eLife: latest articles

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Genome-wide discovery of cis-regulatory elements in a large genome

michalis.averof@ens-lyon.fr (Çağrı Çevrim) — Thu, 01 Oct 2026 00:00:00 +0000

Identifying cis-regulatory elements typically relies on trial and error to test the activity of DNA fragments using reporter constructs. This approach is particularly challenging in large eukaryotic genomes, where cis-regulatory elements can be dispersed over long distances, separated by large stretches of non-functional DNA. Here, we generate two types of resources that can be used to narrow the search for such elements in the 3.6 Gbp genome of Parhyale hawaiensis. First, we use bulk ATAC-seq to uncover genome-wide patterns of chromatin accessibility in Parhyale embryonic and adult tissues, and single-nucleus ATAC-seq to identify regions of open chromatin in diverse cell types. Second, by sequencing the genomes of three congeneric species – P. darvishi, P. aquilina, and P. plumicornis – we identify islands of sequence conservation across the genome, likely corresponding to functionally constrained DNA. We find that low-coverage (10–15×) short-read genome sequencing, without genome assembly, is sufficient to provide reliable maps of sequence conservation. This approach cuts the cost and labour required to generate these maps, making the identification of cis-regulatory elements more widely accessible. We demonstrate the utility of these resources by identifying cis-regulatory elements that drive robust expression of fluorescent reporters ubiquitously and in specific cell types.

Zinc is a key regulator of the sperm-specific K⁺ channel (Slo3) function

kawai.takafumi.ra@ehime-u.ac.jp (Haruhiko Miyata) — Wed, 30 Sep 2026 00:00:00 +0000

The voltage- and pH-gated Slo3 potassium channel is exclusively expressed in mammalian spermatozoa. Its sensitivity to both voltage and alkalization plays a crucial role in sperm fertility, which is tightly coupled to the capacitation process. Here, we show that sperm-enriched divalent cation Zn²⁺ undergoes dynamic alteration in spermatozoa during capacitation. We also found that intracellular Zn²⁺ regulates alkalinization-induced hyperpolarization in mouse spermatozoa, which is mediated by the Slo3 channel. Further examination of zinc regulation in mouse Slo3 (mSlo3) revealed that, in the Xenopus oocyte expression system, intracellular zinc directly inhibits mouse Slo3 currents in a dose-dependent manner at micromolar concentrations, with exceptionally slow dissociation. By combining MD simulations and electrophysiology, we also identified amino acid residues contributing to the Zn²⁺ slow dissociation from Slo3 channels. Our studies uncover the importance of intracellular zinc dynamics and its regulatory role in ion channels during sperm capacitation.

Learning is a fundamental source of individuality

amjaksic@gmail.com (Alireza Modirshanechi) — Wed, 30 Sep 2026 00:00:00 +0000

Learning and memory are essential components of our individuality. While it is established that behaviour can vary across genetically identical individuals, it remains unknown how much of this variation stems from momentary experience during learning compared to genetics and its past interactions with the environment. To address this, we measured behaviour in thousands of flies from 90 genetic backgrounds while they performed tasks in conditions that either did or did not require learning. Flies that were genetically identical, raised under the same conditions, and tested simultaneously in the same environment persistently modified the extent of expressed individuality when they could learn. This learning-induced residual expression of individuality and its dynamics were subdued or absent in innate, learning-independent behaviours. We could quantify and then recreate this phenomenon in computer simulations. The emergence of in silico behaviour individuality was most consistent with the individuality of real flies once we enabled reinforced learning in simulated agents. Moreover, we showed that minor differences in initial conditions of the experiment can exacerbate the expression of individuality within a genotype in a learning-dependent manner. Our results establish that besides the classical genotype × environment (G × E) interactions shared between individuals in the past, learning from individual momentary experience further extends the expression of individuality.

Gβγ engages PLCβ3 at multiple sites to reorient and facilitate its activation

lyonam@purdue.edu (Angeline M Lyon) — Wed, 30 Sep 2026 00:00:00 +0000

Phospholipase C β (PLCβ) enzymes are activated by heterotrimeric G protein subunits, increasing hydrolysis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) at the plasma membrane. All four human PLCβ isoforms (PLCβ1–4) are activated by Gα_q, whereas PLCβ1–3 are activated to varying extents by Gβγ. The binding sites for Gα_q on PLCβ are well established, and much has been learned about its mechanism of activation, but comparatively little is known about Gβγ-dependent activation. In this work, we used cryo-electron microscopy single-particle analysis, functional assays, and bioluminescence resonance energy transfer to investigate how Gβγ interacts with PLCβ3 in concert with activated Gα_q to regulate phospholipase activity. Gβγ heterodimers bind multiple surfaces of PLCβ3 to promote activation, but alone do not recruit the enzyme to the plasma membrane. Instead, Gβγ facilitates activation by Gα_q, most likely by reorienting the phospholipase catalytic site at the membrane to maximize PI(4,5)P2 hydrolysis and downstream Ca²⁺ release. Cell-based functional assays demonstrate that Gβγ is required for maximal PLCβ3 activation, even when G_q heterotrimers are the sole source of Gβγ. Together, these findings demonstrate that Gβγ acts as a critical positive allosteric modulator that regularly acts in concert with Gα_q to activate PLCβ3 at the plasma membrane.

Biophysically inspired mean-field model of neuronal populations driven by ion-exchange mechanisms

giovanni.rabuffo@upf.edu (Abhirup Bandyopadhyay) — Wed, 30 Sep 2026 00:00:00 +0000

Whole-brain simulations are a valuable tool for gaining insight into the multiscale processes that regulate brain activity. Due to the complexity of the brain, it is impractical to include all microscopic details in a simulation. Hence, researchers often simulate the brain as a network of coupled neural masses, each described by a mean-field model. These models capture the essential features of neuronal populations while approximating most biophysical details. However, it may be important to include certain parameters that significantly impact brain function. The concentration of ions in the extracellular space is one key factor to consider, as its fluctuations can be associated with healthy and pathological brain states. In this paper, we develop a new mean-field model of a population of Hodgkin–Huxley-type neurons, retaining a microscopic perspective on the ion-exchange mechanisms driving neuronal activity. This allows us to maintain biophysical interpretability while bridging the gap between micro- and macro-scale mechanisms. Our model is able to reproduce a wide range of activity patterns, also observed in large neural network simulations. Specifically, slow-changing ion concentrations modulate the fast neuroelectric activity, a feature of our model that we validated through in vitro experiments. By studying how changes in extracellular ionic conditions can affect whole-brain dynamics, this model serves as a foundation to measure biomarkers of pathological activity and provide potential therapeutic targets in cases of brain dysfunctions like epilepsy.

Dissociable roles of reward prediction error in the contrasting mood dynamics of depression and anxiety

yunzhe.liu@bnu.edu.cn (André Aleman) — Tue, 29 Sep 2026 00:00:00 +0000

Mood fluctuations, central to human experience, are profoundly influenced by reward prediction errors (RPE). Although depression and anxiety traditionally exhibit contrasting mood fluctuations, their interrelated nature has made it challenging to pinpoint their specific roles in RPE-induced mood variations. In this study, we employed a computational model of momentary mood within a gambling task, involving 2043 participants across five experiments. Participants also completed a battery of questionnaires designed to allow us to dissociate anxiety- and depression-specific traits through bifactor modeling. Results showed that depression was associated with dampened mood fluctuations due to mood hyposensitivity to RPE. Importantly, this pattern was also found in patients with affective disorders. In contrast, anxiety correlated with heightened mood fluctuations stemming from mood hypersensitivity to RPE in non-clinical participants. Moreover, the shared depression/anxiety component was linked to lower affective baseline and greater risk aversion. Collectively, our results uncover computational dissociation of depression vs. anxiety using RPE-based mood modeling and present multi-dimensional computational signatures for these symptoms, with clinical relevance for management of mood disorders.

A real-time, multi-animal model for automatic face detection and identification of freely moving common marmosets based on YOLOv8 algorithms

jiayue.yang@mail.mcgill.ca (James Wang) — Tue, 29 Sep 2026 00:00:00 +0000

Precise and up-to-date information about animal location and identity allows us to better quantify individual behaviors in studies of neural activity, cognition, and animal health. In socially housed laboratory animals, identification is usually defined by observation or invasive markers, making the data collection time-consuming, variable across experimenters, and disruptive to animals. We established an automatic pipeline for real-time identification of common marmosets in captivity using a close-view camera. It uses the supervised deep-learning YOLOv8 model to localize individuals, detect faces, and classify identities. Moreover, we use recognition of uniquely color-coded collar beads to improve detection accuracy among visually similar individuals. Across adult and juvenile marmosets, our system automatically identifies marmosets with >82.9% precision and >91.5% recall, achieving human-level performance. This pipeline is designed to be easy to use and generalizable across non-human primate species, ages, and recording hardware, providing rapid and automatic identity recognition from real-time video.

Single-cell spatial mapping reveals reproducible cell type organization and spatially dependent gene expression in gastruloids

arjunrajlab@gmail.com (Arjun Raj) — Tue, 29 Sep 2026 00:00:00 +0000

Gastruloids are stem-cell-based models that recapitulate key aspects of mammalian gastrulation, including the formation of an anterior-posterior axis. However, we do not have detailed spatial information about gene expression and cell type organization, particularly at the level of individual gastruloids. Here, we report a spatially resolved, single-cell molecular catalog of the transcriptomes of 26 individual gastruloids. We found that cell type composition and tissue-scale spatial organization were largely consistent across gastruloids, but meso-scale patterning of specific cell types varied between samples. Posterior cell types formed distinct, organized clusters, while anterior cell types were more disorganized. To distinguish progressive differentiation from cell type differences, we developed the L-score, a parameter-free quantification of mutually exclusive gene expression. This analysis revealed spatial organization without explicit encoding, recapitulated known cell type relationships, and identified novel gene expression states and spatial subclusters within cell types. We confirmed that in gastruloids, neuromesodermal precursor differentiation occurred through a continuous, spatially coordinated process. We also showed that endothelial precursors exhibited unique spatial organization and had distinct gene expression profiles dependent on their association with anterior somitic or posterior endodermal tissues. This work enables the rigorous use of gastruloids as models for studying the molecular mechanisms underlying mammalian development and tissue organization and introduces new computational tools for analyzing spatially resolved single-cell datasets.

PKD2L1 channels segregated to the apical compartment are the dual-mode pH sensor in cerebrospinal fluid-contacting neurons

federico.trigo@pedeciba.edu.uy (Daniel Prieto) — Tue, 29 Sep 2026 00:00:00 +0000

Cerebrospinal fluid-contacting neurons (CSFcNs) are GABAergic cells that surround the central canal (cc) of the spinal cord. Their soma is located sub-ependymally and they have a dendritic-like process that ends as a bulb (the so-called ‘apical process’; ApPr) inside the cc. It remains unclear how this unique anatomical organization, with the soma and the ApPr located in different extracellular environments, relates to their function as a multimodal sensor of cerebrospinal fluid (CSF) composition. One of the main physiological features of CSFcNs is a prominent spontaneous electrical activity mediated by PKD2L1 channels, a non-selective cation channel of the TRP family. PKD2L1 channels have a high single-channel conductance (around 200 pS) and can be modulated by protons and mechanical forces. In this work, we investigate PKD2L1 channel sensitivity to pH and its effects on CSFcNs excitability. We demonstrate that PKD2L1 spontaneous activity generates not only phasic inward currents, but also a sustained current, both of which are modulated bidirectionally by pH with a high sensitivity around physiological values. By combining electrophysiology (direct recordings from intact and isolated ApPrs) with optical methods (laser photolysis of protons), we further show that functional PKD2L1 channels are specifically localized in the ApPr. The spatial segregation of PKD2L1 channels, along with their biophysical properties (high single-channel conductance and pH sensitivity) and the ApPr’s unique membrane properties (very high input resistance), renders CSFcN excitability exquisitely sensitive to PKD2L1 modulation. Altogether, our findings illustrate how the ApPr’s properties are finely tuned to support its sensory role.

From East to West – an early-career researcher’s voyage across continents

samuel.eziuzor@gmail.com (Samuel C Eziuzor) — Tue, 29 Sep 2026 00:00:00 +0000

One scholarship can open a research career. It can also start a years-long negotiation with loneliness, ambiguous job titles, and the quiet arithmetic of underfunded postdoctoral life. Early-career researchers who have made the journey from West Africa to East Germany and on to Western Canada describe what rarely makes it into the acceptance letter, and what institutions on both sides of the Atlantic could do differently.

Bifunctional architecture enables substrate catalysis and channeling in Paracoccus TMAO demethylase

ttthach@purdue.edu (Gurunath Ramanathan) — Mon, 28 Sep 2026 00:00:00 +0000

Substrate channeling enhances efficiency and prevents toxicity by directing unstable intermediates between active sites. Trimethylamine N-oxide demethylase (TDM) degrades trimethylamine N-oxide (TMAO) to dimethylamine and formaldehyde (HCHO), but the fate of HCHO has remained unclear. We report cryo-EM structures of TDM in apo, substrate-, and product-bound states that reveal a previously unknown channeling pathway. Combined structural, biochemical, and target molecular dynamics analyses show that HCHO is generated in a catalytic core and guided through a tunnel to a remote tetrahydrofolate (THF)-binding site, where it forms methylene-THF. Thus, TDM emerges as a bifunctional enzyme that unites TMAO demethylation with one-carbon transfer, providing a mechanistic explanation for its role in metabolic efficiency and detoxification.

Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons

daniel.beaudet@mcgill.ca (Adam G Hendricks) — Mon, 28 Sep 2026 00:00:00 +0000

Tau, a neuronal microtubule-associated protein (MAP), organizes the axonal cytoskeleton, and regulates intracellular transport. Tau hyperphosphorylation is linked to neurodegeneration in tauopathies, including Alzheimer’s disease. Tau binds microtubules cooperatively to form cohesive envelopes, which are thought to control access to the microtubule lattice and regulate the activity of motor proteins and other MAPs. However, how disease-related perturbations affect tau dynamics and its function as a selective barrier to intracellular transport remains unclear. Using tau phospho-variants in vitro and in live neurons, we show that tau hyperphosphorylation disrupts cooperative microtubule binding and dysregulates lysosome transport. Hyperphosphorylated tau does not form envelopes, distributes more uniformly along the axon, and dissociates faster from microtubules. Tau weakly inhibits KIF5C motility, but strongly inhibits KIF1A. Hyperphosphorylation reduces KIF5C inhibition but increases KIF1A inhibition by decreasing processivity and accelerating detachment. Consistent with these effects, hyperphosphorylated tau alters lysosome transport in neurons. While phospho-resistant tau inhibits processive lysosome motility, hyperphosphorylated tau weakens tau-mediated regulation of lysosome transport, mimicking tau knockout neurons that exhibit enhanced processivity. Altogether, these findings show that hyperphosphorylation disrupts tau envelopes and impairs lysosome trafficking, likely contributing to early defects in degradative pathways that drive neurodegeneration.

Selective lifelong suppression of an odor processing channel in response to critical period experience

htb@case.edu (Abigail J Wilkov) — Mon, 28 Sep 2026 00:00:00 +0000

Sensory circuits undergo experience-dependent plasticity during early-life critical periods, attuning the nervous system to levels of key environmental stimuli. During a critical period in the Drosophila olfactory system, we found that exposure to ethyl butyrate (EB) induces glial phagocytosis of odorant receptor Or42a-positive olfactory sensory neuron (OSN) axon terminals which terminate in the VM7 glomerulus (Leier et al., 2025). Here, we extend these findings by establishing functional significance and circuit selectivity in this critical period paradigm. First, using a combination of two-photon Ca²⁺ imaging and the genetically-encoded voltage indicator ASAP5, we find that Or42a OSN odor-evoked responses are permanently suppressed in animals with critical period odor exposure. Thus, critical period odor exposure results in long-term changes to odor sensitivity in Or42a OSNs. Second, to establish the selectivity of glial pruning for Or42a axon terminals, we examined projection neurons (PNs) postsynaptic to Or42a OSNs as well as a second population of highly EB-responsive OSNs, called Or43b OSNs. We find that (1) within VM7, glial pruning is selective for Or42a terminals, and (2) while Or43b OSNs appear modestly pruned, they maintain their sensitivity to EB. To elucidate this difference, we turned to the Drosophila connectome. We identify striking differences in the scale of inhibitory connectivity to Or42a and Or43b OSNs, although disruption of GABA A receptor expression in both OSN types enhanced pruning. This study expands our understanding of this critical period plasticity paradigm by demonstrating lifelong suppression of pruned Or42a OSNs and establishing its specificity within and between sensory circuits.

Two Glu/Asp residues cooperatively mediate an early step of ATP hydrolysis in GHKL ATPases MutL and GyrB

kenji.fukui@cc.nara-wu.ac.jp (Ayaka Shibuya) — Fri, 25 Sep 2026 00:00:00 +0000

GHKL ATPases share a unique Bergerat ATP-binding fold and regulate diverse biological processes through ATP-dependent conformational changes. An early step of ATP hydrolysis in this family has been attributed to a single highly conserved glutamate residue proposed to function as the general base. However, mutations of this residue impair both the ATPase activity and ATP binding, complicating interpretation of its catalytic role. Re-examination of the high-resolution crystal structures revealed a second conserved acidic residue positioned within a hydrogen-bonding distance from the nucleophilic water molecule. Using Aquifex aeolicus MutL and GyrB as model enzymes, we combined systematic mutagenesis, ATPase and ATP-binding assays, and X-ray crystallography to dissect the roles of these residues. We show that alignment of the nucleophilic water can be maintained as long as the conserved glutamate retains hydrogen-bonding capability, whereas efficient ATP hydrolysis requires proton-accepting capacity at least in one of the two acidic residues. These results indicate that the conserved glutamate primarily governs positioning of the nucleophilic water, while activation of this water for catalysis is achieved through cooperative general base function of the two acidic residues. Extending this framework to human MutL homologs, PMS2 and MLH1, we showed that clinically reported variants of uncertain significance in these DNA mismatch repair proteins substantially reduced the ATPase activity, indicating functional impairment. Together, our findings refine the catalytic mechanism of GHKL ATPases and provide a structural and functional framework for interpreting disease-associated variants in GHKL ATPases. Phylogenetic and ancestral state analysis further indicated that the second acidic residue was likely to be present in the common ancestor of major GHKL ATPase lineages but was later modified in a branch, including Hsp90, suggesting evolutionary remodeling of the catalytic mechanism in the branch.

Opening the black box toward a modular approach to spike sorting

samuel.garcia@cnrs.fr (Alessio Paolo Buccino) — Fri, 25 Sep 2026 00:00:00 +0000

Spike sorting is an algorithmic process that extracts the activity of individual neurons from extracellular electrophysiology recordings. With the ballooning use of high-density probes, such as Neuropixels, this essential processing step is increasingly becoming time-consuming and computationally expensive. Although many software tools have been proposed to address spike sorting, they are usually constructed and benchmarked as monolithic ‘black boxes’, making it difficult to factor out the effects of individual algorithmic steps on the final outcome, especially when varying datasets and parameters. To address this issue, we developed a modular and common framework to develop, benchmark, and assemble the key computational steps that are used in state-of-the-art spike sorting algorithms. Relying on fast and efficient ground truth generation of biophysically plausible recordings, we show that we are able to individually benchmark and precisely quantify the performance of different steps in a spike sorting pipeline (i.e. peak detection, feature extraction, clustering, and template matching). We then leverage these results to create a modular, component-based spike sorter that can outperform Kilosort4 on dense and large simulated recordings, and produce similar quantitative results on real data. In addition, we find that the major bottleneck of all modern spike sorting pipelines is in the physical motion of probes, regardless of the drift-correction strategy. The component-based spike sorting framework presented here has the potential to foster community engagement in the field by lowering the barrier to contributions and providing a flexible yet powerful framework to construct end-to-end spike sorting solutions.

Retinal curl as a functional signal for heading estimation beyond the focus of expansion

j.lopezmoliner@ub.edu (Joan López-Moliner) — Fri, 25 Sep 2026 00:00:00 +0000

Prevailing models aiming at explaining heading assume that humans need to recover the Focus of Expansion (FoE) while accounting for eye-movement-induced rotation. We propose an alternative: the visual system utilizes mean retinal curl from fixations as a surrogate signal for heading, rendering the explicit recovery of the FoE unnecessary. Stationary participants viewed simulated walking paths on a large screen while fixating on points on the projected ground texture at varying eccentricities – a natural behavior inducing sustained retinal curl. Participants continuously reported perceived heading in 3D scene coordinates. To isolate the role of retinal curl, we employed a real-time manipulation that kept translational flow constant while the foveal curl component was either unaltered, canceled, or over-canceled. Under natural conditions (unaltered), participants exhibited systematic heading biases opposite the direction of gaze. Crucially, these biases vanished when we canceled the expected curl and flipped when we over-canceled it, identifying retinal curl as the specific driver of perceptual bias. We modeled these results using a simple feedback controller and a ring-attractor neural network featuring gaze-contingent inhibition and a ‘straight-ahead’ prior. These findings suggest that the brain exploits the geometry of gaze stabilization to simplify navigation, treating retinal curl as a functional signal rather than noise to be filtered.

Cellular basis of accelerated whole-tooth regeneration

todd.streelman@biology.gatech.edu (Anoushka Satoskar) — Thu, 24 Sep 2026 00:00:00 +0000

Teeth are ectodermal organs that have, throughout their long evolutionary history, retained the capacity for full regeneration and replacement, even in adult stages. Yet, because most mammals (e.g., humans, mice) lack lifelong dental replacement, we do not fully understand its tempo and mode, and we do not have a clear picture of the cell populations and signals that contribute to the process. Here, we used cichlid fishes from Lake Malawi, species that differ in tooth formula (tooth shape and number) but share one-for-one tooth replacement, to (i) explore the tempo of dental replacement after plucking and then (ii) identify the cell populations, gene expression signatures, and interactions between cell populations that change in this plucking paradigm. We observed that cichlid species with divergent dentitions accelerated tooth replacement >3× on the plucked half of the jaw. Then, we used single-nucleus RNA-seq to profile cellular and molecular changes across the first week of post-plucking tooth replacement. This approach allowed us to infer cellular trajectories in dental epithelium and mesenchyme that underlie tooth regeneration. We identified distinct gene expression profiles and cellular interactions across four time points of accelerated tooth replacement, with divergent involvement of epithelial, mesenchymal, and immune cell types. Differential signaling of Collagen, BMP, MMP, Semaphorin, and Slit-Robo pathways was evident after plucking and highlights temporally sequenced roles of immune response, odontogenesis, vascularization, and nerve pathfinding as teeth are constructed anew. Overall, this study provides insight into the trajectory of cellular interactions accompanying whole-tooth replacement and offers a comparative foundation for understanding dental regeneration in vertebrates.

Developmental synchrony of retinal waves, apoptosis, and angiogenesis in postnatal retina

michael.savage2@newcastle.ac.uk (Cori Bertram) — Thu, 24 Sep 2026 00:00:00 +0000

Postnatal mouse retinal development is a multi-faceted process involving the coordinated interaction of spontaneous neural activity as retinal waves, vascular plexus growth, and programmed cell death. While these processes are known to interact at a coarse scale, the specific mechanisms integrating them have remained elusive. Using large-scale, wide-field calcium imaging, high-density multielectrode array recordings, single-cell RNA sequencing, and immunohistochemistry, we characterise a tightly aligned centrifugal expansion pattern during retinal development. This pattern is common to stage II retinal wave onsets, vascular development, Heme oxygenase-1 (Hmox1) expressing microglia, apoptotic cell markers, and a novel set of auto-fluorescent cluster complexes (ACCs) identified in this study. Apoptotic cells are known to upregulate functional pannexin-1 (PANX-1) hemichannels. These voltage-gated channels release purinergic molecules which act as ‘eat me’ signals to neighbouring microglia. PANX-1 hemichannel blockade with the drug probenecid results in a profound decrease in spontaneous wave frequency and strength, suggesting that retinal waves are indeed triggered by these apoptotic cells. Taken together, our observations suggest that spontaneous waves are initially triggered in hotspots by hyperactive apoptotic retinal ganglion cells (RGCs) in unvascularised retinal areas. These apoptotic cells release purinergic molecules via PANX-1 hemichannels, leading to wave generation. This hyperactivity leads to local hypoxic conditions, which, coupled with high extracellular ATP concentrations, promotes angiogenesis. Once blood vessels reach a particular hotspot, ATP release activates Hmox1-positive microglia, which engulf the dying RGCs, creating the auto-fluorescent clusters. Herein, we present a unified mechanism linking causally linking early neural activity, programmed cell death, and angiogenesis in the mammalian retina.

Integrated respirometry and metabolomics unveil circadian metabolic dynamics in Drosophila

aalim@upenn.edu (Aalim Weljie) — Thu, 24 Sep 2026 00:00:00 +0000

Sleep and circadian rhythms shape organismal energy patterns, but how this timing connects to oxygen use and carbon dioxide production remains incompletely understood. We combined high-resolution respirometry with liquid chromatography-mass spectrometry (LC-MS)-based metabolomics to characterize respiratory dynamics and metabolic states in Drosophila melanogaster, resolving genotype-specific impacts of sleep disruption and circadian regulation. Wild-type flies under light-dark cycles (WT-LD) showed rhythmic respiratory patterns reflective of anticipatory coordination of mitochondrial energy metabolism, amino acid turnover, and redox cycling. Short-sleep mutants (fmn, sss) exhibited elevated metabolic rates, with reactive shifts of fuel preferences toward lipid and amino acid catabolism, and altered mitochondrial respiration. The clock mutant (per⁰¹) and flies under constant darkness (WT-DD) showed reactive and widespread metabolic dysregulation and impaired redox homeostasis. These findings demonstrate that both sleep and circadian systems contribute to aligning metabolic substrate selection with energy demands, offering mechanistic insights into how disruptions in behavioral states compromise metabolic health.

