eLife

Morphogenetic processes during animal development are remarkably invariant (Duboule, 1994; Hall, 1997; Kalinka et al., 2010; Raff, 1996). This stability is established by the interaction between genetic determination of developmental progression and the constraints imposed by the surrounding embryonic environment (Busby and Steventon, 2021; Gilmour et al., 2017; Gorfinkiel and Martinez Arias, 2021). We discovered that the germ band extension process in Drosophila is rather variable: instead of extending straight towards the head, the germ band tends to twist to the side. Through a combination of experiments and theory, we demonstrated that Scab integrin-mediated attachment to the vitelline envelope stabilizes the germ band and supports its straight extension. Our quantification of germ band extension dynamics also revealed a consistent handedness to the twist of the germ band. We showed that this left-right asymmetry can be altered by manipulating the expression of Myo1D, the molecular determinant of chirality in Drosophila (Lebreton et al., 2018). Our data thus suggest that Myo1D expression causes the early gastrulating blastoderm epithelium to already exhibit inherent chirality and that the resulting destabilization of germ band extension is suppressed by Scab-mediated friction between the blastoderm and the vitelline envelope.

How neighboring sarcomeres redistribute timing while a cardiomyocyte continues to beat, and how that coordination shapes mean HSO amplitude in the segment-average trace, remain unresolved. We reanalyzed sarcomere-length recordings from five consecutive sarcomeres in each of seven living neonatal rat cardiomyocytes and represented each valid time point by the four neighboring-pair phase relations that define a 16-state local phase network. During warming-induced hyperthermal sarcomeric oscillations (HSOs), the fraction of time with trackable local phase relations increased from 0.298 before warming to 0.956 (paired Wilcoxon P = 0.0156), enabling direct analysis of local reconfiguration. Successive local states were almost always connected by Hamming-1 edges, meaning that only one neighboring-pair relation changed at a time (34/35, 97.1%, before warming; 216/230, 93.9%, during HSOs). HSOs also increased occupancy of anti-phase-rich states with three or more anti-phase neighboring pairs (0.254 to 0.509, P = 0.0156). In a complementary cycle-level analysis of the same HSO window, Yvalid, the HSO amplitude of the valid-sarcomere mean trace, was closely approximated by the product of mean local HSO amplitude (A) and weighted synchrony across valid sarcomeres (Rw; pooled r = 0.992, normalized mean squared error = 0.015, {beta}1 = 0.948, {beta}0 {approx} 0). To link the binary local-state description to this continuous synchrony term, we derived a simple state-based synchrony factor from the local phase patterns; cycles with higher values showed higher Rw (cell-adjusted {beta} = 0.197, P = 0.0165). Blocked cross-validation showed that the A x Rw model markedly outperformed an additive alternative (pooled normalized mean squared error 0.0138 vs 0.1006), whereas simple history terms changed error only marginally. HSOs therefore do not reflect unstructured local disorder. Rather, they are characterized by a constrained neighboring-sarcomere phase topology, and mean HSO amplitude in the same segment is largely captured by a cycle-level relation between local amplitude and synchrony.

