Browse Articles

Hypermutability of integrated sequences of viral origin in a chlorarachniophyte

Mutations provide the raw material for evolution, but mutation rates are not uniform across genomes. Using a mutation accumulation experiment in the marine phytoplankton Bigelowiella natans , we found extreme local variation in mutation rate: over 1,000-fold differences across its nuclear genome. While the baseline single-nucleotide mutation rate is approximately 3.5 × 10 –10 per site per generation, a common value for unicellular species, two genomic regions derived from integrated viruses exhibit strikingly elevated rates of about 6 × 10 –7 . These two regions show a distinctive mutational signature with almost exclusively T/A→C/G transitions, a pattern also found in other non-eukaryote-derived sequences in B. natans , contrary to the usual GC to AT mutation bias. Notably, hypermutation occurs only on TpA dinucleotides, and only in a subset of experimental lines, suggesting a regulated process rather than random genomic instability. We propose that B. natans targets invading DNA through localized hypermutation, reminiscent of deamination-based antiviral defense systems in animals. This prompts the idea of genome editing as a recurring immune strategy in eukaryotes.

Human wastewater contamination drives the emergence of multidrug-resistant bacteria in the Galápagos marine ecosystem

The human hippocampus can pattern separate memories by meaning

Hippocampal pattern separation is a neural operation supporting mnemonic discrimination of highly similar memories by orthogonalizing neural inputs into nonoverlapping representations. In humans, pattern separation is thought to support the specificity of episodic memories. Recent neuroimaging studies suggest that the hippocampus can also access and manipulate semantic information. However, it is unclear whether the hippocampus can pattern separate highly similar semantic representations. Here, we tested multiple neural and behavioral signatures of pattern separation using high-resolution functional MRI during a well-established memory discrimination task where we manipulated semantic similarity in a multidimensional conceptual space using word-embeddings. Thirty young adults (Mage = 21.1, 16 females) saw adjective-noun phrases (e.g., “exotic zoo”) that were later repeated exactly as before or modified with semantically similar adjectives (e.g., “strange zoo”). Crucially, we presented exact and modified repeats both during an incidental encoding and a two-choice recognition phase, where mnemonic discrimination was assessed. Consistent with pattern separation, we found attenuated repetition suppression for modified repeats in repetition sensitive clusters of the hippocampal head, which was evident at both high and low levels of similarity with no difference between two a priori defined similarity bins. In addition, within participants, the neural signature of pattern separation was associated with mnemonic discrimination at recognition. Finally, clusters sensitive to repetitions during encoding differentiated lures from foils at recognition. These results suggest that hippocampal pattern separation is triggered by fine-grained differences in meaning and supports the creation of highly specific representations of memories overlapping in semantic memory.

Linking long-range surface-induced mobility enhancement and intrinsic fragility of polymer glasses

Distinct repair processes produce APOBEC-induced deletions, tandem substitutions, and complex mutations in yeast and human cells

APOBEC3A (A3A) and APOBEC3B (A3B) induce single base substitution signatures SBS2 and SBS13, which are composed of C>T and C>G mutations, respectively, at T C W sequences in >50% of sequenced tumors. However, few driver mutations have been attributed to APOBEC-induced SBS mutations. Although SBS2 and SBS13 have been associated with additional mutation types, the contribution of APOBECs to non-SBS mutations and the mechanisms that generate noncanonical APOBEC-induced mutations are uncharacterized. Here, we show that A3A expression generates non-SBS mutations including C deletions within TT C motifs, CC>TT and T C >AT/CT/GT dinucleotide variants (DNVs), distinct classes of paired SNV-SNV events, and complex insertion-SBS mutations in a yeast model system. Furthermore, we found that endogenous APOBEC expression in breast cancer cell lines is a significant driver of all these mutation types. In addition, we show that C deletions and complex insertion-SBS mutations within TT C motifs occur primarily by strand slippage during translesion synthesis (TLS) bypass of APOBEC-induced, UNG-dependent, abasic sites. Additionally, we found that CC>TT and T C >AT/CT/GT DNVs, which comprise the APOBEC-associated DBS11 signature, are generated by dU templating and TLS bypass of APOBEC-induced abasic sites, respectively. We also present data indicating that phased APOBEC-induced SNV-SNV mutations are produced during abasic site bypass by TLS. Analysis of WGS data from cultured human cells and tumors indicates that similar mechanisms generate these noncanonical APOBEC-induced mutations in human cancers, providing additional means by which APOBECs could contribute to carcinogenesis and therapeutic resistance.

