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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.
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.
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.
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.
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.
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.
Correction for Zhang et al., Host genetic regulation of rumen 6-hydroxymelatonin reduces methane emissions in dairy cattle
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.
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 .
Correction for Madangopal et al., Distinct prelimbic cortex ensembles encode response execution and inhibition
Ancestral gene content estimates under gain–loss–duplication depend on the chosen observation threshold
Dual control of PIP2 drives germline/soma segregation in <i>Drosophila</i>
Embryonic cell fate decisions require precise spatial coordination between competing lineage determinants. In the syncytial Drosophila embryo, primordial germ cells (PGCs) and posterior endoderm are specified at the posterior pole in overlapping domains, creating a conflict between germline and somatic fates. PGC formation depends on germ granules, which locally promote production of the phospholipid PIP2 at the posterior plasma membrane. PIP2 regulates actin dynamics leading to membrane protrusions that generate PGCs. We find that the posterior endoderm determinant, the receptor tyrosine kinase (RTK) Torso, antagonizes germ granule activity by activating phosphoinositide 3-kinase (PI3K) which converts PIP2 to PIP3. PIP3 prevents PGC formation, ensuring endoderm specification. Loss of Torso or PI3K expands the posterior PIP2 domain, increasing both the number and spatial extent of PGCs. Germ granules counteract this activity through production of the E3 ubiquitin ligase Germ cell-less (Gcl), which locally eliminates Torso and prevents PI3K-mediated PIP2 depletion at the posterior pole. In gcl mutants, PIP3 accumulates at the posterior membrane and PGC formation fails, a defect that can be partially rescued by targeted posterior expression of the PIP3 phosphatase Pten. Together, these findings demonstrate that mutual antagonism between germ granules and Torso signaling generates a PIP2/PIP3 boundary in the plasma membrane that governs the earliest germline–soma fate decision. Our work reveals how opposing maternal cues can be integrated at the level of membrane phospholipids to pattern cell fate during the earliest stages of development.
Can stimulating ownership increase fertility: Evidence from housing interventions in China
Declining fertility and the emergence of very low TFR’s in the Asian economies has increased the focus on how to change the direction of the fertility trend. Several countries in Europe and Asia have explored a variety of stimulus packages to increase the overall TFR. In this research we review those policies and examine one of those interventions which has the potential to stimulate fertility—the role of access to housing. The core of housing approaches to stimulating fertility is to make housing more accessible and to use various forms of credit assistance with the aim of making ownership easier and more attractive to young families. The research asks how effective are these approaches to reversing the decline in fertility? And, are they a solution to very low fertility? The results provide some evidence that the focus on housing stimulus packages may increase fertility although most successfully for socioeconomically advantaged households.
Abrupt transition to irreversible damage in the overdrafted Sacramento Valley aquifer system
Groundwater extraction decreases water pressure in aquifer systems, causing reversible or irreversible deformation of the water-bearing layers that manifests as recoverable or permanent displacements of the land surface, respectively. Detecting and forecasting when and where an aquifer system transitions from a reversible, poroelastic regime, to an irreversible, inelastic regime remains a crucial challenge given the complex, heterogeneous nature of aquifer systems. Here we leverage high-resolution measurements of ground deformation and groundwater levels from 2016 to 2022 to characterize both regimes at the regional scale and show that a critical transition occurred in large areas of the Sacramento Valley during California’s 2020–2022 extreme drought. Our analysis reveals that, while deformation remained primarily poroelastic during the 2016–2020 interdrought period, land subsidence in areas of intense groundwater extraction accelerated abruptly in 2021, with subsidence rates exceeding the inferred poroelastic rates by several decimeters per year. Such rapid and extensive land subsidence indicates severe inelastic compaction and loss of storage capacity of the underlying aquifer system, which pose a serious threat to California’s water resources and infrastructure. A comparison of present-day deformation with historical groundwater levels reveals that this abrupt transition was not predictable based on the available groundwater records alone.