Cholinergic efferent neurons modulate sensory signaling in the peripheral vestibular system, but the cellular mechanisms underlying this modulation remain incompletely understood. In mammalian vestibular organs, type II hair cells (HC-II) receive efferent input and express 910-containing nicotinic acetylcholine receptors (nAChRs) that activate SK potassium channels and produce rapid hyperpolarization. Here, we examined the functional role of mAChRs in mouse vestibular HC-II using whole cell patch clamp recordings in whole tissue preparations of crista ampularis (P13-P17, male and female mice). Activation of mAChRs with oxotremorine-M inhibited voltage dependent outward currents, with the largest effects at depolarized membrane potentials. Further experiments revealed that this effect was mediated by inhibition of large conductance potassium (BK) channels: the BK antagonist iberiotoxin mimicked and occluded the muscarinic effect and muscarinic suppression was absent in mice with BK channel mutations. In contrast, blockade of SK channels with apamin did not prevent the muscarinic effect, indicating that mAChR signaling specifically targets BK mediated currents. In current clamp recordings, mAChR activation enhanced depolarization during strong current injections, consistent with increased hair cell excitability when BK channels were suppressed. These findings identify a previously unrecognized muscarinic efferent pathway in vestibular hair cells and reveal complementary cholinergic mechanisms that suppress responses to weak stimuli while enhancing responses to strong stimulation, providing a cellular basis for dynamic gain control in the vestibular periphery. Significance statementVestibular efferent signaling shapes how head movements are encoded, but its cellular mechanisms are incompletely understood. While nicotinic acetylcholine receptors are known to reduce excitability of type II vestibular hair cells (HC-II) via small conductance (SK) channels, the role of muscarinic receptors has remained unclear. Here we show that muscarinic receptor activation selectively inhibits large conductance (BK) potassium channels in HC-II, enhancing excitability during strong depolarization. This muscarinic pathway is mechanistically distinct from nicotinic signaling and operates at a different voltage range. Together, these findings reveal a dual efferent control strategy that differentially regulates hair cell responses to slow versus fast head movements, providing new insight into how the vestibular system filters sensory input across dynamic ranges.

Neighboring sarcomeres in a cardiomyocyte need not move in perfect synchrony, but it is unclear whether their local timing differences during hyperthermal sarcomeric oscillations (HSOs) are random or organized. Using the same five-sarcomere recordings that previously revealed a constrained 16-state neighboring-pair topology and an amplitude-synchrony relation for the segment-mean rapid signal (Shintani, 2026), we reanalyzed each fast HSO cycle as one local coordination summary. A topology-based circular coordinate showed that the 16 discrete patterns lie on a continuous within-cell order: adjacent positions were enriched for Hamming-1 changes and cycle-to-cycle angular drift was slower than expected by chance. Because each cell has an arbitrary angular zero point and direction, we aligned the cell-wise circles using shared local states as landmarks. This improved same-state concentration across cells from 0.582 to 0.852 (P = 0.0013). The clearest biological translation of the aligned coordinate was mismatch placement along the observed five-sarcomere segment. Aligned angle predicted edge-biased mismatch placement (joint P = 1.15 x 10-6), whereas raw angle did not (P = 0.55). Beat timing was weaker and signed strain less robust. These findings support a mesoscale view in which local HSO nonuniformity is structured: neighboring sarcomeres share a rephasing order, and that order is most readably expressed by where the local mismatch pocket lies along the chain. Significance statementCardiac contraction must convert noisy local events into a stable beat. This study identifies a measurable intermediate-scale variable in living cardiomyocytes. Fast HSO cycles do not wander randomly among local coordination patterns. After cross-cell alignment, they occupy a shared rephasing compass, and the clearest biological readout of that compass is where a local mismatch pocket sits along the observed five-sarcomere segment. This gives a concrete way to describe how local nonuniformity can remain structured rather than merely disruptive. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=51 SRC="FIGDIR/small/714639v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1d0d6deorg.highwire.dtl.DTLVardef@1cab2c8org.highwire.dtl.DTLVardef@9f9cadorg.highwire.dtl.DTLVardef@e75263_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Five consecutive sarcomere-length traces were condensed into one local coordination summary per fast HSO cycle. A topology-based circular coordinate revealed a within-cell order, and cross-cell alignment turned that order into a shared rephasing compass. The clearest biological translation of that compass was where the local mismatch pocket was positioned along the observed five-sarcomere segment. C_FIG