Real-time closed-loop feedback system for mouse mesoscale cortical signal and movement control

thmurphy@mail.ubc.ca (Pankaj Kumar Gupta) — Thu, 24 Sep 2026 00:00:00 +0000

Increasingly, experiments designed to provide practical perturbations to circuits or behavior are required for hypothesis testing in various disciplines ranging from motor learning to recovery after injury. We present the implementation and efficacy of an open-source closed-loop neurofeedback (CLNF) and closed-loop movement feedback (CLMF) system. In CLNF, we measure mm-scale cortical mesoscale activity with GCaMP6s and provide graded auditory feedback (within ~63 ms) based on changes in dorsal-cortical activation within regions of interest (ROIs) and with a specified rule. Single or dual ROIs (ROI1, ROI2) on the dorsal cortical map were selected as targets. Both motor and sensory regions supported closed-loop training in male and female mice. Mice modulated activity in rule-specific target cortical ROIs to get increasing rewards over days (repeated-measures ANOVA [RM-ANOVA], p=2.83e-5) and adapted to changes in ROI rules (RM-ANOVA, p=8.3e-10, Table 4 for different rule changes). In CLMF, feedback (within ~67 ms) was based on tracking a specified body movement, and rewards were generated when the behavior reached a threshold. For movement training, the group that received graded auditory feedback performed significantly better (RM-ANOVA, p=9.6e-7) than a control group (RM-ANOVA, p=0.49) within 4 training days. Additionally, mice can learn a change in task rule from left forelimb to right forelimb within a day, after a brief performance drop on day 5. Offline analysis of neural data and behavioral tracking revealed changes in the overall distribution of Ca²⁺ fluorescence values in CLNF and body-part speed values in CLMF experiments. Increased CLMF performance was accompanied by a decrease in task latency and cortical ΔF/F₀ amplitude during the task, indicating lower cortical activation as the task gets more familiar.

Identifying a novel mechanism of L-leucine uptake in Mycobacterium tuberculosis using a chemical genomic approach

nisheeth@thsti.res.in (Bappaditya Dey) — Wed, 23 Sep 2026 00:00:00 +0000

Amino acid biosynthesis is vital for Mycobacterium tuberculosis (Mtb) proliferation and tuberculosis (TB) pathogenesis. However, it is not clear how amino acids are transported in Mtb, particularly the branched-chain amino acids (BCAAs) that contribute to the production of the cell-wall lipid component precursors, such as acetyl-CoA and propionyl-CoA. While performing the screening of an FDA-approved repurposed library of small molecule inhibitors against the auxotrophic strain Mtb mc² 6206, which lacks leuC-leuD and panC-panD genes, we identified a molecule, namely semapimod, which exclusively inhibits the growth of the auxotrophic strain, whereas no effect is observed against the wild-type Mtb H₃₇Rv. Interestingly, 24 hr of exposure of Mtb mc² 6206 to semapimod causes massive transcriptional reprogramming with differential expression of >450 genes associated with a myriad of metabolic activities. By performing a series of experiments, we affirm that semapimod indeed inhibits the L-leucine uptake in Mtb mc² 6206 by targeting a protein involved in the cell-wall lipid biosynthesis pathway. Remarkably, semapimod treatment of mice infected with Mtb H₃₇Rv causes a significant reduction of bacterial load in lungs and spleen, despite showing no efficacy against the pathogenic strain in vitro. Overall findings of our study reveal that together with an endogenous pathway for L-leucine biosynthesis, a well-orchestrated machinery for its uptake is functional in Mtb, which is important for intracellular survival of the TB pathogen.

A novel rapid host cell entry pathway determines the intracellular fate of Staphylococcus aureus

martin.fraunholz@uni-wuerzburg.de (Adriana Moldovan) — Wed, 23 Sep 2026 00:00:00 +0000

Staphylococcus aureus is an opportunistic pathogen causing severe diseases. Recently, S. aureus was recognized as an intracellular pathogen, whereby the intracellular niche promotes immune evasion and antibiotic resistance. Interaction of S. aureus with versatile host cell receptors was described previously, suggesting that internalization of the pathogen can occur via several pathways. It remains elusive whether the pathway of internalization can affect the intracellular fate of the bacteria. Here, we identified a mechanism governing cellular uptake of S. aureus which relies on lysosomal Ca²⁺, lysosomal exocytosis, and occurs concurrently to other well-known entry pathways within the same host cell population. This internalization pathway is rapid and active within only a few minutes after bacterial contact with host cells. Compared to slow bacterial internalization, the rapid pathway demonstrates altered phagosomal maturation as well as translocation of the pathogen to the host cytosol and ultimately results in different rates of intracellular bacterial replication and host cell death. We show that these alternative infection outcomes are caused by the mode of bacterial uptake.

Machine learning of honey bee olfactory behavior identifies repellent odorants in free-flying bees in the field

anand.ray@ucr.edu (Anandasankar Ray) — Wed, 23 Sep 2026 00:00:00 +0000

Preventing beneficial insects like honey bees (Apis mellifera) from contacting pesticides on crops using odorants could counter current pollinator declines. However, the discovery of behaviorally aversive odorants is impeded by the complexity of the honey bee olfactory system where >170 olfactory receptors detect volatiles and generate valence. To solve this systems-level challenge, we generated a machine-learning model to predict aversive valence from chemical structure using published olfactory behavior data in honey bees. We refine the predictive model by generating species-level behavioral data for honey bees and Drosophila on an initial set of novel predicted repellents. The improved second computational model was then used to screen a chemical space of >50 million compounds and identify >130 repellent candidates. Behavioral validation using honey bees in the laboratory shows a high predictive success. Additional testing of the top seven candidates using freely foraging honey bees in a field assay confirmed strong repellency, thus predicting a high probability to repel foraging bees from pesticide-treated crops. Machine learning, with iterative testing and modeling, therefore provides a powerful approach for rational discovery of aversive volatiles for control of insects for which limited data is available.

Region-specific mechanosensation modulates Drosophila postural control behaviour

c.alonso@sussex.ac.uk (Claudio R Alonso) — Wed, 23 Sep 2026 00:00:00 +0000

The relation between regional morphological features derived from the bilaterian body plan and the behaviours necessary to extract utility from such structures is not well understood. Here, we use the Drosophila larva to investigate this ‘form-function’ problem focusing on the mapping of the regional stimuli that trigger an adaptive and evolutionarily conserved behaviour termed self-righting: a postural control system that allows the animal to restore its natural position if turned upside-down. Through the development of new methodologies that allow regionally restricted mechanical stimulation and zonal-specific neuronal optogenetics, we find that multidendritic sensory neuron inhibition in anterior areas (thoracic/anterior abdominal) has a profound effect on self-righting performance, while inhibition of posterior sensory elements (mid and posterior abdomen) produces no effects. To gain insight into how regional neuronal inhibition affects the different subcomponents of the self-righting sequence we applied a deep neural network tracking method which revealed that reduction of neural activity in anterior sensory neurons primarily increases head casting behaviour and that this, in turn, is strongly correlated with abnormally long self-righting times. Furthermore, to explore the mechanistic bases of our behavioural observations, we considered the hypothesis that the Hox genes – well known for their roles in axial developmental patterning – might play a role in the functional specification of multidendritic sensory neurons along the body axis. Molecular expression analysis of FACS-sorted neural populations, fluorescent immunolabelling and neuron-specific knockdown experiments demonstrate that normal sensory neuron expression of the Hox genes Antennapedia and Abdominal-b is necessary for self-righting in the Drosophila larva. Altogether, our work shows that region-specific mechanosensory processes mediated by multidendritic sensory neurons and instructed via Hox gene inputs are essential for self-righting, providing a link between regional structural features and an adaptive and widely evolutionarily conserved postural control behaviour.

Brief disruption of activity in a subset of dopaminergic neurons during consolidation impairs long-term memory by fragmenting sleep

szmchlyt@hbmu.edu.cn (Chang Liu) — Wed, 23 Sep 2026 00:00:00 +0000

Sleep disturbances are associated with poor long-term memory (LTM) formation, yet the underlying cell types and neural circuits involved have not been fully decoded. Dopamine neurons (DANs) are involved in memory processing at multiple stages. Here, using both male and female flies, Drosophila melanogaster, we show that, during the first few hours of memory consolidation, disruption of basal activity of a small subset of protocerebral anterior medial DANs (PAM-DANs), by either brief activation or inhibition of the two dorsal posterior medial (DPM) neurons, impairs 24 hr LTM. Interestingly, these brief changes in activity using female flies result in sleep loss and fragmentation, especially at night. Importantly, pharmacological rescue of sleep after manipulation restores LTM. A specific subset of PAM-DANs (PAM-α1) that synapse onto DPM neurons specify the microcircuit that links sleep and memory. MBON-α1 also contributes to the integration of sleep and memory by acting as an additional parallel circuit. PAM-DANs, including PAM-α1, form functional synapses onto DPM mainly via two dopamine receptor subtypes. Dop1R1 primarily mediates the link between sleep and memory. This PAM-α1 to DPM microcircuit exhibits a synchronized, transient, post-training change in activity during the critical memory consolidation window, suggesting an effect of this microcircuit on maintaining the sleep necessary for LTM consolidation. Our results provide a new molecular and circuit basis for the complex relationship between sleep and memory.

Retinotopic coding organizes the interaction between internally and externally oriented brain networks

adamdanielsteel@gmail.com (Adam Steel) — Tue, 22 Sep 2026 00:00:00 +0000

The human brain seamlessly integrates internally generated thoughts with incoming sensory information, yet the large-scale networks that support these functions – the internal default network (DN) and external dorsal attention network (dATN) – are traditionally viewed as functionally independent. This raises a crucial question: how does the brain integrate information across these seemingly noninteractive systems? Here, using densely sampled 7T fMRI, individualized resting-state parcellations, and voxel-wise population-receptive-field mapping, we show that these internal/external networks are more interlocked than previously thought. Spontaneous DN and dATN activity during rest is uncorrelated at the network level. However, voxel-scale functional coupling across networks is shaped by the latent visual field preferences of individual voxels in each network, as measured during independent retinotopic mapping. Voxels that share visual field preferences exhibit stronger spontaneous coupling than those with divergent preferences. These retinotopically specific interactions are bivalent: DN voxels with negative (suppressive) visual response amplitudes are anticorrelated with matched (positive) dATN voxels, while those DN voxels with positive response amplitudes are positively correlated. Thus, distinct subpopulations of visually tuned DN voxels participate in spatially specific interactions with the dATN. Further, retinotopic coding is intrinsic to the DN, persisting even during periods when the DN signal is elevated. These findings reveal a latent, voxel-level architecture of retinotopically grounded interactions between the DN and dATN. Taken together, our results suggest that retinotopic coding underpins the dynamic coordination of perception and thought in the human brain.

PRMT1-SFPQ regulates intron retention to control matrix gene expression during craniofacial development

wpeng@gwu.edu (Amy E Merrill) — Tue, 22 Sep 2026 00:00:00 +0000

Spliceosomopathies, which are a group of disorders caused by defects in the splicing machinery, frequently affect the craniofacial skeleton and limb, but the molecular mechanism underlying this tissue-specific sensitivity remains unclear. Splicing factors and small nuclear ribonucleoproteins (snRNPs) are core components of splicing machinery, and splicing factors are further controlled by post-translational modifications, among which arginine methylation is one of the most prevalent. We determined the splicing mechanisms in the cranial neural crest cells (CNCCs), a multipotent developmental population that gives rise to the majority of the craniofacial skeleton, and focused on an upstream regulator of splicing proteins, protein arginine methyltransferase 1 (PRMT1). PRMT1 is the highest expressing arginine methyltransferase in CNCCs, and its role in craniofacial development is evident from our earlier investigation, where CNCC-specific Prmt1 deletion caused cleft palate and mandibular hypoplasia. PRMT1 catalyzes arginine methylation of splicing factors to modify protein localization, expression, and activity. In the present study, we uncover roles of PRMT1 in the regulation of intron retention, a type of alternative splicing where introns are retained in the mature mRNA. CNCCs from the mandibular primordium of Prmt1-deficient embryos demonstrated an increase in the percentage of intron-retaining mRNA of matrix genes, which triggered nonsense-mediated decay (NMD), causing a reduction in matrix mRNA abundance. We further identified SFPQ as a substrate of PRMT1 that depends on PRMT1 for arginine methylation and protein expression in the developing craniofacial structures. Depletion of SFPQ in CNCCs phenocopied PRMT1 deletion whereby matrix, Wnt signaling components, and neuronal gene transcripts contained higher IR and exhibited lower expression. We further recognized gene length as a common feature among SFPQ-regulated genes in CNCCs. Altogether, these findings demonstrate that the PRMT1-SFPQ pathway modulates matrix gene expression via IR-triggered NMD in CNCCs during craniofacial development.

Wound-induced syncytia outpace mononucleate neighbors during Drosophila wound repair

shane.hutson@vanderbilt.edu (Andrea Page-McCaw) — Tue, 22 Sep 2026 00:00:00 +0000

In response to injury, cells proliferate, migrate, and invade to replace missing cells and close wounds. However, the role of other wound-induced cell behaviors is not understood, including the formation of syncytia (multinucleated cells). Here, we use in vivo live imaging to analyze wound-induced syncytia in mitotically competent Drosophila pupae. We find that almost half the epithelial cells near a wound fuse to form large syncytia. When the autophagy gene Atg1 is knocked down, fewer syncytia form, and wounds close more slowly. Further, a computational model of tissue fluidity indicates that cell fusion speeds wound closure time by about one-third. Syncytia use several routes to speed wound repair: they outpace diploid cells at the wound margin to lead the initial resealing of the wound; they reduce the need for intercalation as the tissue reshapes during closure; and they pool resources of their component cells to concentrate them toward the wound margin. In addition to wound healing, these properties of syncytia are likely to contribute to their roles in development and pathology.