Transitions between persistent climate–carbon regimes coincide with elevated Phanerozoic biosphere vulnerability

Abstract Linking abiotic forcing to coherent biotic responses over Phanerozoic time remains difficult to quantify because both environmental drivers and biological dynamics are heterogeneous, irregularly sampled, and affected by proxy and geochronological uncertainty. Here we introduce a regime-based description of the climate–carbon system in which Phanerozoic evolution is organized into a small number of recurring, long-lived mega-climate states separated by relatively sharp transitions. Using recurrence diagnostics on paired carbon and oxygen stable isotope records, together with complementary early-warning indicators, we identify five persistent regimes and their boundaries. We interpret the resulting structure with a conceptual climate–carbon cycle model that admits multiple coexisting equilibria, providing a mechanistic basis for state changes that switch between stable attractors under changing environmental forcings and perturbations. We connect these results to a biosphere vulnerability metric that incorporates biotic turnover with sample-standardized global diversity to show that vulnerability is systematically elevated near major regime transitions. These results suggest that transitions between persistent climate–carbon attractors provide a dynamical context for why some perturbation intervals coincide with heightened biospheric stress, beyond what is expected from more gradual background environmental changes alone.

Anterior and posterior retrosplenial cortex employ distinct strategies for egocentric–allocentric transformation in spatial coding

The transformation from egocentric to allocentric spatial coordinates is a critical process in neural spatial computation. The retrosplenial cortex (RSC) is hypothesized to serve as a central hub for this conversion, bridging egocentric perceptual inputs with allocentric representations in hippocampal and parahippocampal circuits. However, the regional and projection-specific organization of this function within the RSC remains poorly defined. In this study, we employed two-photon calcium imaging in freely navigating mice to dissect RSC spatial coding. We identified functional differences along the anteroposterior axis: the anterior RSC (aRSC) was predominantly characterized by egocentric boundary vector (EBV) coding, whereas the posterior RSC (pRSC) exhibited enhanced allocentric boundary representation. And it reveals that egocentric boundary vector cells (EBVCs) in the pRSC possess broader egocentric tuning than those in the aRSC. Despite this, pRSC shows tighter integration of allocentric head direction information, which converges specifically onto specialized conjunctive cells, resulting in a more selective boundary representation. Crucially, this work identifies functional differences along the RSC, where spatial coding transforms from more egocentric in aRSC to more allocentric in pRSC. Furthermore, it defines a specialized RSC to medial entorhinal cortex (MEC) projection pathway that is enriched for these global-tuned, conjunctive neurons, providing the MEC with a highly integrated, world-referenced spatial signal for constructing cognitive maps. Our findings elucidate a functional variance and projection-specific circuitry within the RSC, providing experimental evidence for models of hierarchical spatial processing.

Vibrio cholerae-synthesized tryptophan activates innate immune signaling in enteroendocrine cells via phosphorylation of the nuclear receptor ultraspiracle

The global demand and potential public health impact of oral antiviral treatment stockpile for influenza pandemics