Crosstalk across two major receptor families involved in signal transduction, namely receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs), have been observed at different levels of their signaling cascades. Using newly developed enhanced bystander bioluminescence resonance energy transfer (ebBRET)-based biosensors that monitor the recruitment of SH2 domains to activated RTKs, we assessed the ability of GPCRs to modulate cellular localization of SH2 domains. Receptor-mediated activation of either Gq/11 or G12/13 but not Gs or Gi/o (e.g., thromboxane A2 receptor, TP, and type-2 protease activated receptor, PAR2) resulted in the plasma membrane (PM) dissociation of SH2 domains derived from RTKs effectors such as GRB2, STAT5 and PLC{gamma}1. The role of Gq/11, G12/13, Rho and downstream kinases in the subcellular SH2 domain redistribution was further confirmed using both pharmacological and genetic approaches. BRET imaging and spectrometric analyses showed that the dissociation of SH2 domains from the PM was accompanied by their accumulation in the nucleus and a reduction in RTK signaling activity, as determined using a STAT5 transcriptional assay. The effect of Gq/11 and G12/13 activation on STAT5 transcriptional activity was observed both in engineered systems and in HeLa cells endogenously expressing all the components of the regulatory mechanism. The Gq/11 / G12/13-mediated redistribution of SH2 domain-containing proteins represents an undescribed mechanism through which GPCRs regulate RTKs activity. Significance StatementThis study reveals a novel crosstalk mechanism between G protein coupled receptors and receptor tyrosine kinases showing that Gq/11 and G12/13 activation triggers Rho-dependent translocation of SH2-containing effector proteins, such as GRB2, PLC{gamma}1 and STAT5. This process causes compartmentalization inside the nucleus and thus reduces their availability at the plasma membrane, leading to attenuated RTK responses.

The morphology of the palate has long constituted the primary basis for differentiating between the two deepest clades of crown group birds, Neognathae and Palaeognathae. However, published literature on the bird palate is dominated by classical anatomical descriptions pre-dating the advent of contemporary three-dimensional imaging techniques, hindering our understanding of bird palate disparity and development. Pterygoid segmentation, the process by which the rostral portion of the pterygoid separates and fuses with the palatine during ontogeny in neognathous birds, remains a poorly understood aspect of avian cranial development despite giving rise to an important component of the cranial kinetic system. Here, we use micro-computed tomography to explore ontogenetic change of the palate during the process of pterygoid segmentation across an unprecedentedly broad taxonomic sample of immature and mature birds. We found that direct evidence of post-hatching pterygoid segmentation was restricted to the major avian subclade Neoaves. Based on morphological and topological similarities, we hypothesise that the rostral projection of the pterygoid observed in Anatidae/Anseres and potentially Anhimidae and Megapodiidae, which we term the hemipterygoid process, is homologous with the hemipterygoid of neoavians, though it does not undergo segmentation. We posit that the origin of a discrete hemipterygoid (as observable in some crownward stem-birds) originated prior to the origin of the process of pterygoid segmentation; however, it remains ambiguous whether pterygoid segmentation is a synapomorphy of Neornithes, Neognathae, or Neoaves. Overall, our study clarifies the process of avian pterygoid segmentation and raises new questions regarding the major morphological modifications that have characterised the evolutionary history of the avian bony palate.

The influence of explicit strategies on implicit recalibration during visuomotor adaptation has become a central question in motor learning. Because the two systems operate in tandem, explicit strategies could indirectly influence implicit recalibration. However, explicit strategies are not unitary: they may rely on algorithmic-based computations or memory-based retrieval of cached solutions. This raises the possibility that different strategy implementations interact with the cerebellar-based implicit recalibration system in qualitatively distinct ways, especially given that these strategies likely rely on different frontoparietal networks. Here, we tested whether the type of explicit strategy modulates implicit recalibration. Across a set of experiments, we observed subtle differences in the spatial profile of implicit generalization: the algorithmic strategy produced a broader generalization pattern than the retrieval strategy, even after controlling for intertrial decay, generalization structure, and between-target interactions. While this pattern is suggestive of greater flexibility afforded by algorithmic strategy use compared to memory-based retrieval, it could instead arise from increased variability in explicit aiming, which constitutes the input data driving implicit recalibration. Indeed, when we isolated the direct contribution of each strategy to implicit recalibration by rigorously controlling for reach variability and using error-clamp feedback to ensure uniform implicit learning conditions, we found no difference in implicit recalibration across strategies. Together, these findings suggest that while algorithmic and retrieval strategies differ in their behavioral signatures and influence the movement plan, the implicit recalibration process itself remains rigid with respect to the strategy employed. Significance StatementWhether explicit strategies influence implicit recalibration remains debated - a question complicated by the fact that different training conditions give rise to distinct forms of strategy. Because algorithmic and retrieval-based strategies engage partially dissociable frontoparietal networks, they may differentially interface with cerebellar subregions, yielding distinct effects on implicit recalibration, potentially reconciling prior mixed findings. Our results indicate that, once the first order spatial and temporal statistics that typically covary with these different strategies are matched, the strategies themselves do not directly influence implicit recalibration. Instead, the cerebellar-based implicit recalibration system faithfully updates the sensorimotor mapping simply based on the training data it is provided. These findings support prior work suggesting strong independence and stereotyped behavior of implicit recalibration.

