eLife: latest articles

Mettl5 coordinates protein production and degradation of PERIOD to regulate sleep in Drosophila

dujuan9981@cau.edu.cn (Juan Du) — Fri, 08 May 2026 00:00:00 +0000

Sleep plays a critical role in animal physiology, primarily governed by the brain, and its disruption is prevalent in various brain disorders. Mettl5 is associated with intellectual disability (ID), which often includes sleep disturbances. However, the mechanism underlying these sleep disruptions in ID remains poorly understood. In this study, we investigated the sleep phenotypes resulting from Drosophila Mettl5 mutations. Rescue experiments revealed that Mettl5 functions predominantly within neurons and glia marked by Mettl5-Gal4 to regulate sleep. Previous work established that Mettl5 forms a complex with Trmt112 to influence rRNA methylation. Notably, a mutation in Trmt112 recapitulated these sleep disturbances, implicating translational regulation by the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses of Mettl5^1bp mutants uncovered downstream effects, including altered expression of proteasome components and clock genes. Rescue experiments confirmed that the net increase in PERIOD protein underlies the sleep phenotype. This study illuminates the interplay between ribosome function, clock genes, and the proteasome in sleep regulation, highlighting the integrated roles of protein synthesis and degradation. These findings could potentially provide an example for in vivo study of rRNA methylation function, expand our understanding of protein homeostasis in sleep, and offer insights into the sleep phenotypes associated with ID.

Neural representation of time across complementary reference frames

xuya@cbs.mpg.de (Léo Dutriaux) — Fri, 08 May 2026 00:00:00 +0000

Humans conceptualize time in terms of space, allowing flexible time construals from various perspectives. We can travel internally through a timeline to remember the past and imagine the future (i.e., mental time travel) or watch from an external standpoint to have a panoramic view of history (i.e., mental time watching). However, the neural mechanisms that support these flexible temporal construals remain unclear. To investigate this, we asked participants to learn a fictional religious ritual of 15 events. During fMRI scanning, they were guided to consider the event series from either an internal or external perspective in different tasks. Behavioral results confirmed the success of our manipulation, showing the expected symbolic distance effect in the internal-perspective task and the reverse effect in the external-perspective task. We found that the activation level in the posterior parietal cortex correlated positively with sequential distance in the external-perspective task but negatively in the internal-perspective task. In contrast, the activation level in the anterior hippocampus positively correlated with sequential distance regardless of the observer’s perspectives. These results suggest that the hippocampus stores the memory of the event sequences allocentrically in a perspective-agnostic manner. Conversely, the posterior parietal cortex retrieves event sequences egocentrically from the optimal perspective for the current task context. Such complementary allocentric and egocentric representations support both the stability of memory storage and the flexibility of time construals.

A novel 3D visualization method in mice identifies the periportal lamellar complex (PLC) as a key regulator of hepatic ductal and neuronal branching morphogenesis

chongchen@scu.edu.cn (Banglei Yin) — Thu, 07 May 2026 00:00:00 +0000

The liver is a complex organ responsible for multiple functions, including metabolism, energy storage, detoxification, bile secretion, and immune regulation. Its highly organized vascular system plays a crucial role in maintaining functional zonation and tissue homeostasis. Within the liver, the hepatic artery, portal vein, hepatic vein, bile duct, and nerve networks intertwine to form an intricate three-dimensional architecture; however, traditional two-dimensional imaging fails to reveal their true spatial relationships, and current three-dimensional imaging methods remain insufficient to capture fine structural details. To achieve comprehensive visualization of these multi-ductal systems, we established a high-resolution three-dimensional imaging platform that combines multicolor perfusion of metallic compound nanoparticles (MCNPs) with an optimized tissue-clearing protocol (Liver-CUBIC), enabling simultaneous 3D reconstruction of the portal vein, hepatic artery, bile duct, and hepatic vein in mouse livers. Based on these data, we identified and defined a previously unrecognized structure located in the outer layer of the portal vein, termed the periportal lamellar complex (PLC). The PLC encircles the portal vein between the vascular endothelium and the perisinusoidal region, exhibits low-permeability barrier characteristics, and contains a distinctive population of CD34⁺Sca-1⁺ endothelial cells. During liver fibrosis, the PLC extends from the portal vein toward the hepatic lobule, forming a structural scaffold that guides bile duct and nerve migration.

How membranes shape up for lipid transfer

tendo@cc.kyoto-su.ac.jp (Takashi Hirashima) — Thu, 07 May 2026 00:00:00 +0000

The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.

Prolonged oscillating preoptic area kisspeptin neuron activity underlies the preovulatory luteinizing hormone surge in mice

aeh36@cam.ac.uk (Allan Edward Herbison) — Thu, 07 May 2026 00:00:00 +0000

The population of kisspeptin neurons located in the rostral periventricular area of the third ventricle (RP3V) is thought to have a key role in generating the GnRH surge that triggers ovulation. Using a modified GCaMP fibre photometry procedure, we have been able to record the in vivo population activity of RP3V^KISS neurons across the estrous cycle of female mice. A marked increase in GCaMP activity was detected beginning on the afternoon of proestrus that lasted in total for 13±1 hr. This was comprised of slow baseline oscillations with a period of 91±4 min associated with high-frequency rapid transients. Very little oscillating baseline or transient activity was detected at other stages of the estrous cycle. Concurrent blood sampling showed that the peak of the LH surge occurred 3.5±1.1 hr after the first baseline RP3V^KISS neuron baseline oscillation on the afternoon of proestrus. The time of onset of RP3V^KISS neuron oscillations varied between mice and across subsequent proestrous stages in the same mice. To assess the impact of estradiol on RP3V^KISS neuron activity, mice were ovariectomized and given an incremental estradiol replacement regimen. Minimal patterned GCaMP activity was found in OVX mice, and this was not changed acutely by any of the estradiol treatments. However, on the afternoon of the expected LH surge, the same oscillating baseline activity with associated transients occurred for 7.1±0.5 hr. These observations reveal an unexpected prolonged oscillatory pattern of RP3V^KISS neuron activity that is dependent on estrogen and underlies the preovulatory LH surge as well as potentially other facets of reproductive behavior.

HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content

sfrangos@uoguelph.ca (Cezar M Khursigara) — Wed, 06 May 2026 00:00:00 +0000

It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I–IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.

Natural xanthones as α-Mangostin induce vasorelaxation involving key gating residues in the S6 domain of BK channels

m.musinszki@physiologie.uni-kiel.de (Marianne A Musinszki) — Wed, 06 May 2026 00:00:00 +0000

Polyphenolic compounds are widely explored for health benefits, including hypertension, but their active ingredients, molecular targets, and mechanisms remain poorly defined. We identify the xanthone Mangostin from Garcinia mangostana as a potent modulator of several potassium channels, with large-conductance K⁺ (BK) channels as its primary target for vasorelaxation. Mangostin-activated BK channels as α subunits alone, in complexes with vascular β1 subunits, and in reconstituted BKα/β1–Ca_v nanodomains. It shifted BK voltage activation to more negative potentials by antagonizing channel closure and promoting channel opening without markedly altering Ca²⁺ sensitivity. Docking, competition, single-channel analysis, and mutagenesis localized the binding site in the pore cavity below the SF, involving gating-critical S6 residues I308, L312, and A316, and suggest that Mangostin stays bound in closed and open states. These findings establish BK channel activation as the core molecular mechanism driving Mangostin’s vascular effects and define its structural mode of action, informing nutraceutical safety assessment and BK-targeted drug design.

Continuous flash suppression of neural responses and population orientation coding in macaque V1

tangshm@pku.edu.cn (Cai-Xia Chen) — Wed, 06 May 2026 00:00:00 +0000

Continuous flash suppression (CFS), in which a dynamic masker presented to one eye suppresses awareness of a stimulus in the other eye, is widely used to study visual subconsciousness. Although some studies report preserved high-level processing under CFS, these effects have been increasingly questioned and may partly reflect residual low-level feature processing. A key unresolved issue is how strongly neuronal responses in V1, where inputs from the two eyes first converge, are affected by CFS, and how much the remaining signals can support downstream processing. Here, we used two-photon calcium imaging to record large populations of V1 neurons in awake, fixating macaques while presenting grating stimuli under CFS. CFS strongly suppressed V1 orientation responses in an ocular-dominance-dependent manner, nearly abolishing responses in neurons preferring the masker eye or both eyes, and significantly reducing responses in neurons preferring the grating eye. Modeling analyses further indicated that V1 population activity under CFS may still support coarse orientation classification but not accurate stimulus reconstruction. These results suggest that CFS substantially degrades orientation information in V1. The residual signals may support limited low-level processing but are likely insufficient for downstream higher-level visual and cognitive tasks.

Canonical neurodevelopmental trajectories of structural and functional manifolds

Alicja.Monaghan@mrc-cbu.cam.ac.uk (Alicja Monaghan) — Wed, 06 May 2026 00:00:00 +0000

Organisational gradients refer to a continuous low-dimensional embedding of brain regions and can quantify core organisational principles of complex systems like the human brain. Mapping how these organisational principles are altered or refined across development and phenotypes is essential to understanding the relationship between brain and behaviour. Taking a developmental approach and leveraging longitudinal and cross-sectional data from two multi-modal neuroimaging datasets, spanning the full neurotypical-neurodivergent continuum, we charted the organisational variability of structural (610 participants, N=390 with one observation, N=163 with two observations and N=57 with three) and functional (512 participants, N=340 with one observation, N=128 with two observations and N=44 with three). Across datasets, despite differing phenotypes, we observe highly similar structural and functional gradients. These gradients, or organisational principles, are highly stable across development, with the exact same ordering across early childhood into mid-adolescence. However, there is substantial developmental change in the strength of embedding within those gradients: by modelling developmental trajectories as non-linear splines, we show that structural and functional gradients are refined across development. Specifically, structural gradients gradually contract in low-dimensional space as networks become more integrated, whilst the functional manifold expands, indexing functional specialisation. The coupling of these structural and functional gradients follows a unimodal-association axis and varies across individuals, with developmental effects concentrated in the more plastic higher-order networks. Importantly, these developmental effects on coupling, in these higher-order networks, are attenuated in the neurodivergent sample. Finally, we mapped structure-function coupling onto dimensions of psychopathology and cognition and demonstrate that dimensions of cognition, such as working memory, are robust predictors of coupling. In summary, across clinical and community samples, we demonstrate consistent principles of structural and functional brain organisation, with progressive structural integration and functional segregation. These gradients are established early in life, refined through development, and their coupling is predicted by working memory.