Antiviral drugs are among the few countermeasures available during the critical interval between the emergence of a novel influenza pandemic and vaccine availability. Antiviral stockpiling is a key pandemic preparedness measure, yet existing stockpiling estimates vary widely and rest on outdated assumptions about healthcare-seeking behavior and drug-specific effectiveness—limitations that the COVID-19 pandemic and recent clinical trial evidence have made untenable. We developed a multiscale transmission model incorporating heterogeneous healthcare-seeking behavior and direct clinical estimates of antiviral transmission risk reduction to estimate country-specific demand and mortality impact across four pandemic scenarios in 186 countries. We find that baloxavir marboxil (BXM), due to its transmission-reducing potential, could avert 37 to 68% of mean pandemic deaths in the first epidemic wave, approximately double the impact of oseltamivir, while requiring a mean stockpile approximately 5 to 10% smaller (7 to 34% of the population, compared to 28 to 36% for oseltamivir). Uncertainty in viral load dynamics and transmission reduction benefits from clinical trials means that BXM’s impact could vary, but sensitivity analyses consistently suggest that BXM is likely to be more effective than oseltamivir. Under limited drug availability, priority should be given to treatment over postexposure prophylaxis. Although drug rationing for high-mortality populations (e.g., elderly) can substantially reduce BXM demand, doing so leads to greater total pandemic deaths. Critically, each week of delay in initiating antiviral distribution erodes impact by up to 3% of averted deaths, meaning that antiviral stockpiles must be accompanied by rapid deployment infrastructure to deliver their potential impact.

Plastron-mediated direct H2O2 synthesis

Abstract Gas-liquid-solid catalytic reactions are ubiquitous in the chemical industry and environmental chemistry. The efficacy of these reactions is constrained by the inherently low solubility of gases in liquids and poor mass transfer of reactants/products to/from the catalyst surface. We show that a gas layer trapped on a hydrophobic catalyst (plastron) substantially enriches local gas concentration, alleviating mass-transfer limitations and accelerating reaction rates. Using gold-palladium catalyst for direct hydrogen peroxide synthesis as a model, hydrogen/air plastrons on hydrophobic organosilica yield up to a 20-fold rate enhancement without sub-ambient temperatures, high pressures, or alcohol co-solvents. Combined with selective adsorption of butanethiol on gold-palladium nanoparticles, plastrons further inhibit undesirable decomposition pathways of hydrogen peroxide by repelling water from the catalytic center, eliminating the need for acid and halide promoters. This strategy serves as a new class of heterogeneous catalysts for gas-liquid-solid reactions, offering a route to chemical processes with reduced cost and carbon footprint.

The cortical scene processing network emerges in infancy, prior to independent navigation experience

Sighted people rely on vision to recognize and navigate the local environment. By adulthood, human cortex contains at least three regions that respond selectively to visual scene information, but it remains unknown when or how these regions develop. One hypothesis is that development of scene selectivity depends on passive exposure to the low-level visual statistics of scenes. Another hypothesis is that development depends on active experience using scene information to plan and guide navigation. Using ecological momentary assessment, we measured the quantity of forward-facing ego-motion and active navigation that infants experienced in the first months of life. By age 5 mo, infants cumulatively experienced around 340 h of forward facing ego-motion, almost exclusively passive. Next we used functional MRI in infants aged 2 to 9 mo to measure neural responses to scenes. Awake infants watched videos of ego-motion through real-world scenes, as well as videos of faces, objects, and scrambled videos. We found stronger responses to scenes than control conditions in the location of all three cortical scene regions. Responses in infant scene regions a) were dissociable from those in nearby face and object regions; b) could not be fully explained by low-level visual features; and c) were found even in subsamples of infants with no locomotor experience. Thus, the basic signature of scene selectivity emerges prior to independent navigation and with limited passive visual exposure to the diagnostic visual statistics of scenes.