The deepest phylogenetic divergence within crown birds (Neornithes) is that between the reciprocally monophyletic Palaeognathae and Neognathae. Extant palaeognath diversity comprises the iconic flightless "ratites" (ostriches, rhea, kiwi, cassowaries, and emu), as well as 46 species of volant tinamous in Central and South America (Billerman et al., 2020). Although the earliest stages of palaeognath evolution remain shrouded in mystery due to a sparse fossil record, a group of apparently volant extinct palaeognaths from the Paleogene of Europe and North America, the lithornithids, can help to clarify palaeognath origins. Here, we use high resolution microCT scanning to characterize the morphology of two lithornithid specimens from the early Eocene (Ypresian) London Clay Formation: the neotype of Lithornis vulturinus (NHMUK A5204), from the Isle of Sheppey, Kent, England, and a newly discovered clay nodule containing lithornithid postcranial remains from the nearby locality of Seasalter. This three-dimensional dataset reveals bones from the L. vulturinus neotype that are partially or completely covered by matrix, allowing us to redescribe this critical specimen in new detail and present a revised differential diagnosis of L. vulturinus. We refer the new specimen from Seasalter to L. vulturinus on the basis of apomorphies such as a proximally directed lateral process of the coracoid, caudally divergent lateral margins of the sternum, an arcuate deltopectoral crest, as well as its provenance from a nearby penecontemporaneous locality. The Seasalter specimen contains abundant postcranial material that provides new insight into bones damaged or missing in the neotype, including two undamaged scapulae bearing the hooked acromion that is a diagnostic feature of lithornithids, two complete coracoids, and a nearly complete three-dimensionally preserved sternum. Its estimated body mass is one third larger than that of the neotype, indicating intraspecific variation within L. vulturinus that may reflect sexual dimorphism. Molecular divergence dates and Cretaceous neognath fossils indicate the presence of total-clade palaeognaths before the K-Pg mass extinction event; detailed anatomical descriptions of Paleogene palaeognaths will assist in the identification of the first total-clade palaeognaths from the Cretaceous, and provide insight into how and when flight was independently lost among Cenozoic crown palaeognaths.

