eLife: latest articles

Simple methods to acutely measure multiple timing metrics among the sexual repertoire of male Drosophila

wkim@hit.edu.cn (Dongyu Sun) — Fri, 06 Nov 2026 00:00:00 +0000

Male Drosophila courtship behavior is a key model for studying temporal decision-making. While courtship index (CI) is widely used to quantify mating activity, other timing metrics like courtship latency, copulation latency (CL), and mating duration (MD) remain understudied. Traditional methods for quantifying these behaviors are often labor-intensive and prone to human error. In this study, we present a protocol combining a modular chamber system and automated software (DrosoMating) to quantify six key timing metrics during male courtship. Our image-based video analysis enables precise identification of courtship and copulation events, as well as quantification of their timing and duration under controlled conditions. Validation shows <0.05% error rates and 98–99% agreement with manual scoring for CL, CI, and MD. The protocol supports genetic and neural circuit manipulations, detecting subtle genetic, social, and environmental behavioral variations. By minimizing manual effort and standardizing data collection, this approach facilitates scalable, reproducible studies on adaptive trade-offs, learning, and neural mechanisms in mating behavior. This method streamlines timing analysis in male courtship, offering reproducible metrics for behavioral genetics.

Spatial confinement induces oscillatory migration of epidermal keratinocytes and forms a three-compartment epithelial structure with epithelial–mesenchymal transition dynamics

h-ujiie@med.hokudai.ac.jp (Hideki Nakamura) — Fri, 06 Nov 2026 00:00:00 +0000

Epithelial cells undergo epithelial–mesenchymal transition (EMT) during migration and regain their epithelial phenotype in the post-migration phase (mesenchymal–epithelial transition [MET]). We established an experimental system that reproduces a three-compartment epithelial structure comprising the original epithelium, its EMT state, and its MET state. Keratinocytes (KCs), skin epithelial cells, placed on a microporous membrane, migrated through 3.0 µm or larger micropores. The 3.0-µm-pored membrane induced an epithelial structure with three distinct states: stratified KCs above the membrane, KCs showing EMT within the micropores, and a new stratified epithelium under the membrane. The membrane with larger micropores failed to maintain the three-compartment epithelial structure. Live imaging revealed that KCs moved in an oscillatory manner, with actin-rich filopodia-like structures extending into and out of the 3.0 µm micropores, while the cells migrated unidirectionally into larger micropores. Piezo1 and keratin 6 were identified as negative modulators of KC entry into and exit from the 3.0 µm micropores. These results demonstrate that non-cancerous epithelial cells migrate through confined spaces in an oscillatory manner, which might contribute to the formation of a three-compartment epithelial structure that recapitulates key aspects of wound healing.

The hypoxic response extends lifespan through a bioaminergic and peptidergic neural circuit

leiser@med.umich.edu (Cassie Tian) — Fri, 06 Nov 2026 00:00:00 +0000

A coordinated response to stress is crucial for promoting the short- and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in Caenorhabditis elegans. However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity. Here, we interrogate the cell-nonautonomous signaling pathway downstream of genetic activation of the hypoxic response. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit. Together, these insights demonstrate a circuit for how genetic induction of the hypoxic response cell-nonautonomously modifies aging and suggests valuable targets for modulating aging in mammals.

The resource elasticity of control

levi.solomyak@mail.huji.ac.il (Aviv Emanuel) — Fri, 06 Nov 2026 00:00:00 +0000

The ability to determine how much the environment can be controlled through our actions has long been viewed as fundamental to adaptive behavior. While traditional accounts treat controllability as a fixed property of the environment, we argue that real-world controllability often depends on the effort, time, and money we are able and willing to invest. In such cases, controllability can be said to be elastic to invested resources. Here, we propose that inferring this elasticity is essential for efficient resource allocation, and thus, elasticity misestimations result in maladaptive behavior. To test this hypothesis, we developed a novel treasure hunt game where participants encountered environments with varying degrees of controllability and elasticity. Across two pre-registered studies (N=514), we first demonstrate that people infer elasticity and adapt their resource allocation accordingly. We then present a computational model that explains how people make this inference and identify individual elasticity biases that lead to suboptimal resource allocation. Finally, we show that overestimation of elasticity is associated with elevated psychopathology involving an impaired sense of control. These findings establish the elasticity of control as a distinct cognitive construct guiding adaptive behavior and a computational marker for control-related maladaptive behavior.

Large inversions in Lake Malawi cichlids are associated with habitat, lineage, and sex determination

todd.streelman@biology.gatech.edu (Jeffrey Todd Streelman) — Fri, 06 Nov 2026 00:00:00 +0000

Chromosomal inversions are an important class of genetic variation that link multiple alleles together into a single inherited block that can have important effects on fitness. To study the role of large inversions in the massive evolutionary radiation of Lake Malawi cichlids, we used long-read technologies to identify four single and two tandem inversions that span half of each respective chromosome, and which together encompass over 10% of the genome. Each inversion is fixed in one of the two states within the seven major ecogroups, suggesting they played a role in the separation of the major lake lineages into specific lake habitats. One exception is within the benthic sub-radiation, where both inverted and non-inverted alleles continue to segregate within the group. The evolutionary histories of three of the six inversions suggest they transferred from the pelagic Diplotaxodon group into benthic ancestors at the time the benthic sub-radiation was seeded. The remaining three inversions are found in a subset of benthic species living in deep waters. We show that some of these inversions are linked to XY sex-determination systems but are also likely limited to a subset of total lake species. Our work suggests that inversions have been under both sexual and natural selection in Lake Malawi cichlids and that they will be important to understanding how this adaptive radiation evolved.

Expectation-driven gain modulation of preparatory spatial attention

dirkvanmoorselaar@gmail.com (Dirk van Moorselaar) — Fri, 06 Nov 2026 00:00:00 +0000

The visual system can flexibly adjust attentional deployment to match task demands, but whether observers can proactively modulate the spatial scope of attention based on expectations about upcoming search difficulty remains unclear. According to the zoom lens model, attention can narrow or broaden its spatial extent, with narrower focus enhancing processing efficiency, a mechanism that would benefit target discrimination in crowded displays. We tested whether observers adjust attentional scope when expecting sparse versus dense search arrays by combining spatial cueing with block-wise manipulations of display density expectations. Participants performed a visual search task in which endogenous cues predicted target location, while blocks predominantly contained either sparse (1 target, 3 distractors) or dense (1 target, 7 distractors) displays. We applied inverted encoding models to broadband EEG data to reconstruct spatial channel tuning functions, enabling precise characterization of both the locus and breadth of attentional deployment. Behaviorally, expecting difficult searches selectively improved accuracy at cued locations without costs elsewhere. Consistent with this selective benefit, neural measurements revealed that expectancy enhanced the amplitude of spatially selective responses at the attended location but did not alter tuning width. These findings demonstrate that expectations about search difficulty modulate attention through gain-based signal enhancement rather than adjustments to spatial scope, revealing that preparatory attentional control operates via amplitude modulation within a stable spatial focus. This mechanism complements reactive attentional adjustments and provides an efficient means for the visual system to optimize processing under predictable task demands.

Distinct neural representations of perceptual and numerical absence in the human brain

b.barnett@bbk.ac.uk (Benjy Barnett) — Thu, 05 Nov 2026 00:00:00 +0000

The ability to represent absences is fundamental to human perception and cognition. Sensitivity to non-numerical absences depends on inferring a lack of sensory evidence, enabling the recognition of a lack of environmental resources or other objects. In turn, encoding numerical absence as a concept – in the form of the number zero – has enabled a multitude of technological and mathematical advances. Whether perceptual and conceptual absences rely on overlapping or distinct neural representations in the human brain, however, remains unknown. We employed three different tasks together with magnetoencephalography to characterise neural representations of absence evoked within perceptual and numerical domains. Using multivariate decoding and Bayes factor analyses, we replicate previous findings of shared representations of numerical absence across symbolic and non-symbolic formats. In contrast, we show that these representations of numerical absence are distinct from those evoked by non-numerical absences. This result held even after controlling for stimulus-level confounds which generate surface-level similarities between perceptual absences and non-symbolic empty sets. Our results extend a boundary between perception and cognition to the domain of absence and provide insight into the different mechanisms employed by the human brain to both perceive and conceive of absences.