Programmable radio-frequency calculations in electromagnetic-wave domain

Calcitriol–PKM2 axis drives transcriptional and metabolic reprogramming of ILCPs into intestinal dual-cytokine-producing ILC3s

Vitamin D deficiency is associated with dysregulated alloimmune responses, but the mechanisms by which its active metabolite calcitriol shapes innate lymphoid cell (ILC) development and function remain incompletely understood. Here, we elucidate how calcitriol directs the differentiation of bone marrow (BM) ILC progenitors (ILCPs) into anti-inflammatory ILC3s with therapeutic potential in alloimmune diseases. Using murine vitamin D models, integrated omics, 13 C-glucose tracing, humanized mouse models, and clinical samples, we show that calcitriol, through the vitamin D receptor (VDR), selectively promotes the expansion and differentiation of BM ILCPs into IL-10 + IL-22 + ILC3s that exert tissue-protective effects in the intestine. Calcitriol-primed BM ILCP cell therapy attenuates intestinal inflammation in an alloimmune setting. Mechanistically, a VDR–SYK axis triggers nuclear translocation of pyruvate kinase M2 (PKM2). Nuclear PKM2 phosphorylates STAT3 at Tyr705, forming a dimerization complex with c-JUN that drives Il10 transcription. Simultaneously, cytosolic PKM2 channels pyruvate into pyruvate carboxylase–mediated mitochondrial anaplerosis, sustaining oxidative phosphorylation while suppressing reverse electron transport-driven mitochondrial ROS production. In human studies, patients with severe alloimmune complications exhibit reduced circulating ILCPs and low serum 25(OH)D levels. Calcitriol-treated human CD117 + ILCPs efficiently generate IL-10-producing ILCs in vitro and in humanized models, potently suppressing alloreactive T cell responses. Collectively, calcitriol reprograms BM ILCPs via the VDR–SYK–PKM2 axis to generate dual-cytokine IL-10 + IL-22 + ILC3s, establishing PKM2 as a key immunometabolic target and supporting calcitriol-primed ILCP-based cell therapy as a promising approach for alloimmune diseases.

Quantifying environmental co-benefits of nitrogen-based crop restructuring and its implications on India’s interstate trade network

Abstract Addressing sustainability within food systems is challenging due to their multifaceted nature. Here, we evaluate crop-restructuring pathways for Indian agricultural system by integrating nutrient, water, greenhouse gas, economic, and interstate trade-network accounting. We show that the nitrogen-focused crop restructuring strategy reduces nitrogen surplus by 13.4% and water use by 18.6%. This approach maintains baseline calorie production, narrows the benchmarked cereal net-return deficit, and mitigates greenhouse gas emissions by 8.7%. Relative to water-focused restructuring, the nitrogen-focused strategy delivers larger reciprocal co-benefits by about 4.6-fold, resulting in a decrease in socio-environmental costs associated with nitrogen pollution of around $1.19 billion USD. The resulting agricultural restructuring substantially expands alternative-cereal trade in the interstate trade network. Overall, our analysis shows that integrating nutrient management into crop-restructuring strategies can support food-system sustainability in India and other resource-constrained agricultural systems.

Correction for Zhang et al., Host genetic regulation of rumen 6-hydroxymelatonin reduces methane emissions in dairy cattle

Neonatal inflammation disrupts a temporally restricted postnatal Numb-enriched microglial state in mice

Abstract Early-life microglia are diverse and support brain development beyond immune surveillance, but the transient states associated with postnatal maturation remain poorly understood. Here we show, using a time-resolved single-cell atlas of neonatal mouse brain immune cells, that a postnatal Numb -enriched microglial state emerges during early postnatal development, expands during the second postnatal week and subsequently declines. This state is characterized by neurodevelopment-related gene expression programs and distinct metabolic features. Trajectory inference, cross-atlas mapping and RNAscope validation support its temporal pattern. During the period when this state expands, microglial depletion preserves gross myelination but alters synaptic protein composition and disrupts dendritic and cortical layer maturation, particularly in the primary somatosensory cortex. Neonatal lipopolysaccharide challenge impairs the establishment of the Numb -enriched state and induces an early glycolytic response followed by recovery-phase inflammatory states. These findings identify a developmentally timed microglial state associated with cortical maturation and vulnerable to neonatal inflammation in mice.