PLC{beta} enzymes cleave PIP2 from the plasma membrane, producing IP3 and DAG, which regulate intracellular Ca2+ levels and protein kinase C activity, respectively. They are regulated by GPCR signaling through the G proteins G{beta}{gamma} and Gq and have been shown to function as coincidence detectors for dual stimulation of Gq and Gi-coupled receptors via these G proteins. PLC{beta}s are aqueous-soluble enzymes, but partition onto the membrane surface to access their lipid substrate. We previously demonstrated that membrane recruitment and orientation of the catalytic core on the membrane surface underlie G{beta}{gamma}-dependent regulation of PLC{beta} enzymes. Using macrophages as a model system, where PLC{beta} signaling is essential for responses to infection and tissue injury, we investigated the contribution of G{beta}{gamma}-dependent regulation and membrane recruitment of PLC{beta} in the context of endogenous signaling. By measuring Ca2+ mobilization, we demonstrate that both Gi and Gq-coupled receptors independently stimulate PLC{beta} activity, illustrating that G{beta}{gamma} alone is sufficient to activate PLC{beta} in certain contexts. Using total internal reflection and stimulated emission depletion microscopy, we demonstrate that most of the PLC{beta}3 in the cell is localized away from the plasma membrane at rest but is rapidly recruited to the plasma membrane upon stimulation by both Gi and Gq-coupled receptors, illustrating that both G{beta}{gamma} and Gq recruit PLC{beta} to the plasma membrane. These results support an updated model for G protein-dependent regulation of PLC{beta} enzymes, where G{beta}{gamma}-induced regulation in the absence of Gq is context dependent and dictated by the local concentration of receptor, G proteins, and PLC{beta}. Significance StatementPLC{beta} enzymes are critical mediators of signal transduction with roles in neuronal, cardiac, and immunological signaling. Despite this importance, many aspects of their function and regulation remain poorly understood. PLC{beta}s are aqueous soluble but must partition onto the membrane surface to access their lipid substrate, which enables regulation at the partitioning step, the catalytic step, or both. We previously demonstrated that membrane recruitment and orientation of the catalytic core on the membrane surface underlie the PLC{beta} regulation by one effector, G{beta}{gamma}. Using macrophages as a model system for physiological signaling, we demonstrate that G{beta}{gamma} is capable of independently activating PLC{beta} via membrane recruitment under the conditions of endogenous signaling.

As fertility declines with age, unmated senescing female animals experience an increasing need to secure a mate. Elevated pheromone production and extended pheromone release are known mechanisms underlying deceptive sexual signalling in relation to the progressive age of signalers but both mechanisms incur elevated metabolic expenses. Here, we report an intricate new mechanism of deceptive signalling that allows unmated senescing female false widow spiders, Steatoda grossa, to conserve metabolic costs for silk and pheromone production while still achieving sustained attractiveness to mate-seeking males. Senescing females produced "honest" state-dependent signals, saving metabolic expenses by building webs with fewer silk strands and depositing less courtship-inducing contact pheromone on their web. However, senescing females concurrently engaged in deceptive signalling in that they remained as attractive to males as young(er) females by accelerating the hydrolytic conversion of web-borne contact pheromone components to air-borne mate-attractant pheromone components. Accelerated dissemination of mate-attractant pheromone from webs was correlated with an age-linked increase in web pH, which we posit enhanced the enzymatic activity of a web-borne carboxyl-ester-hydrolase. Essentially, senescing females concealed their low residual reproductive value by sustained high-level pheromone dissemination. Because the lifetime reproductive output of females declined with age at mating, old females are indeed poor prospective mates and thus deceptive signalers. Their deceptive mate-attractant signals seem evolutionary stable because they rarely remain unmated. Moreover, the males reproductive fitness benefit of mating with an old(er) female - and thus siring fewer offspring than mating with a young female - may still outweigh the costs of rejecting an old female and resuming mate search for a young female, a search which may not be successful.

Despite longstanding recognition of sex as a biological variable, its integration into biomedical research remains inconsistent. Numerous publishers have introduced policies to improve reporting and inclusion of sex and gender, including Nature, which requires authors to complete a Life Science Reporting Summary documenting sex inclusion. Here, we evaluated the effectiveness of these policies by examining sex inclusion and reporting practices in all original research articles involving humans, vertebrates, or cell lines published in Nature in 2025 (N=513). Nearly two-thirds of articles included both sexes (62.7%); however, inclusion was often nominal. Of these articles reporting inclusion of both sexes, 33% did not maintain inclusion across experiments, used markedly unbalanced sex ratios ([≥]2:1), or alternated between male- and female-only experiments. Another 45.5% of these articles reporting inclusion of both sexes did not report sample size by sex, so it cannot be ascertained whether sex inclusion was maintained across experiments or balanced by sex. Single-sex studies accounted for approximately one-fifth of articles. While male-only and female-only studies occurred at similar overall rates, male-only studies were more than four times more likely to address conditions affecting both sexes while female-only studies were more likely to address sex-specific conditions (e.g., ovarian cancer). Only 7% of articles explicitly analyzed sex as a discovery variable for at least some analyses. These findings suggest that transparency-focused reporting summaries alone are insufficient to ensure sex inclusion and/or meaningful analytical integration of sex. As a leading biomedical journal, Nature plays a central role in shaping research norms; without stronger editorial expectations, reporting requirements risk reinforcing male-default assumptions rather than advancing rigor and generalizability.