Dynamic architecture of mycobacterial outer membranes revealed by all-atom simulations

wonpil@lehigh.edu (Matthieu Chavent) — Wed, 06 May 2026 00:00:00 +0000

Tuberculosis remains a global health crisis due to the resilience of Mycobacterium tuberculosis (Mtb), largely attributed to its unique cell envelope. The impermeability and structural complexity of the outer membrane of this envelope, driven by mycolic acids and glycolipids, pose significant challenges for therapeutic intervention. Here, we present the first all-atom models of an Mtb outer membrane using molecular dynamics simulations. We demonstrate that α-mycolic acids adopt extended conformations to stabilize bilayers, with a phase transition near 338 K that underscores their thermal resilience. Lipids in the outer leaflet, such as PDIM and PAT, induce membrane heterogeneity, migrating to the interleaflet space and reducing lipid order. The simulated mycobacterial outer membrane has ordered inner leaflets and disordered outer leaflets, which contrasts with the outer membrane of Gram-negative bacteria. These findings reveal that PDIM- and PAT-driven lipid redistribution, reduced lipid order, and asymmetric fluidity gradients enable Mtb’s outer membrane to resist host-derived stresses and limit antibiotic penetration, thereby promoting bacterial survival. Our work provides a foundational framework for targeting the mycobacterial outer membrane in future drug development.

Fully computational design of PAM-relaxed Staphylococcus aureus Cas9 with expanded targeting capability using UniDesign

jiex@umich.edu (Jie Xu) — Wed, 06 May 2026 00:00:00 +0000

CRISPR–Cas9 nucleases have transformed genome engineering, yet their application is often constrained by protospacer-adjacent motif (PAM) requirements. Staphylococcus aureus Cas9 (SaCas9) is particularly attractive for in vivo applications due to its compact size; however, its NNGRRT PAM limits targetable genomic sites. Here, we report KRH, a SaCas9 variant designed entirely from the wild-type enzyme through a fully computational point-mutation design workflow, UniDesign, without additional experimental optimization. As expected, KRH efficiently recognizes an expanded NNNRRT PAM and exhibits substantially enhanced editing efficiency at non-canonical PAM sites, with improvements of up to 116-fold over the wild type. KRH achieves genome- and base-editing efficiencies comparable to, or exceeding, those of the well-known evolution-derived KKH variant. Computational modeling by UniDesign provides a mechanistic explanation for the PAM relaxation observed in both KRH and KKH, with structural and energetic analyses revealing that KRH relaxes PAM specificity by fine-tuning the balance between sequence-specific interactions with PAM bases and nonspecific contacts with the DNA backbone. Beyond its practical utility, KRH demonstrates that computational design can identify a minimal set of mutations sufficient to remodel the PAM interface while preserving high nuclease activity. This approach recapitulates—and in some cases surpasses—the performance of evolution-derived variants, offering a scalable strategy for high-throughput Cas9 engineering. Overall, these results establish KRH as a blueprint for rationally engineered, PAM-relaxed nucleases and underscore the power of computational design to accelerate next-generation genome editing.

Human adherent cortical organoids in a multi-well format

sk2602@cumc.columbia.edu (Femke MS de Vrij) — Tue, 05 May 2026 00:00:00 +0000

In the growing diversity of human induced pluripotent stem cell (iPSC)-derived models of brain development, we present here a novel method that exhibits 3D cortical layer formation in a reproducible topography of minimal dimensions. The resulting adherent cortical organoids (ACOs) develop by self-organization after seeding frontal cortex-patterned iPSC-derived neural progenitor cells in 384-well plates during 8 weeks of differentiation. The organoids have stereotypical dimensions of 3 × 3 × 0.2 mm, contain multiple subtypes of neurons, astrocytes, and oligodendrocyte lineage cells, and are amenable to extended culture for at least 10 months. Longitudinal imaging revealed morphologically mature dendritic spines, axonal myelination, and robust neuronal activity. Moreover, ACOs compare favorably to existing free-floating brain organoid models on the basis of robust reproducibility in obtaining topographically standardized radial cortical structures and circumventing internal necrosis. Adherent human cortical organoids hold considerable potential for high-throughput drug discovery applications, neurotoxicological screening, and mechanistic pathophysiological studies of brain disorders.

Are kinocilia motile?

eatock@uchicago.edu (Marina Kabirova) — Tue, 05 May 2026 00:00:00 +0000

Gene expression patterns in the inner ear put an old question about structures called kinocilia back in motion.

Real-time transcriptomic profiling in distinct experimental conditions

buttamer@uni-mainz.de (Anna Wierczeiko) — Tue, 05 May 2026 00:00:00 +0000

Nanopore technology offers real-time sequencing opportunities, providing rapid access to sequenced data and allowing researchers to manage the sequencing process efficiently, resulting in cost-effective strategies. Here, we present focused case studies demonstrating the versatility of real-time transcriptomics analysis in rapid quality control for long-read RNA-seq. We illustrate its utility through four experimental setups: (1) transcriptome profiling of distinct human cellular populations, (2) identification of experimentally enriched transcripts, (3) transcriptional analysis of cells under heat shock conditions, and (4) identification of experimentally manipulated genes (knockout and overexpression) in several yeast strains. We show how to perform multiple layers of quality control as soon as sequencing has started, addressing both the quality of the experimental and sequencing traits. Real-time quality control measures assess sample/condition variability and determine the number of identified genes per sample/condition. Furthermore, real-time differential gene/transcript expression analysis can be conducted at various time points post-sequencing initiation (PSI), revealing dynamic changes in gene/transcript expression between two conditions. Using real-time analysis, which occurs in parallel to the sequencing run, we identified differentially expressed genes/transcripts as early as 1 hr PSI. These changes were consistently observed throughout the entire sequencing process. We discuss the new possibilities offered by real-time data analysis, which have the potential to serve as a valuable tool for rapid and cost-effective quality checks in specific experimental settings and can be potentially integrated into clinical applications in the future.