Pathogenic O-GlcNAc dyshomeostasis is associated with cortical malformations and hyperactivity

daan@mbg.au.dk (Asad Jan) — Tue, 22 Sep 2026 00:00:00 +0000

Missense variants in the O-GlcNAc transferase (OGT) gene have recently been shown to segregate with a syndromic form of intellectual disability (OGT-ID), underscoring the importance of protein O-GlcNAcylation in brain function. However, the underlying pathophysiological mechanisms linking ID to potential OGT malfunction—whether developmental, neurophysiological, or both – remain unclear. Here, we present comprehensive analyses encompassing behaviour and brain architecture of a rodent model carrying the pathogenic C921Y OGT-ID variant. These mice show a range of behavioural deficits, including hyperactivity, impulsivity, and associative learning phenotypes. Structural studies, using micro-computed tomography and magnetic resonance imaging, revealed reduced skull size, microcephaly, reduced cortical thickness and hypoplastic corpus callosum. Detailed histological analyses revealed dysplastic changes in the neocortex, predominantly affecting the superficial layers of the cingulate cortex. Mechanistically, quantitative proteomic analyses revealed O-GlcNAc dyshomeostasis associated with distinct perturbed molecular pathways involved in brain development. Taken together, these data reveal neurodevelopmental defects associated with O-GlcNAc dyshomeostasis and provide a platform for dissecting mechanism and treatments of OGT-ID.

Correction: Degradation of LMO2 in T cell leukaemia results in collateral breakdown of transcription complex partners and causes LMO2-dependent apoptosis

Mon, 21 Sep 2026 00:00:00 +0000

MATR3 is essential for oocyte growth and maturation quality through a dual molecular mechanism

hr7424@126.com (Bingying Liu) — Mon, 21 Sep 2026 00:00:00 +0000

The molecular mechanisms governing mRNA accumulation during oocyte growth, essential for developmental competence, remain poorly understood. This study investigates the role of Matrin-3 (MATR3), a highly expressed RNA-binding protein in growing oocytes (GOs), using oocyte-specific knockout mouse models and human oocyte maturation arrest (OMA) samples. The results showed that MATR3 was more abundant in GOs than fully grown oocytes (FGOs), highly expressed in the nucleus of non-surrounded nucleolus (NSN) oocytes, and exited the nucleus during the NSN-to-surrounded nucleolus (SN) transition. In OMA patients, MATR3 nuclear localization was missed, with smaller oocytes than FGOs. Further, Matr3 deletion in mouse GOs caused restricted oocyte growth, global transcription disorders, follicle development failure, blocked GO-granulosa cell communication (via reduced Gdf9 and Rdx expression), and infertility. Mechanistically, MATR3 regulated transcription by recruiting H3K9me2-demethylating lysine-specific demethylase 3B or binding target gene promoters, like Rdx. These findings reveal a critical role of MATR3 in orchestrating transcription and paracrine signaling during oogenesis and suggest its potential as a diagnostic and therapeutic target for OMA.

Infants at high and low likelihood for autism show different EEG developmental trajectories in speech tracking and statistical learning

michel.godel@unige.ch (Ana Fló) — Mon, 21 Sep 2026 00:00:00 +0000

Delayed onset of canonical babbling and first words is often reported in infants later diagnosed with autism spectrum disorder. Identifying the neural mechanisms underlying language acquisition in autism is therefore critical to inform early diagnosis, prognosis, and intervention strategies. In this study, we investigated two speech processing mechanisms previously identified as atypical in children and adults with autism: the neural ability to track syllables, and statistical learning, the capacity to detect speech regularities beneath surface variability. We recorded 83 longitudinal high-density electroencephalograms from 44 infants (2.5–22.6 months) at high (HL) and low (LL) likelihood for autism and assessed their verbal outcomes at 20 months. Neural entrainment was measured at syllable and word frequencies during exposure to a multi-speaker stream of concatenated tri-syllabic words, followed by a word recognition test using evoked response potential (ERP) recording. Our findings revealed reduced tracking abilities at the syllabic level in HL infants, a measure that correlated with verbal outcomes. While HL infants did not exhibit deficits in statistical learning itself, they displayed reduced novelty orientation during the word recognition test, indicated by a reduced late ERP. By contrast, multi-talker variability temporarily disrupted word segmentation around 12 months in LL infants, but not in HL infants, potentially reflecting decreased sensitivity to human voices variability in the HL group. These results emphasize the importance of longitudinal protocols employing online, implicit measures to track the hierarchical stages of speech processing in both HL and LL infants.

Asymmetric introgression and thermal advantage jointly drive climate-mediated lineage turnover in a mixed-ploidy reed

guowh@email.sdu.edu.cn (Cui Wang) — Mon, 21 Sep 2026 00:00:00 +0000

Species distribution forecasts often ignore intraspecific genetic variation, potentially missing climate-driven lineage shifts within native ranges. We integrated population genomics (495 individuals), common-garden experiments across four sites, and species distribution modeling (837 records) for three genetic lineages of Phragmites australis in China. The octoploid FEAU lineage (haplotype P) showed superior heat tolerance, with T_crit 1.3 °C higher and T₅₀ 0.8 °C higher than the cold-adapted tetraploid CN lineage (haplotypes O/M), and produced greater total biomass in three of four gardens. Genomic analyses revealed bidirectional but asymmetric introgression; admixed individuals exhibited a significant bias toward FEAU ancestry (61.1%), consistent with preferential backcrossing to the octoploid parent. Under the high-emission scenario SSP5-8.5 by 2070, highly suitable habitat for FEAU expanded by 18.6%, whereas CN showed a smaller relative increase, and the subtropical SW lineage remained stable. These results demonstrate that climate change interacts with intraspecific variation through thermal tolerance, biomass advantages, and asymmetric gene flow to drive potential lineage replacement within the native range, a process already suggested by field observations of FEAU expansion in a plateau lake. Our findings argue for integrating evolutionary history and genetic identity into ecological forecasting to better anticipate ecosystem responses under ongoing warming.

Enhanced tactile coding in rat neocortex under darkness

nobuyoshi@matsumoto.ac (Kotaro Yamashiro) — Mon, 21 Sep 2026 00:00:00 +0000

Sensory systems are known for their adaptability, responding dynamically to changes in environmental conditions. A key example of this adaptability is the enhancement of tactile perception in the absence of visual input. Despite behavioral studies showing visual deprivation can improve tactile discrimination, the underlying neural mechanisms, particularly how tactile neural representations are reorganized during visual deprivation, remain unclear. In this study, we explore how the absence of visual input alters tactile neural encoding in the rat primary somatosensory cortex (S1). Rats were trained on a custom-designed treadmill with distinct tactile textures (rough and smooth), and local field potentials (LFPs) were recorded from S1 under light and dark conditions. Machine learning techniques, specifically a convolutional neural network, were used to decode the high-dimensional LFP signals. We found that the neural representations of tactile stimuli became more distinct in the dark, indicating a reorganization of sensory processing in S1 when visual input was removed. Notably, conventional amplitude-based analyses failed to capture these changes, highlighting the power of deep learning in uncovering subtle neural patterns. These findings offer new insights into how the brain rapidly adapts tactile processing in response to the loss of visual input, with implications for multisensory integration.

Linear antibody epitope prediction using AlphaFold2

christopher.snow@colostate.edu (Brian J Geiss) — Fri, 18 Sep 2026 00:00:00 +0000

Defining the binding epitopes of antibodies is essential for understanding how they bind to their antigens and perform their molecular functions. However, while determining linear epitopes of monoclonal antibodies can be accomplished utilizing well-established empirical procedures, these approaches are generally labor- and time-intensive, and costly. To take advantage of the recent advances in protein structure prediction algorithms available to the scientific community, we developed a calculation pipeline based on the localColabFold implementation of AlphaFold2 that can predict linear antibody epitopes by predicting the structure of the complex between antibody heavy and light chains and target peptide sequences derived from antigens. We found that this AlphaFold2 pipeline, which we call PAbFold, was able to accurately flag known epitope sequences for several well-known antibody targets (HA/Myc) when the target sequence was broken into small overlapping linear peptides and antibody complementarity determining regions were grafted onto several different antibody framework regions in the single-chain antibody fragment format. To determine if this pipeline was able to identify the epitope of a novel antibody with no structural information publicly available, we determined the epitope of a novel anti-SARS-CoV-2 nucleocapsid-targeted antibody using our method and then experimentally validated our computational results using peptide competition ELISA assays. These results indicate that the AlphaFold2-based PAbFold pipeline we developed is capable of accurately identifying linear antibody epitopes in a short time using just antibody and target protein sequences. This emergent capability of the method is sensitive to methodological details such as peptide length, AlphaFold2 neural network versions, and multiple-sequence alignment databases. PAbFold is available at https://github.com/jbderoo/PAbFold.

DGKα and ζ deficiency causes regulatory T-cell dysregulation, destabilization, and conversion to pathogenic T-follicular helper cells to trigger IgG1-predominant autoimmunity

xiaoping.zhong@duke.edu (Hongxiang Huang) — Fri, 18 Sep 2026 00:00:00 +0000

Regulatory T cells (Tregs) actively engage in immune suppression to prevent autoimmune diseases, but also inhibit anti-tumor immunity. Although Tregs express a TCR repertoire with relatively high affinities to self, they are normally quite stable, and their inflammatory programs are intrinsically suppressed. We report here that diacylglycerol kinases (DGK) α and ζ are crucial for homeostasis, suppression of proinflammatory programs, and stability of Tregs, and for enforcing their dependence on CD28 costimulatory signal. Treg-specific deficiency of both DGKα and ζ derails signaling, metabolic, and transcriptional programs in Tregs to cause dysregulated phenotypic and functional properties and to unleash conversion to pathogenic exTregs, especially exTreg-T follicular helper (Tfh) 2 cells, leading to uncontrolled effector T cell differentiation, deregulated germinal center B-cell responses, and IgG1/IgE predominant antibodies/autoantibodies, and multiorgan autoimmune diseases. Our data not only illustrate the crucial roles of DGKs in Tregs to maintain self-tolerance, but also unveil a Treg-to-self-reactive-pathogenic-exTreg-Tfh-cell program that is suppressed by DGKs and that could exert broad pathogenic roles in autoimmune diseases if unchecked.

An applicable and efficient retrograde monosynaptic circuit mapping tool for larval zebrafish

forestdu@ion.ac.cn (Fu-Qiang Xu) — Fri, 18 Sep 2026 00:00:00 +0000

The larval zebrafish is a vertebrate model for in vivo monitoring and manipulation of whole-brain neuronal activity. Tracing its neural circuits remains challenging. Here, we report an applicable methodology tailored for larval zebrafish to achieve efficient retrograde trans-monosynaptic tracing from genetically defined neurons via EnvA-pseudotyped glycoprotein-deleted rabies viruses. By combinatorially optimizing multiple factors involved, we identified the CVS strain trans-complemented with advanced expression of N2cG at 36 °C as the optimal combination. It yielded a tracing efficiency of up to 20 inputs per starter cell. Its low cytotoxicity enabled the viable labeling and calcium imaging of infected neurons 10 days post-infection, spanning larval ages commonly used for functional examination. Cre-dependent labeling was further developed to enable cell-type-specific input tracing and circuit reconstruction. We mapped cerebellar circuits and uncovered the ipsilateral preference and subtype specificity of granule cell-to-Purkinje cell connections. Our method offers an efficient way for tracing neural circuits in larval zebrafish.

Defective neuronal differentiation in Lowe syndrome is associated with mitochondrial dysfunction and impaired cilia-related Sonic Hedgehog signaling

yangsun@stanford.edu (Benjamin Lawson) — Fri, 18 Sep 2026 00:00:00 +0000

Human brain development requires tight coordination of metabolic and signaling pathways. Lowe syndrome (LS) is a recessive X-linked disorder characterized by proximal tubular renal disease, congenital cataracts, glaucoma, and neurodevelopmental delays. While LS results from mutations in the OCRL gene, which encodes an inositol polyphosphate 5-phosphatase, the cellular mechanisms driving neuronal dysfunction remain poorly understood. In this study, using patient-derived iPSC neurons, an Ocrl knockout mouse model, and an independent zebrafish OCRL-deficient model, we identified mitochondrial dysfunction as a conserved phenotype of OCRL loss across species. Collectively, our findings showed that OCRL deficiency leads to reduced mitochondrial activity, decreased mtDNA levels, reduced mitochondrial content (TOM20), and increased oxidative stress. We further showed that OCRL-deficient neural cells exhibited an altered balance of neuronal versus astrocytic differentiation, rather than a defect in neurogenesis. Additionally, we observed impaired Sonic Hedgehog (Shh) signaling and ciliary homeostasis. Thus, our findings support a model in which OCRL deficiency is associated with mitochondrial dysfunction, increased oxidative stress, altered neural lineage balance, and reduced Hedgehog pathway activity, providing a framework for understanding these interconnected phenotypes.

The power of theory in the life sciences

jacob.fine@mail.utoronto.ca (Adam MR Groh) — Fri, 18 Sep 2026 00:00:00 +0000

The rapid growth of high-throughput biology and genomics over the past two decades has helped catalogue many different aspects of gene function in diverse cell types and conditions. More recently, advances in artificial intelligence and deep learning have shown tremendous promise in making accurate predictions of functional genomics measurements. These advances make it tempting to equate experimental cataloguing and accurate prediction with the growth of our theoretical understanding of biological processes – an equivalence we believe is ultimately misleading.