Motor adaptation involves the parallel operation of implicit recalibration and explicit re-aiming processes. During naturalistic learning, these systems interact, producing compound behavioral outputs that reflect their combined contributions. It remains unclear whether simultaneously engaged implicit and explicit processes form a single unified representation, or generate parallel memory representations that are merely co-expressed, and how consolidation transforms such representations. We addressed these questions across three visuomotor adaptation experiments (n = 120), in which the implicit process was engaged via gradual cursor rotation and the explicit process via target jump, by systematically manipulating the sequence of learning and the timing of expression. Immediately after learning, behavior reflected an inflexible, integrated memory that could not be decomposed by changing task demands. Following 24-hour consolidation, however, expression became component-selective, with implicit or explicit contributions retrieved in response to task demand. This reorganization had direct consequences on relearning, producing facilitation when the expressed and relearned components matched and interference when they mismatched. Moreover, when implicit adaptation was stabilized prior to compound learning, consolidation preserved the updated state rather than the original implicit representation. Together, these findings demonstrate that consolidation does not merely stabilize compound motor memories. Instead, it actively reorganizes them, transforming the initially integrated representations into independent, context-dependent components.

The subiculum (SUB) is the main output structure of the hippocampus, influencing diverse behaviors through its widespread cortical and subcortical connections. Our previous work creating the mouse Hippocampus Gene Expression Atlas (HGEA) identified four genetically distinct cellular layers across five columnar domains in the SUB, with gene expression boundaries corresponding to distinct connectivity patterns and brain-wide networks involved in spatial navigation, social behavior, and neuroendocrine regulation (Bienkowski et al., 2018). Using the Digital Brain Mouse Projectome Atlas (MPA) tool, we conducted virtual tract-tracing to assess whether connectivity patterns of single-neuron 3D reconstructions aligned with HGEA-defined SUB cell types (Qiu et al., 2024). We classified 689 SUB projection neurons into 12 HGEA cell-type groups based on their laminar and columnar distributions, whose spatial organization recapitulated HGEA-defined 3D boundaries. Using this population sample, we performed a SUB cell-type census, characterized neuronal heterogeneity and projection prevalence, identified common and rare connectivity motifs and axonal collateralization patterns, and defined distinct projection themes for each SUB cell type. Together, this analysis integrates single-neuron and population-level data to advance understanding of SUB cell type organization and its contributions to brain-wide networks regulating diverse behaviors.

Human sensorimotor adaptation critically depends on the ability to map sensory inputs onto motor outputs. While this process was once thought to rely primarily on cerebellar-dependent implicit recalibration, recent work has revealed that explicit, cognitive strategies, relying on working memory and executive function, play a substantial role. However, it remains unclear whether explicit strategies can scale to support learning of complex sensorimotor mappings. Here, we parametrically tested the capacity of explicit strategies to solve a complex visuomotor rotation task by varying the number of target-rotation pairings that participants had to acquire. In experiment 1, participants were tasked with learning four visuomotor mappings - well within working memory capacity, based on prior studies. We found that participants achieved near-perfect compensation, which was best explained by the retrieval of stored target-rotation associations, rather than by computationally demanding algorithmic strategies. In experiment 2, in an attempt to push beyond working memory capacity, participants were tasked with learning eight mappings. Unlike in experiment 1, here we found that participants failed to fully compensate for the rotations, reaching asymptotic performance of only [~]50%, despite evidence of continued strategic engagement. This performance limit was fully predicted by a parameter-free working-memory model where performance is a mixture of a fixed number of stored target-rotation associations and random guessing. These findings reveal a cognitive "bandwidth limit" on the effectiveness of strategies for sensorimotor adaptation: when task complexity exceeds this limit, adaptation plateaus, defining a fundamental constraint on how far higher-order cognition can go to support learning. Significance StatementHuman learners often compensate for perturbations in sensorimotor mappings by deploying explicit, cognitive strategies, but the scalability of these strategies for more complex tasks remains unknown. Here, we tested how performance changes as people must simultaneously learn an increasing number of distinct visuomotor rotation mappings. When presented with only a small set, participants have little difficulty - they learn by opting to forgo computationally demanding algorithmic strategies in favor of storing and retrieving target-specific solutions from working memory. However, as the number of mappings grows, this response caching strategy fails, with performance plateauing in a manner that is consistent with a capacity-limited memory bottleneck. These results highlight the critical constraint that working memory imposes on the utility of explicit strategies for sensorimotor adaptation in complex tasks.