Hugin-AstA circuitry is a novel central energy sensor that directly regulates sweet sensation in Drosophila and mouse

lmwang83@cimrbj.ac.cn (Daihan Li) — Tue, 05 May 2026 00:00:00 +0000

Taste sensation plays a crucial role in shaping feeding behavior and is intricately influenced by internal states like hunger or satiety. Despite the identification of numerous neural substrates regulating feeding behavior, the central neural substrate that linked energy-sensing and taste sensation remained elusive. Here, we identified a novel neural circuitry that could directly sense internal energy state and modulate sweet sensation in the Drosophila brain. Specifically, a subset of neuropeptidergic neurons expressing hugin directly detected elevated levels of circulating glucose via glucose transporter Glut1 and ATP-sensitive potassium channels. Upon activation, these neurons released hugin peptide and activated downstream Allatostatin A (AstA)⁺ neurons via its cognate receptor PK2-R1. Subsequently, the activation of AstA⁺ neurons then directly inhibited sweet sensation via AstA peptide and its cognate receptor AstA-R1 expressed in sweet-sensing Gr5a⁺ neurons. We also showed that Neuromedin U (NMU), the mammalian homolog of fly hugin, served as an energy sensor to suppress sweet sensation. Therefore, these data identify hugin⁺ neuron as a glucose-responsive central energy-sensing module that modulates sweet sensation across species.

Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics

david.papadopoli@mail.mcgill.ca (Daina Avizonis) — Tue, 05 May 2026 00:00:00 +0000

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.

Herbivorous insects independently evolved salivary effectors to regulate plant immunity by destabilizing the malectin-LRR RLP NtRLP4

lijunmin@nbu.edu.cn (Chuan-Xi Zhang) — Tue, 05 May 2026 00:00:00 +0000

Plants utilize receptor-like proteins and receptor-like kinases (RLPs/RLKs) to perceive and respond to a wide variety of invading pathogens and insect herbivores. While the strategies employed by microbial pathogens to suppress plant immunity have been well characterized, it remains unclear how herbivorous insects counteract receptor-mediated defenses. Here, we show that salivary effectors evolve independently in whiteflies and planthoppers to dampen RLP4-mediated plant immunity. RLP4, as a leucine-rich repeat RLP (LRR-RLP), confers plant resistance against herbivorous insects by forming the RLP4/SOBIR1 complexes. In the whitefly Bemisia tabaci, BtRDP, the Aleyrodidae-specific salivary sheath protein, interacts with RLP4 from multiple plant species and promotes its ubiquitin-dependent degradation. Overexpression of NtRLP4 in transgenic plants exerts a detrimental effect on B. tabaci by exploiting the crosstalk between the salicylic acid and jasmonic acid pathways. Conversely, overexpression of BtRDP or silencing of NtRLP4 effectively alleviates such negative effects. In planthopper Nilaparvata lugens, the Delphacidae-restricted salivary protein NlSP104 also targets and promotes the degradation of OsRLP4 from rice plants. These findings reveal convergent evolution of salivary proteins in insects and underscore the complex interactions between plants and herbivorous insects.

Auditory perception and neural representation of temporal features are altered by age but not by cochlear synaptopathy

georg.klump@uni-oldenburg.de (Christine Köppl) — Tue, 05 May 2026 00:00:00 +0000

Age-related hearing loss is a complex phenomenon. The earliest-onset degenerative event is the gradual loss of neural connections between the cochlea and auditory brainstem. To probe for perceptual deficits that might arise from this loss, cochlear synaptopathy was induced pharmacologically in young-adult gerbils, which were then tested in a challenging listening task for the perception of temporal fine structure. Treated gerbils behaved no differently than normal-hearing, young-adult animals. In contrast, old gerbils, which typically express many cochlear and central-neural pathologies, showed impaired perception. To probe for the underlying mechanisms, single-unit responses were obtained from the auditory nerve to the same test stimuli. Responses from old gerbils showed no impairment in temporal locking to the stimulus fine structure. However, responses were significantly more driven by slower temporal fluctuations of the stimulus envelope, suggesting that the central auditory system may be unable to extract the relevant information for discrimination from such altered inputs.

Investments in photoreceptors compete with investments in optics to determine eye design

SL104@cam.ac.uk (Francisco JH Heras) — Tue, 05 May 2026 00:00:00 +0000

Eyes provide opportunities to understand the function, design, development, and evolution of elaborate sense organs. We take a new cost–benefit approach to understanding eye design by considering that optics and photoreceptors compete for the resources invested in an integrated system. We investigate this competition theoretically and empirically using a new measure of cost, specific volume. This common currency for optics and photoreceptors relates investments to image quality via geometrical, optical, and physiological constraints. By covering the morphospace of an eye of given type and cost, we model how trading optics against photoreceptors changes information capacity. In apposition compound eyes and simple eyes, an optimum configuration maximises efficiency. Efficiency requires heavy investment in photoreceptors and depends on photoreceptor energy consumption. Optimum information capacities and efficiencies scale non-linearly with total investment. Diurnal insects’ apposition eyes follow trends that promote efficiency: photoreceptor arrays take 40–80% of total specific volume, photoreceptor length increases systematically with spatial resolution, and photoreceptors are exceptionally long. Thus, competition between optics and photoreceptors shapes eye design, and matching investments in optics and photoreceptors to improve efficiency is a design principle. Our new methodology can be developed to view the adaptive radiation of eyes through a cost–benefit lens.

