eLife: latest articles

Characterisation of cell-scale signalling by the core planar polarity pathway during Drosophila wing development

d.strutt@sheffield.ac.uk (Alexandre Carayon) — Fri, 05 Dec 2025 00:00:00 +0000

In developing epithelia, cells become planar polarised through asymmetric localisation of the core planar polarity proteins to opposite cell membranes, where they form stable intercellular complexes. Current models differ regarding the signalling mechanisms required for core protein polarisation. Here, we investigate the existence of cell-intrinsic cell-scale signalling in vivo in the Drosophila pupal wing. We use conditional and restrictive expression tools to spatiotemporally manipulate core protein activity, combined with quantitative measurement of core protein distribution, polarity, and stability. Our results provide evidence for a robust cell-scale signal, while arguing against mechanisms that depend on depletion of a limited pool of a core protein or polarised transport of core proteins on microtubules. Furthermore, we show that polarity propagation across a tissue is hard, highlighting the strong intrinsic capacity of individual cells to establish and maintain planar polarity.

Neural correlates and reinstatement of recent and remote memory in children and young adults

schommartz@psych.uni-frankfurt.de (Angela M Kaindl) — Fri, 05 Dec 2025 00:00:00 +0000

Memory consolidation tends to be less robust in childhood than adulthood. However, little is known about the corresponding functional differences in the developing brain that may underlie age-related differences in retention of memories over time. This study examined system-level memory consolidation of object-scene associations after learning (immediate delay), one night of sleep (short delay), as well as 2 weeks (long delay) in 5- to 7-year-old children (n=49) and in young adults (n=39), as a reference group with mature consolidation systems. Particularly, we characterized how functional neural activation and reinstatement of neural patterns change over time, assessed by functional magnetic resonance imaging combined with representational similarity analysis (RSA). Our results showed that memory consolidation in children was less robust and strong (i.e. more forgetting) compared to young adults. Contrasting correctly retained remote vs. recent memories across time delay, children showed less upregulation in posterior parahippocampal gyrus, lateral occipital cortex, and cerebellum than adults. In addition, both children and adults showed a decrease in scene-specific neural reinstatement over time, indicating time-related decay of detailed differentiated memories. At the same time, we observed the emergence of generic gist-like neural representations in prefrontal brain regions uniquely in children, indicating qualitative difference in memory trace in children. Taken together, 5- to 7-year-old children, compared to young adults, show less robust memory consolidation, possibly due to difficulties in engaging in differentiated neural representations in neocortical mnemonic regions during retrieval of remote memories, coupled with relying more on gist-like generic neural representations.

Coenzyme-protein interactions since early life

marian.novotny@natur.cuni.cz (Alma Carolina Sanchez Rocha) — Thu, 04 Dec 2025 00:00:00 +0000

Recent findings in protein evolution and peptide prebiotic plausibility have been setting the stage for reconsidering the role of peptides in the early stages of life’s origin. Ancient protein families have been found to share common themes and proteins reduced in composition to prebiotically plausible amino acids have been reported capable of structure formation and key functions, such as binding to RNA. While this may suggest peptide relevance in early life, their functional repertoire, when composed of a limited number of early residues (missing some of the most sophisticated functional groups of today’s alphabet) has been debated. Cofactors enrich the functional scope of about half of extant enzymes, but whether they could also bind to peptides lacking the evolutionary late amino acids remains speculative. The aim of this study was to resolve the early peptide propensity to bind organic cofactors by analysis of protein-coenzyme interactions across the Protein Data Bank (PDB). We find that the prebiotically plausible amino acids are more abundant in the binding sites of the most ancient coenzymes and that such interactions rely more frequently on the involvement of the protein backbone atoms and metal ion cofactors. Moreover, we have identified a few select examples in today’s enzymes where coenzyme binding is supported solely by prebiotically available amino acids. These results imply the plausibility of a coenzyme-peptide functional collaboration preceding the establishment of the Central Dogma and full protein alphabet evolution.

Extracellular matrices regulate extravasation journey of leukocytes and inflammatory tissue fate

tomli_yt@sts.med.osaka-u.ac.jp (Yu-Tung Li) — Thu, 04 Dec 2025 00:00:00 +0000

Leukocyte extravasation across the blood endothelium to inflamed tissues is a crucial defence mechanism against invading pathogens. After the elimination of the pathogen in the tissue, inflammation needs to be resolved back to steady state. This cascade comprises at least three stages: transmigration through the endothelium and the underlying basement membrane, intra-tissue leukocyte activity, and tissue resolution. In each stage, extracellular matrix proteins in the vascular basement membrane and in tissues regulate a multitude of endothelial and leukocyte functions essential to completion of the cascade, either as a collective force-permissive structure or through signaling by individual matrix proteins. Proper orchestration of these diverse processes during the extravasation journey ensures effective defence and avoids development of chronic inflammatory diseases. This review will focus on how these extracellular matrices regulate the extravasation journey of leukocytes to illustrate their tight functional interdependence with profound impacts on the ultimate post-inflammation tissue fate.

Ptbp1 is not required for retinal neurogenesis and cell fate specification

sblack@jhmi.edu (Clayton P Santiago) — Thu, 04 Dec 2025 00:00:00 +0000

The RNA-binding protein Ptbp1 has been proposed as a master regulator of neuronal fate, repressing neurogenesis through its effects on alternative splicing and miRNA maturation. While prior studies using RNA interference suggested that Ptbp1 loss promotes neurogenesis, recent genetic studies have failed to replicate glia-to-neuron conversion following Ptbp1 loss of function. To evaluate the role of Ptbp1 in developmental neurogenesis in vivo, we conditionally disrupted Ptbp1 in mouse retinal progenitors. Ptbp1 was robustly expressed in both retinal progenitors and Müller glia but absent from postmitotic neurons, and efficient loss of function in mutant animals was confirmed using immunostaining for Ptbp1. Furthermore, bulk RNA-seq at E16 revealed accelerated expression of late-stage progenitor and photoreceptor-specific genes and altered splicing patterns in Ptbp1 mutants, including increased inclusion of rod photoreceptor-specific exons. However, we observed no defects in retinal lamination, progenitor proliferation, or cell fate specification in mature retina. ScRNA-seq of mature mutant retinas revealed only modest transcriptional changes which partially recapitulate alterations seen following selective deletion of Ptbp1 in mature glia. Our findings demonstrate that Ptbp1 is dispensable for retinal cell fate specification and suggest that its proposed role as a central repressor of neurogenesis should be reevaluated.

Timely vaccine strain selection and genomic surveillance improve evolutionary forecast accuracy of seasonal influenza A/H3N2

jhuddles@fredhutch.org (John Huddleston) — Thu, 04 Dec 2025 00:00:00 +0000

Evolutionary forecasting models inform seasonal influenza vaccine design by predicting which current genetic variants will dominate in the influenza season 12 months later. Forecasting models depend on hemagglutinin sequences from global public health networks to identify current genetic variants (clades) and estimate clade fitnesses. The lag between collection of a clinical sample and public availability of its sequence averages ∼3 months, complicating the 12-month forecasting problem by reducing our understanding of current clade frequencies. Despite continued methodological improvements to forecasting models, these constraints of a 12-month forecast horizon and 3-month submission lags impose an upper bound on any model’s accuracy. The SARS-CoV-2 pandemic revealed that modern vaccine technology reduces forecast horizons to 6 months and expanded sequencing support reduces submission lags to 1 month on average. We quantified the potential effects of these public health policy changes on forecast accuracy for A/H3N2 populations. Reducing forecast horizons to 6 months reduced average absolute forecasting errors to 25% of the 12-month average, while reducing submission lags decreased uncertainty in current clade frequencies by 50%. These results show the potential to improve the accuracy of existing forecasting models through realistic changes to public health policy.

