Iceland.

Clonal haematopoiesis of indeterminate potential (CHIP) involves the gradual expansion of mutant pre-leukaemic haematopoietic cells, which increases with age and confers a risk for multiple diseases, including leukaemia and immune-related conditions1. Although the absolute risk of leukaemic transformation in individuals with CHIP is very low, the strongest predictor of progression is the accumulation of mutant haematopoietic cells2. Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during ageing remains rudimentary. Here we show that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes pre-leukaemic cell expansion. Specifically, ADP-D-glycero-β-D-manno-heptose (ADP-heptose), a biosynthetic bi-product specific to Gram-negative bacteria3-5, is uniquely found in the circulation of older individuals and favours the expansion of pre-leukaemic cells. ADP-heptose is also associated with increased inflammation and cardiovascular risk in CHIP. Mechanistically, ADP-heptose binds to its receptor, ALPK1, triggering transcriptional reprogramming and NF-κB activation that endows pre-leukaemic cells with a competitive advantage due to excessive clonal proliferation. Collectively, we identify that the accumulation of ADP-heptose represents a direct link between ageing and expansion of rare pre-leukaemic cells, suggesting that the ADP-heptose-ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukaemia and immune-related conditions.

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism1,2. For example, PDAC uses, and is dependent on, high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the difficulty in identifying and characterizing favourable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase that is integral to lysosomal functioning7, as a targetable vulnerability in PDAC. Using a genetically engineered mouse model, we established that PIKfyve is essential to PDAC progression. Furthermore, through comprehensive metabolic analyses, we found that PIKfyve inhibition forces PDAC to upregulate a distinct transcriptional and metabolic program favouring de novo lipid synthesis. In PDAC, the KRAS-MAPK signalling pathway is a primary driver of de novo lipid synthesis. Accordingly, simultaneously targeting PIKfyve and KRAS-MAPK resulted in the elimination of the tumour burden in numerous preclinical human and mouse models. Taken together, these studies indicate that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.

Understanding the human de novo mutation (DNM) rate requires complete sequence information1. Here using five complementary short-read and long-read sequencing technologies, we phased and assembled more than 95% of each diploid human genome in a four-generation, twenty-eight-member family (CEPH 1463). We estimate 98-206 DNMs per transmission, including 74.5 de novo single-nucleotide variants, 7.4 non-tandem repeat indels, 65.3 de novo indels or structural variants originating from tandem repeats, and 4.4 centromeric DNMs. Among male individuals, we find 12.4 de novo Y chromosome events per generation. Short tandem repeats and variable-number tandem repeats are the most mutable, with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 16% of de novo single-nucleotide variants are postzygotic in origin with no paternal bias, including early germline mosaic mutations. We place all this variation in the context of a high-resolution recombination map (~3.4 kb breakpoint resolution) and find no correlation between meiotic crossover and de novo structural variants. These near-telomere-to-telomere familial genomes provide a truth set to understand the most fundamental processes underlying human genetic variation.

Several hydrogen-rich superconductors have been found to show unprecedentedly high critical temperatures1-4, stimulating investigations into the nature of the superconductivity in these materials. Although their macroscopic superconducting properties are established1,5-7, microscopic insights into the pairing mechanism remains unclear. Here we characterize the superconducting gap structure in the high-temperature superconductor H3S and its deuterium counterpart D3S by performing tunnelling spectroscopy measurements. The tunnelling spectra reveal that H3S and D3S both have a fully gapped structure, which could be well described by a single s-wave Dynes model, with gap values 2Δ of approximately 60 meV and 44 meV, respectively. Furthermore, we observed gap features of another likely H-depleted HxS superconducting phase in a poorly synthesized hydrogen sulfide sample. Our work offers direct experimental evidence for superconductivity in the hydrogen-rich superconductor H3S from a microscopic perspective. It validates the phonon-mediated mechanism of superconducting pairing and provides a foundation for further understanding the origins of high-temperature superconductivity in hydrogen-rich compounds.

Incidence rates of colorectal cancer vary geographically and have changed over time1. Notably, in the past two decades, the incidence of early-onset colorectal cancer, which affects individuals below 50 years of age, has doubled in many countries2-5. The reasons for this increase are unknown. Here we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite-unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown aetiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin6,7, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals who were diagnosed before 40 years of age than in those over 70 years of age, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 being responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that mutagenic exposure to colibactin-producing bacteria in early life may contribute to the increasing incidence of early-onset colorectal cancer.