Collective epithelial migration mediated by the unbinding of hexatic defects

giomi@lorentz.leidenuniv.nl (Dimitrios Krommydas) — Tue, 05 May 2026 00:00:00 +0000

Collective cell migration in epithelia relies on cell intercalation: a local remodeling of the cellular network that allows neighboring cells to swap their positions. Unlike foams and passive cellular fluid, in epithelial intercalation, these rearrangements crucially depend on activity. During these processes, the local geometry of the network and the contractile forces generated therein conspire to produce a burst of remodeling events, which collectively give rise to a vortical flow at the mesoscopic length scale. In this article, we formulate a continuum theory of the mechanism driving this process, built upon recent advances toward understanding the hexatic (i.e., sixfold ordered) structure of epithelial layers. Using a combination of active hydrodynamics and cell-resolved numerical simulations, we demonstrate that cell intercalation takes place via the unbinding of topological defects, naturally initiated by fluctuations and whose late-times dynamics is governed by the interplay between passive attractive forces and active self-propulsion. Our approach sheds light on the structure of the cellular forces driving collective migration in epithelia and provides an explanation of the observed extensile activity of in vitro epithelial layers.

RadD from Fusobacterium nucleatum engages NKp46 to promote antitumor cytotoxicity

oferm@ekmd.huji.ac.il (Ahmed Rishiq) — Fri, 01 May 2026 00:00:00 +0000

Fusobacterium nucleatum, a gram-negative bacterium implicated in periodontal disease, contributes to tumor progression in various cancers. Whether the presence of F. nucleatum inhibits tumor progression of some cancers is largely unknown. Here, we identify an interaction between F. nucleatum and the natural killer (NK) cell receptor NKp46. Analysis of TCGA datasets revealed that the co-occurrence of F. nucleatum and high NKp46 expression correlates with improved survival in head and neck cancers but not in colorectal cancers. Using binding assays, we demonstrate that both human NKp46 and its murine ortholog, Ncr1, directly recognize the fusobacterial adhesin RadD. Genetic deletion of radD or blockade of NKp46 significantly impaired NK cell-mediated cytotoxicity in vitro and promoted tumor-cell growth. In vivo, infection with F. nucleatum accelerated tumor progression, with an exacerbated effect observed in the absence of RadD or NKp46. These findings highlight RadD as a critical ligand for NKp46 and establish the NKp46–RadD axis as a key interface in host–microbe–tumor interactions, offering a novel target for immunotherapeutic intervention in cancer influenced by microbial factors.

Evidence of off-target probe binding affecting 10x Genomics Xenium gene panels compromise accuracy of spatial transcriptomic profiling

jeanfan@jhu.edu (Caleb Hallinan) — Fri, 01 May 2026 00:00:00 +0000

The accuracy of spatial gene expression profiles generated by probe-based in situ spatially resolved transcriptomic technologies depends on the specificity with which probes bind to their intended target gene. Off-target binding, defined as a probe binding to something other than the target gene, can distort a gene’s true expression profile, making probe specificity essential for reliable transcriptomics. Here, we investigated off-target binding affecting the 10x Genomics Xenium technology. We developed a software tool, Off-target Probe Tracker (OPT), to identify putative off-target binding via alignment of probe target sequences and assessing whether mapped loci corresponded to the intended target gene across multiple reference annotations. Applying OPT to a Xenium human breast gene panel, we identified at least 14 out of the 313 genes in the panel potentially impacted by off-target binding to protein-coding genes. To substantiate our predictions, we leveraged a Xenium breast cancer dataset generated using this gene panel and compared results to orthogonal spatial and single-cell transcriptomic profiles from Visium CytAssist and 3′ single-cell RNA-seq derived from the same tumor block. Our findings indicate that for some genes, the expression patterns detected by Xenium demonstrably reflect the aggregate expression of the target and predicted off-target genes based on Visium and single-cell RNA-seq, rather than the target gene alone. We further applied OPT to identify potential off-target binding in custom gene panels and integrate tissue-specific RNA-seq data to assess effects. Overall, this work enhances the biological interpretability of spatial transcriptomics data and improves reproducibility in spatial transcriptomics research.

Adapting clinical chemistry plasma as a source for liquid biopsies

weigu@stanford.edu (Benjamin A Pinsky) — Fri, 01 May 2026 00:00:00 +0000

Circulating cell-free DNA (cfDNA) is valuable for molecular testing, but typically requires specialized collection tubes or immediate processing. We investigated whether residual plasma from heparin separators, routinely used in clinical chemistry, could serve as an accessible and underused source for cfDNA. We analyzed matched plasma samples from healthy volunteers in two experiments: an immediate-processing comparison across EDTA, Streck, and heparin separator tubes (n=5), and a clinical-handling simulation comparing EDTA and heparin separator tubes under delayed processing at room temperature or 4°C (n=6). We also analyzed matched plasma samples from viral PCR-positive patients in a hospital cohort (n=38). Whole-genome sequencing and enriched methylation sequencing were performed to assess concordance across metagenomics, copy number, methylation, and fragmentomic features. Under immediate processing, heparin separator plasma showed high concordance with EDTA and Streck plasma for methylation patterns (Spearman’s ρ=0.65–0.70) and fragmentation features. In the Hospital Cohort, heparin separator plasma showed strong concordance with matched EDTA plasma for viral detection (Spearman’s ρ=0.95), copy number alteration profiling (Spearman’s ρ=0.72–0.96), and methylation patterns (Spearman’s ρ=0.50–0.83). These findings support the feasibility of using refrigerated, promptly processed residual plasma from routine clinical chemistry as a supplementary source for cfDNA biobanking and molecular analyses.