Sub-surface deformation of individual fingerprint ridges during tactile interactions

gcorniani@mgh.harvard.edu (Benoit P Delhaye) — Thu, 04 Dec 2025 00:00:00 +0000

The human fingertip can detect small tactile features with a spatial acuity roughly the width of a fingerprint ridge. However, how individual ridges deform under contact to support accurate and high-precision tactile feedback is currently unknown. The complex mechanical structure of the glabrous skin, composed of multiple layers and intricate morphology within which mechanoreceptors are embedded, makes this question challenging. Here, we used optical coherence tomography to image and track sub-surface deformations of hundreds of individual fingerprint ridges across ten participants and four individual contact events at high spatial resolution in vivo. We calculated strain patterns in both the stratum corneum and viable epidermis in response to a variety of passively applied tactile stimuli, including static indentation, stick-to-slip events, sliding of a flat surface in different directions, and interaction with small tactile features, such as edges and grooves. We found that ridges could stretch, compress, and undergo considerable shearing orthogonal to the skin surface, but there was limited horizontal shear. Therefore, it appears that the primary components of ridge deformation and, potentially, neural responses are deformations of the ridge flanks and their relative movement, rather than overall bending of the ridges themselves. We conclude that the local distribution of mechanoreceptors across the ridges might be ideally suited to extract the resulting strain gradients and that the fingertip skin may possess a higher mechanical spatial resolution than that of a single ridge.

Crossover in aromatic amino acid interaction strength between tyrosine and phenylalanine in biomolecular condensates

david.desancho@ehu.eus (David De Sancho) — Thu, 04 Dec 2025 00:00:00 +0000

Biomolecular condensates often form through the self-assembly of disordered proteins with low-complexity sequences. In these polypeptides, the aromatic amino acids phenylalanine and tyrosine act as key ‘sticker’ residues, driving the cohesion of dense phases. Recent studies on condensates suggest a hierarchy in sticker strength, with tyrosine being more adhesive than phenylalanine. This hierarchy aligns with experimental data on amino acids solubilities and potentials of mean force derived from atomistic simulations. However, it contradicts conventional chemical intuition based on hydrophobicity scales and pairwise contact statistics from experimental structures of proteins, which suggest that phenylalanine should be the stronger sticker. In this work, we use molecular dynamics simulations and quantum chemistry calculations to resolve this apparent discrepancy. Using simple model peptides and side-chain analogues, we demonstrate that the experimentally observed hierarchy arises from the lower free energy of transfer of tyrosine into the condensate, mediated by both stronger protein-protein interactions and solvation effects in the condensate environment. Notably, as the dielectric constant of the media surrounding the stickers approaches that of an apolar solvent, the trend reverses, and phenylalanine becomes the stronger sticker. These findings highlight the role of the chemical environment in modulating protein-protein interactions, providing a clear explanation for the crossover in sticker strength between tyrosine and phenylalanine in different media.

Mechanism of SK2 channel gating and its modulation by the bee toxin apamin and small molecules

jonathan.whicher@novartis.com (Jonathan R Whicher) — Thu, 04 Dec 2025 00:00:00 +0000

Small-conductance calcium-activated potassium channel 2 (SK2) serves a variety of biological functions by coupling intracellular calcium dynamics with membrane potential. SK2 modulators are in development for the treatment of neurological and cardiovascular diseases, though the mechanisms of pharmacological modulation remain incompletely understood. We determined structures of an SK2–4 chimeric channel in Ca²⁺-bound and Ca²⁺-free conformations and in complex with the bee toxin apamin, a small molecule inhibitor, and a small molecule activator. The structures revealed that the S3–S4 linker forms a hydrophobic constriction at the extracellular opening of the pore. Apamin binds to this extracellular constriction and blocks the exit of potassium ions. Furthermore, we identified a structurally related SK2 inhibitor and activator that bind to the transmembrane domains. The compounds exert opposing effects on gating by differentially modulating the conformation of the S6 helices. These results provide important mechanistic insights to facilitate the development of targeted SK2 channel therapeutics.

Biophysical network modeling of temporal and stereotyped sequence propagation of neural activity in the premotor nucleus HVC

arij.daou@aub.edu.lb (Arij Daou) — Thu, 04 Dec 2025 00:00:00 +0000

Stereotyped neural sequences are often exhibited in the brain, yet the neurophysiological mechanisms underlying their generation are not fully understood. Birdsong is a prominent model to study such behavior, particularly because juvenile songbirds progressively learn from their tutors and by adulthood are able to sing stereotyped song patterns. The songbird premotor nucleus HVC coordinates motor and auditory activity responsible for learned vocalizations. The HVC comprises three neural populations that have distinct in vitro and in vivo electrophysiological responses. Typically, models that explain HVC’s network either rely on intrinsic HVC circuitry to propagate sequential activity, rely on extrinsic feedback to advance the sequence, or rely on both. Here, we developed a physiologically realistic neural network model incorporating the three classes of HVC neurons based on the ion channels and the synaptic currents that had been pharmacologically identified. Our model is based on a feedforward chain of microcircuits that encode for the different sub-syllabic segments (SSSs) and that interact with each other through structured feedback inhibition. The network reproduced the in vivo activity patterns of each class of HVC neurons and unveiled key intrinsic and synaptic mechanisms that govern the sequential propagation of neural activity by highlighting important roles for the T-type Ca²⁺ current, Ca²⁺-dependent K⁺ current, A-type K⁺ current, hyperpolarization-activated inward current, as well as excitatory and inhibitory synaptic currents. The result is a biophysically realistic model that suggests an improved characterization of the HVC network responsible for song production in the songbird.

Dorsal hippocampus mediates light–tone associations in male mice

abusquets@researchmar.net (Arnau Busquets-Garcia) — Wed, 03 Dec 2025 00:00:00 +0000

Daily choices are often influenced by environmental cues that are not directly associated with reinforcers. This phenomenon, known as higher-order conditioning, can be studied using sensory preconditioning tasks in rodents. This behavioral paradigm involves the repeated pairing of two innocuous stimuli, such as a light and a tone, followed by a devaluation phase in which one stimulus is associated with an unconditioned stimulus, such as a mild footshock. The result is a conditioned response (e.g., freezing) to both the conditioned stimulus (direct learning) and the non-conditioned stimulus (mediated learning). In our study, we successfully established a light–tone sensory preconditioning task specifically in male mice, as sex differences were observed in both control experimental groups and in sensory preconditioning responses. We employed in vivo, freely moving fiber photometry to monitor neural activity in the dorsal and ventral subregions of the hippocampus in male mice during the formation of associations between innocuous stimuli and reinforcers. Additionally, we combined our sensory preconditioning task with chemogenetic approaches to investigate the roles of these hippocampal subregions in sensory preconditioning. Our results indicate that dorsal, but not ventral, CaMKII-positive neurons are involved in encoding innocuous stimuli during the preconditioning phase. Overall, we developed a novel light–tone sensory preconditioning protocol in male mice, enabling the detection of sex differences and furthering our understanding of how specific hippocampal subregions and cell types regulate complex cognitive processes.

Dominant spinal muscular atrophy linked mutations in the cargo binding domain of BICD2 result in altered interactomes and dynein hyperactivity

ggonsalvez@augusta.edu (Avneesh Prabakar) — Wed, 03 Dec 2025 00:00:00 +0000

Cytoplasmic dynein-1 (dynein) is responsible for the transport of most cellular cargo towards the minus end of microtubules. Dynein activation requires the multi-subunit dynactin complex and an activating cargo adaptor. The adaptors serve to link dynein with cargo and to fully activate the motor. Mutations in one of these activating adaptors, Bicaudal-D2 (BICD2), are associated with a neurodegenerative disease called Spinal Muscular Atrophy with Lower Extremity Predominance (SMALED2). The molecular defect that underlies SMALED2 is largely unknown. In addition to interacting with dynein, BICD2 has also been shown to associate with KIF5B, a plus-end directed microtubule motor. We hypothesized that interactome changes associated with mutant versions of BICD2, and the resulting differences in cargo transport, might underlie the etiology of SMALED2. To test our hypothesis, we first defined the interactome of wild-type human BICD2. This led to the identification of known BICD2 interacting proteins in addition to potentially novel cargo such as components of the HOPS complex, a six-subunit complex involved in endo-lysosomal trafficking. We next determined the interactome of three SMALED2-linked mutants in BICD2, two of which reside in the cargo binding domain. Interestingly, all three mutations resulted in BICD2-mediated dynein hyper-activation. Furthermore, all three mutants were associated with interactome changes. One of these mutants, BICD2_R747C, was deficient in binding to HOPS complex components and the nucleoporin RANBP2. In addition, this mutant also resulted in a gain-of-function interaction with GRAMD1A, a protein localized to the endoplasmic reticulum. This gain-of-function interaction resulted in mislocalization of GRAMD1A in BICD2_R747C expressing cells. Collectively, our results suggest that dynein hyperactivity, interactome changes, and cargo transport defects might contribute to the symptoms associated with SMALED2.

