eLife: latest articles

In vivo virus-free lineage tracing and live imaging reveal that NeuroD1 does not reprogram microglia into neurons

peng@fudan.edu.cn (Baozhi Yang) — Fri, 16 Oct 2026 00:00:00 +0000

In situ glia-to-neuron conversion induced by a single transcription factor is a promising regenerative strategy for treating central nervous system injuries and neurodegenerative diseases. Previous studies reported that NeuroD1 can induce microglia-to-neuron cross-lineage conversion and improve recovery after brain injury. However, these findings remain controversial. To examine the ability of NeuroD1 in inducing microglia-to-neuron conversion, we employed virus-free genetic lineage-tracing systems in mice to specifically induce NeuroD1 expression in microglia and track the cell fate of NeuroD1-expressing cells at multiple timepoints. Meanwhile, we longitudinally monitored NeuroD1-expressing microglia via two-photon imaging and characterized their transcriptional profile by single-cell RNA sequencing. All observations across these methods revealed that NeuroD1-expressing cells retained their microglia identity and cannot convert into neurons, no matter under physiological and injury conditions. Instead, sustained expression of NeuroD1 facilitated microglia apoptosis in vivo. Collectively, our findings provide strong evidence that NeuroD1 alone is not sufficient to induce microglia-to-neuron conversion. This study further highlights the importance of rigorous lineage-tracing and cell fate-mapping strategies for validating in situ glia-to-neuron conversion.

Individual dopaminergic neurons induce unique, yet overlapping combinations of behavioural modulations, including safety learning, memory retrieval, and acute locomotion

m.schleyer@oia.hokudai.ac.jp (Alice Weiglein) — Fri, 16 Oct 2026 00:00:00 +0000

Two evolutionary highly conserved functions of dopamine are to carry ‘teaching’ signals during associative learning and to control movement. In mammals and humans, these functions are generally thought to be produced by different populations of neurons. Here, we investigated in the larva of Drosophila melanogaster whether both these functions can be induced by the same individual dopaminergic neurons in the central brain. Focusing on the dopaminergic neurons of the DL1 cluster, we asked whether the optogenetic activation of individual neurons established associative punishment and/or safety memories, controlled the retrieval of the established memories, and acutely modulated locomotion. We found that each neuron had a unique yet overlapping set of behavioural effects. Several individual neurons both established a memory and modulated acute locomotion by increasing the animals’ bending and decreasing their velocity. Our results demonstrate that individual dopaminergic neurons can fulfil a surprisingly broad range of functions in different behavioural contexts. Given the highly conserved roles of the dopaminergic system across the animal kingdom, this study raises the question whether a similarly diverse functionality can be found also in other animals, including humans.

Separable downmodulation of meiotic axis protein deposition and DNA break induction at chromosome ends

andi@nyu.edu (Adhithi R Raghavan) — Fri, 16 Oct 2026 00:00:00 +0000

In many organisms, meiotic crossover recombination is suppressed near the extreme ends of chromosomes. Here, we show that multiple, often chromosome-specific, suppressive mechanisms with differing ranges contribute to the consistently low enrichment of recombination-promoting axis proteins and the downregulation of DNA double-strand breaks (DSBs) within 20 kb of telomeres in Saccharomyces cerevisiae. Suppression of axis proteins is associated with cis-encoded signals and correlates with reduced coding density, although whether this sequence feature actively drives suppression remains to be determined. In addition, axis protein suppression requires the histone methyltransferase Dot1 and the Sir silencing complex. We show that Dot1 suppresses Sir complex activity at least in part independently of its canonical target, H3K79, to downmodulate axis protein deposition near chromosome ends. In parallel, the Sir complex, but not Dot1, suppresses the induction of DSBs at a small number of cryptic hotspots by limiting the openness of promoters, the preferred sites of meiotic DSB formation. Much of the reduced DSB induction near chromosome ends persists in dot1 and sir3 mutants, indicating that additional layers of regulation contribute to the robust reduction of meiotic recombination effectors near chromosome ends.

RiboTRAP-seq identifies spatially distinct functions for the anterior and posterior intestine in immune and metabolic regulation in Caenorhabditis elegans

supriya@scripps.edu (Chung-Chih Liu) — Fri, 16 Oct 2026 00:00:00 +0000

The intestine integrates food-derived cues to coordinate organismal physiology, yet the molecular specialization of discrete regions along the intestinal epithelium remains unclear. Here, we generate cell type-specific translatomes of the Caenorhabditis elegans intestine during fasting and refeeding using discrete promoters for the anterior quartet of intestinal cells (INT1) and the remaining eight pairs of intestinal cells (INT2-9). We found that the anterior-most INT1 cells are a translationally distinct intestinal subcompartment that is particularly enriched for immune- and stress response genes. Functional assays using novel INT1-specific genes emerging from this study reveal that these specialized cells play a previously unappreciated role in pathogen avoidance and organismal survival. A second critical function of INT1 cells is their role in sensing and responding to the contents of the gut lumen. We show that luminal pyruvate is the key signal linking bacterial nutrients in the gut to secretion of the gut insulin antagonist INS-7. These findings establish INT1 as sentinel enteroendocrine cells that integrate metabolic and immune cues to couple food status with immune and endocrine responses. Our studies also provide a rich resource for dissecting segment-specific intestinal biology, an overlooked and fertile area for future research.

Correction: Engineered migrasomes provide a robust and thermally stable vaccination platform

Fri, 16 Oct 2026 00:00:00 +0000

Correction: Mask family proteins ANKHD1 and ANKRD17 regulate YAP nuclear import and stability

Fri, 16 Oct 2026 00:00:00 +0000

The cow udder as an influenza mixing ground

r.vries@uu.nl (Robert P de Vries) — Thu, 15 Oct 2026 00:00:00 +0000

Bovine mammary tissue can support infection and replication of diverse influenza A viruses and may provide an environment in which different viral strains can co-infect cells.

The petal identity gene PhDEF has a major binding and regulatory action in the epidermis

daniel.bouyer@ens-lyon.fr (Brice Letcher) — Thu, 15 Oct 2026 00:00:00 +0000

In flowering plants, floral organ identity is specified by the combinatorial action of homeotic genes. While the role of these genes in the early specification of organ identity is well established, their late function throughout floral organ development and in specific cell types is much less characterized. In particular, since plant organs are structured in clonally independent cell layers, whether and how homeotic identity interacts with cell layer identity is unknown. We have previously identified cell layer-specific mutants for the petal identity gene PhDEF in petunia flowers, resulting in drastically different petal phenotypes whether PhDEF is expressed in the petal epidermis or in the mesophyll. In this study, using a combination of single-cell RNA-Seq and chromatin immunoprecipitation on phdef cell layer-specific mutants, we find that PhDEF regulates a different set of target genes in the petal epidermis and mesophyll, with a major regulatory action in the epidermis. We uncover a high diversity of binding profiles in PhDEF target genes, with a complex combination of layer-specific or non-specific binding sites, and a much more prominent binding of PhDEF in the epidermis than in the mesophyll. Our study highlights that floral homeotic genes like PhDEF can have different regulatory actions in different cell contexts, here different cell layers, demonstrating that cell layer identity indeed influences the regulatory processes underlying homeotic identity.

Foveated metamers of the early visual system

billbrod@gmail.com (Eero Simoncelli) — Thu, 15 Oct 2026 00:00:00 +0000

The ability of humans to discriminate and identify spatial patterns varies across the visual field and is generally worse in the periphery than in the fovea. This decline in performance is revealed in many kinds of tasks, from detection to recognition. A parsimonious hypothesis is that the representation of any visual feature is blurred (spatially averaged) by an amount that differs for each feature, but that in all cases increases with eccentricity. Here, we examine models for two such features: local luminance and spectral energy. Each model averages the corresponding feature in pooling windows whose diameters scale linearly with eccentricity. We performed perceptual experiments with synthetic stimuli to determine the largest window scaling for which human and model discrimination abilities match (the ‘critical’ scaling). We used much larger stimuli than those of previous studies, subtending 53.6 by 42.2° of visual angle. We found that the critical scaling for the luminance model was approximately one-fourth that of the energy model and, consistent with earlier studies, that the estimated critical scaling value was smaller when discriminating a synthesized stimulus from a natural image than when discriminating two synthesized stimuli. Moreover, we found that initializing the generation of the synthesized images with natural images reduced the critical scaling value when discriminating two synthesized stimuli, but not when discriminating a synthesized from a natural image stimulus. Together, the results show that critical scaling is strongly affected by the image statistic (pooled luminance vs. spectral energy), the comparison type (synthesized vs. synthesized or synthesized vs. natural), and the initialization image for synthesis (white noise vs. natural image). We offer a coherent explanation for these results in terms of alignments and misalignments of the models with human perceptual representations.