Unbend, correction of local beam-induced sample motion in cryo-EM images using a 3D spline model

lingli.kong1@umassmed.edu (Johannes Elferich) — Thu, 30 Apr 2026 00:00:00 +0000

The exposure of frozen biological samples to the high-energy electron beam in a cryo-electron microscope commonly leads to beam-induced sample motion and distortions. Previously, we described Unblur, software to correct for beam-induced motion based on the alignment of full frames in a movie collected during the beam exposure (Grant and Grigorieff, 2015). Here, we present Unbend, extending Unblur by accommodating more localized sample bending and distortions using a 3D cubic B-spline model. Unbend is integrated into our cisTEM software with a new local motion visualization panel. We processed movie frames from various in situ sample types, including whole cells, lamellae, and cell lysates, to analyze motion behavior across different specimen types. To quantify the improvement in high-resolution signal, we utilized the 2D template matching method to search large ribosomal subunits from the motion-corrected micrographs. Overall, the signal-to-noise ratio of detected particles improved by 3–8% across different samples compared with full-frame aligned micrographs, while the number of detected target particles increased by up to ~300%. Furthermore, we processed micrograph montages to study motion patterns across an entire sample, revealing considerable variance in distortion scale within the same sample, suggesting a complex underlying mechanism.

On-demand seizures facilitate rapid screening of therapeutics for epilepsy

takanoh@chop.edu (Brian Litt) — Thu, 30 Apr 2026 00:00:00 +0000

Animal models of epilepsy are critical in drug development and therapeutic testing. However, dominant methods for evaluating epilepsy treatments face a tradeoff between higher throughput and etiological relevance. Screening models are either based on acutely induced seizures in wild-type, naive animals or spontaneous seizures in chronically epileptic animals. Each has its disadvantages – acute convulsant or kindling-induced seizures do not account for the myriad neuropathological changes in the diseased, epileptic brains, and spontaneous behavioral seizures are sparse in chronically epileptic models, making it time-intensive to sufficiently power experiments. In this study, we developed the Opto-IHK (optogenetically induced seizures in intrahippocampal kainate mice) model, a mechanistic approach to precipitate seizures ‘on demand’ in chronically epileptic mice. We briefly synchronized principal cells in the CA1 region of the diseased hippocampus to reliably induce stereotyped on-demand behavioral seizures. These induced seizures resembled naturally occurring spontaneous seizures in the epileptic animals and could be stopped by commonly prescribed anti-seizure medications such as levetiracetam and diazepam. Furthermore, we showed that seizures induced in chronically epileptic animals differed from those in naive animals, highlighting the importance of evaluating therapeutics in the diseased circuit. Taken together, we envision the Opto-IHK model to accelerate the evaluation of both pharmacological and closed-loop interventions for epilepsy.

The FAM53C/DYRK1A axis regulates the G1/S transition of the cell cycle

julsage@stanford.edu (Anca M Pasca) — Thu, 30 Apr 2026 00:00:00 +0000

A growing number of therapies are being developed to target the cell cycle machinery for the treatment of cancer and other human diseases. Consequently, a greater understanding of the factors regulating cell cycle progression becomes essential to help enhance the response to these new therapies. Here, using data from the Cancer Dependency Map, we identified FAM53C as a new regulator of cell cycle progression. We found that FAM53C is critical for this cell cycle transition and that it acts upstream of the Cyclin D-CDK4/6-RB axis and of p53 in the regulation of the G1/S transition. By mass spectrometry, biochemical, and cellular assays, we identified and validated DYRK1A as a cell cycle kinase that is inhibited by and directly interacts with FAM53C. Consistent with the role for FAM53C identified in cells in culture, FAM53C knockout human cortical organoids display increased cell cycle arrest and growth defects. Fam53C knockout mice show minor behavioral phenotypes. Because DYRK1A dysregulation contributes to developmental disorders such as Down syndrome as well as tumorigenesis, future strategies aiming at regulating FAM53C activity may benefit a broad range of patients.

The sound of neural silence

lin.tian@mpfi.org (Lin Tian) — Thu, 30 Apr 2026 00:00:00 +0000

A new fluorescent sensor makes it possible to track the neurotransmitter GABA in freely moving animals.

Prickle and Ror modulate Dishevelled-Vangl interaction to regulate non-canonical Wnt signaling during convergent extension in Xenopus

j18wang@uab.edu (Allyson R Angermeier) — Thu, 30 Apr 2026 00:00:00 +0000

Convergent extension (CE) is a fundamental morphogenetic process where oriented cell behaviors lead to polarized extension of diverse tissues. In vertebrates, regulation of CE requires both non-canonical Wnt, its co-receptor Ror, and several ‘core members’ of the planar cell polarity (PCP) pathway. PCP was originally identified as a mechanism to coordinate the cellular polarity in the plane of static epithelium, where core proteins Frizzled (Fz)/Dishevelled (Dvl) and Van Gogh-like (Vangl)/Prickle (Pk) partition to opposing cell cortex. But how core PCP proteins interact with each other to mediate non-canonical Wnt/Ror signaling during CE is not clear. We found previously that during CE, Vangl cell-autonomously recruits Dvl to the plasma membrane and keeps Dvl inactive. In this study, we show that non-canonical Wnt induces Dvl to transition from Vangl to Fz in Xenopus embryos. Pk inhibits the transition and functionally synergizes with Vangl to suppress Dvl during CE. Conversely, Ror is required for the transition and functionally antagonizes Vangl. Biochemically, Vangl interacts directly with both Ror and Dvl. Ror and Dvl do not bind directly but can be co-fractionated with Vangl. Collectively, we propose that Pk assists Vangl to function as an unconventional adaptor that brings Dvl and Ror into a complex to serve two functions: (1) simultaneously preventing both Dvl and Ror from ectopically activating non-canonical Wnt signaling; and (2) relaying Dvl to Fz for signaling activation upon non-canonical Wnt-induced dimerization of Fz and Ror.