Gcn5 and mTORC1 mediated regulation of autophagy controls Drosophila blood cell homeostasis

rkhadilkar@actrec.gov.in (Arjun Aji Reeja) — Thu, 05 Nov 2026 00:00:00 +0000

Blood progenitors are regulated by a variety of systemic and nutritional cues from their environment. In the Drosophila lymph gland (LG), the Posterior Signaling Center acts as a stem cell niche striking a balance between progenitors and differentiated blood cells. Autophagy is a vital cellular process that maintains homeostasis by removing unnecessary or dysfunctional cell components through autophagic degradation and recycling. Here, using genetic perturbation analysis, we show that autophagy plays a critical role in regulating LG blood cell homeostasis. General control non-derepressible 5 (Gcn5), a histone acetyltransferase, is expressed in the primary LG lobe, and modulation of Gcn5 levels perturbs LG homeostasis. Our results show that hemocyte-specific Gcn5 modulation controls autophagic flux in the hemocytes. Furthermore, we show that modulation of mTORC1 activity can perturb hematopoiesis. Our results indicate that organismal Gcn5 levels respond to dietary shifts and are modulated by mTORC1 signaling. Chemical intervention shows that mTORC1 overrides the effect exerted by Gcn5 in regulating LG hematopoiesis. Taken together, our findings demonstrate that Gcn5 and mTORC1 regulate autophagy to maintain blood cell homeostasis in Drosophila.

Dopaminergic neurons linking threat processing to cardiac modulation and locomotor responses

mtsuji@bs.s.u-tokyo.ac.jp (Ayako Ogasawara) — Thu, 05 Nov 2026 00:00:00 +0000

Heartbeat and behavior are tightly coordinated during defensive states, yet the neuronal mechanisms linking threat processing to cardiac modulation—and the potential contribution of cardiac dynamics to behavioral output—remain poorly understood. Here, using simultaneous recordings of heartbeat and behavior in tethered Drosophila, we show that mechanical threat triggers locomotion together with rapid cardiac deceleration. We identify two pairs of dopaminergic neurons, termed DA-WED neurons, that mediate this cardiac response. Silencing these neurons markedly attenuates threat-induced cardiac deceleration, whereas optogenetic activation induces cardiac deceleration in the absence of threat. Two-photon calcium imaging further shows that DA-WED neurons are activated by mechanical threat, and manipulating their activity bidirectionally modulates threat-induced locomotion. Linking cardiac dynamics to behavior, direct optogenetic manipulation of cardiomyocytes that quantitatively reproduces threat-evoked cardiac deceleration is accompanied by increased locomotion. Together, these results identify a dopaminergic descending pathway that links threat processing to cardiac modulation and suggest that cardiac dynamics may contribute to shaping defensive behavior.

Spectraplakin is required for dendritic microtubule organization via a tip-based mechanism in Drosophila

rumpfsebastian4@gmail.com (Ines Hahn) — Thu, 05 Nov 2026 00:00:00 +0000

The differential microtubule organization in axons and dendrites underlies neuronal polarity and developmental processes, like neurite pruning. How neurons achieve their specific microtubule organization during development is an area of active research, and it has been especially hard to explain how dendritic microtubules are oriented with their plus ends toward the soma. Transient microtubule nucleation from tips of early growing dendrites has been proposed as a mechanism that would explain how this orientation is set up. In a survey for cytoskeletal regulators involved in dendrite pruning and microtubule organization in Drosophila, we found the spectraplakin Short stop (Shot), an actin/microtubule crosslinker. Loss of Shot causes microtubule orientation defects already during early dendrite development, when Shot is transiently recruited to tips of growing dendrites via its actin-binding domain. Genetic and functional evidence suggests that Shot’s primary function in this process is to locally stabilize microtubules. We also provide evidence for an independent, developmentally transient microtubule nucleation mechanism. Our data highlight the importance of transient and localized microtubule regulation for dendritic microtubule organization.

A novel mechanism for morphological change during bacterial sporulation based on programmed peptidoglycan degradation

felipe.cava@umu.se (Assariel J Garcia Avila) — Thu, 05 Nov 2026 00:00:00 +0000

Many bacteria form spores to endure unfavorable conditions. While Firmicutes generate endospores through cell division, sporulation in non-Firmicutes remains less understood. The Gram-negative bacterium Myxococcus xanthus undergoes sporulation through two distinct mechanisms: rapid sporulation triggered by chemical induction and slow sporulation driven by starvation, both occurring independently of cell division. Instead, these processes depend on the complete degradation of the peptidoglycan (PG) cell wall by two lytic transglycosylases (LTGs), LtgA and LtgB. Remarkably, LtgB programs the pace of PG degradation by LtgA during rapid sporulation, ensuring a controlled process that prevents abrupt PG breakdown and the formation of non-resistant pseudospores. In addition to regulation between LTGs, PG degradation is also influenced by its synthesis; cells exhibiting increased muropeptide production often circumvent sporulation. These findings not only reveal novel mechanisms of bacterial sporulation but also shed light on the regulatory network governing PG dynamics.

Targeting tankyrase scaffolding in the β-catenin destruction complex by PROTAC overcomes the limitation of catalytic inhibitors in colorectal cancer

Chuo.Chen@utsouthwestern.edu (Andrew Lemoff) — Wed, 04 Nov 2026 00:00:00 +0000

Aberrant WNT/β-catenin signaling drives tumorigenesis and metastasis in cancer. Although enzymatic inhibitors of tankyrase (TNKS) effectively block AXIN degradation and stabilize the β-catenin destruction complex (DC), they have demonstrated limited efficacy in various colorectal cancer (CRC) models. Here, we demonstrate that, unexpectedly, the induction of AXIN puncta represents a major barrier to achieving therapeutic efficacy. Mechanistically, catalytic inhibition of TNKS prevents TNKS turnover and drives its accumulation in the DC, wherein the scaffolding function of TNKS induces AXIN puncta formation, rigidifies the DC, and impedes β-catenin turnover. Chemically induced degradation of TNKS overcomes this limitation by stabilizing AXIN without puncta formation, providing a deeper suppression of the WNT/β-catenin pathway activity and the proliferation of CRC cells harboring dysfunctional APC mutations. Collectively, these findings provide an explanation for the unsatisfactory outcomes of drugging the WNT/β-catenin signaling pathway by TNKS inhibitors and highlight TNKS degradation as a promising approach to treat WNT/β-catenin-driven CRC.

Expression of concern: Insect metamorphosis is regulated differently between sexes by members of a microRNA cluster

Wed, 04 Nov 2026 00:00:00 +0000

Estimating bone marrow adiposity from head MRI and identifying its genetic architecture

tobias.kaufmann@med.uni-tuebingen.de (Kevin O'Connell) — Wed, 04 Nov 2026 00:00:00 +0000

Bone marrow (BM) adiposity changes radically through the lifespan, but this phenomenon is poorly characterized and understood in humans. Large datasets of magnetic resonance imaging (MRI) scans of the head have been collected to study the human brain, but also contain unexploited information about other organs. We developed an artificial neural network that localizes calvarial BM in T1-weighted MRI head scans, enabling us to study its composition in several large MRI datasets, and to model sex-dimorphic age trajectories, including the effect of menopause. We revealed high heritability in single-nucleotide polymorphism and twin data, and identified 41 genetic loci significantly associated with the trait, including six sex-specific loci. Integrating mapped genes with existing BM single-cell RNA-sequencing data revealed patterns of adipogenic lineage differentiation and lipid loading. Finally, we identified significant genetic correlations with several human traits, including cognitive ability and Parkinson’s disease, which is intriguing in light of the recently discovered channels that link calvarial BM to the meninges.

Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments

mvh@mit.edu (Anna Shevzov-Zebrun) — Wed, 04 Nov 2026 00:00:00 +0000

The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine-limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine-depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affect cancer cell proliferation.

A validated antibody toolbox for ALS research

carl.laflamme@uottawa.ca (Aled M Edwards) — Tue, 03 Nov 2026 00:00:00 +0000

A substantial fraction of amyotrophic lateral sclerosis (ALS)-associated proteins remains poorly characterized, in part because of the limited availability of validated research antibodies. We established knockout (KO)-based antibody characterization workflows and demonstrated that widely used antibodies against the major ALS-associated protein C9orf72 lacked specificity (Laflamme et al., 2019). We subsequently scaled this framework to systematically benchmark research antibodies, revealing that up to 61% fail to perform as recommended by manufacturers (Ayoubi et al., 2023b). Here, we extend this approach by establishing the ALS-Reproducible Antibody Platform (ALS-RAP), a comprehensive effort to generate a publicly available dataset of KO-validated antibodies targeting proteins encoded by ALS risk genes. In total, we characterized 303 antibodies against 33 ALS-associated proteins to identify high-quality reagents for use in western blot, immunoprecipitation, and immunofluorescence. Using these antibodies, we profiled protein levels across human induced pluripotent stem cell-derived and primary neurological cell types. These analyses revealed diverse cellular distributions and higher levels of several ALS-associated proteins in glial populations, consistent with emerging evidence for immune contributions to ALS. Together, ALS-RAP provides a validated antibody toolbox and protein expression resource to support the study of ALS-associated proteins.

Impacts of mutation accumulation and order on tumor initiation revealed by engineered murine colorectal cancer organoids

fangl@sustech.edu.cn (Daqi Deng) — Tue, 03 Nov 2026 00:00:00 +0000

Tumorigenesis typically follows a multi-hit trajectory, driven by accumulating oncogenic mutations. Colorectal cancer (CRC) has long served as a paradigmatic model of multi-hit tumorigenesis, characterized by adenoma-carcinoma transition accompanied by acquisition of specific oncogene and tumor suppressor mutations. However, how the temporal order of early mutations influences CRC initiation remains poorly understood. To address this, we established a CRC tumorigenesis model using murine intestinal organoids. By introducing defined combinations of key CRC driver mutations (Kras, Apc, and Trp53) in distinct orders, we systematically investigated how the order of mutation accumulation affects tumor initiation. Our results reveal that the mutation accumulation confers growth advantages in both in vitro and in vivo models. Strikingly, mutation order also influenced the tumorigenic properties of the organoids. Whereas organoids with Trp53 loss before or after Apc loss similarly affected organoid phenotypes in vitro or tumorigenicity in immunodeficient mice, organoids with Trp53 loss preceding Apc inactivation exhibited reduced tumor-forming potential in immunocompetent mice, likely due to their distinct immunological features. Collectively, our study reveals a critical role of ordered mutation accumulation in CRC initiation, an insight that may hold clinical relevance.

Class-wide sequence, structural, and docking-profile diversity of insect odorant receptors and structural specialization of Orco

xuchang@snnu.edu.cn (Chang Xu) — Tue, 03 Nov 2026 00:00:00 +0000

Insect olfaction is facilitated by a heterotetrameric odorant receptor–odorant receptor co-receptor (OR-Orco) complex. However, extensive sequence divergence and lineage-specific expansion have complicated large-scale comparisons of OR repertoires across insects. Here, we integrated sequence similarity, structural similarity, and molecular docking to analyze ORs from 115 insect species. OR repertoire size was associated with adult diet, larval diet, and habitat, but not with circadian rhythm. We developed a ‘trunk–branch’ network framework to classify ORs according to sequence and structural similarity and used large-scale molecular docking to derive comparative docking profiles. Despite marked differences in sequence- and structural-community composition, almost all sampled orders contained ORs assigned to all six docking-profile communities. Holometabolous insects showed higher OR sequence-community diversity than non-holometabolous insects, and docking-profile composition differed between extant lineages whose order-level origins predate or postdate the end-Permian mass extinction. Most notably, we identified a highly conserved extracellular β-sheet in Orco that restricts ligand access to the binding pocket and may contribute to its reduced capacity to bind natural odorants. The emergence of Orco represents a key evolutionary transition from homomeric receptors to heteromeric OR–Orco complexes, and our results suggest that this transition may have been accompanied by pronounced specialization of the extracellular domain and binding pocket. Together, these analyses provide a class-wide framework for comparing insect OR diversity and generate testable hypotheses for future experimental and evolutionary studies.

Spyglass is a framework for reproducible and shareable neuroscience research

Loren.Frank@ucsf.edu (Alessio Paolo Buccino) — Tue, 03 Nov 2026 00:00:00 +0000

Scientific progress depends on reliable and reproducible results. Progress can be accelerated when data are shared and re-analyzed to address new questions. Current approaches to storing and analyzing neural data involve bespoke formats and software that make replication and reuse of data difficult. To address these challenges, we created Spyglass, an open-source data management and analysis framework written in Python. Spyglass provides reproducible pipelines for common neuroscience analyses and sharing of raw data, intermediate analyses, and final results within and across labs. Spyglass uses the Neurodata Without Borders (NWB) standard and includes pipelines for spectral filtering, spike sorting, pose tracking, and neural decoding. Spyglass can be extended to apply existing and newly developed pipelines to datasets from multiple sources. We demonstrate these features in the context of a cross-laboratory replication by applying advanced state space decoding algorithms to publicly available data. New users can try out Spyglass on a Jupyter Hub hosted by HHMI and 2i2c: https://spyglass.hhmi.2i2c.cloud/.

Quantifying microbial fitness in high-throughput experiments

justus.fink@caltech.edu (Justus Wilhelm Fink) — Mon, 02 Nov 2026 00:00:00 +0000

Few concepts are as central to evolution as is fitness, and yet the quantification of fitness is often ambiguous. In particular, high-throughput experiments to measure mutant fitness in microbes are increasingly common, but vary widely in their definitions of fitness, which makes their results difficult to compare. What are the consequences of these different fitness statistics, and is there a best way to quantify fitness in a given context? Here, we systematize the set of possible fitness statistics according to the following three choices: (1) the encoding of relative abundance (e.g., transforming by a log or logit function), (2) the time scale over which to measure the change in relative abundance, and (3) the choice of a reference subpopulation for calculating relative fitness in bulk competition experiments, such as those using DNA-barcoded mutants. We show that these different choices can lead to significantly different interpretations of mutant fitness in Saccharomyces cerevisiae and Escherichia coli, affecting the magnitude of fitness effects, the apparent presence of epistasis, and even the fitness ranking across mutants. This can confound predictions for evolutionary dynamics and gene functions. Altogether, our results demonstrate the importance of consistent fitness definitions for reproducible results across experiments.

Simplifying principles underlying the highly complex peptide motif of the promiscuous chicken MHC class I molecule, BF2*21:01

susan.lea@stjude.org (Clemens Hermann) — Mon, 02 Nov 2026 00:00:00 +0000

In chickens and humans, classical class I molecules of the major histocompatibility complex (MHC) have a spectrum of correlated properties, including cell surface expression and peptide repertoire. Understanding the impact of these promiscuous generalists and fastidious specialists is of considerable interest. The promiscuous BF2 molecule from the chicken B21 haplotype, BF2*21:01, binds a wide range of peptides by remodelling the peptide-binding site, allowing co-variation of the anchor residues at peptide positions P₂ and P_c-2, and binding of an anchor residue at Pc. Using in vitro refolding assays with peptides and peptide libraries, determining thermostability and crystal structures, and analysing a chicken B21 cell line by immunopeptidomics, we found that BF2*21:01 will accommodate many possible combinations at P₂ and P_c-2, as well as several hydrophobic amino acids at P_c. However, marked preferences for particular peptide lengths, particular amino acids at the three anchor residues, and particular combinations of amino acids at P₂ and P_c-2 as well as at P₃ and P_c-3 together lead to high frequencies of major peptides while still allowing the possibility of presenting a wide peptide repertoire. These simplifying principles may eventually allow predictions of pathogen peptides with stable binding for this iconic promiscuous class I molecule, as well as providing the data for more sophisticated peptide prediction methods.