Correction: A Ctnnb1 enhancer transcriptionally regulates Wnt signaling dosage to balance homeostasis and tumorigenesis of intestinal epithelia

Wed, 14 Oct 2026 00:00:00 +0000

The 42 problem in AI-assisted research

giovanni.spitale@ibme.uzh.ch (Federico Germani) — Wed, 14 Oct 2026 00:00:00 +0000

Large language models are very good at providing concise answers. But if we only see the answer without knowing the original question or the context behind it, that answer may not be very useful. The important issue is not simply how much information an AI summary removes but whether we can still recover the missing context. Thus, AI literature tools should also report how much information was removed and how recoverable their omissions are.

Salmonids elicit an acute behavioral response to heterothermal environments

rnaudascher@yahoo.de (Jonasz Slomka) — Wed, 14 Oct 2026 00:00:00 +0000

Most fish species are ectothermic and rely on behavioral strategies to control their body temperature in heterothermal environments. Both thermotaxis and thermokinesis have been suggested as important underlying mechanisms. However, to what extent these behaviors allow fish to respond to rapid (timescales of minutes) and strong thermal disturbances, like those caused by anthropogenic water releases into natural freshwater systems, is poorly understood. Here, we quantify this response for a salmonid species with a novel laboratory approach coupled with image-based tracking. We exposed brown trout parr (Salmo trutta), acclimated to 12 °C, to rapidly forming cold- and warm-water interfaces with temperatures ranging from 4 to 20 °C. We found that fish actively avoided colder water (≤8 °C) through a rapid response that combined thermotaxis and thermokinesis. In contrast, fish did not avoid warmer water and frequently crossed interfaces having temperature contrasts of up to 8 °C. This study shows that brown trout parr swiftly deploy multiple behavioral strategies to minimize exposure to cold water and take advantage of warm water, illustrating their capability to cope with rapidly occurring thermal alterations.

Gluconeogenic compensation renders glycogen phosphorylase non-essential as an insecticidal target in Plutella xylostella

yalinzh@nwsuaf.edu.cn (Chong Yi) — Tue, 13 Oct 2026 00:00:00 +0000

Glycogen phosphorylase (GP) catalyzes the rate-limiting step of glycogenolysis and supplies precursors for chitin biosynthesis in insects. Acyl urea compounds structurally related to benzoylphenylurea (BPU) insecticides are potent inhibitors of mammalian GP, raising the question of whether insect GP could serve as an independent insecticidal target. Here, we show that a mammalian GP inhibitor (GPI) potently inhibits recombinant Plutella xylostella GP (PxGP; IC₅₀=2.96 nM), while the BPU insecticide diflubenzuron does not. Molecular docking and MM/GBSA analysis predict that this selectivity reflects differential side-chain engagement. Despite potent in vitro inhibition, GPI exhibits no insecticidal activity, and RNAi-mediated knockdown of PxGP does not impair development or survival. We provide evidence that insects compensate through upregulation of gluconeogenic enzymes (PEPCK, G-6-Pase) and protein catabolism, with enzyme activity measurements confirming ~29% reduction in GP-a activity following RNAi. Fitness assessment reveals transient larval weight loss with complete recovery of pupal weight, adult morphology, and fecundity. These findings demonstrate that GP is functionally non-essential under the tested conditions, likely through gluconeogenic compensation and alternative carbon sources, and highlight the importance of metabolic network redundancy in target-based insecticide design.

Reduced dorsal CA1 activity limits retention of the temporal component of declarative memory in the Cntnap2 knockout mouse model of autism

shaam.alabed@anu.edu.au (Alice Shaam Al-Abed) — Tue, 13 Oct 2026 00:00:00 +0000

Growing evidence implicates the hippocampus in the pathophysiology of autism spectrum disorder, particularly in the domains of social interactions and cognition. Yet, the mechanisms driving the hippocampal-dependent cognitive atypicalities in autism remain poorly defined. Here, we characterized how dysfunction of the CA1 subfield of the dorsal hippocampus drives abnormalities in critical components of declarative memory. Using trace fear conditioning in the Cntnap2 knockout mouse model of autism, we found that capabilities to retain the association of temporally distant stimuli (i.e. temporal binding) were reduced relative to wildtype mice. Fiber photometry and optogenetic experiments demonstrated that reduced CA1 activity during temporal gaps underlies this impairment, linking CA1 dysfunction to a deficit in long-term memory retention in autism. Using a relational/declarative memory task, we also revealed a deficit in flexible spatial memory, and a preferential use of egocentric learning strategy. This inflexible learning strategy resulted from an imbalance between memory system activity, promoting frontostriatal-dependent procedural learning instead of dorsal CA1/hippocampus-dependent relational/declarative memory. Overall, this study establishes dorsal CA1 dysfunction as a circuit-level mechanism underlying cognitive inflexibility in autism, providing a neurobiological framework for hippocampal-dependent memory deficits in the condition.

Designing optimal perturbation inputs for system identification in neuroscience

ogino-m@g.ecc.u-tokyo.ac.jp (Daiki Sekizawa) — Tue, 13 Oct 2026 00:00:00 +0000

Investigating the dynamics of neural networks, which are governed by connectivity between neurons, is a fundamental challenge in neuroscience. Because passive (spontaneous) activity provides only limited information for estimating connectivity, perturbation-based approaches are widely applied in neuroscience as they can evoke underlying hidden dynamics. However, the characteristics of such perturbations have typically been designed based on empirical or biological intuition. To enable more accurate estimation of connectivity, we propose a data-driven and theoretically grounded framework for optimally designing perturbation inputs, based on formulating the neural model as a control system. The core theoretical insight underlying our approach is that neural signals observed in the passive state lack sufficient latent information, which leads to failures in the system identification. Perturbations reveal these hidden dynamics and lead to improved estimation. Guided by these insights, we derive a theoretical basis for optimizing perturbation inputs that minimize estimation errors in neural system identification. Building upon this, we further explore the relationship of this theory with stimulation patterns commonly used in neuroscience, such as frequency, impulse, and step inputs. We demonstrate the effectiveness of this framework for neuroscience through simulations grounded in experimental paradigms, such as neural state classification and optimal control of neural states. Our theoretical analysis, together with multiple simulations, consistently shows that perturbations designed according to our framework achieve substantially more accurate system identification compared to the conventional, intuition-based inputs. This study provides a theoretical foundation for designing perturbation inputs to achieve accurate estimation of neural dynamics. This, in turn, enables reliable discrimination of neural states such as levels of consciousness and pathological conditions, and facilitates precise control of their transitions toward recovery from abnormal states.

Anatomy and mechanics of tsetse fly blood feeding

laura.hauf@uni-wuerzburg.de (Alexander Kovalev) — Tue, 13 Oct 2026 00:00:00 +0000

Human African trypanosomiasis (HAT) is a neglected tropical disease transmitted by infected tsetse flies (Glossina spp.) in sub-Saharan Africa. Infected tsetse flies can transmit trypanosomes, including Trypanosoma brucei subspecies that cause HAT in humans, as well as other trypanosome species that cause animal African trypanosomiasis in domestic animals and infect wildlife. Tsetse flies feed on a broad spectrum of hosts, including humans, elephants, buffaloes, rhinos, hippos, turtles, and monitor lizards. To understand how the insects can penetrate such diverse skin types, we detailed the anatomical structures involved in tsetse blood feeding, their mechanical properties, and the forces exerted by the fly during probing. We found that the tsetse fly’s feeding apparatus does not rely on exceptionally unique structures or extraordinary forces. Instead, the tsetse fly has evolved subtle yet highly efficient adaptations, which include a labellum equipped with arrays of small teeth. When combined with a robust retraction movement of the proboscis, these structures create lesions on various types of skin, thus facilitating blood pool feeding on a broad host spectrum.