The electrogenicity of the Na⁺/K⁺-ATPase poses challenges for computation in highly active spiking cells

s.schreiber@hu-berlin.de (Jan-Hendrik Schleimer) — Wed, 03 Dec 2025 00:00:00 +0000

The evolution of the Na⁺/K⁺-ATPase laid the foundation for ion homeostasis and electrical signaling. While not required for restoration of ionic gradients, the electrogenicity of the pump (resulting from its 3:2 stoichiometry) is useful to prevent runaway activity. As we show here, electrogenicity could also come with disadvantageous side effects: (1) an activity-dependent shift in a cell’s baseline firing and (2) interference with computation, disturbing network entrainment when inputs change strongly. We exemplify these generic effects in a mathematical model of the weakly electric fish electrocyte, which spikes at hundreds of Hz and is exposed to abrupt rate changes when producing behaviorally relevant communication signals. We discuss biophysical strategies that may allow cells to mitigate the consequences of electrogenicity at additional metabolic cost and postulate an interesting role for a voltage dependence of the Na⁺/K⁺-ATPase. Our work shows that the pump’s electrogenicity can open an additional axis of vulnerability that may play a role in brain disease.

The primate Major Histocompatibility Complex as a case study of gene family evolution

afortier@stanford.edu (Alyssa Lyn Fortier) — Wed, 03 Dec 2025 00:00:00 +0000

Gene families are groups of evolutionarily related genes. One large gene family that has experienced rapid evolution lies within the Major Histocompatibility Complex (MHC), whose proteins serve critical roles in innate and adaptive immunity. Across the ∼60 million year history of the primates, some MHC genes have turned over completely, some have changed function, some have converged in function, and others have remained essentially unchanged. Past work has typically focused on identifying MHC alleles within particular species or comparing gene content, but more work is needed to understand the overall evolution of the gene family across species. Thus, despite the immunologic importance of the MHC and its peculiar evolutionary history, we lack a complete picture of MHC evolution in the primates. We readdress this question using sequences from dozens of MHC genes and pseudogenes spanning the entire primate order, building a comprehensive set of gene and allele trees with modern methods. Overall, we find that the Class I gene subfamily is evolving much more quickly than the Class II gene subfamily, with the exception of the Class II MHC-DRB genes. We also pay special attention to the often-ignored pseudogenes, which we use to reconstruct different events in the evolution of the Class I region. We find that despite the shared function of the MHC across species, different species employ different genes, haplotypes, and patterns of variation to achieve a successful immune response. Our trees and extensive literature review represent the most comprehensive look into primate MHC evolution to date.

Eed controls craniofacial osteoblast differentiation and mesenchymal proliferation from the neural crest

david.raleigh@ucsf.edu (Angelo Pelonero) — Tue, 02 Dec 2025 00:00:00 +0000

The histone methyltransferase Polycomb repressive complex 2 (PRC2) is required for specification of the neural crest, and mis-regulation of neural crest development can cause severe congenital malformations. PRC2 is necessary for neural crest induction, but the embryonic, cellular, and molecular consequences of PRC2 activity after neural crest induction are incompletely understood. Here, we show that Eed, which encodes a protein that is a core subunit of PRC2, is required for craniofacial osteoblast differentiation and mesenchymal proliferation after induction of the neural crest. Integrating mouse genetics with single-cell RNA sequencing and epigenetic profiling, our results reveal that conditional knockout of Eed after neural crest cell induction causes severe craniofacial hypoplasia, impaired craniofacial osteogenesis, and attenuated craniofacial mesenchymal cell proliferation that is first evident in post-migratory neural crest cell populations. We show that Eed drives mesenchymal differentiation and proliferation in vivo and in primary craniofacial cell cultures by epigenetically regulating diverse transcription factor programs that are required for specification of post-migratory neural crest cells. These data enhance understanding of epigenetic mechanisms that underlie craniofacial development and shed light on the embryonic, cellular, and molecular drivers of rare congenital syndromes in humans.

MorphoNet 2.0: An innovative approach for qualitative assessment and segmentation curation of large-scale 3D time-lapse imaging datasets

emmanuel.faure@lirmm.fr (Ange Clement) — Tue, 02 Dec 2025 00:00:00 +0000

Thanks to recent promising advances in AI, automated segmentation of imaging datasets has made significant strides. However, the evaluation and curation of 3D and 3D+t datasets remain extremely challenging and highly resource-intensive. We present MorphoNet 2.0, a major conceptual and technical evolution designed to facilitate the segmentation, self-evaluation, and correction of 3D images. The application is accessible to non-programming biologists through user-friendly graphical interfaces and works on all major operating systems. We showcase its power in enhancing segmentation accuracy and boosting interpretability across five previously published segmented datasets. This new approach is crucial for producing ground-truth datasets of discovery-level scientific quality, critical for training and benchmarking advanced AI-driven segmentation tools, as well as for competitive challenges.

Keeping track of moving targets

renata.brito@einsteinmed.edu (Geoffrey Terral) — Tue, 02 Dec 2025 00:00:00 +0000

A new method for tracking the activity of individual neurons day after day in the growing brain has revealed a key developmental transition in neuronal activity.

Correction: ZC3H11A mutations cause high myopia by triggering PI3K-AKT and NF-κB-mediated signaling pathway in humans and mice

Mon, 01 Dec 2025 00:00:00 +0000

Using step selection functions to analyse human mobility using telemetry data in infectious disease epidemiology: a case study of leptospirosis

p.ruizcuenca@lancaster.ac.uk (Ariane Goncalves da Silva) — Mon, 01 Dec 2025 00:00:00 +0000

Individual differences in tail risk sensitive exploration using Bayes-adaptive Markov decision processes

kshentingke@gmail.com (Peter Dayan) — Mon, 01 Dec 2025 00:00:00 +0000

Novelty is a double-edged sword for agents and animals alike: they might benefit from untapped resources or face unexpected costs or dangers such as predation. The conventional exploration/exploitation tradeoff is thus colored by risk sensitivity. A wealth of experiments has shown how animals solve this dilemma, for example, using intermittent approach. However, there are large individual differences in the nature of approach, and modeling has yet to elucidate how this might be based on animals’ differing prior expectations about reward and threat, and differing degrees of risk aversion. To capture these factors, we built a Bayes-adaptive Markov decision process model with three key components: an adaptive hazard function capturing potential predation, an intrinsic reward function providing the urge to explore, and a conditional value at risk (CVaR) objective, which is a contemporary measure of trait risk sensitivity. We fit this model to a coarse-grain abstraction of the behavior of 26 animals who freely explored a novel object in an open-field arena. We show that the model captures both quantitative (frequency, duration of exploratory bouts) and qualitative (with distinguished, cautious, tail-behind approach) features of behavior, including the substantial idiosyncrasies that were observed. Some animals begin with cautious exploration and quickly transition to a confident approach to maximize exploration for reward; we classify them as potentially more risk neutral and enjoying a flexible hazard prior. By contrast, other animals only ever approach in a cautious manner and display a form of self-censoring; they are characterized by potential risk aversion and high and inflexible hazard priors. Explaining risk-sensitive exploration using factorized parameters of reinforcement learning models could aid in the understanding, diagnosis, and treatment of psychiatric abnormalities such as anxiety disorders.

Joint profiling of cell morphology and gene expression during in vitro neurodevelopment

helena.kilpinen@helsinki.fi (Adithi Sundaresh) — Mon, 01 Dec 2025 00:00:00 +0000

Differentiation of induced pluripotent stem cells (iPSCs) toward neuronal lineages has enabled diverse cellular models of human neurodevelopment and related disorders. Here, we jointly profiled neuronal morphology and gene expression at single-cell resolution across 60,000 iPSC-derived cortical neurons at three developmental time points with Cell Painting (CP) and single-cell RNA-sequencing (scRNA-seq). By modeling the relationship between morphological features and gene expression within our differentiation system, we annotated image-based features with biological functions and showed that while CP resolves broader neuronal classes than scRNA-seq, it complements transcriptomic data by quantifying the biological processes that drive neuronal differentiation over time, such as mitochondrial function and cell cycle. Further, we found that while over 60% of the cells resembled those seen in the fetal brain, 28% represented metabolically abnormal cell states and broader neuronal classes specific to in vitro cells. We show that iPSC-derived cortical neurons are nonetheless a relevant model for a range of brain-related complex traits, including schizophrenia and bipolar disorder, and that disease heritability can also be captured in the morphological feature space. Finally, we applied CP to iPSC-derived neural progenitors from patients with Kabuki syndrome, revealing morphological signatures of precocious differentiation and altered cell cycling. These results highlight the potential of multi-modal single-cell characterization to reveal complementary and disease-relevant cellular and molecular phenotypes.