Environmental temperature is a strong driver of subspecies competition in the Drosophila microbiome

schlotc@gmail.com (Christian Schlötterer) — Fri, 18 Sep 2026 00:00:00 +0000

Most microbiome research focuses on the taxonomic composition at the species level to understand the impact of environmental factors, but intraspecific diversity has largely been ignored. To address this significant knowledge gap, we took advantage of the simple, culturable microbiome of Drosophila. First, we documented that natural populations of D. simulans harbor three diverged clades of Lactiplantibacillus plantarum, a key nutritional symbiont. We studied the distinct ecological roles of these three clades by exposing flies with their native microbiome to two temperature regimes in the laboratory. Tracking the three clades within the complete Drosophila microbiome over a period of more than 10 years at two temperatures, we identified strikingly distinct dynamics in response to the selection regime. We confirmed the functional differentiation of the three clades using in vitro growth measurements and in vivo mono-association assays. Our results highlight that environmental selection operates at the subspecies level. Therefore, we conclude that the functional diversification of the microbiome can only be understood when intra- and interspecific diversity is considered.

Synergistic inhibition of Notch signaling and forced cell cycle re-entry drive Müller glia reprogramming in uninjured mouse retina

wenjun.xiong@cityu.edu.hk (Baoshan Liao) — Thu, 17 Sep 2026 00:00:00 +0000

In regenerative species, such as teleost fish, Müller glia (MG) autonomously re-enter the cell cycle after injury and give rise to functional retinal neurons. In contrast, the loss of retinal neurons in mammals is irreversible due to the limited proliferative and regenerative ability of MG. Various strategies have been developed to induce proliferation of mature mouse MG with or without injury, yet most MG daughter cells retain glial cell fate. Here, we found that MG progenies maintain high Notch signaling, which may constrain their neurogenic potential. Conditional deletion of Rbpj, the central transcriptional effector of Notch, induced limited MG-to-neuron conversion in mature MG without proliferation. However, Rbpj deletion, combined with forced MG proliferation by overexpressing Ccnd1 and suppressing Cdkn1b, significantly promoted MG dedifferentiation and ectopic expression of the neuronal marker Otx2 in MG daughter cells in uninjured mouse retina. Combining Notch inhibition with MG cell cycle re-activation not only increased the numbers of bipolar- and amacrine-like cells generated from MG but also promoted the further differentiation toward ON-cone, OFF-cone, and rod-bipolar subtypes. Single-nucleus RNA and ATAC sequencing data revealed that Notch inhibition facilitated the formation of MG-derived progenitor-like cells while MG proliferation increased chromatin accessibility of neurogenic genes. Notably, most MG-derived cells survived long term despite incomplete maturation. Together, our findings delineate how Notch inhibition and MG proliferation, alone or in combination, influence the regenerative potential of MG in the mammalian retina.

Screening the MMV Pathogen Box reveals the mitochondrial bc₁-complex as a drug target in mature Toxoplasma gondii bradyzoites

blumem@rki.de (Deborah Maus) — Thu, 17 Sep 2026 00:00:00 +0000

The apicomplexan parasite Toxoplasma gondii infects 25–30% of the global human population and can cause life-threatening diseases in immunocompromised patients. The chronically infectious forms of the parasite, bradyzoites, persist within cysts in brain and muscle tissue, and are responsible for its transmission and remission of the disease. Currently available treatment options are very limited and are only effective against the fast-replicating tachyzoites, but fail to eradicate the chronic stages of T. gondii. The cause of these treatment failures remains unclear. Here, we utilized our recently developed human myotube-based culture model to screen compounds from the MMV Pathogen Box against pan-resistant in vitro bradyzoites, and identified multiple compounds with simultaneous activity against tachyzoites and bradyzoites. Stable isotope-resolved metabolic profiling on tachyzoites and bradyzoites identified the mitochondrial bc₁-complex as a target of bradyzocidal compounds and defined their metabolic impacts on both parasite forms. Our data suggest that mature bradyzoites rely on mitochondrial ATP production.

Larger language models better align with neural representations of natural language

kw1166@princeton.edu (Adeen Flinker) — Wed, 16 Sep 2026 00:00:00 +0000

Recent research has used large language models (LLMs) to study the neural basis of naturalistic language processing in the human brain. LLMs have rapidly grown in complexity, leading to improved language processing capabilities. Here, we utilized several families of transformer-based LLMs to investigate the relationship between model size and their ability to capture linguistic information in the human brain. Crucially, a subset of LLMs were trained on a fixed training set, enabling us to dissociate model size from architecture and training set size. We used electrocorticography (ECoG) to measure neural activity in epilepsy patients while they listened to a 30 min naturalistic audio story. We fit electrode-wise encoding models using contextual embeddings extracted from each hidden layer of the LLMs to predict word-level neural signals. In line with prior work, we found that larger LLMs better capture the structure of natural language and better predict neural activity. We also found a logarithmic relationship where the encoding performance peaks in relatively earlier layers as model size increases. We also observed variations in the best-performing layer across different brain regions, corresponding to an organized language processing hierarchy.

Modulating task-outcome value to mitigate real-world procrastination via noninvasive brain stimulation

chenzhiyi@tmmu.edu.cn (Bernhard Hommel) — Wed, 16 Sep 2026 00:00:00 +0000

Procrastination is a prevalent behavioral problem associated with individual health and societal productivity. A leading model posits that procrastination reflects an imbalance between task aversiveness and the pursuit of positive task outcomes, yet this theoretical framework has neither been validated in real-world settings nor effectively applied to guide interventions. To address this gap, we conducted a double-blind, randomized, sham-controlled trial. Adults with chronic procrastination received seven sessions of high-definition transcranial direct current stimulation (HD-tDCS) to the left dorsolateral prefrontal cortex (DLPFC). Using the intensive experience sampling method, we assessed the effect of anodal HD-tDCS on real-world procrastination behavior at offline after-effect (2-day interval) and long-term after-effect (6-month follow-up). This neuromodulation produced a lasting reduction in real-world procrastination, with effects sustained at a 6-month follow-up. The mediation analysis indicated that increased outcome value, but not reduced task aversiveness, statistically accounted for variation in behavioral improvement. These findings are consistent with the hypothesis that enhancing DLPFC function may reduce procrastination by selectively amplifying the valuation of future rewards, not by reducing negative feelings about the task, which also suggests a targeted, theory-informed avenue for future behavioral interventions.

A systematic interactome of Saccharomyces cerevisiae SET1C expands its functional landscape and identifies candidate regulatory connections

kimjaehoon@kaist.edu (Bernhard Dichtl) — Wed, 16 Sep 2026 00:00:00 +0000

Set1 is the catalytic subunit of SET1C or COMPASS, which methylates histone H3K4 and serves as a scaffold for the association of seven tightly bound polypeptides. We have employed yeast two-hybrid screenings to determine the interactome of Set1 and each subunit, providing a unique resource for exploring known and novel roles of the complex. Our screenings identified a multitude of potential interactors involved in chromatin regulation, DNA replication, meiotic breaks, and Ty transposition, processes previously associated with SET1C. Consistent with Set1 being an RNA-binding protein, the screens link SET1C to multiple aspects of RNA biogenesis, including pre-mRNA splicing and polyadenylation. The results reveal that several importins are candidate interactors of Set1, along with RGG motif-containing proteins, providing insights into the mechanisms by which Set1 moves between cytoplasmic and nuclear compartments. We further reveal that reconstituted SET1C interacts with the AT-hook domain of the chromatin remodeler Snf2 and methylates multiple arginines within this domain. In vivo, we report that the ARTSTRGR AT-hook motif is methylated in a Set1-dependent manner, revealing new interplay between lysine and arginine methylation.

The chromokinesin Kid (KIF22) forms a homodimer, moves processively along microtubules, and transports double-stranded DNA

shinsuke.niwa.c8@tohoku.ac.jp (Kyoko Chiba) — Wed, 16 Sep 2026 00:00:00 +0000

During prometaphase in mitosis, chromosomes are pushed toward the spindle equator. The chromokinesin Kid, also known as KIF22, moves chromosomes along spindle microtubules during prometaphase. Kid has long been considered a monomeric and nonprocessive motor, different from typical kinesins. In this study, we demonstrate that the full-length Kid forms a homodimer and moves processively along microtubules. A conserved coiled-coil domain within the stalk region of Kid is sufficient for homodimer formation and is required for the processivity of Kid. Furthermore, the neck linker and coiled-coil domains of Kid could add processive activity to the motor domain of KIF1A, suggesting that Kid contains a functional neck linker and dimerization capability, a prerequisite for the processivity of kinesin motor domains. The full-length Kid, containing a helix–hairpin–helix domain, can transport double-stranded DNA along microtubules in vitro. AlphaFold3 prediction suggests that the dimerization of Kid stabilizes the association with DNA. These findings collectively suggest the reclassification of Kid as a processive and dimeric motor that transports DNA along microtubules.

Comprehensive RNA velocity by modeling the cascade of gene regulation, transcription, and splicing from single-cell RNA sequencing data with TSvelo

yyuan@ipe.ac.cn (Hong-Bin Shen) — Tue, 15 Sep 2026 00:00:00 +0000

RNA velocity approaches fit gene dynamics and infer cell fate by modeling the splicing process using single-cell RNA sequencing (scRNA-seq) data. However, due to the short time scale of splicing, high noise, and large complexity of data, existing RNA velocity methods often fail to precisely capture the complex velocity dynamics for individual genes and single cells, which makes their downstream analysis less reliable and less robust. We propose TSvelo, a comprehensive RNA velocity mathematics framework that can model the cascade of gene regulation, Transcription and Splicing using highly interpretable neural ordinary differential equations. TSvelo can precisely capture the transcription–unspliced–spliced 3D dynamics of all genes simultaneously, infer unified latent time shared by genes within a single cell, and be applied to multi-lineage datasets. Experiments on six scRNA-seq datasets, including two multi-lineage datasets, demonstrate TSvelo’s superiority.

Correction: Post-retrieval noradrenergic activation impairs subsequent memory depending on cortico-hippocampal reactivation

Tue, 15 Sep 2026 00:00:00 +0000

Rank- and threat-dependent social modulation of innate defensive behaviors

lingyunli@ccmu.edu.cn (Jun Zhang) — Tue, 15 Sep 2026 00:00:00 +0000

Fear and defense are among the most fundamental survival behaviors and are profoundly influenced by the social environment in group-living animals. However, it remains poorly understood how social context—and particularly dominance hierarchy, a defining feature of many social species—modulates defensive strategies under naturalistic conditions. To address this question, we investigated the social modulation of innate fear in mice exposed to two ethologically relevant threats: a transient visual looming stimulus and a sustained predatory threat posed by a live rat. We found that social presence alleviated threat-induced stress and modulated defensive behaviors in a rank- and threat-specific manner. During looming exposure, it reduced immediate defensive responses and alleviated post-looming anxiety, with dominants deriving greater benefit. During rat exposure, it promoted a shift from passive to active defense, again most prominently in dominants. These behavioral changes were accompanied by reorganization of transitions between defensive states, indicating that dominance hierarchy shapes both the expression and temporal organization of innate defensive behaviors. Conversely, threat exposure strengthened social engagement, with dominant mice exhibiting more proactive social behaviors and subordinate mice responding more readily to dominant social initiations. Together, these findings demonstrate how dominance hierarchy modulates defensive responses to distinct naturalistic threats and, in turn, how threat experience shapes social behavior, providing a behavioral framework for probing the neural basis of socially modulated innate fear.

+Clonal stochasticity in early NK cell response to mouse cytomegalovirus is generated by mature subsets of varying proliferative ability

darren.wethington@nationwidechildrens.org (Darren Wethington) — Mon, 14 Sep 2026 00:00:00 +0000

Natural killer (NK) cells are classically defined as innate immune cells, but experiments show that mouse cytomegalovirus (MCMV) infection in C57BL/6 mice can cause NK cells to undergo antigen-specific proliferation and memory formation, similar to adaptive CD8+ T cells. One shared behavior between CD8+ T cells and NK cells is clonal expansion, where a single stimulated cell proliferates rapidly to form a diverse population of cells. For example, clones derived from single cells are most abundant during expansion when they are primarily CD27- for NK cells and CD62L- for T cells, phenotypes derived from precursor CD27+ and CD62L + cells, respectively. Here we determined the mechanistic rules involving proliferation, cell death, and differentiation of endogenous and adoptively transferred NK cells in the expansion phase of the response to MCMV infection. We found that the interplay between cell proliferation and cell death of mature CD27- NK cells and a highly proliferative CD27-Ly6C- mature subtype and intrinsic stochastic fluctuations in these processes play key roles in regulating the heterogeneity and population of the NK cell subtypes. Furthermore, we estimate rates for maturation of endogenous NK cells in homeostasis and in MCMV infection and found that only NK cell growth rates, and not differentiation rates, are appreciably increased by MCMV. Taken together, these results quantify the differences between the kinetics of NK cell antigen-specific expansion from that of CD8+T cells and unique mechanisms that give rise to the observed heterogeneity in NK cell clones generated from single NK cells in the expansion phase.