Rapid microbial production of long-lived dissolved organic carbon in the global ocean

Marine microbes have long been regarded as central to replenishing the ocean’s reservoir of recalcitrant dissolved organic matter (RDOM). However, molecular-level evidence for their role remains inconclusive because RDOM persists for years to millennia, far exceeding timescales accessible to laboratory experiments, and because conventional analytical approaches lack the resolution to discern structural isomers of RDOM that confer functionally important differences in persistence. Using polarity-based liquid chromatography coupled to ultrahigh-resolution mass spectrometry capable of discriminating RDOM isomer clusters, we reveal that marine microbial consortia rapidly (≤ 90 d) convert diverse organic substrates into RDOM with extensive structural isomerism that closely mirrors natural seawater RDOM. A subset of these microbially derived RDOM compounds exhibits near-ubiquitous occurrence (> 99%) in a global dataset and accumulates progressively in the ocean’s interior. Together, our findings substantiate the direct microbial contribution to the long-lived oceanic carbon reservoir through the rapid diversification of RDOM isomers, a mechanism that contributes to sustaining the complexity and long-term persistence of the planetary-scale carbon reservoir.

A prolonged hydrothermal past at Santorini Caldera revealed by sedimentary trace metal and microbial signatures

Abstract Hydrothermal systems in volcanic calderas are critical in signalling volcanic unrest, forming ore deposits, and sustaining chemosynthetic microorganisms. Analysis of a ~3500-year sequence of sediments collected from the Santorini caldera, Greece, during International Ocean Discovery Program (IODP) Expedition 398 reveals the behaviour of a prolonged paleo-hydrothermal system. Sediment geochemical and metagenomic data record vigorous hydrothermal activity and metal fluxes for ~1100 years, within a 2270-year window between two major eruptions. Sediment hydrothermally-derived trace metals are significantly enriched over background (~200-fold for As and Hg, and 10–50-fold for Mn, Sb, Mo, and V), with long-term metal fluxes (9 t yr −1 As, 2.5 t yr −1 Cu, 7 kg yr −1 Ag) comparable to fluxes from present-day geothermal fields in the Taupo Volcanic Zone. Metagenomic analysis identifies elevated metal resistance genes—signals of microbial adaptation to heightened hydrothermal stressors. Here we integrate geological and genomic evidence to decipher the paleoenvironmental and biogeochemical history of the past hydrothermal system at Santorini caldera.

The free-living wellspring of symbiotic nitrogen fixation in <i>Bradyrhizobium</i>

The evolutionary origin of nitrogen-fixing symbiosis has been a long-standing question. To address this, we focused on Bradyrhizobium , a globally abundant bacterial genus that includes classic symbiotic lineages, which rely on the common Nod factor signaling pathway to form nodules, and close relatives capable of fixing nitrogen in a free-living state. We isolated 88 strains carrying the key genes for nitrogen fixation ( nif ) from nonlegume environments and analyzed them alongside 586 public Bradyrhizobium genomes harboring these genes to reconstruct a robust phylogeny of nif genes. Analysis suggests that the earliest-diverging nif lineages are members capable of free-living nitrogen fixation, supporting the interpretation that this lifestyle is ancestral. The Nod factor-dependent symbiotic lineages are polyphyletic, with our data supporting at least three independent origins via horizontal acquisition of symbiosis islands. This evolutionary history is reflected in a genomic dichotomy: lineages capable of free-living nitrogen fixation possess a conserved nif island architecture that consistently includes the oxygen-protective gene glbO , whereas the symbiotic nif -associated regions are highly variable and universally lack glbO . Using both loss-of-function and gain-of-function genetic approaches, we show that glbO contributes significantly to nitrogenase activity under free-living conditions, whereas it is dispensable within the protected nodule environment. This work provides a framework for the evolution of nitrogen-fixing symbiosis, supporting the view that free-living nitrogen-fixing ancestors gave rise repeatedly and independently to symbiotic lineages in Bradyrhizobium .

Quantum-memory-assisted on-demand microwave-optical transduction