Behavioural and neurogenetic evidence for emotion primitives in the fruit fly Drosophila from an open field test

yi.wang@uni-wuerzburg.de (Christian Wegener) — Mon, 02 Nov 2026 00:00:00 +0000

Emotions are based on evolutionarily conserved building blocks (‘emotion primitives’) that are present across mammals. Whether these building blocks are found in insects is largely undefined. Here, we employ the open field test (OFT) in Drosophila and focus on wall-following and total walking activity as behavioural indicators of emotion-like states. Wildtype and transgenic flies were subjected to various conditions prior to behavioural testing. The results indicate that wall-following and total walking activity are independent measures that are modulated, with generally increased wall-following observed under aversive stimuli and decreased values under positive conditions, independent of the time of day. The effects of genetic manipulation of selected neuromodulatory systems support their role in modulating emotion-like states in Drosophila. Activation of reward-related neurons decreased wall-following while inhibition increased it. Moreover, treatment with ethanol or diazepam produced predictable changes in behaviour. Our findings suggest that Drosophila shares conserved core emotion-like building blocks with vertebrates, and show that wall-following and total walking activity in the OFT can serve as a reliable indicator of emotional valence and arousal in the fruit fly. This positions Drosophila as a powerful genetic model to dissect the neuronal and neurochemical substrates of emotion primitives.

Glycolipid MPIase is essential for the TAT (twin-arginine translocation) pathway

nishiyam@iwate-u.ac.jp (Hanako Nishikawa) — Mon, 02 Nov 2026 00:00:00 +0000

TAT (twin-arginine translocation) is a preprotein translocation system dedicated to membrane translocation of prefolded proteins in plants and bacteria. The TAT translocon, consisting of the TatABC subunits, drives translocation using proton motive force. However, there have been no reports on the successful reconstitution of the TAT system. In this report, we show that MPIase, a glycolipid that has been known to catalyze membrane protein integration, is essential for the TAT system. Our findings in recombinant Escherichia coli demonstrate that overproducing TatABC increases MPIase levels, and that depleting MPIase results in TAT precursor accumulation in the cytosol. Furthermore, co-reconstitution of MPIase with TatABC revealed the translocation activities of TAT substrates in a proton motive force-dependent manner. This is the first successful reconstitution of the TAT system and will be advantageous for understanding its mechanisms.

Knockdown of a regulatory barcode shifts macrophage polarization destination from M1 to M2 and increases pathogen burden upon S. aureus infection

nchandra@iisc.ac.in (Awantika Shah) — Mon, 02 Nov 2026 00:00:00 +0000

Macrophages are driven to form distinct functional phenotypes in response to different immunological stimuli, in a process widely referred to as macrophage polarization. Transcriptional regulators that guide macrophage polarization in response to a given trigger remain largely unknown. In this study, we interrogate the programmable landscape in macrophages to find regulatory panels that determine the precise polarization state that a macrophage is driven to. Toward this, we configure an integrative network analysis pipeline that utilizes macrophage transcriptomes in response to 28 distinct stimuli, reconstructs contextualized human gene regulatory networks, and identifies epicenters of perturbations in each case. We find that these contextualized regulatory networks form a spectrum of 13 distinct clusters, with M1 and M2 at the two ends. Using our computational pipeline, we identify combinatorial panels of epicentric regulatory factors (RFs) for each polarization state. We demonstrate that a set of three RFs, that is, CEBPB, NFE2L2, and BCL3, is sufficient to change the polarization destination from M1 to M2. siRNA knockdown of the 3-RF-set in THP1-derived M0 cells, despite exposure to an M1 stimulant, significantly attenuated the shift to M1 phenotype and instead increased the expression of M2 markers. Single knockdown of each RF also showed a similar trend. The siRNA-mediated knockdown of the 3-RF-set rendered the macrophages hyper-susceptible to Staphylococcus aureus infection, demonstrating the importance of these factors in modulating immune responses. Overall, our results provide insights into the transcriptional mechanisms underlying macrophage polarization and identify key RFs that may be targeted to modulate immune responses.

Compensation of hyperexcitability with simulation-based inference

daniel.muller@oist.jp (Daniel Müller-Komorowska) — Fri, 30 Oct 2026 00:00:00 +0000

The activity of healthy neuronal networks is tightly regulated, and a shift toward hyperexcitability can cause various problems, such as epilepsies, memory deficits, and motor disorders. Numerous cellular, synaptic, and intrinsic mechanisms of hyperexcitability and compensatory mechanisms to restore healthy activity have been proposed. However, quantifying multiple compensatory mechanisms and their dependence on specific pathophysiological mechanisms has proven challenging, even in computational models. We use simulation-based inference to quantify the interactions of putative compensatory mechanisms in a spiking neuronal network model. Various parameters of the model can compensate for the changes in other parameters to maintain baseline activity, and we estimated their compensatory potential. Furthermore, specific causes of hyperexcitability – interneuron loss, excitatory recurrent synapses, and principal cell depolarization – have distinct compensatory mechanisms that can restore normal excitability. Our results show that spiking neuronal network simulators could generate hypotheses about the mechanisms of pathophysiological network mechanisms.

SVEP1 enables efficient binding of angiopoietin-2 to the TIE1 receptor, allowing receptor phosphorylation and downstream signaling

Jorg.Stetefeld@umanitoba.ca (Dörte Schulte-Ostermann) — Fri, 30 Oct 2026 00:00:00 +0000

The molecular mechanisms that drive (lymph-)angiogenesis are crucial to understanding diseases, such as lymphedema, that are caused due to malformations of the lymphatic vasculature. Recently, an interaction between the secreted protein Svep1, a key regulator in lymphangiogenesis, and the transmembrane receptor Tie1 was shown in zebrafish, humans, and mice. Here, guided by in silico AlphaFold-multimer structure predictions of SVEP1 complexes, we assert with protein binding studies that the human CCP20 domain is the primary binding site for TIE1. We further demonstrate that SVEP1 mediates strong binding of ANG2 and TIE1, and that combined stimulation of hdLECs with SVEP1 and ANG2 leads to phosphorylation of TIE1. TIE1 activation by SVEP1 and ANG2 enables downstream signaling and, in turn, potentiates nuclear exclusion of FOXO1 and phosphorylation of AKT compared to SVEP1 or ANG2 alone. We present a model in which ANG1/2 dimers bind to both SVEP1 and TIE1, resulting in the recruitment of multiple TIE1 receptor molecules to a multimeric complex at the cell membrane, potentially amplifying its signaling capacity.

Distinct gradients of cortical architecture capture visual representations and behavior across the lifespan

zhenzonglei@bnu.edu.cn (Edan Daniel Hertz) — Fri, 30 Oct 2026 00:00:00 +0000

The microstructure of cells within the human cerebral cortex varies across the cortical ribbon, where changes in cytoarchitecture and myeloarchitecture are thought to endow each region of the cortex with its unique function. While fine-scale relative to a cell, these changes at the population level impact architectural properties of the cortex measurable in vivo by noninvasive MRI, such as the thickness and myelin content of the cortex. This raises the question of whether or not we can use these in vivo architectural measures to understand cortical organization, function, and development more broadly. Using the human visual cortex as a test bed, we demonstrated two architectural gradients, one in which cytoarchitecture and myeloarchitecture converge and another in which they diverge. These two gradients underlie the structural and functional topography of the visual cortex, even predicting the presence of new visual representations. Moreover, the two gradients show distinct visual behavior relevance and lifespan trajectory. These findings provide a more general framework for understanding the human cortex, showing that architectural gradients are a measurable fingerprint of functional organization and ontogenetic routines in the human brain.