Intracellular growth of Chlamydia trachomatis leads to global histone hypermethylation by impairing demethylation

asubtil@pasteur.fr (Adrian Gabriel Torres) — Mon, 14 Sep 2026 00:00:00 +0000

Chlamydia trachomatis, an intracellular bacterium, highjacks metabolites from the host cell for its own proliferation. We provide evidence of global hypermethylation of the host proteome, including histones, during the late stages of infection. Single cell analyses revealed co-occurrence of several methylated residues on histones, while infection did not alter S-adenosyl methionine levels. Histone hypermethylation correlated positively with bacterial load and was prevented by antibiotic treatment. Mapping of trimethylation of histone 3 at residues K4 and K9 revealed a broad distribution throughout chromatin. Nuclear fractions of infected cells exhibited a fourfold decrease of demethylase activity against H3K4me3 and a twofold increase in succinate concentration, a competitive inhibitor for the demethylase co-factor a-ketoglutarate. Supplementation of the culture medium with dimethyl-ketoglutarate (DMKG) or with iron, a second co-factor of histone lysine demethylases, reduced histone hypermethylation. DMKG supplementation modified the transcription of about one third of the infection-responsive genes, indicating that histone hypermethylation contributes to modulating the transcriptional response of the host to infection. Finally, chemical inhibition of histone demethylases in a mouse model of infection showed a moderate benefit regarding the outcome of infection. Overall, our data show that the metabolic pressure exerted by a pathogen with an intracellular lifestyle drives epigenetic changes in infected cells.

Sarcomere dynamic instability and stochastic heterogeneity drive robust cardiomyocyte contraction

w.zimmermann@med.uni-goettingen.de (Christoph F Schmidt) — Mon, 14 Sep 2026 00:00:00 +0000

Cardiac contraction is driven by the collective action of cardiomyocytes (CMs) that contain parallel bundles of myofibrils consisting of linear chains of sarcomeres, the basic force-generating units. The dynamics of individual sarcomeres within intact CMs remain incompletely understood. While most models assume uniform, synchronized contractions, recent studies hint at unexpected heterogeneity, whose origins and significance are not yet clear. By combining the culture of fluorescent sarcomere-reporter human induced pluripotent stem cell-derived CMs on micropatterned soft gels of different stiffness (5–85 kPa) with AI-based tracking of sarcomere motion, we found that increasingly stiff substrates inhibited overall CM contraction, but, surprisingly, did not diminish individual sarcomere dynamics. Instead, sarcomeres competed in a tug-of-war, causing increasing heterogeneity, including rapid length oscillations and overextensions (popping). Statistical analysis showed that the heterogeneous dynamics were not caused by static structural differences but were largely stochastic. Stochastic heterogeneity is thus an intrinsic property of cardiac sarcomeres and likely mediates the adaptation of CM contractility to mechanical constraints. A mesoscopic model of coupled sarcomeres shows that these phenomena can be explained by a non-monotonic force–velocity relationship and stochastic fluctuations, where dynamic instability at a critical yielding force creates heterogeneity. Stochastic heterogeneity compensates for structural disorder by randomizing yield events beat-to-beat, preventing damage to specific sarcomeres. Our findings recast cardiac sarcomeres as active, dynamically unstable, and stochastic units engaged in a stochastic tug-of-war, where transient, velocity-dependent forces dominate. We propose that pathological disorder in cardiomyopathy drives a transition from protective stochastic fluctuations to more deterministic, persistently overloaded sarcomeres.

Acyl carrier protein is essential for apicoplast biogenesis in malaria parasites independent of fatty acid synthesis

sprigge2@jhu.edu (James A Wohlschlegel) — Mon, 14 Sep 2026 00:00:00 +0000

Acyl carrier protein (ACP) and its 4-phosphopantetheine prosthetic group canonically function as the soluble scaffold for acyl chain assembly and elongation during type II fatty acid biosynthesis (FASII). Plasmodium malaria parasites retain a FASII pathway in the apicoplast organelle that has been the subject of considerable scrutiny and confusion. Although apicoplast FASII is essential for Plasmodium falciparum growth within mosquitoes and the human liver, this pathway is dispensable and largely inactive in blood-stage parasites that can scavenge host fatty acids. In contrast to FASII enzymes that can be disrupted without fitness defect, we report that knockout or ligand-dependent knockdown of apicoplast ACP is lethal to blood-stage P. falciparum, indicating an essential FASII-independent function. Loss of ACP impairs the biosynthesis of essential isoprenoid precursors and blocks apicoplast biogenesis. Using proximity biotinylation and biochemical interaction studies, we identified a key role for ACP in binding and stabilizing apicoplast pyruvate kinase II (PKII). This critical enzyme is the only known source of nucleoside triphosphates (NTPs) in this organelle and is required for isoprenoid synthesis and apicoplast biogenesis. Our work reveals that ACP knockdown results in destabilization and loss of PKII, which is sufficient to explain ACP essentiality in this stage. This work unveils essential ACP function at a key biochemical hub controlling broad apicoplast metabolism in malaria parasites that is independent of the canonical ACP role in FASII.

Nerve injury-induced protein 2 preserves lysosomal membrane integrity to suppress ferroptosis

jinzhang@ucdavis.edu (Jin Zhang) — Fri, 11 Sep 2026 00:00:00 +0000

Nerve injury-induced protein 1 (NINJ1), a cell adhesion molecule, is oligomerized during lytic cell death and mediates plasma membrane rupture to release large intracellular molecules that propagate the inflammatory response. We and others previously showed that NINJ2, a close relative of NINJ1, does not promote plasma membrane rupture to spread inflammation. Here, we identify that NINJ2 is necessary for lysosome membrane integrity to protect cells from ferroptosis. Specifically, we found that NINJ2 localizes to lysosomes and interacts with LAMP1, an anchor glycoprotein of the lysosome membranes and a sensor of stressed lysosomes. We also found that loss of NINJ2 exacerbates lysosomal membrane permeabilization (LMP), which allows for selective leakage of lysosomal contents, such as labile iron, into the cytosol. Accordingly, loss of NINJ2 elevates cellular labile iron accumulation and decreases expression of ferritins, the primary intracellular iron storage protein complexes. Mechanistically, we found that loss of NINJ2 promotes ferritin FTH degradation in lysosomes, which can be reversed by knockdown of LAMP1. Moreover, we found that loss of NINJ2 sensitizes cells to ferroptosis induced by RSL3 and Erastin, consistent with a recent study that loss of NINJ2 predisposes mice to chronic inflammation. Together, these findings uncover a previously unrecognized activity of NINJ2 from lysosome homeostasis to ferroptosis, which can be explored as a cancer therapeutic strategy, especially considering that NINJ2 and ferritins are found to be overexpressed and positively associated with iron-addicted cancers.

PRRT2 as an auxiliary regulator of Nav channel slow inactivation

lubin@ion.ac.cn (Bin Lu) — Fri, 11 Sep 2026 00:00:00 +0000

During sustained activity, voltage-gated sodium (Nav) channels enter a slow-inactivated state to limit cellular hyperexcitability. Disruption of this regulatory process has been implicated in skeletal, cardiac, and neurological disorders. While the kinetics of this process are well characterized, its endogenous modulators remain unclear. Here, we identify Proline-Rich Transmembrane Protein 2 (PRRT2) as a native regulator of Nav channel slow inactivation. We show that PRRT2 facilitates the entry of Nav channels into the slow-inactivated state and delays their recovery, a regulatory effect conserved from zebrafish to humans. PRRT2 forms molecular complexes with Nav channels both in vitro and in vivo. In the mouse cortex, PRRT2 deficiency impairs the slow inactivation of Nav channels in neuronal axons, leading to reduced cortical resilience in response to hyperexcitable challenges. Together, these findings establish PRRT2 as a physiological modulator of Nav channel slow inactivation and reveal a mechanism that supports cortical resilience to pathological perturbations.

How experience shapes individuality

bassem.hassan@icm-institute.org (Bassem A Hassan) — Fri, 11 Sep 2026 00:00:00 +0000

Behavioural diversity across fruit flies changes with individual learning, even when genetic, past and momentary environmental factors are held constant.

Intersecting experimental evolution and CRISPR screens to identify novel toxin resistance loci

Richard.Benton@unil.ch (Camilla Roselli) — Fri, 11 Sep 2026 00:00:00 +0000

Understanding toxin resistance in insects is key to appreciating niche adaptations but remains challenging due to its often-polygenic basis. A well-known example is the specialized association of Drosophila sechellia with noni fruit (Morinda citrifolia), which is toxic to other insects, including Drosophila simulans and Drosophila melanogaster. The main noni toxin is octanoic acid (OA), but the mechanisms that determine sensitivity or resistance to OA in different species remain unclear. Here, we experimentally evolved D. simulans with increased OA resistance, identifying multiple loci under selection. Cross-referencing these with a genome-wide, OA resistance CRISPR screen in a D. melanogaster cell line highlighted two proteins: Kraken, a putative detoxification enzyme expressed in digestive and renal tissues, and Alkbh7, a mitochondrial protein linked to fatty acid metabolism. Both genes show elevated expression in D. sechellia and OA-resistant D. simulans. In D. melanogaster, kraken mutants are more OA-sensitive, while Alkbh7 overexpression increased OA resistance. Mutation of these genes in D. sechellia reduced OA tolerance. Our identification of genes contributing to OA resistance in laboratory and natural contexts demonstrates how complementary selection approaches can provide insights into complex mechanisms of toxin susceptibility and adaptation. Such methods could have practical applications in the characterization of natural and artificial insecticides.

The genetic control of rapid genome content divergence in Arabidopsis thaliana

daniel.koenig@ucr.edu (Christopher J Fiscus) — Thu, 10 Sep 2026 00:00:00 +0000

Genome evolution in eukaryotes is predominantly driven by the dynamics of repetitive sequences, which vary widely in both copy number and sequence composition. Rates of repeat evolution differ between and within species and are likely modulated by both genetics and environment. To uncover factors shaping the rate of genome content evolution, we analyzed 1043 resequenced Arabidopsis thaliana genomes using a novel K-mer-based approach to characterize genome content variation and identify hypervariable regions underlying differences in repeat abundance. We next treated repeat abundance as a quantitative trait and performed genome-wide association analyses across more than 400 repeat families to identify the genetic basis of copy number variation. Integrating these results through a meta-GWAS approach revealed both cis-acting variants and more than 50 candidate trans-acting loci associated with repeat abundance genome-wide. Cis-acting variation was predominantly localized to pericentromeric and centromeric regions, whereas trans-acting loci were enriched for candidate genes involved in DNA replication, DNA repair, and DNA methylation regulation. The results are consistent with purifying selection acting against mutations that accelerate genome content divergence, favoring alleles that constrain repeat expansion. Together, these findings provide new insights into the genetic architecture and evolutionary forces shaping genome evolution in A. thaliana and establish a framework for investigating these processes in other plant species.

Correction: Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo

Thu, 10 Sep 2026 00:00:00 +0000

The C3–C3aR axis modulates trained immunity in alveolar macrophages

alexander.earhart@wustl.edu (Aasritha Nallapu) — Thu, 10 Sep 2026 00:00:00 +0000

Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination, and enhances inflammation. While trained immunity – enhanced secondary responses of innate immune cells after prior exposure – is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that alveolar macrophage (AM) C3 and C3aR1 expression increased in humans after an intranasal exposure to a training stimulus. In vivo, trained wild-type mice showed significantly elevated proinflammatory cytokines and increased C3a levels upon a second stimulus. Ex vivo, trained C3-deficient AMs displayed reduced chemokine and cytokine output as well as impaired phagocytosis and reactive oxygen species production compared to wild-type AMs. Real-time confocal microscopy of live, intact mouse alveoli revealed that AMs internalize C3 rapidly after alveolar microinstillation, as compared to C3a. Correspondingly, the blunted cytokine output was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs – a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling and highlight a novel role for C3 in trained immunity.

In vitro sexual dimorphism establishment in schistosomes

Matt.Berriman@glasgow.ac.uk (Benjamin J Hulme) — Thu, 10 Sep 2026 00:00:00 +0000

Schistosomes are parasitic flatworms that cause Schistosomiasis, a major neglected tropical disease that affects more than 250 million people worldwide. With two distinct sexes, a heterogametic female (ZW) and a homogametic male (ZZ), schistosomes are an exception among flatworms, which are largely hermaphroditic. Sexual dimorphism in schistosomes only becomes apparent by adulthood within the mammalian host. However, the cellular and molecular mechanisms underlying the sexual differentiation of are poorly understood, partly due to intrinsic challenges in assessing parasite development in vivo. Therefore, robust and reproducible approaches for maintaining and developing parasites in vitro are needed to overcome these difficulties. To date, few studies have focused on protocols that allow cultured parasites to reach sexual dimorphic stages, and none have been reproduced, limiting the ability to understand the sexual biology of this major human parasite. Here, we refine a protocol for long-term culture of newly transformed cercariae that developed in vitro into sexually dimorphic forms. We assessed the effect of adding two different sera, foetal bovine serium (FBS) and human serum (HS), to culture medium supplemented with red blood cells. In contrast to FBS-culture parasites, those grown in HS digested red blood cells, a crucial step for long term parasite development. Furthermore, sexual dimorphism was clearly established in the HS-cultured parasites, albeit delayed, in contrast to most FBS-cultured parasites that did not progress beyond an early liver stage. Moreover, in EdU-pulse experiments, cells within HS-cultured parasites continuously proliferated, but markedly fewer proliferated in FBS-culture. By enabling reproducible parasite develoment in vitro, this protocol creates new opportunities for dissecting mechanisms that underly sexual dimorphim, as well as for screening in vitro for new interventions across the life cycle of these major human parasites.