Allosteric disulfide control of ligand binding and endocytosis of KIR2DL4, the natural killer cell receptor for HLA-G

elong@nih.gov (Eric O Long) — Tue, 13 Oct 2026 00:00:00 +0000

Human Leukocyte Antigen (HLA)-G is selectively expressed by fetal trophoblast cells that encounter maternal natural killer (NK) cells early in pregnancy. In response to HLA-G, the endosomal NK cell receptor KIR2DL4 induces a transcriptional program to support placental development. Structural features of KIR2DL4 that control HLA-G binding and endocytosis are unclear. Random mutagenesis revealed that three cysteines in the first immunoglobulin domain of KIR2DL4 regulate endocytosis and uptake of HLA-G. The atypical Cys10–Cys28 disulfide bond in the KIR2DL4 structure is an allosteric disulfide with potential to switch to a conventional Cys28–Cys74 bond. KIR2DL4 in human cells exists in both disulfide-bonded states, as shown by mass spectrometry analysis. The Cys10–Cys28 bond in a Cys74Ser KIR2DL4 mutant was reduced by protein disulfide isomerase (PDI) in vitro. Inhibition of PDI prevented HLA-G uptake by KIR2DL4 in NK cells. Mutants in the Cys10–Cys28 configuration endocytosed spontaneously but did not bind HLA-G. Conversely, KIR2DL4 with a Cys28–Cys74 bond was detectable at the plasma membrane and internalized soluble HLA-G. A purified Cys10Leu KIR2DL4 mutant bound HLA-G with micromolar affinity in a peptide-dependent manner. Thus, allosteric disulfide-mediated conversion from an inactive to an HLA-G binding form regulates KIR2DL4 trafficking and a functional response that promotes fetal development.

Endosome-associated Rab GTPases control distinct aspects of neural circuit assembly

lluo@stanford.edu (Colleen N McLaughlin) — Tue, 13 Oct 2026 00:00:00 +0000

Neural circuit assembly relies on the precise regulation of cell-surface receptors that mediate signaling and adhesion. Endocytosis controls receptor activity and availability by internalizing and routing proteins through early endosomes to one of two main pathways: recycling back to the cell-surface or delivery to lysosomes for degradation. Rab GTPases direct receptors into these distinct pathways, but their specific contributions to circuit formation remain opaque. Using clonal analyses with null alleles, we dissected the roles of Rab-mediated trafficking to early, late, and recycling endosomes across multiple stages of circuit assembly in vivo. Our approach revealed that Rab5 and Rab11 regulate extensive and largely distinct developmental events, highlighting the pivotal roles of early endosome sorting and recycling pathways in circuit assembly. As neurons mature, both the spatial distribution and abundance of specific endocytic compartments change to reflect evolving trafficking demands. Our findings underscore how distinct post-endocytic trafficking fates are necessary to build neural circuits.

JAK-STAT pathway heterogeneity governs immunotherapy response in breast cancer

yulei@itm-oncolab.cn (Fu Peng) — Tue, 13 Oct 2026 00:00:00 +0000

The JAK-STAT pathway (JSP) is a well-known oncogenic cascade; however, recent clinical trials have detected JSP upregulation in breast cancer following anti-PD-1 immunotherapy. This paradoxical observation warrants further investigation into JSP’s intercellular heterogeneity, tumor dynamics, molecular mechanisms, and clinical implications for immunotherapy. JSP expression showed dynamic shifts during breast cancer progression, with higher levels in T cells and paracancerous epithelial cells. In human breast cancer tumor cells, elevated JSP is highly correlated with malignant phenotypes. JSP-high tumor cells overexpressed oncogenic pathways, while exhibiting increased immunosuppressive signaling via the MIF-CD74 signaling axis. In T cells, higher JSP levels were associated with enhanced cytotoxic activity, improved differentiation, and reduced exhaustion, reflecting robust anti-tumor immunity. Analysis of immunotherapy datasets revealed that higher JSP levels were associated with improved responses toward PD-1 inhibitors, particularly in triple-negative breast cancer (TNBC) patients, with JSP serving as a predictive biomarker for immunotherapy sensitivity. As a key JSP component, STAT4 exerts dual roles in breast cancer: it drives tumorigenesis in malignant cells, sustains breast epithelial cell proliferation, and bolsters T-cell anti-tumor functionality, while also acting as a highly accurate biomarker for predicting immunotherapy response. This indicates that JSP targeting demands a nuanced approach: broad inhibition may impair anti-tumor immunity, and optimized therapeutic strategies paired with precise biomarkers are critical to maximize JSP’s utility in breast cancer immunotherapy. Our findings highlight JSP’s functional heterogeneity in epithelial, tumor, and T cells, with high JSP activity correlating with enhanced immunotherapy efficacy in breast cancer.

A framework for analyzing global Caenorhabditis elegans neural activity

sharpee@salk.edu (Eviatar Yemini) — Tue, 13 Oct 2026 00:00:00 +0000

Neurons represent changes in external and internal environments by altering their activity patterns. While coherent brain-wide patterns of neural activity have been observed in neuronal populations, very little is known about their dimensionality, geometry, and how they are correlated with sensory inputs. Here, we recorded the activity of most head neurons in Caenorhabditis elegans experiencing changes in bacterial or control buffer stimuli around their nose. We first classified active neurons into six functional clusters: two sensory neuron clusters (ON and OFF responding to addition and removal of stimuli, respectively) and four motor/command neuron clusters (AVA, RME, SMDD, and SMDV). Next, we estimated stimulus selectivity for each cluster and found that while sensory neurons exhibit their maximal responses within 15 s, changes in bacterial stimuli drive maximal responses in command and motor neuron clusters after tens of seconds. Furthermore, we show that bacterial stimuli induce neural dynamics that are best described by a hyperbolic, not Euclidean, space indicating hierarchical organization in C. elegans neural population dynamics. This space was 8-dimensional, with dimensions that aligned in one sensory direction (ON and OFF neurons), two motor directions (forward-backward and dorsal-ventral), and the rest of dimensions corresponding with unclassified neurons. Collectively, we show that C. elegans neural activity can be effectively represented in low-dimensional hyperbolic space and describe how sensory information is processed by the neural network.

Synaptic connectome of a neurosecretory network in the Drosophila brain

mzandawala@unr.edu (Ariana J Gayban) — Mon, 12 Oct 2026 00:00:00 +0000

Hormones mediate inter-organ signaling, which is crucial in orchestrating diverse behaviors and physiological processes, including sleep and activity, feeding, growth, metabolism, and reproduction. The pars intercerebralis and pars lateralis in insects represent major hubs that contain neurosecretory cells (NSCs) that produce various peptide hormones. To obtain insight into how hormonal signaling is regulated, we have characterized the synaptic connectome of NSCs in the adult Drosophila brain. Identification of neurons providing inputs to multiple NSC classes implicates diuretic hormone 44-expressing NSCs as a major coordinator of physiology and behavior. Surprisingly, despite most NSCs having dendrites in the subesophageal zone (primary taste processing center), inputs from peripheral gustatory neurons to NSCs are largely indirect. We also deciphered pathways via which diverse olfactory inputs are relayed to NSCs. Using an influence metric, based on a linear dynamical systems approach, we identify enteric neurons as the strongest influencers of NSC activity compared to other sensory modalities. Further, our analyses revealed substantial inputs from brain descending neurons to NSCs, suggesting that descending neurons regulate both endocrine and motor output to synchronize physiological changes with appropriate behaviors. In contrast to NSC inputs, synaptic output from NSCs is sparse and mostly mediated by corazonin NSCs. We show that both corazonin-expressing NSCs and their downstream synaptic partner DNg27 influence egg-laying. We additionally explore putative paracrine interconnectivity between NSC classes and peptide hormone pathways from NSCs to peripheral tissues by analyzing single-cell transcriptomic datasets. Our comprehensive characterization of the Drosophila neurosecretory network connectome provides a platform to understand complex hormonal networks and how they orchestrate animal behaviors and physiology.

Large-scale prospective evaluation of co-folding across hundreds of Mac1–ligand complexes and three virtual screens

bshoichet@gmail.com (Adam R Renslo) — Mon, 12 Oct 2026 00:00:00 +0000

Accurate prediction of ligand-bound protein complexes and ranking them by affinity are central problems in drug discovery. While deep-learning co-folding methods can help address these challenges, their evaluation has been hampered by the difficulties in assessing independence from training data and insufficiently large test sets. Here, we test the ability of co-folding methods to predict the structures of 551 ligands, 489 of which are of sufficient quality for evaluation, bound to the SARS-CoV-2 NSP3 macrodomain (Mac1) that were determined after the training cutoff dates. AlphaFold3 (AF3), Boltz-2, and Chai-1 each reproduced >50% of the Mac1 ligand poses to better than 2 Å root-mean-square deviation of experiment. Despite the potential for co-folding to describe protein conformational changes that stabilize ligand binding, we did not find that common conformational rearrangements, including peptide flip and a large loop opening, were recapitulated by the co-folding prediction. For AF3 and Chai-1, ligand pose prediction confidence weakly, but significantly, tracked experimental potency, while DOCK3.7 energies were only weakly correlated. Boltz-2 affinity predictions showed the strongest correlation with measured potency and, after calibration, achieved lower mean absolute error than a baseline predictor. We next assessed whether co-folding scores could rescore docking hit lists to distinguish true ligands from non-binders among hundreds of molecules prospectively experimentally tested against AmpC β-lactamase, the dopamine D4, and the σ₂ receptors. AF3 ligand pose confidence values did not separate true ligands from high-scoring false positives as effectively as docking scores or Boltz-2 affinity predictions did. Taken together, the modest, but independent correlations of docking score and co-folding confidence or affinity suggest that integrating physics-based and deep-learning approaches may help with hit prioritization and subsequent optimization in structure-based ligand discovery.

Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity

jfraser@fraserlab.com (Angelika Arada) — Mon, 12 Oct 2026 00:00:00 +0000

To maintain metabolic homeostasis, enzymes must adapt to fluctuating nutrient levels through mechanisms beyond gene expression. Here, we demonstrate that human glutamine synthetase (GS) can reversibly polymerize into filaments aided by a composite binding site formed at the filament interface by the product, glutamine. Time-resolved cryo-electron microscopy (cryo-EM) confirms that glutamine binding stabilizes these filaments, which in turn exhibit reduced catalytic specificity for ammonia at physiological concentrations. This inhibition appears induced by a conformational change that remodulates the active site loop ensemble gating substrate entry. Metadynamics ensemble refinement revealed >10 Å conformational range for the active site loop and that the loop is stabilized by transient contacts. This disorder is significant, as we show that the transient contacts which stabilize this loop in a closed conformation are essential for catalysis both in vitro and in cells. We propose that GS filament formation constitutes a negative-feedback mechanism, directly linking product concentration to the structural and functional remodeling of the enzyme.

Robust and replicable effects of ageing on resting-state brain electrophysiology measured with MEG

a.quinn@bham.ac.uk (Andrew J Quinn) — Mon, 12 Oct 2026 00:00:00 +0000

Non-invasive recordings of brain electrophysiology provide credible insights into decline in neuronal functioning with age. New approaches are required to translate these results into compelling clinical metrics and meet the global challenge of preserving brain health in ageing. Changes in neuronal dynamics with ageing are observable in the power spectra of EEG and MEG recordings. Highly promising candidates for electrophysiological markers have been identified, but progress is hindered by substantial methodological variability across studies. This makes it challenging to establish a clear consensus on the frequency, location, and direction of any single reported effect within the larger body of research. We estimate a full-frequency whole-head profile of the ageing effect on eyes-closed resting-state MEG using the GLM-Spectrum. This data representation is easily sharable, facilitates meta-analyses, and provides a framework for estimating statistical power of age effects for future study planning. We use this to show that the effect of age replicates across open-access MEG datasets and is robust to modelling of common covariates. Distinct components within the full-frequency profile have different effect sizes, indicating that sample-size planning for ageing effects must consider the specific features of interest. The frequency profile of ageing is strongly robust to a range of common covariates and partially robust to modelling of grey matter volume. We establish that what seems a well-powered study may become underpowered when analyses target an age effect that is linearly separable from an age-relevant covariate such as grey matter volume. These results provide a pathway towards formal comparison and assessment of candidate markers for brain health in ageing.

Synaptic vesicle undocking induces low-frequency depression

alain.marty@parisdescartes.fr (Alain Marty) — Mon, 12 Oct 2026 00:00:00 +0000

Synaptic depression is often interpreted as reflecting depletion of the readily releasable pool (RRP) following exocytosis. Such a mechanism predicts little or no depression at low stimulation frequency, as RRP replenishment should then offset the loss of vesicles by exocytosis. Nevertheless, in several types of mammalian central synapses, repetitive presynaptic stimulation at low frequency (<5 Hz) elicits synaptic depression (low-frequency depression or LFD). In the present work, we count the number of synaptic vesicles released at individual active zones to study the RRP and its replenishment during LFD. Contrary to depletion models of synaptic depression, we find that LFD does not depend on previous SV consumption. We find that LFD displays a long recovery time course (tens of seconds) when challenged by isolated stimulations but is immediately reversed by a high-frequency train. We suggest that LFD results from undocking, a shift between two classes of synaptic vesicles organized sequentially inside the RRP (replacement vs. docked vesicles) in favor of the upstream (replacement) state. To explain the dependence of LFD recovery on stimulation frequency, we propose that, while undocking is apparent hundreds of milliseconds after a stimulation, calcium-dependent docking takes only a couple of milliseconds. Consistent with the undocking model, we find that double presynaptic stimulations alleviate LFD as they favor vesicular docking and RRP replenishment. Finally, we expand our model to explain how stimulation frequency shapes short-term synaptic depression, changing from depression at low frequency to a facilitation-depression sequence at medium- or high-frequency trains.

Genome-wide mapping of Cas9-induced sister chromatid exchange across single and over 200 genomic sites in human cells

yeastyin@g.ucla.edu (Peter Chovanec) — Mon, 12 Oct 2026 00:00:00 +0000

CRISPR/Cas9-induced DNA double-strand breaks (DSBs) are widely used for genome engineering, yet their capacity to provoke sister chromatid exchange (SCE) remains incompletely understood because exchanges between identical sisters leave no sequence change and are invisible to conventional sequencing. Using sci-L3-Strand-seq, a scalable single-cell template-strand sequencing platform, we mapped SCE following targeted Cas9 cleavage. Cas9 targeting of a unique genomic locus strongly enriched SCE at the break site, reaching 41% in the same cell cycle and 17% in the subsequent division, indicating frequent non-local inter-sister repair. Targeting 237 repetitive Alu sites produced mild enrichment of on-target SCE, whereas cells with elevated SCE burden showed significant enrichment at programmed cut sites, suggesting context-dependent recombination at repetitive loci. Reciprocal daughter-cell pair analysis revealed large-scale structural alterations on chromosomes with induced SCEs and at SCE junctions, indicating that Cas9-induced SCE does not universally reflect error-free homologous recombination. Disruption of LIG3, LIG4, XRCC1, and XRCC4 at Cas9 cut sites did not measurably alter SCE frequency, consistent with delayed functional loss following editing. Together, these findings identify Cas9-induced DSBs as potent local triggers of SCE and reveal structural outcomes invisible to conventional sequencing.

Svep1 orchestrates distal airway patterning and alveolar differentiation in murine lung development

carol.bult@jax.org (Carol J Bult) — Mon, 12 Oct 2026 00:00:00 +0000

Disruptions in airway branching or alveolar differentiation during lung development can lead to severe respiratory deficiencies and neonatal death. The molecular mechanisms governing branching patterning and early alveolar formation remain elusive. Loss of Svep1 function in mice results in various developmental defects, including lung hypoplasia and perinatal lethality. Our examination of the lungs of Svep1 knockout (Svep1^-/-) mouse embryos, both in vivo and in vitro, revealed that Svep1 mutants exhibit an increase in the number of disorganized distal airway tips, progressively greater disruption of lung lobe morphology over time, and disrupted saccular development. Svep1 interacts with FGF signaling to regulate smooth muscle differentiation and, together with Fgf9, guides airway branching patterning. Transcriptomic data from the lungs of Svep1^-/- embryos revealed dysregulated gene expression affecting saccular maturation. Our findings demonstrate that Svep1 is a key extracellular matrix player shaping airway morphology and influencing alveolar fate. These insights offer potential avenues for therapeutic interventions in congenital lung disorders.

Obtaining maximum information from colony counts with REPOP

spresse@asu.edu (Carol Yunxiao Slayton) — Fri, 09 Oct 2026 00:00:00 +0000

Bacterial counts from native environments, such as soil or the animal gut, often show substantial variability across replicate samples. This heterogeneity is typically attributed to genetic or environmental factors. A common approach to estimating bacterial populations involves successive dilution and plating, followed by multiplying colony counts by dilution factors. This method, however, overestimates the heterogeneity in bacterial population because it conflates the inherent uncertainty in drawing a subsample from the total population with the uncertainty in the sample arising from biological origins. In other words, this approach may obscure features that may otherwise be present in the data, hinting at the presence of genuine subpopulations. For example, in plate counting applied to Caenorhabditis elegans gut microbiota, observed multimodality is often interpreted as large host-to-host variance, while the randomness introduced by measurement is frequently ignored. To explicitly account for the uncertainty introduced by dilution and plating randomness, we introduce REPOP, a PyTorch-based library to REconstruct POpulations from Plates within a Bayesian framework. Beyond simple cases, REPOP addresses more complex scenarios, including multimodal populations and correcting the mathematically subtle, but experimentally relevant, bias introduced by excluding plates deemed too crowded to distinguish individual colonies. We demonstrate REPOP’s ability to resolve distinct population peaks otherwise obscured by standard multiplication methods. Applications to both simulated and experimental datasets, including bacterial samples of different concentrations and ones from the gut microbiota of C. elegans, show that REPOP accurately recovers the underlying multimodality by properly accounting for error propagation, where naive multiplication fails. REPOP is available on GitHub: https://github.com/LabPresse/REPOP.