Acidocalcisome-like vacuoles constitute a feedback-controlled phosphate buffering system for the cytosol

andreas.mayer@unil.ch (Andreas Mayer) — Mon, 01 Dec 2025 00:00:00 +0000

Cells experience strong variations in the consumption and availability of inorganic phosphate (P_i). Since P_i is an essential macronutrient but excess P_i has negative impacts on nucleotide hydrolysis and metabolism, its concentration must be maintained in a suitable range. Conserved storage organelles, acidocalcisomes, provide this buffering function. We used acidocalcisome-like yeast vacuoles to study how such organelles are set up to perform this task. Our combined in vitro and in vivo analyses revealed that their ATP-driven polyphosphate polymerase VTC converts cytosolic P_i into inorganic polyphosphates (polyP), which it transfers into the vacuole lumen. Luminal polyphosphatases immediately hydrolyse this polyP to establish a growing reservoir of vacuolar P_i. Product inhibition by this P_i pool silences the polyphosphatases, caps P_i accumulation, and favours vacuolar polyP storage. Upon cytosolic P_i scarcity, the declining inositol pyrophosphate levels activate the vacuolar P_i exporter Pho91 to replenish cytosolic P_i. In this way, acidocalcisome-like vacuoles constitute a feedback-regulated buffering system for cytosolic P_i, which the cells can switch between P_i accumulation, P_i release, and high-capacity phosphate storage through polyP.

Cerebellar Purkinje cell stripe patterns reveal a differential vulnerability and resistance to cell loss during normal aging in mice

sillitoe@bcm.edu (Amanda M Brown) — Mon, 01 Dec 2025 00:00:00 +0000

Age-related neurodegenerative diseases involve reduced cell numbers and impaired behavioral capacity. Neurodegeneration and behavioral deficits also occur during aging, and notably in the absence of disease. The cerebellum, which modulates movement and cognition, is susceptible to cell loss in both aging and disease. Here, we demonstrate that cerebellar Purkinje cell loss in aged mice is not spatially random but rather occurs in a pattern of parasagittal stripes. We also find that aged mice exhibit impaired motor coordination and more severe tremor compared to younger mice. However, the relationship between patterned Purkinje cell loss and motor dysfunction is not straightforward. Examination of postmortem samples of human cerebella from neurologically typical individuals supports the presence of selective loss of Purkinje cells during aging. These data reveal a spatiotemporal cellular substrate for aging in the cerebellum that may inform how neuronal vulnerability leads to neurodegeneration and the ensuing deterioration of behavior.

Nanophysiology approach reveals diversity in calcium microdomains across zebrafish retinal bipolar ribbon synapses

tvaithia@uthsc.edu (Abhishek P Shrestha) — Mon, 01 Dec 2025 00:00:00 +0000

Rapid and high local calcium (Ca²⁺) signals are essential for triggering neurotransmitter release from presynaptic terminals. In specialized bipolar ribbon synapses of the retina, these local Ca²⁺ signals control multiple processes, including the priming, docking, and translocation of vesicles on the ribbon before exocytosis, endocytosis, and the replenishment of release-ready vesicles to the fusion sites for sustained neurotransmission. However, our knowledge about Ca²⁺ signals along the axis of the ribbon active zone is limited. Here, we used fast confocal quantitative dual-color ratiometric line-scan imaging of a fluorescently labeled ribbon binding peptide and Ca²⁺ indicators to monitor the spatial and temporal aspects of Ca²⁺ transients of individual ribbon active zones in zebrafish retinal rod bipolar cells (RBCs). We observed that a Ca²⁺ transient elicited a much greater fluorescence amplitude when the Ca²⁺ indicator was conjugated to a ribeye-binding peptide than when using a soluble Ca²⁺ indicator, and the estimated Ca²⁺ levels at the ribbon active zone exceeded 26 μM in response to a 10 millisecond stimulus, as measured by a ribbon-bound low-affinity Ca²⁺ indicator. Our quantitative modeling of Ca²⁺ diffusion and buffering is consistent with this estimate and provides a detailed view of the spatiotemporal [Ca²⁺] dynamics near the ribbon. Importantly, our data demonstrates that the local Ca²⁺ levels may vary between ribbons of different RBCs and within the same cells. The variation in local Ca²⁺ signals is found to correlate with ribbon size and active zone extent. Our serial electron microscopy results provide new information about the heterogeneity in ribbon size, shape, and area of the ribbon in contact with the plasma membrane.

Cross-species standardised cortico-subcortical tractography

Stamatios.Sotiropoulos@nottingham.ac.uk (Ali-Reza Mohammadi-Nejad) — Mon, 01 Dec 2025 00:00:00 +0000

Despite their importance for brain function, cortico-subcortical white matter tracts are under-represented in diffusion magnetic resonance imaging tractography studies. Their non-invasive mapping is more challenging and less explored compared to other major cortico-cortical bundles. We introduce a set of standardised tractography protocols for delineating tracts between the cortex and various deep subcortical structures, including the caudate, putamen, amygdala, thalamus, and hippocampus. To enable comparative studies, our protocols are designed for both human and macaque brains. We demonstrate how tractography reconstructions follow topographical principles obtained from tracers in the macaque and how these translate to humans. We show that the proposed protocols are robust against data quality and preserve aspects of individual variability stemming from family structure in humans. Lastly, we demonstrate the value of these species-matched protocols in mapping homologous grey matter regions in humans and macaques, both in cortex and subcortex.

Complex opioid-driven modulation of glutamatergic and cholinergic neurotransmission in a GABAergic brain nucleus associated with emotion, reward, and addiction

ramesh.chittajallu@nih.gov (Adam P Caccavano) — Mon, 01 Dec 2025 00:00:00 +0000

The medial habenula (mHb)/interpeduncular nucleus (IPN) circuitry is resident to divergent molecular, neurochemical, and cellular components which, in concert, perform computations to drive emotion, reward, and addiction behaviors. Although housing one of the most prominent mu-opioid receptor (mOR) expression levels in the brain, remarkably little is known as to how they impact mHb/IPN circuit function at the granular level. In this study, our systematic functional and pharmacogenetic analyses in mice demonstrate that mOR activation attenuates glutamatergic signaling while producing an opposing potentiation of glutamatergic/cholinergic co-transmission mediated by mHb substance P and cholinergic neurons, respectively. Intriguingly, this latter non-canonical augmentation is developmentally regulated only emerging during later postnatal stages. In addition, we reveal that specific potassium channels act as a molecular brake on nicotinic receptor signaling in the IPN with the opioid-mediated potentiation of this arm of neurotransmission being operational only following attenuation of Kv1 function. Thus, mORs play a complex role in shaping the salience of distinct afferent inputs and transmitter modalities that ultimately influence synaptic recruitment of downstream GABAergic IPN neurons. Together, these observations provide a framework for future investigations aimed at identifying the neural underpinnings of maladaptive behaviors that can emerge when opioids, including potent synthetic analogs such as fentanyl, modulate or hijack this circuitry during the vulnerable stages of adolescence and in adulthood.

C. elegans food choice exhibits effort discounting-like behavior

shawn@uoregon.edu (Aaron B Schatz) — Mon, 01 Dec 2025 00:00:00 +0000

Cost–benefit decisions are ubiquitous in both human and animal behavior. Economists have developed formal models of cost–benefit decision-making by focusing on discounting behavior, the devaluation of a reward based on the costs associated with it. The phylogenetic limits of discounting behavior remain unknown. Here, we provide evidence that the nematode C. elegans exhibits behavior closely resembling effort discounting. Given a choice between food options that are easy or difficult to consume, worms devalue the latter in a manner predicted by economic models. We identified a plausible mechanism for this behavior based on differential rates of leaving food patches and demonstrated that this mechanism is disrupted by deficits in dopamine signaling, as in rodents. Together, these results establish C. elegans as a potential invertebrate model for discounting behavior and set new phylogenetic bounds on this type of cost–benefit decision-making.