Discovery of a phenazine–thiol conjugase from sparse data using genome-informed machine learning
Machine learning has enabled powerful biological discoveries using models trained on large datasets. However, for many important biological questions, such as identifying enzymes that transform understudied substrates, sparsity of training data is often a major bottleneck. Here, using phenazine natural products as a case study, we show that integrating genome-informed data augmentation with contrastive learning in protein language space enables identification of phenazine-interacting proteins starting from only 14 known phenazine modifying sequences. We name this approach ML-CITO (Machine Learning for genomic Context-Informed Transferable discOvery). Applying this framework led to the discovery of PTC (phenazine–thiol conjugase), an enzyme known to catalyze phenazine thioconjugation, a phenazine modification reaction long observed but previously presumed to occur only through nonenzymatic chemistry. In silico simulation and experimental measurements demonstrate that PTC binds to both phenazine and glutathione as substrates. Recombinant expression and biochemical characterization reveal that PTC promotes glutathione-dependent modification of phenazines, yielding distinct reaction outcomes that depend on substrate identity. Although thiol-conjugated phenazine products exhibit reduced toxicity to bacterial cells, deletion of the gene encoding PTC does not confer a strong fitness disadvantage, illustrating how direct learning of sequences can uncover relevant enzymes that might evade phenotype-based genetic screens. Together, these results demonstrate that coupling comparative genomics with protein machine learning can convert “small data” typically outside the scope of machine learning into actionable predictive power, thereby facilitating enzyme discovery.
Coupled metabolic reactions relevant to early biological evolution
Dominant functional group explains global bird diversity responses to farmland abandonment
Reversing biodiversity declines will require redesigning agricultural landscapes and their management. Farmland abandonment and intensification are emerging as major drivers of biodiversity changes, and their consequences vary widely from negative to positive among continents. Despite decades of research on agricultural biodiversity, no generalizable framework has been established to predict these variations globally, hindering the development of effective conservation strategies. Here, we combine broad-scale, multiseason avian field surveys across Japan with a global meta-analysis spanning four continents. In field surveys, we compared avian species richness among 2-ha plots in abandoned farmland (≤ 50 y since abandonment), traditional farmland, and intensive farmland, controlling for the surrounding land-use cover. We showed that the dominant functional group robustly explains the direction and strength of community-level responses to abandonment and intensification. When mature-habitat species comprise over 50% of communities, abandonment enhances species richness by over 240%, reaching levels comparable to natural wetlands. Abandoned farmlands hold the potential to offset past biodiversity declines and thus merit considerations for inclusion within the conservation area networks. Conversely, when disturbed-habitat species comprise more than 48% of communities, abandonment and intensification reduce species richness, underscoring the importance of biodiversity-friendly farming. This study provides a basis to understand how to address varied spatial variations in biodiversity responses to management and land-cover changes—a long-standing hurdle in conservation science. Complex bird diversity responses can be predicted globally by simply identifying the dominant functional group, thereby helping develop the most effective conservation strategies. Transferability beyond birds and across taxa should be evaluated empirically.
From fruit flies to football: Violent <i>Drosophila</i> provide novel ideas about CTE
Climate warming and atmospheric deposition jointly accelerate the Antarctic Peninsula atmosphere–glacier–land–ocean mercury loop
Mercury (Hg) is a toxic pollutant of global concern that threatens ecosystem and human health. Its cycle is being jointly reshaped by anthropogenic emissions and polar warming, yet the response of the Antarctic system remains poorly constrained. Here, we reconstruct the past 200 y of Hg source–sink dynamics in the Antarctic Peninsula (AP), Antarctica’s fastest-warming region with the most pronounced glacier melting, by combining geochemical and isotopic records from 16 sediment cores collected across the AP shelf, with a developed observation-constrained multimedia Hg budget model. We find that despite its remoteness from anthropogenic emission sources, the modern AP shelf exhibits an Hg accumulation rate of 93 ± 58 µg m −2 y −1 , twice the global shelf average. Since industrialization, this accumulation rate has increased by 160%, making the AP one of the major hotspots of marine Hg enrichment. The model further reveals that this acceleration is driven by two coupled mechanisms: 1) enhanced atmospheric deposition and expanding open water strengthen the direct uptake of atmospheric Hg by seawater within the atmosphere–ocean loop, and 2) ice melt and erosion activate the long-overlooked atmosphere–glacier–land–ocean loop, remobilizing legacy Hg stored on land. The coupling of these two loops has increased ice melt-driven terrestrial Hg release by 550% and air–sea exchange by 350%. Thus, climate warming is turning the large historical Hg reservoir in Antarctica into an active secondary pollution source, amplifying polar Hg pollution risk.