Role of desolvation on biomolecular liquid–liquid phase separation

wfli@nju.edu.cn (Kai Zhang) — Fri, 09 Oct 2026 00:00:00 +0000

Biomolecular condensates play essential roles in cellular organization and are implicated in diverse pathological processes. Their formation is driven by liquid–liquid phase separation (LLPS), a process that requires coordinated multistep desolvation of biomolecular chains and multivalent inter-chain interactions. Although coarse-grained (CG) models with implicit solvent are widely used to probe LLPS thermodynamics and kinetics, they typically neglect water-mediated desolvation effects, limiting their accuracy and mechanistic interpretability. Here, guided by all-atom simulations and experimental measurements, we develop a desolvation-aware implicit-solvent CG model by incorporating residue-level desolvation terms directly into the pairwise energy function, and apply it to investigate LLPS of intrinsically disordered proteins. Incorporating these desolvation interactions reshapes the phase diagram, alleviating dense-phase overcompaction. Notably, we observe an approximately linear correlation between the temperature gap (simulation temperature relative to the critical point) and the extent of conformational expansion accompanying the dilute-to-dense phase transition, a result further supported by theoretical analysis. We also find that desolvation barriers slow early density-fluctuation growth and shorten transient kinetic arrest, whereas solvent-separated contact interactions exert the opposite effects. Both terms further modulate chain mobility within mature condensates through competing packing and energy-landscape effects. Together, this framework enables an efficient representation of desolvation in CG simulations and reveals how desolvation energetics shape both the thermodynamic landscape and kinetic properties of biomolecular LLPS.

Punctuated mutagenesis promotes multi-step evolutionary adaptation in human cancers

michor@jimmy.harvard.edu (Christopher J Graser) — Fri, 09 Oct 2026 00:00:00 +0000

The rate of acquisition of genomic changes in cancer has been the topic of much discussion, with several recent investigations finding evidence of punctuated evolution instead of gradual accumulation of such changes. Despite forays into the description and quantification of these punctuated events, the effects of such changes on subsequent cancer evolution remain incompletely understood. Here we investigate how non-gradual mutagenesis affects the ability of tumor cells to acquire and retain fitness-enhancing adaptations. We find that punctuated mutagenesis significantly facilitates adaptation in scenarios where adaptation requires crossing a fitness valley, that is when multiple mutations are required which individually are maladaptive but jointly confer a fitness advantage. By increasing the probability that multiple mutations occur in close succession, punctuation increases the chance that mutants in a fitness valley mutate further to reach a fitness peak before going extinct. Analyzing data from The Cancer Genome Atlas, we find that tumors with signatures of APOBEC mutagenesis, which has been shown to proceed in episodic bursts, exhibit patterns consistent with higher rates of crossing fitness valleys. Lastly, we characterize how the interplay between this enhanced ability to cross fitness valleys and adaptation-limiting effects of clonal interference affects overall adaptability in complex fitness landscapes.

Starvation transforms signal encoding in C. elegans thermoresponsive neurons and suppresses heat avoidance via bidirectional glutamatergic and peptidergic signaling

dominique.glauser@unifr.ch (Dominique A Glauser) — Fri, 09 Oct 2026 00:00:00 +0000

Animals must continuously adapt their behavioral outputs in response to changes in internal state, including nutritional state. Here, we show that starvation induces a profound and progressive suppression of thermonociceptive behavior in Caenorhabditis elegans. During early food deprivation (1 hr without food), the thermoresponsive AWC sensory neurons mediate robust heat-evoked reversals over a broad range of stimulus intensities via glutamate and FLP-6 neuropeptide signaling, each covering distinct heat intensity ranges. After 6 hr of food deprivation (prolonged starvation), heat-evoked reversal responses are nearly abolished, independently of external food odor cues. Starvation shifts the distribution of AWC heat-evoked calcium response polarity, from mostly excitatory responses to a heterogeneous pattern combining excitatory and inhibitory activities. This switch relies on ASI neurons, proposed to sense internal state. INS-32 and NLP-18 neuropeptide signals from ASI switch from reversal-promoting to reversal-inhibiting effects. In addition, reversal-promoting glutamatergic transmission by AWC is antagonized by glutamatergic transmission from non-AWC neurons that suppress FLP-6-dependent reversals. Our findings define a circuit logic by which gating of nociceptive responsiveness by internal nutritional state is linked to dynamic modulation of sensory neuron activity patterns and orchestrated by bidirectional glutamatergic and neuropeptidergic signals.

The structural context of mutations in proteins predicts their effect on antibiotic resistance

annagreen@umass.edu (Anna G Green) — Fri, 09 Oct 2026 00:00:00 +0000

In Mycobacterium tuberculosis, a prevalent and deadly pathogen, resistance to antibiotics evolves primarily through non-synonymous mutations in proteins. Sequence-based analyses can uncover the genetic basis of antibiotic resistance, but these methods focus on primary sequence and often neglect other biological signals, such as protein structural information. We hypothesize that integrating the structural context of mutations improves the prediction of effects on function and phenotype. We curate high-confidence structural annotations for the M. tuberculosis proteome from 1350 crystallography and 2337 AlphaFold predictions, and mutations from over 31,000 M. tuberculosis isolates. We demonstrate that mutations in proteins known to cause resistance are clustered in 3D space, even in proteins where inactivating mutations at any position are thought to cause resistance. We find over 450 proteins in the M. tuberculosis proteome that display signals of clustered mutations, many of which have a known relationship with antibiotic resistance. We show that a supervised classifier trained on 3D distance to known resistance sites alone has an F1 score of 96.5% at classifying mutations as resistance-conferring on a held-out test set. This work demonstrates that protein structure provides useful information for categorizing which variants may cause antibiotic resistance, even when the majority of structures are AI-predicted.

A membrane-disruptive action of VBIT-4 challenges its role as a widely used VDAC1 oligomerization inhibitor

lbergdoll@imm.cnrs.fr (Bethel G Beyene) — Fri, 09 Oct 2026 00:00:00 +0000

Voltage-dependent anion channel (VDAC) is the most abundant protein of the mitochondrial outer membrane and a key regulator of metabolite exchange and mitochondrial physiology. Its oligomerization has been proposed to control processes such as mitochondrial DNA release and membrane remodeling, yet the underlying mechanisms remain poorly defined. VBIT-4 has been widely used as a putative inhibitor of VDAC1 oligomerization, despite limited mechanistic validation. Here, using high-speed atomic force microscopy (AFM), we visualized VDAC1 assemblies in lipid membranes and examined the effect of VBIT-4. Unexpectedly, VBIT-4 induced membrane defects and permeabilization at micromolar concentrations, independently of VDAC1. Quantitative AFM analysis further shows that VBIT-4 does not alter VDAC1 cluster organization. Complementary electrophysiology, microscale thermophoresis, and coarse-grained molecular dynamics demonstrate that VBIT-4 partitions into lipid bilayers, increases membrane permeability, and destabilizes membrane structure, without detectable effects on VDAC1 channel properties or assemblies. Consistent with this mechanism, VBIT-4 induces VDAC1-independent cytotoxicity in HeLa cells at concentrations above 10 µM. Together, these results demonstrate that VBIT-4 does not act as a specific inhibitor of VDAC1 oligomerization but instead functions as a membrane-active compound. This work provides a revised framework for interpreting studies using VBIT-4 and highlights the importance of systematically assessing drug-membrane interactions when targeting membrane proteins.