Towards a unified molecular mechanism for ligand-dependent activation of NR4A-RXR heterodimers

douglas.kojetin@vanderbilt.edu (Douglas J Kojetin) — Thu, 30 Apr 2026 00:00:00 +0000

A subset of nuclear receptors (NRs) function as permissive heterodimers with retinoid X receptor (RXR), defined by transcriptional activation in response to RXR agonist ligands. Permissive NR-RXR activation is generally understood to operate through a classical pharmacological mechanism in which RXR agonist binding enhances coactivator recruitment to the heterodimer. However, we previously demonstrated that transcriptional activation of permissive Nurr1-RXRα (NR4A2-NR2B1) heterodimers by an RXR ligand set, which included pharmacological RXR agonists and selective Nurr1-RXRα agonists that function as antagonists of RXRα homodimers, is explained by a non-classical activation mechanism involving ligand-binding domain (LBD) heterodimer dissociation (Yu et al., 2023). Here, we extend mechanistic ligand profiling of the same RXR ligand set to the evolutionarily related Nur77-RXRγ (NR4A1-NR2B3) heterodimer. Biochemical and NMR protein-protein interaction profiling, together with cellular transcription studies, indicate that activation of Nur77-RXRγ transcription by the RXR ligand set, which lacks selective Nur77-RXRγ agonists, is consistent with contributions from both classical pharmacological activation and LBD heterodimer dissociation. However, reanalysis of our previously published data for Nurr1-RXRα revealed that inclusion of selective Nurr1-RXRα agonists was essential for elucidating the LBD heterodimer dissociation mechanism. Together, our findings highlight the importance of using a more functionally diverse RXR ligand set to define the mechanism of Nur77-RXRγ activation and to further evaluate whether LBD heterodimer dissociation represents a shared activation mechanism among NR4A-RXR heterodimers relevant to neurodegenerative and inflammatory diseases.

Bivalent mRNA booster encoding virus-like particles elicits potent polyclass receptor-binding domain antibodies in pre-vaccinated mice

bjorkman@caltech.edu (Alexander A Cohen) — Thu, 30 Apr 2026 00:00:00 +0000

mRNA vaccines emerged as a leading vaccine technology during the COVID-19 pandemic. However, their sustained protective efficacies were limited by relatively short-lived antibody responses and the emergence of SARS-CoV-2 variants, necessitating frequent and variant-updated boosters. We recently developed the ESCRT- and ALIX-binding region (EABR) mRNA vaccine platform, which encodes engineered immunogens that induce budding of enveloped virus-like particles (eVLPs) from the plasma membrane, thereby resulting in presentation of immunogens on cell surfaces and eVLPs. Prior studies showed that spike (S)-EABR mRNA-LNP immunizations elicited enhanced neutralizing antibody responses against ancestral and variant SARS-CoV-2 compared with conventional S mRNA-LNP in naïve mice, but the effectiveness of S-EABR mRNA-LNP boosters in the context of pre-existing immunity has not been investigated. Here, we evaluated monovalent Wuhan-Hu-1 (Wu1) and bivalent (Wu1/BA.5) S-EABR mRNA-LNP boosters in mice pre-vaccinated with conventional Wu1 S mRNA-LNP. Compared to conventional S mRNA-LNP boosters, the EABR approach enhanced monovalent and bivalent mRNA-LNP booster-induced neutralizing responses against Omicron subvariants BA.1, BA.5, BQ.1.1, and XBB.1, with bivalent S-EABR mRNA-LNP consistently eliciting the highest titers. Epitope mapping of polyclonal antisera by deep mutational scanning revealed that bivalent S-EABR mRNA-LNP boosted diverse ‘polyclass’ anti-receptor-binding domain (RBD) responses, suggesting balanced targeting of multiple RBD epitope classes. In contrast, monovalent S, bivalent S, and monovalent S-EABR mRNA-LNP boosters elicited less diverse polyclonal serum responses primarily targeting immunodominant RBD epitopes. Cryo-electron microscopy (cryo-EM) structures demonstrated that bivalent mRNA immunizations promote S heterotrimer formation, potentially enhancing bivalent S-EABR mRNA-LNP booster-induced antibody breadth and polyclass epitope targeting by activating cross-reactive B cells through intra-S crosslinking. These findings support the future design of bivalent or multivalent S-EABR mRNA-LNP boosters as a promising strategy to confer broader, and therefore potentially more durable, protection against emerging SARS-CoV-2 variants and other rapidly evolving viruses.

Inference of germinal center evolutionary dynamics via simulation-based deep learning

dralph@fredhutch.org (Ashni A Vora) — Tue, 28 Apr 2026 00:00:00 +0000

B cells and the antibodies they produce are vital to health and survival, motivating research on the details of the mutational and evolutionary processes in the germinal centers (GCs) from which mature B cells arise. It is known that B cells with higher affinity for their cognate antigen (Ag) will, on average, tend to have more offspring. However, the exact form of this relationship between affinity and fecundity, which we call the ‘affinity–fitness response function’, is not known. Here we use deep learning and simulation-based inference to learn this function from a unique experiment that replays a particular combination of GC conditions many times in mice. All code is freely available at https://github.com/matsengrp/gcdyn, while datasets and inference results can be found at https://doi.org/10.5281/zenodo.15022130.