Human RAP2A homolog of the Drosophila asymmetric cell division regulator Rap2l targets the stemness of glioblastoma stem cells

acarmena@umh.es (Ana Carmena) — Fri, 28 Nov 2025 00:00:00 +0000

Asymmetric cell division (ACD) is a fundamental process to balance cell proliferation and differentiation during development and in the adult. Cancer stem cells (CSCs), a very small but highly malignant population within many human tumors, are able to provide differentiated progeny by ACD that contribute to the intratumoral heterogeneity, as well as to proliferate without control by symmetric, self-renewing divisions. Thus, ACD dysregulation in CSCs could trigger cancer progression. Here, we consistently find low expression levels of RAP2A, the human homolog of the Drosophila ACD regulator Rap2l, in glioblastoma (GBM) patient samples, and observe that scarce levels of RAP2A are associated with poor clinical prognosis in GBM. Additionally, we show that restitution of RAP2A in GBM neurosphere cultures increases the ACD of glioblastoma stem cells (GSCs), decreasing their proliferation and expression of stem cell markers. Our results support that ACD failures in GSCs increase their spread and ACD amendment could contribute to reduce the expansion of GBM.

The SAFE Labs Handbook as a tool for improving lab culture

stephane.bugeon@inserm.fr (Chiara Sinigaglia) — Fri, 28 Nov 2025 00:00:00 +0000

Creating positive and equitable lab environments has become a growing priority for the scientific community and funders of scientific research. Research institutions typically respond to this need by providing mandatory or optional training opportunities for their staff. However, there are limited resources for group leaders to improve the culture in their labs. Here, we introduce the SAFE Labs Handbook: a collection of 30 “commitments” that can be implemented by individual group leaders to improve research culture in the life sciences. The commitments were collaboratively developed by 13 group leaders working in eight different European countries. We also report the results of a survey in which we asked more than 200 researchers, at various career stages, about the commitments. Even though all 30 commitments were rated as significantly important by respondents, implementation rates were notably low (<25%). However, more than 95% of group leaders said they would consider implementing them. The SAFE Labs Handbook therefore represents a unique, community-driven tool with the potential to improve lab culture on a global scale.

Center-surround inhibition in expectation and its underlying computational and artificial neural network models

xlzhang@m.scnu.edu.cn (Floris P de Lange) — Fri, 28 Nov 2025 00:00:00 +0000

Expectation is beneficial for adaptive behavior through quickly deducing plausible interpretations of information. The profile and underlying neural computations of this process, however, remain unclear. When participants expected a grating with a specific orientation, we found a center-surround inhibition profile in orientation space, which was independent from attentional modulations by task relevance. Using computational modeling, we showed that this center-surround inhibition could be reproduced by either a sharpening of tuning curves of expected orientation or a shift of tuning curves of unexpected orientations. Intriguingly, these two computations were further supported by orientation-adjustment and orientation-discrimination experiments. Finally, the ablation studies in convolutional neural networks revealed that predictive coding feedback played a critical role in the center-surround inhibition in expectation. Altogether, our study reveals for the first time that expectation results in both enhancement and suppression, optimizing plausible interpretations during perception by enhancing expected and attenuating similar but irrelevant and potentially interfering representations.

Functional and molecular insights into muscle proprioceptors

francois.lallemend@ki.se (Francois Lallemend) — Fri, 28 Nov 2025 00:00:00 +0000

Proprioception, the innate ability to perceive body positions and movements, enables us to perform daily activities without thinking about it. In mammals, this process primarily involves the activation of three types of proprioceptive neuron (PN) endings in muscles (Ia and II-PNs) or tendons (Ib-PNs). However, recent research indicates that these cardinal classes exhibit molecular diversity that likely reflects differences in connectivity, morphology, and activity patterns, contributing to the detection of various kinematic parameters. In this review, we summarize the properties and functions of PNs and propose a comprehensive cell-type classification. By systematically mapping functionally relevant molecular markers to specific PN subtypes, we establish a tentative, yet insightful taxonomy based on their functional characteristics. This foundational work lays the groundwork for future research aimed at elucidating the distinct physiological properties of each PN subtype and their interactions within central motor circuits. Understanding these nuances will be critical for advancing our knowledge of sensorimotor circuitry and its role in movement control.

The Shigella flexneri effector IpaH1.4 facilitates RNF213 degradation and protects cytosolic bacteria against interferon-induced ubiquitylation

jorn.coers@duke.edu (Jorn Coers) — Fri, 28 Nov 2025 00:00:00 +0000

A central signal that marshals host defense against many infections is the lymphocyte-derived cytokine interferon-gamma (IFNγ). The IFNγ receptor is expressed on most human cells, and its activation leads to the expression of antimicrobial proteins that execute diverse cell-autonomous immune programs. One such immune program consists of the sequential detection, ubiquitylation, and destruction of intracellular pathogens. Recently, the IFNγ-inducible ubiquitin E3 ligase RNF213 was identified as a pivotal mediator of such a defense axis. RNF213 provides host protection against viral, bacterial, and protozoan pathogens. To establish infections, potentially susceptible intracellular pathogens must have evolved mechanisms that subdue RNF213-controlled cell-autonomous immunity. In support of this hypothesis, we demonstrate here that a causative agent of bacillary dysentery, Shigella flexneri, uses the type III secretion system (T3SS) effector IpaH1.4 to induce the degradation of RNF213. S. flexneri mutants lacking IpaH1.4 expression are bound and ubiquitylated by RNF213 in the cytosol of IFNγ-primed host cells. Linear (M1-) and lysine-linked ubiquitylation of S. flexneri requires RNF213 but is independent of the linear ubiquitin chain assembly complex (LUBAC). We find that ubiquitylation of S. flexneri is insufficient to kill intracellular bacteria, suggesting that S. flexneri employs additional virulence factors to escape from host defenses that operate downstream from RNF213-driven ubiquitylation. In brief, this study identified the bacterial IpaH1.4 protein as an inhibitor of mammalian RNF213 and highlights evasion of RNF213-driven immunity as a characteristic of the human-tropic pathogen Shigella.

Prosapip1 (encoded by the Lzts3 gene) in the dorsal hippocampus mediates synaptic protein composition, long-term potentiation, and spatial memory

yann.ehinger@gmail.com (Alexandra Salvi) — Wed, 26 Nov 2025 00:00:00 +0000

Prosapip1 is a brain-specific protein, encoded by Lzts3, localized to the postsynaptic density, where it promotes dendritic spine maturation in primary hippocampal neurons. However, nothing is known about the role of Prosapip1 in vivo. To examine this, we utilized the Cre-loxP system to develop a Prosapip1 neuronal knockout mouse. We found that Prosapip1 controls the synaptic localization of its binding partner SPAR, along with PSD-95 and the GluN2B subunit of the NMDA receptor (NMDAR) in the dorsal hippocampus (dHP). We next sought to identify the potential contribution of Prosapip1 to the activity and function of the NMDAR and found that Prosapip1 plays an important role in NMDAR-mediated transmission and long-term potentiation (LTP) in the CA1 region of the dHP. As LTP is the cellular hallmark of learning and memory, we examined the consequences of neuronal knockout of Prosapip1 on dHP-dependent memory. We found that global or dHP-specific neuronal knockout of Prosapip1 caused a deficit in learning and memor,y whereas developmental, locomotor, and anxiety phenotypes were normal. Taken together, Prosapip1 in the dHP promotes the proper localization of synaptic proteins which, in turn, facilitates LTP driving recognition, social, and spatial learning and memory.

SMC5/6-mediated plasmid silencing is directed by SIMC1–SLF2 and antagonized by the SV40 large T antigen

totomo@sdbri.org (Martina Oravcová) — Wed, 26 Nov 2025 00:00:00 +0000

SMC5/6 is unique among the Structural Maintenance of Chromosomes (SMC) complexes in its ability to repress transcription from extrachromosomal circular DNA (ecDNA), including viral genomes and plasmids. Previously, we showed that human SMC5/6 is regulated by two mutually exclusive subcomplexes—SIMC1–SLF2 and SLF1/2—the counterparts of yeast Nse5/6 (Oravcová et al., 2022). Notably, only SIMC1–SLF2 recruits SMC5/6 to SV40 large T antigen (LT) foci in PML nuclear bodies (PML NBs), suggesting that these regulatory subcomplexes direct distinct roles of SMC5/6 on chromosomal versus ecDNA. However, their roles in plasmid repression remain unclear. Here, we demonstrate that SMC5/6-mediated repression of plasmid transcription depends exclusively on SIMC1–SLF2, whereas SLF1/2 is dispensable. Reinforcing its specialized role in ecDNA suppression, SIMC1–SLF2 does not participate in SMC5/6 recruitment to chromosomal DNA lesions. We further show that plasmid silencing requires a conserved interaction between SIMC1–SLF2 and SMC6, mirroring the functional relationship observed between yeast Nse5/6 and Smc6. As for viral silencing, plasmid repression depends on the SUMO pathway; however, unlike viral silencing, it does not require PML NBs. Additionally, we find that LT interacts with SMC5/6 and increases plasmid transcription to levels observed in SIMC1–SLF2-deficient cells—echoing the antagonistic roles of HBx (HBV) and Vpr (HIV-1) in viral genome repression. These findings expand the paradigm of viral antagonism against SMC5/6-mediated silencing, positioning LT as a novel player in this evolutionary tug-of-war.

Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (p97-PROTAC)

alejandro.rojas@uach.cl (Alejandro Rojas-Fernandez) — Wed, 26 Nov 2025 00:00:00 +0000

The p97 protein is a member of the AAA+ family of ATPases. This protein is encoded by the VCP gene. It is a mechanoenzyme that uses energy from ATP hydrolysis to promote protein unfolding and segregation actively. The unfolded products are subsequently presented to the 26S proteasome for degradation. p97 substrate recognition is mediated by adaptors, which interact with substrates directly or indirectly through ubiquitin modifications, resulting in substrate funnelling into the central pore of the p97 hexamer and unfolding. Here, we engineered synthetic adaptors to target specific substrates to p97, using the extraordinary intracellular binding capabilities of camelid nanobodies fused to the UBX domain of the p97 adaptor protein Fas-associated factor-1 (FAF1). In such a way, we created a p97-directed proteolysis-targeting chimera (PROTAC), representing a novel and unique E3 ubiquitin ligase-independent strategy to promote specific proteolysis. All functional assays were performed in human cell lines to evaluate the system’s efficacy and specificity in a physiologically relevant context.

The RAB27A effector SYTL5 regulates mitophagy and mitochondrial metabolism

anne.simonsen@medisin.uio.no (Ana Lapão) — Wed, 26 Nov 2025 00:00:00 +0000

SYTL5 is a member of the Synaptotagmin-Like (SYTL) protein family that differs from the Synaptotagmin family by having a unique N-terminal Synaptotagmin homology domain that directly interacts with the small GTPase RAB27A. Several SYTL protein family members have been implicated in plasma membrane transport and exocytosis, but the specific function of SYTL5 remains unknown. We here show that SYTL5 is a RAB27A effector and that both proteins localise to mitochondria and vesicles containing mitochondrial material. Mitochondrial recruitment of SYTL5 depends on its interaction with functional RAB27A. We demonstrate that SYTL5-RAB27A positive vesicles containing mitochondrial material, autophagy proteins and LAMP1 form during hypoxia and that depletion of SYTL5 and RAB27A reduces mitophagy under hypoxia mimicking conditions, indicating a role for these proteins in mitophagy. Indeed, we find that SYTL5 interacts with proteins involved in vesicle-mediated transport and cellular response to stress and that its depletion compromises mitochondrial respiration and increases glucose uptake. Intriguingly, SYTL5 expression is significantly reduced in tumours of the adrenal gland and correlates positively with survival for patients with adrenocortical carcinoma.

Decapping activators Edc3 and Scd6 act redundantly with Dhh1 in post-transcriptional repression of starvation-induced pathways

ahinnebusch@nih.gov (Alan G Hinnebusch) — Tue, 25 Nov 2025 00:00:00 +0000

Degradation of many yeast mRNAs involves decapping by the Dcp1:Dcp2 complex. Previous studies on decapping activators Edc3 and Scd6 suggested their limited roles in mRNA decay. RNA-seq analysis of mutants lacking one or both proteins revealed that Scd6 and Edc3 have largely redundant activities in targeting numerous mRNAs for degradation that are masked in the single mutants. These transcripts are frequently targeted by decapping activators Dhh1 and Pat1, and the collective evidence suggests that Scd6/Edc3 act interchangeably to recruit Dhh1 to Dcp2. Ribosome profiling shows that redundancy between Scd6 and Edc3 and their functional interactions with Dhh1 and Pat1 extend to translational repression of particular transcripts, including a cohort of poorly translated mRNAs displaying interdependent regulation by all four factors. Scd6/Edc3 also participate with Dhh1/Pat1 in post-transcriptional repression of proteins required for respiration and catabolism of alternative carbon sources, which are normally expressed only in limiting glucose. Simultaneously eliminating Scd6/Edc3 increases mitochondrial membrane potential and elevates metabolites of the tricarboxylic acid and glyoxylate cycles typically observed only during growth in low glucose. Thus, Scd6/Edc3 acts redundantly, in parallel with Dhh1 and in cooperation with Pat1, to adjust gene expression to nutrient availability by controlling mRNA decapping and decay.

Avoidance of hydrogen sulfide is modulated by external and internal states in Caenorhabditis elegans

patrick.laurent@ulb.be (Changchun Chen) — Tue, 25 Nov 2025 00:00:00 +0000

Hydrogen sulfide (H₂S) acts as an energy source, a toxin, and a gasotransmitter across diverse biological contexts. We use the robust locomotory responses of Caenorhabditis elegans to high levels of H₂S to elucidate the molecular mechanisms underlying its acute and adaptive responses. We find that the H₂S-evoked behavioral response is shaped by multiple environmental factors including oxygen (O₂) levels and nutritional state and is modulated by various pathways such as insulin, TGF-β, and HIF-1 signaling, as well as by input from O₂-sensing neurons. Prolonged exposure to H₂S activates HIF-1 signaling, leading to the upregulation of stress-responsive genes, including those involved in H₂S detoxification. This promotes an adaptive state in which locomotory speed is reduced in H₂S, while responsiveness to other stimuli is preserved. In mutants deficient in HIF-1 signaling, iron storage, and detoxification mechanisms, animals display a robust initial response but rapidly enter a sleep-like behavior characterized by reduced mobility and diminished responsiveness to subsequent sensory stimuli. Furthermore, while acute production of mitochondria-derived reactive O₂ species (ROS) appears to initiate the avoidance response to H₂S, persistently high ROS promotes an adaptive state, likely by activating various stress-response pathways, without substantially compromising cellular H₂S detoxification capacity. Taken together, our study provides comprehensive molecular insights into the mechanisms through which C. elegans modulates and adapts its response to H₂S exposure.

Evolution of gene expression in seasonal environments

satake.akiko.269@m.kyushu-u.ac.jp (Akiko Satake) — Tue, 25 Nov 2025 00:00:00 +0000

The biological activities of organisms are closely linked to seasonality. Phenology, the temporal orchestration of biological activities, is governed by gene expression, yet the evolutionary dynamics underlying seasonal gene expression remain unclear. To investigate these dynamics, we compared genome-wide expression dynamics (molecular phenology) in four dominant evergreen Fagaceae species in Asia (Quercus glauca, Q. acuta, Lithocarpus edulis, and L. glaber), using leaf and bud tissues over two seasonal cycles. We assembled high-quality reference genomes, identifying 11749 single-copy orthologous genes. Seasonal transcriptomic profiling of these orthologous genes revealed highly conserved gene expression across species in winter when temperatures fall below ~10 °C. Rhythmic gene expression with significant periodic oscillations was more prevalent in buds (51.9%) than in leaves (40.6%), with most rhythmic genes (78.4–92.0%) exhibiting annual periodicity, while a smaller fraction (1.2–11.9%) followed half-annual cycles. The seasonal peaks of rhythmic genes were highly synchronized across species in winter but diverged during the growing season, reflecting species-specific timing of leaf flushing and flowering. These findings suggest that the four species share a common molecular calendar in winter, which constrains the evolution of gene expression under seasonal environments.