Nim1-related kinases regulate septin organization and cytokinesis by modulating Hof1 at the cell division site

spalani@iisc.ac.in (Anubhav Dhar) — Wed, 09 Sep 2026 00:00:00 +0000

The septin scaffold recruits and organizes actomyosin ring (AMR) components; thus, ensuring faithful cytokinesis. The septin-associated kinases – Elm1, Gin4, Hsl1, and Kcc4 are thought to stabilize and regulate the septin architecture at the bud neck, but the underlying mechanisms remain largely unknown. Here, we present a comprehensive, quantitative analysis of these four septin-associated kinases and reveal major roles for Elm1 and Gin4 in septin stability and architectural transitions during the cell cycle. We find that Elm1 and Gin4 play a previously overlooked role in AMR organization and constriction during cytokinesis. We report that the Gin4 kinase interacts directly with the AMR component and F-BAR protein Hof1 via its C-terminal membrane-binding kinase associated-1 (KA1) domain, and is likely involved in the proper organization and anchoring of Hof1 at the bud neck, representing an unappreciated mode of regulation during cytokinesis. We further show that Gin4 controls septin organization and AMR constriction in a kinase-independent manner, similar to Elm1. Using an extensive GFP-GBP-based tethering assay in elm1Δ and gin4Δ cells, we identify an important role for Hsl1 in maintaining septin organization and cell shape in coordination with Elm1, Gin4, and Kcc4, independent of its role in the morphogenetic checkpoint. Furthermore, our data indicate that Hsl1 acts downstream of Elm1, with its membrane-binding KA1 domain being critical for its function. Together, these findings reveal new insights into the modes by which the kinases Gin4 and Elm1 regulate cytokinesis, highlight a redundant role for Hsl1 in controlling septin organization and cytokinesis, and uncover the inherent redundancy and adaptability of the septin kinase network in Saccharomyces cerevisiae.

Serum, cell-free, HPV-human DNA junction detection and HPV typing for predicting and monitoring cervical cancer recurrence

aarsdale@montefiore.org (Anne R Van Arsdale) — Wed, 09 Sep 2026 00:00:00 +0000

Almost all cervical cancers are caused by human papillomaviruses (HPVs). In most cases, HPV DNA is integrated into the human genome. We found that tumor-specific, HPV-human DNA junctions are detectable in serum cell-free DNA of a fraction of cervical cancer patients at the time of initial treatment and/or at 6 months following treatment. Retrospective analysis revealed these junctions were more frequently detectable in women in whom the cancer later recurred. We also found that cervical cancers caused by HPV types outside of phylogenetic clade α9 had a higher recurrence frequency than those caused by α9 types in both our study and The Cancer Genome Atlas cervical cancer database, despite the higher prevalence ofα9 types, including HPV16, in cervical cancer. Thus, HPV-human DNA junction detection in serum cell-free DNA and HPV type determination in tumor tissue may help predict recurrence risk. Screening serum cell-free DNA for junctions may also offer an unambiguous non-invasive means to monitor absence of recurrence following treatment.

Cellular modifiers of TDP-43 phase transition and cytoplasmic aggregation

yihongye@gmail.com (Jizhong Zou) — Tue, 08 Sep 2026 00:00:00 +0000

RNA-binding protein TAR DNA-binding protein 43 (TDP-43) can form liquid-like nuclear assemblies whose phase behavior is thought to influence its aggregation propensity and neurotoxic activity. The mechanisms that govern the liquid-to-solid phase transition of TDP-43 remain poorly defined. Here, we combined chemical and genome-wide genetic screens to identify cellular factors that modulate the phase behavior of an RNA-binding-defective TDP-43 mutant. Our screens uncovered multiple cellular processes, including RNA splicing, protein translation, proteostasis imbalance, and nuclear export as TDP-43 phase regulators. We also developed a semi-permeabilized cell system that partially recapitulates the TDP-43 phase transition in vitro, and showed that nuclear export inhibition reshapes the nuclear environment to favor RNA-dependent liquid-liquid phase separation (LLPS) of TDP-43, which mitigates its aggregation. Nuclear export inhibition in a brain organoid model bearing an ALS-associated mutation reduces pathogenic phospho-TDP-43 accumulation. These findings identify multiple modulators of TDP-43 phase transitions in a sensitized model system and establish a framework for further dissecting the link between nuclear transport and TDP-43 phase dynamics.

Slap restricts oncogenic Src-family kinase signaling to maintain colonic epithelial homeostasis

audrey.sirvent@crbm.cnrs.fr (Audrey Sirvent) — Tue, 08 Sep 2026 00:00:00 +0000

Src-family kinases (SFKs) regulate proliferation in colonic epithelial cells (CECs), but the mechanisms that restrain their activity remain poorly defined. We identify Src-like adaptor protein (SLAP), a negative regulator of receptor tyrosine kinase signaling, as a key suppressor of SFK activity in the colon. Constitutive and inducible epithelial-specific Slap deletion using a villin-CreERT2 model increases CEC proliferation and accelerates tumorigenesis in the azoxymethane/dextran sodium sulfate model. Slap deficiency also enhances SFK-dependent expansion of normal and tumor-derived colonic organoids. Mechanistically, we identify the receptor tyrosine kinase EPHB2 as a critical upstream activator of SFKs and a direct target of SLAP-mediated regulation. Loss of Slap increased EphB2 protein abundance and tyrosine phosphorylation, and enhanced its association with active SRC. Pharmacological inhibition of EPHB2 suppressed SRC activation and reversed the hyperproliferative phenotype induced by Slap deficiency. Together, these findings uncover a non-genetic mechanism driving SFK activation during colonic transformation and establish SLAP as a tumor suppressor that constrains oncogenic EPHB2–SFK signaling in the colonic epithelium.

Small mammalian herbivores at moderate densities facilitate livestock growth by improving vegetation composition in grasslands

gaoy823@nenu.edu.cn (Bingbo Ni) — Tue, 08 Sep 2026 00:00:00 +0000

Small mammals and large herbivores have co-evolved in grasslands for millions of years, yet how they interact remains unclear. Although large herbivores can significantly affect the smaller ones, the reverse effect is largely unknown. On the Qinghai–Tibetan Plateau, plateau pikas (Ochotona curzoniae) are often considered pests that compete with livestock at high densities. Using field experiments, we show that the presence of pikas facilitates weight gains of yaks (Bos grunniens) by improving vegetation composition at a moderate density level. Compared to the pika-present treatment, pika removal dramatically increased cover of the poisonous Stellera forbs by twofold, reducing the abundance and protein content of palatable grasses and sedges, yak foraging efficiency, and yak weight gain by up to 42%. Notably, we found a humped relationship between yak weight gains and pika burrow densities in the pika-present plots; the facilitative effect of pikas on yaks was highest at about 200 burrows/ha, but shifted to a competitive effect at pika densities exceeding 400 burrows/ha. These results provide the first empirical evidence that maintaining a moderate density of small mammalian herbivores can benefit growth performance of livestock by improving vegetation composition. Our study highlights the significance of moderate populations of ecosystem-engineering small mammals in sustaining pastoral productivity in rangelands.

Primordial cardiomyocytes orchestrate myocardial morphogenesis and vascularization but are dispensable for regeneration

jisheng_sun@fudan.edu.cn (Jinhu Wang) — Tue, 08 Sep 2026 00:00:00 +0000

The vertebrate heart is composed of heterogeneous cardiomyocyte (CM) populations; however, the roles of distinct CM subpopulations in heart development and repair remain poorly defined. Here, using single-cell RNA sequencing analysis of adult zebrafish heart, we identified a unique CM subpopulation marked by the expression of phlda2, which is associated with anaerobic metabolism and different from mature CMs, which are enriched for oxidative phosphorylation genes. We demonstrated that phlda2⁺ cells constituted a primordial CM compartment localized between compact and trabecular muscles. Genetic ablation of phlda2⁺ CMs during development severely disrupted heart morphogenesis, leading to defective myocardial trabeculation and compaction, and impaired coronary vascularization. Surprisingly, despite their essential roles in development, the depletion of phlda2⁺ CMs didn’t impair myocardial restoration and revascularization following ventricular resection. We found that this was probably due to the limited regenerative capacity of the primordial CMs themselves, as they failed to regenerate after either surgical amputation or genetic ablation. Our findings identify primordial CMs as an organizer for heart morphogenesis but not essential for regeneration, revealing a fundamental difference between developmental and regenerative programs in the vertebrate heart.

A simplified and highly efficient cell-free protein synthesis system for prokaryotes

zhezhang@sdu.edu.cn (Changbin Zhang) — Tue, 08 Sep 2026 00:00:00 +0000

Cell-free protein synthesis (CFPS) systems are a powerful platform with immense potential in fundamental research, biotechnology, and synthetic biology. Conventional prokaryotic CFPS systems, particularly those derived from Escherichia coli, often rely on complex reaction buffers containing up to 35 components, limiting their widespread adoption and systematic optimization. Here, we present an optimized E. coli cell-free protein synthesis (eCFPS) system, which is significantly streamlined for high efficiency. Through systematic screening, we successfully reduced the essential core reaction components from 35 to a core set of 7. The thorough optimization of these seven key components ensured that protein expression levels were not only maintained but even substantially improved. Furthermore, we developed a much simpler procedure for preparing the bacterial cytosolic extracts, a ‘fast lysate’ protocol that eliminates the traditional time-consuming runoff and dialysis steps, thereby enhancing the overall accessibility and robustness of eCFPS. This optimized and user-friendly eCFPS efficiently synthesizes challenging proteins, including functional, self-assembling vimentin, and active restriction endonuclease BsaI despite its strong cytotoxicity, and serves as a powerful tool that will facilitate diverse applications in basic life science research and beyond.

Centrosome migration and apical membrane formation during epithelial polarization in MDCK cysts

kenghui@gate.sinica.edu.tw (Keng-Hui Lin) — Tue, 08 Sep 2026 00:00:00 +0000

Polarization is crucial for the proper functioning of epithelial cells. Early hallmarks include the trafficking and enrichment of polarity molecules to form the apical membrane (AM) or cell–cell junctions, and the apical positioning of the centrosome. However, the dependencies among polarity molecules, AM formation, and centrosome positioning remain poorly understood. When cultured in Matrigel, de novo polarization of a single epithelial cell is often coupled with cytokinesis. During mitotic exit, centrosomes move to the future AM site, raising questions about their role in polarization. We perturbed centrosomes and polarity regulators in Matrigel-cultured cells and manipulated polarity direction using suspension culture to examine the relationships among polarization features. Surprisingly, centrosomal microtubules may not be necessary for centrosome positioning or AM formation, but their absence reduces the efficiency of AM formation. The polarity regulator Par3, rather than AM component trafficking, influences centrosome positioning. In suspension culture, centrosomes migrate in the direction opposite to AM formation. Taken together, our findings define the hierarchical relationships among several polarization features and show that centrosome-based polarity is not universal in epithelial cells, providing new insights into the mechanisms of epithelial polarization.

BetaII-spectrin gaps and patches emerge from the patterned assembly of the actin/spectrin membrane skeleton in human motor neuron axons

thomas.durcan@mcgill.ca (Agustín Anastasía) — Tue, 08 Sep 2026 00:00:00 +0000

The actin/spectrin membrane-associated periodic skeleton (MPS) is a cytoskeletal structure that supports axonal integrity and function. Lower spinal motor neurons (MNs) are characterized by exceptionally long axons and are particularly susceptible to degeneration in a wide range of hereditary neuromuscular disorders, including amyotrophic lateral sclerosis. Using confocal and super-resolution imaging, we characterized the spatial distribution of βII-spectrin and the assembly pattern of the MPS in human MN axons derived from induced pluripotent stem cells. We discovered a striking gap-and-patch pattern in the medial axon, where sharply demarcated βII-spectrin gaps alternate with patches containing a well-organized MPS. The pattern is acutely induced by the kinase inhibitor staurosporine and pharmacological inhibition of actin polymerization prevents patch formation, indicating a requirement for actin nucleation in MPS assembly. Our data supports a model in which spectrin incorporation into nascent MPS patches depletes neighboring regions, producing long-range gaps-and-patches patterns.

Cortical layer 6b mediates state-dependent changes in brain activity and effects of orexin on waking and sleep

vladyslav.vyazovskiy@dpag.ox.ac.uk (Anna Hoerder-Suabedissen) — Tue, 08 Sep 2026 00:00:00 +0000

One of the most distinctive features of the mammalian cerebral cortex is its laminar structure. Of all cortical layers, layer 6b (L6b) is by far the least studied, despite exhibiting direct sensitivity to orexin and having widespread connectivity, suggesting an important role in regulating cortical oscillations and brain state. We performed chronic electroencephalogram (EEG) recordings in mice in which a subset of L6b neurons was conditionally ‘silenced’, during undisturbed conditions, after sleep deprivation (SD), and after intracerebroventricular (ICV) administration of orexin. While the total amount of waking and sleep or the response to SD were not altered, L6b-silenced mice showed a slowing of theta frequency (6–9 Hz) during wake and rapid eye movement (REM) sleep, and a marked reduction of total EEG power, especially in non-rapid eye movement (NREM) sleep. The infusion of orexin A increased wakefulness in both genotypes, but subsequent levels of EEG slow-wave activity during NREM sleep were lower in L6b-silenced animals in the occipital derivation. In summary, these results demonstrate a role for cortical L6b in state-dependent brain oscillations and in the response to orexinergic neurotransmission. Our findings provide new insights in functions of L6b neurons and could inform the understanding of abnormal regulation of brain states in neurodevelopmental and psychiatric disorders.