Fitness level, but not sex, affects exercise-induced pain modulation

j.nold@uke.de (Christian Büchel) — Fri, 30 Oct 2026 00:00:00 +0000

In a previous study by our group (Nold et al., 2025), we investigated exercise-induced pain modulation after high-intensity compared to low-intensity exercise in a heterogeneous sample of diverse fitness levels. Exploratory analyses suggested an interaction of sex, fitness level, and drug treatment, indicating that males showed increasing hypoalgesia after high- compared to low-intensity exercise with increasing fitness levels, which was diminished when naloxone was administered. In contrast, these effects were not evident in females. These exploratory findings warranted further investigation to determine if and to what extent exercise-induced pain modulation depends on fitness level and/or sex. In this current study, we investigated an all-female sample (N=21) of high fitness levels using a similar paradigm as in the previous study, comparing heat and pressure pain ratings after high-intensity and low-intensity exercise. Our data show an interaction of exercise intensity and stimulus intensity in heat pain, with greater pain relief following high-intensity exercise, especially at the highest stimulus intensity. Despite results for pressure pain not reaching significance, a similar trend was evident. These results suggest that females at a high fitness level also show exercise-induced pain modulation for high-intensity compared to low-intensity exercise. Furthermore, we pooled the data of the current and previous study, providing evidence for fitness level but not sex to moderate exercise-induced pain modulation in heat pain. These findings suggest that exercise-induced pain modulation depends on fitness level but not on sex.

Glutamate receptor composition at Drosophila neuromuscular junctions depends on developmental stage and muscle identity

tuthill@uw.edu (Anne Sustar) — Fri, 30 Oct 2026 00:00:00 +0000

The neuromuscular junction (NMJ) of larval Drosophila is widely used for studying synaptic transmission. Larval body wall muscles express five ionotropic glutamate receptor (iGluR) subunits that assemble into two tetrameric complexes, with subunit composition determining the strength and plasticity of synaptic transmission. Because NMJ function has been extensively characterized in larvae, it has commonly been assumed that adult fly NMJs share this molecular composition, despite substantial differences between life stages. Here, we systematically compare glutamate receptor expression across larval and adult Drosophila muscles. We find that adult leg and flight muscles exhibit different iGluR expression than larvae, lacking expression of several receptors previously considered essential. Adjacent muscles within the adult femur express distinct iGluRs, suggesting specialization of flexor and extensor muscles. Finally, the glutamate-gated chloride channel (GluClα) is expressed extrasynaptically in adult but not larval muscle fibers. Our results reveal unexpected heterogeneity in glutamate receptor expression across muscles and developmental stages, demonstrating the need for muscle-specific analyses in flies and other animals.

Oxytocin neurons signal state-dependent transitions from rest to thermogenesis and behavioral arousal

anelso74@uwyo.edu (Adam Nelson) — Fri, 30 Oct 2026 00:00:00 +0000

Core body temperature (Tb) is defended within narrow limits through thermoregulatory behaviors like huddling, nesting, and physical activity, as well as autonomic responses like brown fat thermogenesis. While Tb displays regulated fluctuations across different behavioral states and rest/arousal cycles, the neural control of these transitions remains poorly understood. Here, we investigate the relationship between oxytocin neurons of the paraventricular hypothalamus (PVN^OT) and behavioral and autonomic thermoeffector pathways across physiological states in mice. First, we show that PVN^OT neurons are activated during social thermoregulation. We then demonstrate that in vivo PVN^OT calcium dynamics align with transitions from rest to thermogenesis and behavioral arousal. Counter to our initial hypothesis, these dynamics were observed in both social and non-social contexts. Using a computer vision model to track thermoeffector pathways, we demonstrate that precisely timed stimulation of PVN^OT neurons during low-Tb resting states increases thermogenesis followed by behavioral arousal. We therefore suggest a model in which PVN^OT neurons facilitate homeostatic state-dependent transitions in thermo-behavioral states.

Whole-brain mapping of spinal-projecting neurons in larval zebrafish

martincarbotano@proton.me (Claire Wyart) — Thu, 29 Oct 2026 00:00:00 +0000

To elicit voluntary movements and integrative reflexes underlying behavior, the brain sends command signals to the spinal cord via specialized long-range descending neurons, known as spinal-projecting neurons (SPNs). The vast and widespread distribution of SPNs, combined with their complex long-distance connectivity, poses a significant challenge for mapping their anatomical organization and associating specific populations with distinct functions. Here, we took advantage of the transparency and genetic accessibility of larval zebrafish to uncover the fundamental principles of SPN anatomical organization in a teleost. Using an optical backfilling method relying on photoactivable GFP, we generate a whole-brain map of all neurons sending axons toward the spinal cord. This approach reveals far more SPNs than previously described through conventional strategies, offering an unparalleled opportunity to revisit distinct spinal-projecting nuclei distributed across the hindbrain, midbrain, and diencephalic structures. Combining information on cell location, morphology, and projection patterns, we propose tentative homological designations for zebrafish of SPN nuclei based on established descriptions in mammals and other vertebrates.

Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling

sung.hoon.cho@emory.edu (Ariel L Raybuck) — Thu, 29 Oct 2026 00:00:00 +0000

The proliferation and development of activated B lymphocytes into antibody (Ab)-secreting plasma cells are critical determinants of humoral immunity and sustain certain autoimmune diseases. Specific pathways and substrate supplies in intermediary metabolism influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases B cell proliferation and differentiation into plasma cells, glutaminolysis – a major metabolic use of this amino acid – was only conditionally crucial in B cells and the Ab responses derived from them. Gls, the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases if either glucose uptake into mouse B cells or pyruvate into their mitochondria was also impaired. Otherwise, it was dispensable. This synthetic auxotrophy, that is, the conditional requirement of glutaminase for processes in addition to survival, involved supporting progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel decreased IL-21 stimulation of STAT3 phosphorylation as well as interferon stimulation of STAT1 activation. Together, our findings establish a powerful collaboration of metabolic pathways in programming increased respiration and the development of Ab-secreting cells, but also reveal modulation of cytokine receptor signaling by metabolism.

Lateral opening site of human oligopeptide transporter 2 plays a key role in the interaction with polymyxins

fanfan.zhou@sydney.edu.au (Fanfan Zhou) — Thu, 29 Oct 2026 00:00:00 +0000

Multidrug-resistant (MDR) Gram-negative bacteria pose a critical global health threat, while polymyxins remain a last-line therapy. However, their clinical use is limited by nephrotoxicity. Human oligopeptide transporter 2 (hPepT2) is a membrane transporter mediating the reabsorption of polymyxins in renal cells and contributes to their nephrotoxicity, but the molecular basis of their interaction remains unclear. Here, we investigated the structure-interaction relationship (SIR) of polymyxins with hPepT2 by integrating computational, chemical, and cell biology approaches. Bioinformatic modeling predicted an outward-facing hPepT2 structure and a potential transport pathway, with polymyxins interacting at the lateral opening, particularly E214, D215, D317, D342, and E622. Transporter mutagenesis and molecular analyses confirmed that D215 is critical for polymyxin binding, while other residues influence transporter turnover and/or expression. We subsequently synthesized polymyxin analogs with modifications at Dab1, Dab3, Dab5, and Dab9 of polymyxins, which reduced interactions with hPepT2. Notably, alanine substitution at Dab3 reduced nephrotoxicity in mice while retaining antibacterial activity. Overall, this proof-of-concept study demonstrates that the hPepT2-polymyxin SIR model provides a viable strategy for developing novel, safer lipopeptide antibiotics.