Smell allows animals to find food, avoid danger, and communicate through the binding of odorants to chemosensory receptors on olfactory sensory neurons. The vision-priority hypothesis predicts an antagonistic relationship between olfaction and vision, in which olfactory ability increases as visual acuity decreases along evolutionary lineages, a tradeoff that often occurs through expansion and contraction of chemosensory receptor gene families. The Mexican tetra (Astyanax mexicanus), a fish species with both sighted surface-dwelling and blind cave-dwelling populations, presents an ideal model for exploring the mechanisms underlying this tradeoff. Here we show that although cavefish can sense odorants at lower concentrations than surface fish, they do not have an expanded repertoire of chemosensory receptors, increased sensory neuron number or density, or enhanced expression of receptors compared to surface fish. Instead, cavefish have physiological adaptations to the olfactory epithelium, including more motile cilia and decreased flow rate through the olfactory pits. Pharmacological attenuation of flow rate in the olfactory pits in surface fish increased visits to the odorant source, suggesting that the reduced flow rate in cavefish is an adaptation leading to better foraging. This unexpected evolutionary path to enhanced olfaction as a compensation for loss of vision underscores the need for mechanistic understanding of comparative genomics.

The fossil record is the most important tool in palaeosciences, so continually reviewing and attempting to reduce biases in its collection is necessary to curate the best possible record of past life on Earth. Biases in the fossil record are introduced through both biological processes and data collection. Here we have investigated the extent to which anthropocentric data collection has contributed to sampling bias in the assembly of the current fossil record. We have found that the current fossil record (represented in this study by the NOW database) is anthropocentrically biased, both temporally and spatially. Specifically, fossil locality density is higher in time periods when hominins are found, and in known hominin-bearing locations. This demonstrates the need to stop essentializing the narrative of human evolution in paleoscience to reduce bias in sampling of fossil localities.

Public health monitoring traditionally relies on active reporting from diverse data sources, including clinical and administrative data, disease registries, and population-based surveys. Yet these surveillance methods often face challenges such as incomplete reporting, time lags, and variable population coverage. Meanwhile, diagnostic laboratories routinely generate vast volumes of operational data that are currently untapped for public health monitoring. As these data are not collected for scientific inquiry or population-level surveillance, they often lack formal validation and may contain sensitive information. We developed a Bayesian hierarchical model to decompose aggregated laboratory assay volume data for 1.1 billion clinician-ordered assays across the U.S. from October 2019 to March 2023 into interpretable epidemiological and health system signals. The signals generated by these models were compared with known perturbances to health systems, such as the COVID-19 pandemic. The method does not rely on assay outcomes or individual-level data, providing quantitative signals of epidemiological trends and health system responses while protecting both the privacy of patients and commercially sensitive information. Temporal analysis reveals qualitatively different responses of assay volumes to major public health events, identifying assays whose use paralleled surges in hospitalization rates during the COVID-19 pandemic documented through traditional public health reporting structures. This framework suggests that routine operational data can be used to augment traditional surveillance by identifying anomalous patterns for expert epidemiological investigation. To be truly effective, data from multiple vendors must be integrated to create a comprehensive real-time national or supranational public health surveillance platform.