Generation of biophysical neuron model parameters from recorded electrophysiological responses

qiangliuemail@gmail.com (Eli Shlizerman) — Mon, 24 Nov 2025 00:00:00 +0000

Recent advances in connectomics, biophysics, and neuronal electrophysiology warrant modeling of neurons with further details in both network interaction and cellular dynamics. Such models may be referred to as ElectroPhysiome, as they incorporate the connectome and individual neuron electrophysiology to simulate neuronal activities. The nervous system of Caenorhabditis elegans is considered a viable framework for such ElectroPhysiome studies due to advances in connectomics of its somatic nervous system and electrophysiological recordings of neuron responses. In order to achieve a simulated ElectroPhysiome, the set of parameters involved in modeling individual neurons needs to be estimated from electrophysiological recordings. Here, we address this challenge by developing a deep generative estimation method called ElectroPhysiomeGAN (EP-GAN), which, once trained, can instantly generate parameters associated with the Hodgkin–Huxley neuron model (HH-model) for multiple neurons with graded potential response. The method combines generative adversarial network (GAN) architecture with recurrent neural network encoder and can generate an extensive number of parameters (>170) given the neuron’s membrane potential responses and steady-state current profiles. We validate our method by estimating HH-model parameters for 200 simulated neurons with graded membrane potential followed by nine experimentally recorded neurons (where six of them are newly recorded) in the nervous system of C. elegans. Comparison of EP-GAN with existing estimation methods shows EP-GAN's advantage in the accuracy of estimated parameters and inference speed for both small and large numbers of parameters being inferred. In addition, the architecture of EP-GAN permits input with arbitrary clamping protocols, allowing inference of parameters even when partial membrane potential and steady-state currents profiles are given as inputs. EP-GAN is designed to leverage the generative capability of GAN to align with the dynamical structure of the HH-model and thus is able to achieve such performance.

RBMX2 links Mycobacterium bovis infection to epithelial–mesenchymal transition and lung cancer progression

aizhen@mail.hzau.edu.cn (Abdul Karim Khalid) — Mon, 24 Nov 2025 00:00:00 +0000

Tuberculosis (TB) is a complex disease caused by the interaction of pathogen, host, and environmental factors. In 2022, TB affected 10.6 million people and caused 1.3 million deaths globally. In high-burden zoonotic TB regions, Mycobacterium bovis accounts for ~10% of human TB cases. The immune evasion and latency of Mycobacterium tuberculosis hinder understanding of host responses. Here, we identify RNA-binding motif protein X-linked 2 (RBMX2) as a novel host factor facilitating M. bovis infection. RBMX2 expression is significantly upregulated in multiple cell types, including EBL, BoMac, bovine alveolar primary cells, and human A549 cells. Multi-omics analyses, cell adhesion assays, and ChIP-PCR demonstrate that RBMX2 suppresses cell adhesion and tight junctions while enhancing M. bovis adhesion and invasion via p65 signaling. Integrated transcriptomic, proteomic, and metabolomic data reveal that RBMX2 regulates epithelial–mesenchymal transition (EMT), a process linked to cancer progression. TIMER2.0 analysis shows elevated RBMX2 expression in lung adenocarcinoma and lung squamous cell carcinoma tissues, validated by immunofluorescence. Using an M. bovis-induced BoMac-EBL EMT model and H1299 cells, we show that RBMX2 promotes EMT through p65/MMP-9 pathway activation. Collectively, RBMX2 is a novel host factor that enhances M. bovis infection and drives infection-induced EMT. These findings provide new insight into TB pathogenesis and highlight RBMX2 as a potential target for TB vaccine and therapeutic development.

Peripheral glia and neurons jointly regulate activity-induced synaptic remodeling at the Drosophila neuromuscular junction

changkt@usc.edu (Annie Wen) — Fri, 21 Nov 2025 00:00:00 +0000

In the nervous system, reliable communication depends on the ability of neurons to adaptively remodel their synaptic structure and function in response to changes in neuronal activity. While neurons are the main drivers of synaptic plasticity, glial cells are increasingly recognized for their roles as active modulators. However, the underlying molecular mechanisms remain unclear. Here, using Drosophila neuromuscular junction (NMJ) as a model system for a tripartite synapse, we show that peripheral glial cells collaborate with neurons at the NMJ to regulate activity-induced synaptic remodeling, in part through a protein called shriveled (Shv). Shv is an activator of integrin signaling previously shown to be released by neurons during intense stimulation at the fly NMJ to regulate activity-induced synaptic remodeling. We demonstrate that Shv is also present in peripheral glia, and glial Shv is both necessary and sufficient for synaptic remodeling. However, unlike neuronal Shv, glial Shv does not activate integrin signaling at the NMJ. Instead, it regulates synaptic plasticity in two ways: (1) maintaining the extracellular balance of neuronal Shv proteins to regulate integrin signaling, and (2) controlling ambient extracellular glutamate concentration to regulate postsynaptic glutamate receptor abundance. Loss of glial cells showed the same phenotype as loss of Shv in glia. Together, these results reveal that neurons and glial cells homeostatically regulate extracellular Shv protein levels to control activity-induced synaptic remodeling. Additionally, peripheral glia maintain postsynaptic glutamate receptor abundance and contribute to activity-induced synaptic remodeling by regulating ambient glutamate concentration at the fly NMJ.

Hierarchical Bayesian modeling of multiregion brain cell count data

sd14814.2014@my.bristol.ac.uk (Alessio Delogu) — Fri, 21 Nov 2025 00:00:00 +0000

We can now collect cell-count data across whole animal brains quantifying recent neuronal activity, gene expression, or anatomical connectivity. This is a powerful approach since it is a multiregion measurement, but because the imaging is done postmortem, each animal only provides one set of counts. Experiments are expensive, and since cells are counted by imaging and aligning a large number of brain sections, they are time-intensive. The resulting datasets tend to be undersampled with fewer animals than brain regions. As a consequence, these data are a challenge for traditional statistical approaches. We present a ‘standard’ partially pooled Bayesian model for multiregion cell-count data and apply it to two example datasets. These examples demonstrate that hierarchical Bayesian methods are well suited to these data. In both cases, the Bayesian model outperformed standard parallel t-tests. Overall, inference for cell-count data is substantially improved by the ability of the Bayesian approach to capture nested data and by its rigorous handling of uncertainty in undersampled data.

PTBP1 depletion in mature astrocytes reveals distinct splicing alterations without neuronal features

sika.zheng@ucr.edu (Ayden Arient) — Fri, 21 Nov 2025 00:00:00 +0000

Astrocyte-to-neuron reprogramming via depletion of PTBP1, a potent repressor of neuronal splicing, has been proposed as a therapeutic strategy, but its efficacy remains debated. While some reported successful conversion, others disputed this, citing a lack of neuronal gene expression as evidence of failed reprogramming. This interpretation was further challenged, attributed to incomplete PTBP1 inactivation, fueling ongoing controversy. Mechanistic understanding of the conversion, or the lack thereof, requires investigating, in conjunction with lineage tracing, the effect of Ptbp1 loss of function in mature astrocytes on RNA splicing, which has not yet been examined. Here, we genetically ablated PTBP1 in adult Aldh1l1-Cre/ERT2 Ai14 mice to determine whether lineage-traced Ptbp1 knockout astrocytes exhibited RNA splicing alterations congruent with neuronal differentiation. We found no widespread induction of neurons, despite a minuscule fraction of knockout cells showing neuron-like transcriptomic signatures. Importantly, PTBP1 loss in mature astrocytes induced splicing alterations unlike neuronal splicing patterns. These findings suggest that targeting PTBP1 alone is ineffective to drive neuronal reprogramming and highlight the need for combining splicing and lineage analyses. Loss of astrocytic PTBP1 is insufficient to induce neuronal splicing, contrasting with its well-known role in other non-neuronal cells, and instead affects a distinct astrocytic splicing program.

Functional characterization of neuropeptides that act as ligands for both calcitonin-type and pigment-dispersing factor-type receptors in a deuterostome

m.r.elphick@qmul.ac.uk (Huachen Liu) — Fri, 21 Nov 2025 00:00:00 +0000

The calcitonin (CT) family of related peptides exerts diverse physiological effects in mammals via two G-protein-coupled receptors: CTR and the CTR-like receptor CLR. Phylogenetic analysis of CT-type signaling has revealed the presence of CT-type peptides and CTR/CLR-type proteins in both deuterostome and protostome invertebrates. Furthermore, experimental studies have demonstrated that in the protostome Drosophila melanogaster, the CT-like peptide DH₃₁ can act as a ligand for a CTR/CLR-type receptor and a pigment-dispersing factor (PDF) receptor. Here, we investigated the signaling mechanisms and functions of CT-type neuropeptides in a deuterostome invertebrate, the sea cucumber Apostichopus japonicus (phylum Echinodermata). In A. japonicus, a single gene encodes two CT-type peptides (AjCT1 and AjCT2), and both peptides act as ligands for a CTR/CLR-type receptor (AjCTR) and two PDF-type receptors (AjPDFR1, AjPDFR2), but with differential activation of downstream cAMP/PKA, Gαq/Ca²⁺/PKC, and ERK1/2 signaling pathways. AjCT1/AjCT2-encoding transcripts were detected in the central nervous system and a variety of organ systems, and neuropeptide expression was visualized immunohistochemically using an antiserum to a starfish CT-type peptide (ArCT). In vitro pharmacological experiments demonstrated that AjCT1 and/or AjCT2 cause dose-dependent relaxation of longitudinal muscle and intestine preparations. Furthermore, in vivo pharmacological experiments, combined with gain- and loss-of-function experiments, revealed a potential physiological role for AjCT2/AjPDFR2 signaling in promoting feeding and growth in A. japonicus. To our knowledge, this is the first study to obtain evidence that CT-type peptides can act as ligands for both CTR/CLR-type and PDF-type receptors in a deuterostome. Moreover, it provides the first evidence for appetite-stimulating and growth-promoting effects of CT-type neuropeptides in bilaterians. Given the economic importance of A. japonicus as a foodstuff, the discovery of CT-type peptides as potential regulators of feeding and growth in this species may offer novel strategies for aquaculture applications.