Lymphatic vessels under pressure

Osama.Harraz@uvm.edu (Asser F Bedair) — Thu, 29 Oct 2026 00:00:00 +0000

Lymphatic vessels beat faster as they fill with fluid through a chain of calcium signaling, though the first pressure sensor remains a mystery.

Molecular and functional analysis of calcium binding by a cancer-linked calreticulin mutant

malinir@umich.edu (Amanpreet Kaur) — Thu, 29 Oct 2026 00:00:00 +0000

Calreticulin (CRT) is an endoplasmic reticulum (ER) chaperone with low-affinity calcium-binding sites in its C-terminal domain. This region is altered by somatic mutations in the CRT gene (CALR), which drive a subset of myeloproliferative neoplasms (MPNs). Perturbations in ER calcium storage and signaling are reported for the MPN type I mutant, CRT_Del52, and are linked to disease pathogenesis. Using recombinant CRT proteins, we found similar low-affinity calcium-binding characteristics for wild-type CRT and CRT_Del52, as determined by isothermal titration calorimetry (ITC). Residues 340–349, conserved in both wild-type CRT and CRT_Del52, contribute to binding. Furthermore, ER and cytosolic calcium levels, and store-operated calcium entry (SOCE), were comparable in CRT knockout (CRT-KO) cells reconstituted with wild-type CRT or CRT_Del52. Notably, the CRT-KO induces expression of multiple ER proteins known to contain low-affinity calcium-binding sites or regulate ER calcium levels. Overall, these findings indicate that CRT_Del52 retains at least some low-affinity calcium-binding capacity and that CRT deficiency induces compensatory cellular changes that maintain ER calcium homeostasis.

Revealing the benefit of eye motion for acuity under emulated cone loss

aroorda@berkeley.edu (Austin Roorda) — Thu, 29 Oct 2026 00:00:00 +0000

Retinal degenerative diseases progressively erode the cone photoreceptor mosaic, reducing the retina’s spatial sampling power, yet visual acuity is remarkably resilient to cone loss. Prior work has shown that clinically normal visual acuity (20/25 or better) can persist despite up to 50% of cone cells being lost (Ratnam et al., 2013; Foote et al., 2018). However, studies on individuals with retinal degeneration cannot control for patients’ stage of disease progression, creating the need for an experimental paradigm that can mimic these diseases in healthy subjects. The Oz Vision system creates visual percepts through programmable, per-cell stimulation of thousands of cone cells. We reprogram this system to emulate cone loss in healthy eyes by withholding stimulation from a subset of randomly selected cones, rendering them inactive, in a method we term ‘cone dropout’. Using this approach, we characterize the visual system’s robustness to cone loss, showing that visual acuity declines nonlinearly with increasing cone dropout. Importantly, we uncover the compensatory benefit that eye motion provides under cone-deprived conditions, finding that at the highest level of dropout, a visual system with eye motion has an equivalent acuity to a static dropout condition with nearly twice as many sampling elements. Through analysis of eye motion and stimulation data, we find that this benefit arises from the additional information accumulated by ‘surviving’ cones as they sample more of the letter through fixational eye motion.

Structural insights into peptidoglycan hydrolysis by the FtsEX system in Escherichia coli during cell division

dbslmin@nus.edu.sg (David I Roper) — Wed, 28 Oct 2026 00:00:00 +0000

Bacterial cell division relies on precise peptidoglycan (PG) remodeling, a process orchestrated by the FtsEX complex. Comprised of FtsE and FtsX, this complex collaborates with EnvC, a periplasmic lytic enzyme activator, to regulate septal PG hydrolysis by amidases like AmiB. While recent structural investigations, particularly of Pseudomonas aeruginosa FtsEX (PaeFtsEX), have shed light on complex interactions and proposed activation mechanisms, the structural intricacies governing PG degradation by the FtsEX complex and EnvC in Escherichia coli cytokinesis remain unexplored. In this study, we present a comprehensive biochemical and structural analysis of E. coli FtsEX complexes, unveiling a key role for ATP in complex stabilization that extends across bacterial species. Upon EnvC binding, ATPase activity markedly increases. High-resolution structures of EcoFtsEX, both in the presence and absence of EnvC, reveal a symmetrical conformation of EcoFtsEX capable of accommodating the inherent asymmetry of EnvC, mediated by flexible loops within the periplasmic domain. Our negative-staining imaging showcases an elongated EcoFtsEX/EnvC/AmiB complex reminiscent of the PaeFtsEX system. These findings collectively provide intricate insights into the regulation of PG cleavage by FtsEX in E. coli—a pivotal model system used in pilot genetic studies, suggesting a conserved mechanism for precise hydrolase activation in bacteria.

Out-of-balance growth enables cost-free synthesis of the flagellum and other proteins in a single bacterium

cluzel@mcb.harvard.edu (Josiah C Kratz) — Wed, 28 Oct 2026 00:00:00 +0000

The cost of expressing unnecessary genes on growth has been explained at the population level through balanced growth assumptions. However, due to the high degree of stochasticity in growth and gene regulation, it remains unclear how classical growth laws derived from bulk measurements manifest at the level of individual cells. For example, flagellar gene expression, one of the most energy-intensive processes in Escherichia coli, is typically associated with reduced growth rates in bulk measurements. By contrast, we find at the single-cell level that a strikingly opposite behavior coexists: flagellar gene activity is associated with an increase in growth rate. We show that this apparent contradiction, reminiscent of Simpson’s paradox, results from examining in each cell instantaneous growth and gene expression without indiscriminately aggregating the single-cell data like in bulk measurements. We attribute this unrecognized behavior to out-of-balance growth boosts that temporarily offset the burden of flagellum production, likely driven by a surplus of growth factors inherited across cell division. Furthermore, we show that this non-intuitive relationship between growth and gene expression at the single-cell level is general, as we observe similar effects with synthetic systems driving the expression of fluorescent proteins downstream of constitutive promoters. Finally, we use a computational model to show that the inheritance of parental growth factors can explain the apparent contradiction and constitutes a general mechanism for mitigating the short-term cost of nonessential and biosynthetically demanding genes in the single cell.

Ultrasound neuromodulation hypotheses on the directionality of effects and community resource

mario-zanaty@uiowa.edu (Aaron Boes) — Wed, 28 Oct 2026 00:00:00 +0000

Low-intensity transcranial ultrasound stimulation (TUS) is a promising non-invasive technique for brain stimulation and focal neuromodulation. Research with humans and animal models has raised the possibility that TUS can be biased towards enhancing or suppressing neural function. Here, we first collate a set of hypotheses on the directionality of TUS effects and conduct an initial meta-analysis on available healthy human participant TUS studies reporting stimulation parameters and outcomes (n=47 studies, 52 experiments). In initial exploratory analyses with univariate tests, we find that parameters, such as the intensity and continuity of stimulation (duty cycle, DC) show statistical trends towards likely TUS neural enhancement or suppression of function. Machine-learning analyses were limited by the currently small sample size. Given that human TUS sample sizes are expected to increase, predictability on the directionality of TUS effects could improve if a database is available. Therefore, we establish an inTUS database and resource for the systematic reporting of TUS parameters and outcomes to assist in greater precision in TUS use for brain stimulation and neuromodulation. The paper concludes with a selective review of human clinical TUS studies illustrating how hypotheses on the directionality of TUS effects could be developed for empirical testing in the intended clinical application, not limited to the examples provided.