Genome-wide synthetic lethality screen of Bam complex-associated genes in Escherichia coli

jack.bryant@nottingham.ac.uk (Charly D Neilson) — Thu, 08 Oct 2026 00:00:00 +0000

Biogenesis of the bacterial outer membrane is key to bacterial survival and antibiotic resistance. Central to this is the β-barrel assembly machine (Bam) complex and its associated chaperones, which are responsible for transport, folding, and insertion of outer membrane proteins (OMPs). The Escherichia coli Bam complex is composed of two essential subunits, BamA and BamD, and three non-essential accessory lipoproteins, BamB, BamC, and BamE. Optimal Bam function is further dependent on the non-essential periplasmic chaperones DegP, Skp, and SurA. Despite intensive study, the specific function of these non-essential Bam-associated proteins is not fully understood. Here, we analysed ΔbamB, ΔbamC, ΔbamE, ΔsurA, Δskp, and ΔdegP knockout strains by phenotypic screening, conservation analysis and high-throughput genetics. We identified hundreds of synthetic-lethal interactions and revealed that Bam complex activity is impacted by changes in outer membrane lipid composition and that enterobacterial common antigen is essential in the absence of the chaperone SurA. We also show that genes responsible for synthesis of peptidoglycan are synthetically lethal with Bam accessory lipoprotein encoding genes. Together, our data indicate potential mechanisms for coordination of OMP biogenesis with other cellular growth processes, such as LPS and peptidoglycan biogenesis.

Photo-downregulation of SIRT4 mitigates aging in mice by enhancing H3K9ac via fatty acid metabolism

yangyingchun@xiyi.edu.cn (Fangqing Deng) — Thu, 08 Oct 2026 00:00:00 +0000

As organisms age, mitochondrial metabolic activity declines, and disrupted gene expression regulation mediated by histone acetylation induces the emergence of senescent physiological phenotypes in tissues. In this study, we found that periodic exposure to red light significantly increased histone H3 Lys9 acetylation (H3K9ac) levels in the tissues and organs of aged mice. Following red light exposure, silent information regulation factor 4 (SIRT4) protein levels in keratinocytes were notably reduced, whereas glycolysis, fatty acid metabolism, and the tricarboxylic acid (TCA) cycle were significantly activated in keratinocytes. The reduction in mitochondrial SIRT4 levels enhances the acetylation of mitochondrial metabolic proteins, particularly malonyl-CoA decarboxylase, a potent inhibitor of the key rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A) in fatty acid oxidation. This process promotes mitochondrial fatty acid oxidation and the TCA cycle. Additionally, the decrease in SIRT4 activates SIRT1 through feedback mechanisms, thereby alleviating its inhibition on PPAR-α in senescent keratinocytes and comprehensively activating the expression of genes related to lipid metabolism. This lipid metabolism activation ultimately facilitates the accumulation of acetyl-CoA within keratinocytes, increases H3K9ac levels, and reshapes the expression patterns of senescence-related genes. Eventually, cellular aging is effectively mitigated by the synergistic regulation of metabolism, inflammation, and gene expression.

Early recruitment of membrane-bound DNaseX to phagocytic cups in macrophages

xuefeng.wang@uc.edu (Arghajit Pyne) — Thu, 08 Oct 2026 00:00:00 +0000

Macrophages engulf and degrade pathogens and cellular debris through phagocytosis. The degradation process was generally believed to occur only after phagosome internalization and maturation. Here, we report an early DNase activity at the nascent phagocytic cup (PC) prior to its closure. Using a fluorescent DNase sensor, we revealed rapid and ubiquitous DNase activity upon PC formation across various macrophage types. We further identified the responsible enzyme as the membrane-bound DNaseX, which is constitutively recruited to the PC during PC formation. F-actin polymerization was found to correlate with DNase activity in the PC, likely by promoting physical engagement of DNaseX with solid DNA materials. Functionally, we show that macrophages degrade extracellular DNA (eDNA) within bacterial biofilms through direct physical contact, clearing the eDNA structures without internalization. These findings reveal a previously unrecognized DNA degradation mechanism operating at the macrophage membrane, suitable for degrading bulky eDNA materials which cannot be directly internalized by macrophages.

Circadian photoreceptor CRYPTOCHROME promotes wakefulness under short winter-like days via a GABAergic circuitry

zhangluoying@hust.edu.cn (Chang Su) — Thu, 08 Oct 2026 00:00:00 +0000

A cardinal symptom of seasonal affective disorder (SAD, also known as winter depression) is hypersomnolence, while the cause of this ‘winter sleepiness’ is not known. Here, we found that lack of the circadian photoreceptor cryptochrome (cry) leads to increased sleep under short winter-like days in the fruit fly Drosophila, reminiscent of the hypersomnolence in SAD. CRY functions in neurons that synthesize the major inhibitory neurotransmitter GABA, including the small ventral lateral neurons, which are known to be circadian pacemakers, and downregulates the GABAergic tone. This, in turn, leads to increased neural activity of the wake-promoting large ventral lateral neurons, a subset of circadian neurons that are inhibited by GABA-A receptors. CRY protein is known to be degraded by light, thus rendering CRY to be functional within this GABAergic circuitry to enhance wakefulness only under short-day length. Taken together, we demonstrate a mechanism that specifically regulates wakefulness under short winter-like days, which may provide insights regarding the winter sleepiness in SAD.

Heterogeneity and ontogeny of mouse thymic macrophages reveal a requirement for Csf1r-expressing myeloid cells during early T cell development

jczp@sri.utoronto.ca (Anthony Wong) — Wed, 07 Oct 2026 00:00:00 +0000

Thymic macrophages (TMs) maintain tissue homeostasis by clearing the large numbers of apoptotic cells generated during T cell development, but how TM heterogeneity relates to their developmental origin and role in thymocyte maturation remains incompletely understood. Using complementary flow-cytometric, single-cell transcriptomic, and genetic approaches, we resolved two major TM populations corresponding to TIMD4⁺ cortical and CX3CR1⁺ medullary/cortico-medullary macrophages. TIMD4⁺ VCAM1⁺ TMs displayed a prominent efferocytosis and apoptotic-cell-clearance program, whereas TIMD4^- VCAM1⁺ TMs were enriched for antigen-presentation and interferon-response pathways. Fate mapping revealed unequal progenitor contributions to these populations, and CCR2 deficiency selectively reduced TIMD4^- VCAM1⁺ TMs, and thymic monocytes, supporting ongoing input from circulating precursors. Exploratory pseudotime analysis further identified a transcriptional continuum from Ly6c2⁺Ccr2⁺ monocytes toward macrophage states. Using MaFIA fetal thymic organ cultures, AP20187-mediated depletion of Csf1r-expressing myeloid cells reduced CD4⁺CD8⁺ thymocyte differentiation and produced a coordinated accumulation of DN3 cells, loss of DN4 cells, and reduction in CD27 expression. These convergent changes identify the DN3-to-DN4 transition as a developmental stage that requires an intact Csf1r-expressing myeloid compartment and establish a functional connection between the thymic myeloid niche and early αβ T cell development. Together, our study refines the phenotypic and developmental organization of mouse TMs and reveals a previously underappreciated requirement for myeloid-cell support during progression through the β-selection checkpoint.

Cell-cycle-resolved Hi-C reveals unexpected plasticity of A/B compartments across interphase

ichiro.hiratani@riken.jp (Asami Oji) — Tue, 06 Oct 2026 00:00:00 +0000

The spatial organization of chromatin into active (A) and inactive (B) nuclear compartments is fundamental to genome regulation, yet their cell-cycle dynamics remain largely unexplored. Most research on chromatin dynamics during the cell cycle has primarily focused on events surrounding mitosis, providing only limited insight into chromatin behavior during S-phase. To address this gap, we developed a simple, drug-free approach that combines the Fucci cell-cycle indicator with in situ Hi-C to comprehensively analyze A/B compartment dynamics throughout interphase in mouse embryonic stem cells (mESCs). Unexpectedly, and contrary to prevailing views, we found that A/B compartment strength increased abruptly upon S-phase entry, stabilized during S-phase, and subsequently declined in late S/G2. This abrupt strengthening, which we termed ‘compartment maturation’, required passage through the G1/S transition but was independent of active DNA synthesis. This maturation involved substantial architectural remodeling, particularly within the A compartment, which consolidated into a more organized structure as individual A domains rearranged to form long-range interactions. Moreover, compartment maturation was not limited to mESCs but was also evident across different developmental contexts in mice. Based on these observations, we propose a revised, stepwise model of nuclear compartmentalization during cell-cycle progression, consisting of four distinct stages: chromosome unfolding (G1), chromatin maturation (G1/S), stabilization (S phase), and refolding (G2). These findings reveal the unexpected plasticity of A/B compartments and underscore the G1/S transition as a critical period for their reorganization.