HoxB-derived hoxba and hoxbb clusters are essential for the anterior–posterior positioning of zebrafish pectoral fins

akawamur@mail.saitama-u.ac.jp (Akinori Kawamura) — Fri, 21 Nov 2025 00:00:00 +0000

Vertebrate paired appendages, such as the pectoral fins in fish and the forelimbs in tetrapods, arise at specific regions along the anterior–posterior axis of the body. Hox genes have long been considered prime candidates for determining the anteroposterior positioning of these paired appendages during development. Evidence from various model organisms, including mouse and chick, supports a role for Hox genes in limb positioning. However, despite extensive phenotypic analyses of numerous single and compound Hox knockout mice, clear genetic evidence for substantial defects in limb positioning has been limited, leaving questions unresolved. In a previous study, we generated seven distinct hox cluster-deficient mutants in zebrafish. Here, we provide genetic evidence that zebrafish hoxba;hoxbb cluster-deleted mutants specifically exhibit a complete lack of pectoral fins, accompanied by the absence of tbx5a expression in pectoral fin buds. In these mutants, tbx5a expression in the pectoral fin field of the lateral plate mesoderm fails to be induced at an early stage, suggesting a loss of pectoral fin precursor cells. Furthermore, the competence to respond to retinoic acid is lost in hoxba;hoxbb cluster mutants, indicating that tbx5a expression cannot be induced in the pectoral fin buds. We further identify hoxb4a, hoxb5a, and hoxb5b as pivotal genes underlying this process. Although the frameshift mutations in these hox genes do not recapitulate the absence of pectoral fins, we demonstrate that deletion mutants at these genomic loci show the absence of pectoral fins with low penetrance. Our results suggest that, by establishing the expression domains along the anteroposterior axis, hoxb4a, hoxb5a, and hoxb5b within hoxba and hoxbb clusters cooperatively determine the positioning of zebrafish pectoral fins through the induction of tbx5a expression in the restricted pectoral fin field. Our findings also provide insights into the evolutionary origin of paired appendages in vertebrates.

Progressive remote memory decline coincides with parvalbumin interneuron hyperexcitability and enhanced inhibition of cortical engram cells in a mouse model of Alzheimer’s disease

michel.vanden.oever@vu.nl (August B Smit) — Fri, 21 Nov 2025 00:00:00 +0000

Patients with Alzheimer’s disease (AD) initially show temporally graded retrograde amnesia, which gradually progresses into more severe retrograde amnesia. Although mouse models of AD have provided insight into neurobiological mechanisms contributing to impaired formation and retrieval of new memories, the process underlying the progressive loss of remote memories in AD has remained elusive. Here, we demonstrate age-dependent remote memory decline in APP/PS1 mice, which coincides with progressive hyperexcitability of parvalbumin (PV) interneurons in the medial prefrontal cortex (mPFC). Analysis of Fos expression showed that the remote memory deficit is not mirrored by changes in reactivation of memory-encoding neurons, so-called engram cells, nor PV interneuron (re)activation, in the mPFC. However, inhibitory input is enhanced onto engram cells compared to non-engram cells specifically in APP/PS1 mice. Our data indicate that age-dependent remote memory impairment in APP/PS1 mice is due to increased innervation of cortical engram cells by hyperexcitable PV interneurons, suggesting that dysfunctional inhibitory microcircuits in the neocortex mediate progressive retrograde amnesia in AD.

Martinize2 and Vermouth provide a unified framework for molecular topology generation

Fabian.Gruenewald@h-its.org (Chris Brasnett) — Thu, 20 Nov 2025 00:00:00 +0000

Ongoing advances in force field and computer hardware development enable the use of molecular dynamics (MD) to simulate increasingly complex systems with the ultimate goal of reaching cellular complexity. At the same time, rational design by high-throughput (HT) simulations is another forefront of MD. In these areas, the Martini coarse-grained force field, especially the latest version (i.e. v3), is being actively explored because it offers an enhanced spatial-temporal resolution. However, the automation tools for preparing simulations with the Martini force field, accompanying the previous version, were not designed for HT simulations or studies of complex cellular systems. Therefore, they become a major limiting factor. To address these shortcomings, we present the open-source Vermouth python library. Vermouth is designed to become the unified framework for developing programs, which prepare, run, and analyze Martini simulations of complex systems. To demonstrate the power of the Vermouth library, the Martinize2 program is showcased as a generalization of the martinize script, originally aimed to set up simulations of proteins. In contrast to the previous version, Martinize2 automatically handles protonation states in proteins and post-translation modifications, offers more options to fine-tune structural biases such as the elastic network (EN), and can convert non-protein molecules such as ligands. Finally, Martinize2 is used in two high-complexity benchmarks. The entire I-TASSER protein template database as well as a subset of 200,000 structures from the AlphaFold Protein Structure Database are converted to CG resolution and we illustrate how the checks on input structure quality can safeguard HT applications.

Cholecystokinin modulates age-dependent thalamocortical neuroplasticity

xli293@cityu.edu.hk (Dingxuan Zeng) — Thu, 20 Nov 2025 00:00:00 +0000

The thalamocortical pathways exhibit neuroplasticity not only during the critical period but also in adulthood. In this study, we investigated how cholecystokinin (CCK) modulates age-dependent thalamocortical plasticity. Our findings demonstrated that CCK is expressed in thalamocortical neurons and that high-frequency stimulation (HFS) of the thalamocortical pathway triggers the release of CCK in auditory cortex (ACx), as detected by a CCK sensor. HFS of the medial geniculate body (MGB) induced thalamocortical long-term potentiation (LTP) in wild-type young adult mice. However, knockdown of CCK expression in MGB neurons or blockade of the CCK-B receptor (CCKBR) in the ACx abolished HFS-induced LTP. Interestingly, this LTP could not be elicited in juvenile (3-week-old) or aged mice (over 18-month-old) due to distinct mechanisms: the absence of CCKBR in juveniles and the inability to release CCK in aged mice. Notably, exogenous administration of CCK into the ACx rescued LTP in aged mice and significantly improved frequency discrimination. These findings highlight the potential of CCK as a therapeutic intervention for ameliorating neuroplasticity deficits associated with thalamocortical connectivity.

A stochastic RNA editing process targets a select number of sites in individual Drosophila glutamatergic motoneurons

troy@mit.edu (Andrés B Crane) — Thu, 20 Nov 2025 00:00:00 +0000

RNA editing is a post-transcriptional source of protein diversity and occurs across the animal kingdom. Given the complete profile of mRNA targets and their editing rate in individual cells is unclear, single-cell RNA transcriptomes obtained by Patch-seq from Drosophila larval glutamatergic motoneuron subtypes were analyzed to determine the most highly edited targets and identify single neuron editing rules. 316 high-confidence A-to-I canonical RNA edit sites were identified, with 60 causing missense amino acid changes predicted to alter proteins regulating membrane excitability, synaptic transmission, or neuronal function. Twenty-seven canonical sites were edited at >90% frequency as observed for editing of mammalian AMPA receptors. However, most sites were edited at lower levels and generated variable expression of edited and unedited mRNAs, suggesting stochastic editing that may provide a mechanism to fine-tune synaptic function similar to alternative splicing. Noncanonical editing was also found to occur in these neurons, including a C-to-U edit that altered an amino acid in the capsid hinge domain of the synaptic plasticity regulator Arc1. Together, these data provide insights into how the RNA editing landscape may alter protein function to modulate the properties of two well-characterized neuronal populations in Drosophila.