Plasticity associated with adoption of social roles in clown anemonefish

lvizer@bu.edu (Annabel Hughes) — Wed, 28 Oct 2026 00:00:00 +0000

Central questions of animal behavior are how individual phenotypes shape and how individual phenotypes are shaped by dominance hierarchies. Using clownfish (Amphiprion percula) as a model system, we investigated how individuals strategically modify their phenotype during hierarchy formation. We tested the overarching hypothesis that interactions among size- and age-matched rivals will lead to the emergence of social roles (dominant, subordinate, solitary), accompanied by divergence in four aspects of individual phenotypes: growth, feeding behavior, agonistic behaviors (aggression, submission), and gene expression. To test this, we created 30 replicates of juvenile clownfish, each comprising a size-matched pair housed together, and a solitary size-matched individual housed separately. Our results show that an individual’s social context shapes its growth trajectory through coordinated changes in feeding behavior, agonistic behaviors, and gene expression. Individuals emerging as dominant within pairs grew twice as much compared to those emerging as subordinates, while subordinate and solitary individuals showed comparable growth. Initially, paired individuals consumed more food per capita than solitary individuals, but this difference declined as size hierarchies became established. Agonistic behaviors also decreased over time among paired individuals as size differences emerged. Transcriptomic analyses revealed upregulation of conserved vertebrate growth pathways and ossification-related genes, and downregulation of satiety-associated genes, in dominant individuals compared to subordinates and solitaries. Here, we identify associations between changes in gene expression, growth, and feeding behavior regulation that reinforce social role differentiation during dominance hierarchy formation in clownfish. Our findings lay the foundation for a broader framework to explore the mechanisms underpinning strategic growth in social vertebrates.

Cell cycle-coupled CK1δ turnover, autoinhibition, and activity

michael.brunner@bzh.uni-heidelberg.de (Axel CR Diernfellner) — Wed, 28 Oct 2026 00:00:00 +0000

Casein kinase 1δ (CK1δ) is a ubiquitously expressed kinase involved in diverse cellular processes, including cell-cycle regulation. CK1δ activity is attenuated by (auto)phosphorylation. However, inhibitory phosphorylation is efficiently opposed by cellular phosphatases as CK1δ accumulates in its hypophosphorylated, active state. CK1δ is a target of the nuclear ubiquitin ligase APC/C-CDH1, yet the kinase is apparently stable. Thus, the physiological relevance of CK1δ (auto)phosphorylation, autoinhibition, and regulated turnover has remained unclear. Previously, we showed that CK1δ is dynamically regulated in a manner that is dependent on kinase activity, subcellular localization, and interaction with its binding partners, such as PER2 (Serrano et al., 2026). Here, we show that CK1δ activity and abundance are additionally coordinated in a cell cycle-dependent manner. During G1, assembled CK1δ kinase is stable while free active kinase is degraded. In S phase, unassembled CK1δ seems to be no longer degraded, likely to support functions in DNA damage signaling. Upon mitotic entry, the downregulation of phosphatases promotes CK1δ (auto)phosphorylation and consequent autoinhibition, thereby preserving a pool of kinase to rapidly re-establish the post-mitotic steady state.

Loose coupling between Ca²⁺ channels and release sensors as a synaptic correlate of higher-order brain function

Hartmut.Schmidt@medizin.uni-leipzig.de (Akanksha Arshia) — Wed, 28 Oct 2026 00:00:00 +0000

In the mature neocortex, functionally distinct areas are built by the same archetypes of neurons, but depending on the area, these neurons and their synapses are engaged in very different functions, ranging from lower-order processing of sensory information to higher-order associations and cognitive functions. We found significant differences in the functional presynaptic nanoarchitectures of the same types of pyramidal neuron synapses, depending on whether they are located in the prefrontal cortex (PFC) or in the primary somatosensory cortex (S1) of mice. Mature synapses in PFC operated with loose microdomain coupling, as opposed to tight nanodomain coupling in S1. These differences were associated with significant differences in synaptic timing, efficacy, and plasticity between areas. Our data suggest that the mature neocortex uses tuning of synaptic topographies to specialize seemingly identical types of neurons for their required function. They suggest that microdomain coupling in pyramidal neuron synapses could be a presynaptic structure-function correlate of higher-order neocortical functions.

A GCN1-independent activator of the kinase GCN2

sjm20@cam.ac.uk (Aldo Bader) — Tue, 27 Oct 2026 00:00:00 +0000

Mutations of EIF2AK4, which encodes the eIF2α kinase GCN2, cause a severe inherited form of pulmonary hypertension called pulmonary veno-occlusive disease (PVOD). Some pathogenic variants of GCN2 are amenable to pharmacological reactivation by low concentrations of ATP pocket-binding inhibitors. Kinase inhibition at modestly elevated concentrations limits the clinical utility of these drugs against PVOD. We therefore performed an in cellulo chemical screen for GCN2 activators and identified three structurally distinct compounds with low micromolar stimulatory activities. Unlike previously described GCN2 activators, one of these molecules activated GCN2 independently of GCN1. Modelling supported by structure activity screens suggested it binds within the ATP pocket of GCN2, but unlike existing ligands does not protrude inward into the allosteric pocket or outward into the solvent. This overcomes a key requirement of other GCN2 activators.

Tracking West Nile virus dynamics using viral loads from trapped mosquitoes

punya.alahakoon@ndm.ox.ac.uk (Ian Marchinton) — Tue, 27 Oct 2026 00:00:00 +0000

Mosquito-borne virus transmission is increasing globally. Due to a lack of effective vaccines or targeted treatments, mitigation relies on reducing human exposure to infectious mosquitoes. Entomological surveillance provides estimates of human risk by quantifying the prevalence of arboviruses in mosquito populations. Testing of pooled mosquitoes via RT-qPCR is often used to infer infection prevalence; however, these data are often binarised and ignore semi-quantitative cycle threshold (Ct values) that may provide valuable information on virus kinetics, mosquito infectiousness, and ultimately human risk. West Nile virus (WNV) is a globally distributed arbovirus and endemic to the United States. In this study, we analysed pooled Ct values from retrospective mosquito surveillance and found substantial variation that could not be explained by laboratory factors alone. To understand how underlying viral load and epidemiological dynamics might explain this variation, we developed a multi-scale model linking pooled Ct values to heterogeneous within-host viral kinetics in mosquitoes and birds and seasonal transmission dynamics. Our modelling suggests that Ct values from positive pools might reflect a mixture of potentially infectious and non-infectious mosquitoes, indicating that a substantial proportion of PCR-positive mosquitoes might not contribute to transmission. We then developed a method to estimate mosquito infection prevalence using only pooled Ct values that distinguishes infectious from non-infectious prevalence. Estimates of overall prevalence were comparable to standard methods using binarised data and remained accurate at higher prevalences where standard approaches fail. Overall, these findings demonstrate that entomological viral load data reflect biologically meaningful variation in mosquito infection status that is lost through binarisation. Accounting for heterogeneous mosquito viral kinetics can improve interpretation of surveillance data and estimates of transmission risk, with implications for arbovirus surveillance beyond WNV.

foxQ2 marks fast-acting interneurons including dopaminergic neurons of mushroom bodies and central complex in the beetle Tribolium castaneum

gbucher1@uni-goettingen.de (Bastian Klußmann-Fricke) — Tue, 27 Oct 2026 00:00:00 +0000

The brain is one of the most complex animal organs, and the development of the many different neuron types remains enigmatic. A set of brain-specific transcription factors is involved in brain patterning, but their specific contributions mostly remain to be elucidated, including foxQ2II. This transcription factor is conserved in anterior neuroectodermal patterning of most animals, while it has been lost from vertebrates. The contribution of foxQ2II-positive neurons to the adult brain has remained enigmatic. Here, we use our enhancer trap, immunostainings, and our newly established beetle brainbow system to categorize Tc-foxQ2II-positive neurons into nine clusters with different projection patterns. All clusters contain neurons with the fast-activating neurotransmitters acetylcholine and glutamate, while no Tc-foxQ2II-positive neuron is GABA-ergic or serotonin-positive. Interestingly, we found that many dopaminergic neurons were Tc-foxQ2II positive and homologize them with dopaminergic neurons of the PPL2c, PPM1, and PPL1 cluster described in the Drosophila brain. Our results show that Tc-foxQ2II marks subsets of fast-acting interneurons contributing to the higher-order brain centers mushroom bodies and central complex. Taken together, our work expands the known functional range of foxQ2 genes from sensory and neurosecretory cell specification to interneurons involved in the function of higher-order brain centers.