In behavioral science, "extinction" refers to the change that follows when a previously rewarded pursuit no longer yields reward; accordingly, this phenomenon is central to behavioral reorganization across species. Although one might expect a monotonic transition from engagement to disengagement in goal-directed behavior, in mammals this transition is often non-monotonic: behavior can transiently intensify before declining--a phenomenon known as the "extinction burst." Detecting this effect requires a metric and time window that capture the transient, non-monotonic change and enable comparison to counterfactual continued-reward performance. We preregistered a study in which participants earned money by producing grip-force responses on a hand dynamometer. Peak standardized force in short, time-matched blocks was pre-specified as the primary index; analyses contrasted before-to-after change at different tiers where extinction was present versus absent. Mixed-effects models pooled within-participant contrasts while controlling for the secular trend across blocks. Peak force increased upon extinction onset, yielding a large and robust stage-by-treatment interaction effect. Exploratory analyses showed changes in response rate, minimum idle force, response duration, and force variability throughout extinction. We highlight that the extinction burst is better conceived as a before-after contrast at reward[->]extinction transitions, benchmarked against matched reward[->]reward transitions, rather than a raw post-onset elevation.

Activity regulated transcription modifies the intrinsic excitability of cells, which is proposed to promote neuronal and behavioral plasticity; however, the transcriptional targets involved have not been identified. Here, we identify a single MEF-2 and CRH-1/CREB transcriptional target, gem-4/Copine, whose expression in C. elegans body muscles inhibits gap junction coupling, thereby increasing excitability. We show that gem-4 also promotes a form of experience and CRH-1 dependent neuronal plasticity. Inactivating gem-4 diminishes the ability of AFD thermosensory neurons to adjust their sensory response threshold following shifts in cultivation temperature. These results describe a mechanism linking activity regulated gem-4 expression to the plasticity of intrinsic excitability and sensory responses. Significance StatementActivity induced gene expression (e.g. that produced by activating the transcription factors CREB and MEF-2) is required for behavioral plasticity, including several forms of learning and memory. The effects of activity-induced gene expression on behavior are thought to be mediated by changes in synaptic connectivity and by changes in the intrinsic excitability of neurons. The role of altered excitability on behavioral plasticity has been difficult to assess because specific transcriptional targets regulating excitability have not been identified. Here we identify the gem-4 Copine gene as a MEF-2 and CREB transcriptional target that regulates intrinsic excitability by inhibiting gap junction coupling.

The 100 kDa hexokinase (HK) enzyme family represents an attractive model to investigate the molecular origins of allosteric regulation in multidomain enzymes. Extant HK homologs are subject to various allosteric phenomena, including activation and inhibition by both homotropic and heterotropic ligands. Here, we report the results of a phylogenetic investigation of this enzyme family using the recently developed Topiary ancestral sequence reconstruction pipeline. The results agree with prior studies that used a smaller number of sequences from individual HK domains and suggest that modern HK3 isozymes diverged first from a 100 kDa ancestor, followed by gene duplication and divergence of the HK2 isozymes. A subsequent gene duplication event led to divergence of HK1 and the hexokinase domain containing protein 1 (HKDC1). To probe the ability of Topiary to yield functional, allosterically regulated ancestral enzymes, we resurrected and biochemically characterized two HKs from early vertebrate evolution, Anc1 and Anc2. Both enzymes were functionally similar to extant HK1, and possessed a low activity, regulatory N-terminal domain that governs allosteric regulation of the C-terminal active site by two heterotropic effectors, glucose 6-phosphate and inorganic phosphate. Neither ancestor was subject to homotropic regulation by substrate glucose, a characteristic observed in several extant HK3 family members. Our phylogenetic analysis provides a foundation for investigating the evolution of allostery in this enzyme family. It also demonstrates the need to sequence and biochemically characterize additional full-length HKs, especially those from jawless vertebrates, to enable more robust inferences of ancestral regulatory traits.