eLife: latest articles

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

+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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.