Scanning and active sampling behaviours emerge from conserved insect neural circuits

freascody@gmail.com (Antoine Wystrach) — Tue, 06 Oct 2026 00:00:00 +0000

Navigating insects often pause and rotate to sample their surroundings, behaviours termed scanning. These and other active sampling behaviours embody navigational uncertainty and are key for spatial learning, yet their neural basis remains unclear and existing models impose scanning behaviours rather than explaining its emergence. Here, we show that desert ants’ scanning dynamics can emerge spontaneously from the same conserved neural circuits used for goal-directed navigation, without requiring a specialised scanning module. We built a biologically grounded model combining central complex steering and lateral accessory lobe oscillators and added a downstream stochastic inhibition of forward speed. This minimal system produced diverse, realistic scan dynamics; saccades, fixations, and reversals, whose features were qualitatively compared to high-speed video recordings of Melophorus bagoti scanning. Detailed analysis of these natural scans confirmed model predictions, including how scan structure depends on oscillator phase, goal-heading deviation, and navigational uncertainty. Furthermore, the model reveals that simple modulation of forward speed unifies a broad range of behaviours across ant species, from dashes to smooth oscillatory trajectories to pirouettes and voltes. Crucially, this model suggests a distributed control principle where forward speed acts as a single adjustable parameter, for both individuals and through evolution, to regulate the balance between goal-driven exploitation and information-seeking exploration.

A high-throughput assay for the measurement of Ca²⁺ oscillations and insulin release from uniformly sized mouse β-cell (MIN6) spheroids

thomas.voets@kuleuven.be (Patricia Davidson) — Mon, 05 Oct 2026 00:00:00 +0000

Diabetes mellitus is a rapidly growing global health challenge, necessitating the development of more effective anti-diabetic therapies, including drugs that improve insulin release from pancreatic β-cells. Traditional high-throughput screening methods typically rely on 2D β-cell cultures, but such cultures do not mimic the 3D organization and cell-to-cell communication of β-cells in pancreatic islets of Langerhans. Existing 3D β-cell culture models are hindered by high costs, technical complexity, and limited compatibility with high-throughput screening platforms. In this work, we developed an approach for generating 19 homogeneously shaped pancreatic β-cell spheroids in each well of a 96-well plate, using micropatterned polyethylene glycol (PEG)-based hydrogels and murine mouse insulinoma 6 (MIN6) insulinoma cells. The uniform shape and positioning of the individual spheroids enabled the simultaneous, real-time imaging of Ca²⁺ signals in up to 1824 independent spheroids in response to glucose and various test compounds. Using this approach, we show that increasing glucose causes concentration-dependent Ca²⁺ oscillations in individual spheroids, that these Ca²⁺ oscillations are sensitive to modulators of ATP-sensitive K⁺ channels, and that the frequency of Ca²⁺ oscillations correlates with insulin secretion. Finally, we demonstrate that the neurosteroid pregnenolone sulfate, an agonist of the cation channel TRPM3, increases the frequency of glucose-induced Ca²⁺ oscillations and enhances insulin release; the TRPM3 antagonist isosakuranetin inhibited these responses. In conclusion, we established a cost-effective and scalable 3D β-cell platform for high-throughput screening of insulin release-modifying compounds, with potential applications in drug development and personalized medicine for the management of diabetes mellitus.

Human CD1c-autoreactive T-cells recognise Mycobacterium tuberculosis-infected antigen-presenting cells and display cytotoxic effector programmes

s.mansour@soton.ac.uk (Alasdair Leslie) — Mon, 05 Oct 2026 00:00:00 +0000

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from infection globally yet the contribution of non-classical T-cell pathways to human immunity remains poorly defined. CD1c-autoreactive T-cells, which recognise self-lipids presented by the antigen-presenting molecule CD1c, are frequent in human blood but their role during infection remains unclear. Here, we investigate how CD1c-expressing antigen-presenting cells (APCs) and Mtb infection shape CD1c-autoreactive T-cell responses using engineered human APC systems, complemented by single-cell transcriptomic profiling to define the ex vivo phenotypic landscape of these T-cells. CD1c is present within human TB granulomas, whereas Mtb down-modulates CD1c expression on infected APCs, consistent with an immune evasion strategy. CD1c-autoreactive T-cells respond more strongly to Mtb-infected CD1c⁺ APCs than to uninfected cells, exhibiting enhanced activation, cytotoxicity, and diverse cytokine secretion via CD1c-dependent recognition. Under in vitro conditions, these T-cells reduce relative Mtb burden in infected phagocytes. Single-cell RNA sequencing reveals cytotoxic effector-memory programmes and expression of antimicrobial molecules, providing a mechanistic basis for these responses. Together, these findings define a human CD1c-restricted T-cell response to Mtb-infected APCs and identify autoreactive CD1c-restricted T-cells as a candidate cellular axis for lipid-directed immunity in TB.

NK2R signaling governs intestinal lipid mobilization and mucosal inflammation

supriya@scripps.edu (Alessandra Ferrari) — Mon, 05 Oct 2026 00:00:00 +0000

Neuropeptidergic control of lipid metabolism is conserved and increasingly implicated in metabolic diseases, but receptor-level mechanisms remain unclear. Here, we identify the neurokinin-2 receptor (NK2R) as a central node linking tachykinin signals to intestinal lipid mobilization, epithelial composition, and mucosal inflammation. Across complementary genetic and pharmacological perturbations, modulation of NK2R drives bidirectional effects. Loss or blockade of NK2R increases postprandial triglyceridemia and expands intestinal lipid stores, whereas agonism suppresses chylomicron output, reduces adiposity, and improves glycemia in diet-induced obesity. Transcriptomic and cellular analyses indicate coordinated upregulation of lipid-metabolic programs with a concomitant dampening of immune pathways in the absence of NK2R, accompanied by sex-specific remodeling of secretory lineages and male-biased protection from colitis. NK2R signaling also shaped the fecal microbiota in a genotype- and diet-dependent manner, highlighting crosstalk among neuropeptide signaling, epithelial physiology, and host-microbe interactions. These findings position NK2R as a molecular switch for intestinal lipid handling and mucosal inflammation and suggest that NK2R-targeted agonists or antagonists could be deployed as context- and sex-dependent therapeutic strategies for metabolic disease and inflammatory bowel disease.

Mapping human visual contrast sensitivity and vision loss across the visual field with model-based fMRI

hugo.chow-wing-bom.15@ucl.ac.uk (Frederic Dick) — Fri, 02 Oct 2026 00:00:00 +0000

Peripheral vision is crucial for daily activities and quality of life, yet traditional measures of visual function like visual acuity primarily assess central vision. Visual field tests can evaluate peripheral vision but require extended focus and precise fixation, often challenging for patients with severe sight loss. Functional MRI (fMRI) with population receptive field (pRF) mapping offers a non-invasive way to map scotomas but relies on single contrast levels and accurate fixation. We developed an fMRI-based approach to measure contrast sensitivity across the visual field without requiring precise fixation. Combining large-field stimulation with varying spatial frequencies and contrast levels, and either pRF mapping or a structure-based retinotopic atlas, we modeled contrast sensitivity in the primary visual cortex (V1) over a large (40 deg) expanse of the visual field. In seven normally sighted participants, we characterized differences in V1 sensitivity across eccentricities and visual quadrants, finding reliable and reproducible patterns at individual and session levels. To test robustness to fixation variability, we investigated how varying levels of eye movement affected V1 sensitivity patterns in two participants: cortical sensitivity patterns were largely preserved despite eye movements, particularly at low spatial frequencies. This suggests our approach can accommodate several degrees of fixation instability, making it suitable for populations with unstable or biased fixation for whom visual field maps are harder to acquire behaviorally (e.g., patients with dense central scotoma or strabismus). Additionally, our method effectively visualized simulated and disease-linked sensitivity loss at the cortical level. Crucially, these results could be largely recovered using the structure-based retinotopic atlas, eliminating the need for pRF mapping and precise fixation, although with reduced sensitivity. This approach, integrating large-field stimulation with a retinotopic atlas, offers a promising tool for monitoring vision loss and recovery across a range of visual impairments, addressing a significant challenge in current clinical assessments.

Distinct allosteric remodeling of HIV-1 Env dynamics on virions by gp41-directed antibodies reveals two modes of neutralization

maolin.lu@uthct.edu (Baoshan Zhang) — Fri, 02 Oct 2026 00:00:00 +0000

HIV-1 envelope glycoprotein (Env), a gp120–gp41 trimer, undergoes coordinated conformational changes that drive membrane fusion and allow immune evasion by transiently concealing neutralization-sensitive epitopes. Most broadly neutralizing antibodies (bNAbs) target gp120, whereas a distinct subset recognizes conserved gp41 regions, such as the fusion peptide and the membrane-proximal external region; however, their impact on Env dynamics and associated neutralization mechanisms remains unclear. By using bioorthogonal tagging for single-molecule FRET, we monitored real-time bNAb-induced conformational sampling of Env on intact virions. Most gp41-directed bNAbs allosterically stabilized the prefusion-closed (PC) state, whereas the bivalent 10E8.4/iMab favored both PC and CD4-bound open (predominant) states. Antibodies redistributed the conformational populations of Env with modest kinetic effects, preserving a sequential transition pathway. These findings reveal two modes of neutralization for gp41-directed antibodies, fixing the PC conformation and opening it up – in both cases, with neutralization occurring via long-range allosteric control of Env dynamics.