Light-entrained chromatin priming poises rapid metamorphosis in a marine sponge

b.degnan@uq.edu.au (Bernard M Degnan) — Tue, 27 Oct 2026 00:00:00 +0000

The most widespread animal life cycle includes a planktonic larval stage that is environmentally induced to settle and rapidly metamorphose into a benthic juvenile. Although this transition is critical for survival, how planetary cues such as light interact with local ecological signals to prepare the genome for such rapid reprogramming remains poorly understood. Here, using the sponge Amphimedon queenslandica, we integrate time-resolved transcriptomic and chromatin accessibility profiling across larval competence, settlement, and the first hours of metamorphosis. We show that diminishing light at sunset is associated with extensive chromatin remodelling in swimming larvae prior to settlement despite relatively modest changes in gene expression. Upon environmental induction by a coralline alga, metamorphosis is accompanied by the rapid and transient activation of a large suite of deeply conserved transcription factors (TFs), including AP-1/bZIP family members, whose binding motifs are enriched in newly accessible regulatory regions near differentially expressed genes. Larvae prevented from experiencing sunset by constant light fail to settle and instead adopt an alternative transcriptional and chromatin state characterised by widespread loss of accessibility and repression of competence-associated TFs, including the circadian regulator CLOCK and other bHLH-PAS factors. These observations support a model in which light-entrained transcriptional activity establishes an anticipatory, permissive chromatin landscape that enables immediate and coordinated transcriptional reprogramming upon environmental induction. We propose that such chromatin priming may represent a broadly deployed regulatory strategy underlying the speed and robustness of metamorphosis in biphasic animal life cycles.

Integration of ATAC- and RNA-sequencing identifies chromatin and transcriptomic signatures in classical and non-classical zebrafish osteoblasts and indicates mechanisms of entpd5a regulation

schultes@ukmuenster.de (Ferenc Müller) — Tue, 27 Oct 2026 00:00:00 +0000

Two types of osteoblasts are required to assemble the zebrafish embryonic skeleton: classical osteoblasts homologous to the mammalian cell and notochord sheath cells which serve as non-classical osteoblasts. The gene entpd5a is critically required for ossification via both types of osteoblasts. Despite the indispensability of zebrafish models in vertebrate research, the genetic regulation of bone formation, as well as mechanisms of transcriptional control of entpd5a, remains largely unknown. Here, using a newly generated transgenic line, we isolate classical and non-classical osteoblasts from zebrafish embryos and performed both assay for transposase-accessible chromatin (ATAC)-seq and RNA-seq. We analysed results independently and integratively to understand those chromatin dynamics and accompanying transcriptomic changes that occur in different skeletal cell types. We show that although Dlx family factors are playing important roles in classical osteoblast regulation, Hox family factors are involved in governing spinal ossification via non-classical osteoblasts. We further present a resource-driven analysis of the entpd5a promoter, experimentally validating the ATAC-seq dataset and proposing mechanisms of regulating the complex entpd5a expression pattern during zebrafish osteogenesis. Our results thus provide a necessary comprehensive resource for the field of bone development and indicate spatio-temporally regulated promoter/enhancer interactions taking place in the entpd5a locus.

Small brown planthopper infestation enhances it reproduction and insecticide tolerance by manipulating glucose distribution and levels in rice

gangfenglh@163.com (Hai Li) — Mon, 26 Oct 2026 00:00:00 +0000

The evolutionary arms race between plants and insects involves not only direct defense and counter-defense but also sophisticated resource manipulation. However, how herbivorous insects respond to host nutritional signals to modulate their fitness traits remains unclear. This study investigates how the small brown planthopper (SBPH, Laodelphax striatellus) manipulates host plant carbohydrate allocation, and to elucidate the molecular mechanisms by which the acquired glucose enhances SBPH fecundity and insecticide tolerance. Using molecular, pharmacological, and biochemical approaches, we found that SBPH infestation induced systemic carbohydrate reallocation in rice, elevating whole-plant glucose levels by promoting aerial accumulation while depleting root reserves. Host-derived glucose enhanced SBPH fecundity by activating the target of rapamycin (TOR) pathway, upregulating juvenile hormone (JH) signaling, and increasing vitellogenin production. For imidacloprid tolerance, glucose boosted glutathione S-transferase (GST) activity via two synergistic mechanisms: by upregulating glutamate cysteine ligase (GCL) to increase glutathione synthesis, and transcriptionally via the glucose-TOR-JH axis to induce LsGSTe1 (SBPH epsilon class GST) and LsGSTo1 (SBPH omega class GST) expression. Our findings establish host-derived glucose as a central signaling molecule that SBPH utilizes to modulate conserved pathways for simultaneous optimization of reproduction and insecticide resistance. This reveals a multifaceted nutrient-responsive mechanism in insect pests and identifies the glucose-TOR-JH axis as critical molecular targets for developing nutrient-based pest control strategies, such as disrupting insect nutrient-sensing pathways or modulating host carbohydrate metabolism.

Improved cryo-EM reconstruction of sub-50 kDa complexes using 2D template matching

Kexin.Zhang1@umassmed.edu (Kexin Zhang) — Mon, 26 Oct 2026 00:00:00 +0000

Visualizing the structures of small proteins and complexes has been a longstanding challenge in single-particle cryo-electron microscopy (cryo-EM). Some of these targets have been successfully resolved by binding to antibody fragments (Fabs) or fusing with external scaffolds to increase their size. Recent advances in conventional single-particle techniques have enabled the determination of an increasing number of structures smaller than 100 kDa, achieving resolutions relevant to drug research. Compared to X-ray crystallography, cryo-EM preserves the near-native states of biomolecules, can resolve structural heterogeneity, and has the potential to apply to a wide range of targets. In this work, we demonstrate that the alignment and reconstruction of small macromolecular complexes can be improved using high-resolution structures as priors, combined with 2D template matching. Using this method, we reconstructed a previously intractable ∼43 kDa protein kinase and improved the density of its ligand-binding site. Our theoretical analysis predicts that this method can further extend single-particle cryo-EM to important drug-binding complexes well below 50 kDa.

The transcription factor BCL11A restores differentiation potential to aged oligodendrocyte progenitor cells

writetotanay@gmail.com (Amar Sharma) — Mon, 26 Oct 2026 00:00:00 +0000

In young animals, oligodendrocyte progenitor cells (OPCs) in the CNS efficiently differentiate into myelinating oligodendrocytes (OLs), whereas ageing reduces this capacity, impairing remyelination following demyelinating injury and adaptive myelination involved in learning. To identify factors that restore resilience in aged OPCs, we developed gSWITCH (https://altoslabs.shinyapps.io/gSWITCH/, https://github.com/Tanay-math/gSWITCH), a computational pipeline that captures dynamic gene-expression patterns to identify ‘switch’ genes during lineage progression and ordered biological transitions, including time-series experiments. gSWITCH identified OPC-characteristic switch genes, which we compared between young and aged OPCs to determine whether their regulation is altered with ageing. This revealed several transcription factors with reduced expression in aged OPCs. Transcription-factor binding-site enrichment highlighted Bcl11a as a potential master-regulator of multiple switch genes. Bcl11a inhibition reduced OPC differentiation into OLs, whereas its overexpression in aged OPCs significantly enhanced OL differentiation without affecting proliferation. In aged mice subjected to demyelination injury in spinal cord white matter, Bcl11a overexpression increased OPC differentiation within lesions. We found that Bcl11a has undergone pervasive purifying selection throughout vertebrate evolution, preserving its amino acid sequence by eliminating deleterious mutations. Our study shows that reversing the age-related decline of this evolutionarily conserved factor in aged OPCs restores their impaired capacity for differentiation.