REM sleep prefrontal high-frequency oscillation chains mediate distinct cortical – hippocampal reactivation patterns compared to NREM sleep

shantanu@brandeis.edu (Justin D Shin) — Mon, 07 Sep 2026 00:00:00 +0000

REM (rapid eye movement) and non-REM (NREM) sleep stages contribute to systems memory consolidation in hippocampal–cortical circuits. However, the physiological mechanisms underlying REM memory processes remain relatively unclear compared to NREM memory reactivation. Here we report, in rodents, the existence of prefrontal cortical (PFC) high-frequency oscillation (HFO) chains in REM sleep during the consolidation of recently acquired spatial memory. High-density tetrode recordings in hippocampal area CA1 and PFC reveal that REM cortical HFOs occur in characteristic chains that are phase-modulated by theta oscillations, corresponding to increased CA1-PFC theta coherence and delineating periods of enhanced hippocampal–cortical communication. REM HFO chains sequentially organize sparse PFC ensemble reactivation of behavioral activity during periods of local suppression, distinct from widespread reactivation bursts during NREM ripple oscillations. REM HFO chains also preferentially engage CA1 neuronal populations that demonstrate a shift in their preferred theta-phase from behavior to REM sleep. CA1 neuronal activation during REM HFO chains was correlated with CA1 activity suppression during NREM PFC ripples, and linked to differential changes in CA1 firing rates in sleep, suggesting REM-driven regulation of hippocampal excitability. A cortical network model incorporating the effects of acetylcholine can reproduce the distinct REM and NREM activity patterns, providing a mechanistic basis for widespread coactivity during NREM cortical ripples, compared to sparse, temporally extended reactivation on a background of local suppression during REM HFO chains. Overall, these findings establish a role for PFC HFOs in regulating distinct dual sleep stage reactivation patterns.

Preserved cerebellar functions despite structural degeneration in older adults

jj.orban@kuleuven.be (Anda de Witte) — Mon, 07 Sep 2026 00:00:00 +0000

Aging is frequently perceived negatively due to its association with declines in brain and motor function yet not all aspects of brain function are equally affected. The cerebellum, a brain region closely linked to motor control, undergoes clear structural changes with age, but the impact of this degeneration on cerebellar function remains debated. The present study thoroughly investigates the impact of age on cerebellar function by measuring cerebellar motor and cognitive performance across the lifespan in 50 young adults (20–35 years), 80 older adults (55–70 years), and 30 older-old adults (over 80 years). Participants completed a test battery comprising seven motor control tasks and one cognitive task each designed to probe both cerebellar-specific and general sensorimotor function. Our results revealed that, despite age-related changes in cerebellar structure, cerebellar-specific functions remained intact in older adults compared to young adults, even among those above 80 years old. In contrast, general sensorimotor measures showed a clear pattern of decline with age. Together, these findings indicate that cerebellar function is largely preserved despite pronounced structural degeneration, providing compelling evidence for the cerebellum’s remarkable functional resilience.

Stage-specific threats reveal the inadequacy of adult-centered conservation

doublelqq@163.com (Qing-Qing Li) — Mon, 07 Sep 2026 00:00:00 +0000

In an era of severe global biodiversity threats, understanding the link between species’ traits and their endangerment helps uncover causes of risk and infer threats to understudied species. Most animals have complex life cycles with distinct stages that may face stage-specific threats. Current conservation frameworks rely heavily on adult traits, potentially misjudging extinction risk. Using Chinese anurans as a model, we integrated functional traits from both adult and tadpole stages to examine their association with extinction risk. We found that body size positively correlates with risk in both stages. Microhabitat use is related to extinction risk in tadpoles, but shows no significant link in adults. Adult relative tympanum diameter and head length also correlate with extinction risk. These results indicate that species vulnerability is correlated with multi-stage traits, with both shared and stage-specific threats. Conservation based solely on adult traits may fail to accurately assess species threats. We call for integrating a whole-life-history perspective into biodiversity assessment and conservation to more effectively address the global biodiversity crisis.

Trpv4 links environmental temperature to testicular differentiation in hermaphroditic ricefield eel

sunyh@ihb.ac.cn (Tingting Luo) — Mon, 07 Sep 2026 00:00:00 +0000

The ricefield eel (Monopterus albus), an economically important aquaculture species in China, is a freshwater teleost fish that exhibits protogynous hermaphroditism. Although progress has been made in understanding the sex determination and differentiation of this species, the underlying mechanisms remain unclear. Here, we show that warm temperature promotes gonadal transformation by up-regulating testicular differentiation genes, such as dmrt1/sox9a in ovaries. Trpv4, a Ca²⁺-permeable cation channel expressed in gonadal somatic cells, is highly sensitive to ambient temperature and links environmental temperature to testicular differentiation in ricefield eel. In female fish reared at cool temperature, injection of Trpv4 agonist into the ovaries leads to a significant upregulation of male pathway genes and in female fish exposed to warm temperature, Trpv4 inhibition or trpv4 siRNA knockdown suppresses warm temperature-induced male gene expression. pStat3 signaling is downstream of Trpv4 and transduces Trpv4-controlled calcium signaling into the sex determination cascades. Inhibition of pStat3 activity prevents the up-regulation of testicular differentiation genes by warm temperature treatment and ovarian injection of Trpv4 agonist, whereas activation of pStat3 is sufficient to induce the expression of male genes in the presence of Trpv4 antagonist. pStat3 binds and activates jmjd3/kdm6b, an activator of the dmrt1 gene. Consistently, ovarian injection of Kdm6b inhibitor blocks the up-regulation of testicular differentiation genes by warm temperature exposure. We propose that environmental factors, such as temperature, promote gonadal transformation of ricefield eel by inducing the expression of male pathway genes in ovaries via the Trpv4-pStat3-Kdm6b-dmrt1 axis. Our results provide new insights into the molecular mechanism underlying natural sex change of ricefield eel, which will be useful for sex control in aquaculture.

Ribosomal RNA methylation by GidB modulates discrimination of mischarged tRNA

jfraser@fraserlab.com (Babak Javid) — Fri, 04 Sep 2026 00:00:00 +0000

Despite redundant cellular pathways to minimize translational errors, errors in protein synthesis are common. Pathways and mechanisms to minimize errors are classified as pre-ribosomal or ribosomal. Pre-ribosomal pathways are primarily concerned with the appropriate charging of tRNAs with their cognate amino acids. By contrast, the ribosomal decoding center is considered ‘blind’ to mischarged tRNAs since these have cognate codon•anti-codon pairing. Here, we identified that in mycobacteria, deletion of the 16S ribosomal RNA methyltransferase gidB led to increased ribosomal discrimination of mischarged tRNAs. Discrimination only occurred in mycobacteria enriched from environments or genetic backgrounds with high rates of mistranslation. GidB deletion was necessary, but not sufficient for reducing mistranslation due to misacylation. Analysis of new cryo-EM structures of the M. smegmatis ribosomes derived from wild-type and gidB-deleted strains point to the interaction between the base methylated by GidB on the 16S RNA and an asparagine on the ribosomal S12 protein that, when mistranslated to aspartate, may be involved in altering translational fidelity. Our data suggest a mechanism by which mycobacterial ribosomes can discriminate mischarged tRNAs and that 16S rRNA differential methylation by GidB may act to prevent catastrophic translational error.

Low-frequency tibial neuromodulation excites bladder activity in humans

a.mcconnell-trevillion@ed.ac.uk (Abbas Erfanian) — Fri, 04 Sep 2026 00:00:00 +0000

Despite widespread clinical adoption for disorders of incontinence such as overactive bladder, there remain unknowns surrounding the mechanism that underpins tibial nerve stimulation (TNS). Current understanding suggests that TNS counteracts incontinence by the inhibition of brainstem and spinal cord activity. How this inhibition alters bladder function is not fully understood. We hypothesize that the supraspinal components of the system act as a high-pass filter, allowing voiding signals to proceed only when bladder filling reaches a critical level. Testing this hypothesis may explain how TNS is able to induce both an inhibitory and a little-explored excitatory effect on bladder activity in response to high-frequency (20 Hz) and low-frequency (1 Hz) stimulation, respectively. We performed a single-blinded trial in healthy human participants administered high- and low-frequency transcutaneous TNS. We also developed a computational model of the lower-urinary tract and control circuit to study the frequency-dependent effects of TNS. For the first time, we report a frequency-dependent effect of TNS via the ability to alter urge perception and upregulate and downregulate bladder activity, corroborating model predictions. These results provide a foundation for the development of targeted and effective TNS therapies, benefiting from in silico models. We hope that future clinical research will determine the efficacy of low-frequency TNS as a non-invasive treatment option for urinary retention.

Soil extracellular DNA fragments show variable degradation rates among sequences and environmental conditions

cherongxiao@ynu.edu.cn (Dong Liu) — Fri, 04 Sep 2026 00:00:00 +0000

While extracellular DNA (eDNA) persistence substantially influences soil microbiome investigations, its degradation kinetics remain poorly quantified. Here, we developed a primer-labeled DNA approach coupled with microcosm incubation to determine the overall and sequence-specific degradation rates of eDNA amplicon fragments across China. We observed substantial variations in the overall degradation rates of extracellular 16S rRNA gene amplicon fragments among the study sites, with degradation rate constants ranging from 0.05 to 0.16 day⁻¹. The overall degradation rate constants showed significant correlations with soil moisture content, prokaryotic abundance, prokaryotic community profiles, and mean annual precipitation. The significant influences of moisture content on the overall degradation rates were further verified by a moisture gradient microcosm experiment. The sequence-specific degradation rate constant profiles were additionally correlated with pH, nitrogen content, and mean annual temperature. Furthermore, propidium monoazide-based exclusion of eDNA signals significantly altered soil prokaryotic abundance, richness, and prokaryotic community profiles, and the pool sizes of sequence-specific extracellular 16S rRNA gene amplicon fragments were significantly correlated with their respective degradation rates. This study developed a methodology for determining the overall and sequence-specific degradation rates of eDNA amplicon fragments, highlighting the profound influences of eDNA on soil microbial research and informing the optimization of environmental DNA technologies.

Polo-like kinase phosphorylation of the orphan kinesin KIN-G negatively regulates centrin arm biogenesis in Trypanosoma brucei

Ziyin.Li@uth.tmc.edu (Huiqing Hu) — Fri, 04 Sep 2026 00:00:00 +0000

The unicellular parasite Trypanosoma brucei assembles a motile flagellum that is required for locomotion, cell division plane placement, and cell-cell communication. Inheritance of the flagellum during the cell cycle relies on the faithful duplication/segregation of multiple flagellum-associated cytoskeletal structures, including a centrin-marked, bar-shaped structure termed centrin arm, which also determines the site for Golgi assembly. Biogenesis of the centrin arm requires the Polo-like kinase homolog TbPLK and the orphan kinesin KIN-G, but the mechanistic role of TbPLK in centrin arm biogenesis remains elusive. Here, we report that TbPLK phosphorylates KIN-G, disrupts its microtubule-binding activity, and negatively regulates its function. TbPLK phosphorylates KIN-G in vitro at multiple residues, two of which are in vivo TbPLK phosphosites, including the Thr301 residue within one of the microtubule-binding motifs of the kinesin motor domain. Phosphorylation of Thr301 by TbPLK inhibits the microtubule-binding activity of KIN-G in vitro, and expression of a Thr301 phospho-mimic mutant in T. brucei disrupts centrin arm integrity, Golgi duplication, flagellum attachment zone elongation, flagellum positioning, and cell division plane placement. In wild-type T. brucei cells, Thr301 phosphorylation occurs on a small portion of the KIN-G population, suggesting that KIN-G undergoes phosphorylation/dephosphorylation cycles to regulate its activity. Together, these findings uncover a negative role of TbPLK-mediated phosphorylation of KIN-G in regulating centrin arm biogenesis in trypanosomes.

Realistic coupling enables flexible macroscopic traveling waves in the mouse cortex

forger@umich.edu (Daniel B Forger) — Fri, 04 Sep 2026 00:00:00 +0000

Traveling waves are ubiquitous in neuronal systems across different spatial scales. While microscopic and mesoscopic waves are relatively well studied, the emergence of macroscopic traveling waves remains less understood. Here, by modeling the mouse cortex using spatial transcriptomic and connectivity data, we show that realistic cortical connectivity can generate a significantly higher level of macroscopic traveling waves than artificial local and uniform connectivity across multiple oscillation frequency bands, with the strongest advantage appearing in the theta, alpha, and beta frequency bands. By probing the model in different dynamic regimes, we find that macroscopic wave activity depends on both network connectivity and excitatory coupling strength, with a non-monotonic dependence on coupling. Together, our work shows how flexible macroscopic traveling waves can emerge in the mouse cortex and offers a computational framework to further study traveling waves in the mouse brain at the single-cell level.