The type VI secretion system governs strain maintenance in a wild mammalian gut microbiome

joseph.mougous@yale.edu (Andrew L Goodman) — Fri, 02 Oct 2026 00:00:00 +0000

Bacteria inhabiting the mammalian gut coexist in dense communities where contact-dependent antagonism mechanisms are widespread. The type VI secretion system (T6SS) is an interbacterial toxin delivery pathway prevalent among gut Bacteroidales, yet its function in naturally evolved microbiomes remains poorly defined. Here, we examine the role of the T6SS in Bacteroides within a physiologically relevant gut community derived from wild mice (the WildR microbiome). Using newly developed genetic tools and a strategy for functional replacement of strains within the WildR community, we demonstrate that the WildR isolate B. acidifaciens employs a T6SS to antagonize co-resident Bacteroidales. We also show that loss of T6SS function compromises the long-term maintenance of B. acidifaciens in the community but not its initial colonization, establishing the system as a determinant of strain persistence. The T6SS we identified resides on an integrative and conjugative element (ICE). ICE-seq, a targeted sequencing approach, reveals that the T6SS-ICE is distributed among select Bacteroidales and Muribaculaceae species in the WildR microbiome, between which it appears to be recently exchanged. We also show that transfer of the T6SS-ICE to WildR isolate Phocaeicola vulgatus confers transient colonization benefits in mice, but is linked to eventual population decline. Our findings demonstrate that the T6SS can stabilize the presence of specific strains within a complex, co-evolved gut microbiome, yet its value is context dependent and constrained by the ecological and physiological landscape of the host community.

Sex-biased expression of enteroendocrine cell-derived hormones contributes to higher fat storage in Drosophila females

elizabeth.rideout@ubc.ca (Elizabeth J Rideout) — Thu, 01 Oct 2026 00:00:00 +0000

Enteroendocrine (EE) cells in the Drosophila gut produce and release multiple factors, including Allatostatin A (AstA), Allatostatin C (AstC), neuropeptide F (NPF), tachykinin (Tk), Diuretic hormone 31 (Dh31), Bursicon, CCHamide 1, CCHamide 2, and short neuropeptide F. Collectively, these peptides ensure that physiology (e.g., fat storage, fluid balance) and behavior (e.g., feeding, sleep) are coordinated with environmental factors such as nutrient quantity and quality. Despite notable sex differences in physiology and behavior, it remains unclear whether the regulation and function of these EE cell-derived factors are shared between males and females. Given that recent data identified sex-biased physiological effects of two EE cell-derived hormones on Drosophila food intake and energy mobilization, we performed a detailed characterization of these hormones in male and female flies. Despite an overall male bias in mRNA levels of AstA, AstC, Tk, NPF, and Dh31 in whole-body and head samples, we observed a strong female bias in mRNA levels of AstC, Tk, and NPF in the gut. To determine whether this sex-biased regulation was physiologically significant, we monitored triglyceride levels in flies with gut-specific knock-down of EE cell-derived hormones. In 5-day-old flies, knock-down of EE cell-derived AstC significantly reduced fat storage in females with no effect in males, whereas knock-down of EE cell-derived Tk produced a non-significant trend toward reduced fat storage in females. These female-specific effects on fat storage were reproduced in flies with neuron-specific knock-down of the AstC (AstC-R2) and Tk receptors (TkR99D). Together, these data uncover strongly sex-biased regulation of EE cell-derived hormones and show that gut-specific knock-down of at least one of these hormones had a female-specific effect on body fat.

A cortical–hippocampal communication undergoes rebalancing after new learning

dw657@drexel.edu (Arron F Hall) — Thu, 01 Oct 2026 00:00:00 +0000

The brain’s ability to consolidate a wide range of memories while maintaining their distinctiveness across experiences remains poorly understood. Sharp-wave ripples, neural oscillations that occur predominantly within CA1 of the hippocampus during immobility and sleep, have been shown to play a critical role in the consolidation process. More recently, evidence has uncovered functional heterogeneity of pyramidal neurons within distinct sublayers of CA1 that display unique properties during ripples, potentially contributing to memory specificity. Despite this, it remains unclear exactly how ripples shift the activity of CA1 neuronal populations to accommodate the consolidation of specific memories and how sublayer differences manifest. Here, we studied interactions between the anterior cingulate cortex (ACC) and CA1 neurons during ripples and discovered a reorganization of their communication following learning. Specifically, using a generalized linear model decoder, we demonstrated the pre-existence of ACC-to-CA1 communication, which is weakened during post-training sleep following learning, suggesting that ACC activity reallocates the contribution of CA1 neurons during memory formation. Interestingly, the reorganization appeared unique for a subset of CA1 superficial (CA1sup) neurons that were task inactive, whereas communication between the ACC and CA1deep neurons remained largely stable across pre- and post-training sleep. Consistent with this sublayer-selective reorganization, we found that optogenetic stimulations of the ACC preferentially suppressed CA1sup neurons while activating a unique subset of CA1 interneurons. Overall, these findings highlight an important role of the ACC in rebalancing CA1 neuronal populations’ contribution in learning and memory consolidation.

Bidirectional redistribution of actomyosin drives epithelial invagination in ascidian siphon tube morphogenesis

libome@tsinghua.edu.cn (Bo Dong) — Thu, 01 Oct 2026 00:00:00 +0000

How epithelia perform a spatiotemporal heterogeneous force-generating program to drive a sequential tissue morphogenesis remains unclear, particularly the underlying precise mechanical mechanisms. This study investigated dynamic actomyosin reorganization between apical and lateral membrane cortex regions during two sequentially invaginated stages of atrial siphon tube morphogenesis in the ascidian Ciona. At the initial invagination stage, the originally lateral-located actomyosin redistributed to the apical domains, while that actomyosin redistributed back to lateral domains at the accelerated invagination stage. Using genetic mutants to modulate myosin activities, the initial invagination was strengthened or abolished, indicating invagination is apical constriction-dependent. Optogenetic inhibition of myosin activities in lateral domains after initial invagination stage blocked the further processes, suggesting lateral constriction of actomyosin is required for the accelerated invagination. Vertex model simulations uncovered a coupled mechanism underlying epithelial invagination driven by apicobasal tension imbalance and lateral contraction. We thus propose an actomyosin redistribution mechanical model: lateral actomyosin first redistributes apically to drive apical constriction and shape the initial invagination, then apical actomyosin redistributes laterally to promote lateral contractility and accelerate invagination. Our findings reveal a bidirectional reorganization of the actomyosin network as a central mechanism driving epithelial invagination, providing insights on epithelial invagination and organ morphogenesis during development.

Negative affect influences the computations underlying food choice in bulimia nervosa

laura.berner@mssm.edu (Blair RK Shevlin) — Thu, 01 Oct 2026 00:00:00 +0000

Individuals often consume tasty, calorically dense foods in response to negative emotions, a phenomenon exemplified by notions of ‘stress eating’ and ‘comfort food’. While this link between food and mood can become pathological in binge eating, the decision-making processes underlying this link are poorly understood. Here, we investigated the impact of acute increases in negative affect on when and how strongly the perceived tastiness and healthiness of foods influence food choices in healthy adults and individuals with bulimia nervosa (BN), an eating disorder characterized by cycles of over- and under-consumption of food. In a randomized crossover design, 25 women with BN and 21 healthy controls completed two sessions where they received either a neutral or negative affect induction and then completed a food choice task. Using a time-varying diffusion decision model, we assessed how negative affect influences food choice dynamics for high- and low-fat foods. In the neutral affect condition, individuals with BN considered tastiness relative to healthiness of high-fat foods sooner than healthy controls but maintained a restrictive food choice policy by reducing the weight on tastiness. After a negative affect induction, both groups showed a stronger bias toward considering tastiness before healthiness, but this bias was exaggerated in individuals with BN. This affect-induced bias for high-fat foods predicted more frequent subjective binge episodes over 3 months. These results provide insights into how negative emotion influences food choices and may explain why binge eating in BN is more likely during high negative affect, while dietary restriction is more likely during low negative affect.