Interrogating the structure and function of the human voltage-gated proton channel (hH_v1) with a fluorescent noncanonical amino acid

zagotta@uw.edu (Emerson M Carmona) — Tue, 28 Apr 2026 00:00:00 +0000

The human voltage-gated proton channel (hH_v1) is a dimer of voltage-sensor domains (VSDs) containing highly selective proton permeation pathways in each monomer. In addition to voltage, hH_v1 is regulated by other stimuli, including pH gradients, mechanical forces, and ligands, such as Zn²⁺. Aside from the VSDs, this membrane protein contains an N-terminal domain and a C-terminal coiled-coil domain (CC) formed between the monomers. To address the need for direct measurements of conformational rearrangements in hH_v1, we developed a Förster resonance energy transfer (FRET) approach to measuring the conformational rearrangements in full-length hH_v1 purified from E. coli. We used genetic code expansion (GCE) to generate a library of 14 full-length hH_v1 constructs, each incorporating the fluorescent noncanonical amino acid acridon-2-ylalanine (Acd) at a different site throughout the various structural domains. Following the expression and purification of these hH_v1-Acd proteins, we found that 12 sites yielded stable and functional proton-permeable channels. The fluorescence properties of Acd at each site showed small site-specific differences. Furthermore, we measured site-specific FRET efficiencies from tryptophan (Trp) and tyrosine (Tyr) to Acd in the hH_v1-Acd proteins and found results consistent with correct folding in detergent micelles. Finally, the addition of Zn²⁺ produced reversible changes in FRET, with affected residues clustered on the intracellular side of the channel.

B cell expression of an enzymatic intermediary in ether lipid biosynthesis promotes antibody responses and germinal center size

sung.hoon.cho@emory.edu (Clay F Semenkovich) — Mon, 27 Apr 2026 00:00:00 +0000

The qualities of antibody (Ab) responses provided by B lymphocytes and their plasma cell (PC) descendants are crucial facets of responses to vaccines and microbes. Metabolic processes and products regulate aspects of B cell proliferation and differentiation into germinal center (GC) and PC states along with Ab diversification. However, there is little information about lymphoid-cell-intrinsic functions of enzymes that mediate ether lipid biosynthesis. Imaging mass spectrometry (IMS) results had indicated that concentrations of a number of these phospholipids were substantially enhanced in GC compared to the background average in spleens, but it was unclear if biosynthesis in B cells was a basis for this finding, or whether cell-intrinsic biosynthesis contributes to B cell physiology or Ab responses. Ether lipid biosynthesis can involve the enzyme PexRAP, encoded by the Dhrs7b gene. Using IMS and immunization experiments in mouse models with inducible Dhrs7b loss of function, we now show that B-lineage-intrinsic expression of PexRAP promotes the magnitude and affinity maturation of a serological response. Moreover, the data revealed a Dhrs7b-dependent increase in ether phospholipids in primary follicles with a more prominent increase in GC. Mechanistically, PexRAP impacted B cell proliferation via enhanced survival associated with controlling levels of ROS and membrane peroxidation. These findings reveal a vital role of this peroxisomal enzyme in B cell homeostasis and the physiology of humoral immunity.

Distinct mechanisms of inhibition of Kv2 potassium channels by tetraethylammonium and RY785

jfg4wrk@gmail.com (Esam A Orabi) — Mon, 27 Apr 2026 00:00:00 +0000

Voltage-gated K⁺ channels play central roles in human physiology, in health, and disease. A repertoire of inhibitors that are both potent and specific would, therefore, be of great value. RY785 has been described as promising in this regard, as it selectively inhibits channels in the Kv2 subfamily with high potency. Its mechanism of action has not yet been determined at the molecular level, but functional studies indicate it differs from those of less specific inhibitors, such as quaternary-ammonium compounds or aminopyridines. To examine this mechanism at the single-molecule level, we have carried out a series of all-atom molecular dynamics simulations based on the structure of the Kv2.1 channel in the ion-conducting state. The simulations demonstrate both RY785 and tetraethylammonium spontaneously enter the channel interior through the cytoplasmic gate, but with distinct effects. Tetraethylammonium binds to a site adjacent to the selectivity filter, on the pore axis, thus blocking the flow of K⁺ ions. RY785, by contrast, binds to the channel walls, off-axis, and allows K⁺ flow while the gate remains open. This observation indicates RY785 inhibits Kv2.1 by fostering the occlusion of the gate, through a network of hydrophobic interactions therein, explaining why it also modulates the voltage-sensing mechanism of the channel, 3 nanometers away.

AFD thermosensory neurons mediate tactile-dependent locomotion modulation in C. elegans

jbai@fredhutch.org (Jihong Bai) — Mon, 27 Apr 2026 00:00:00 +0000

Sensory neurons drive animal behaviors by detecting environmental stimuli and relaying information to downstream circuits. Beyond their primary roles in sensing, these neurons often form additional synaptic connections outside their main sensory modality, suggesting broader contributions to behavior modulation. Here, we uncover an unexpected role for the thermosensory neuron AFD in coupling tactile experience to locomotion modulation in Caenorhabditis elegans. We show that while AFD employs cyclic guanosine monophosphate (cGMP) signaling for both thermotaxis and tactile-dependent modulation, the specific molecular components of the cGMP pathway differ between these two processes. Interestingly, disrupting the dendritic sensory apparatus of AFD, which is essential for thermotaxis, does not impair tactile-based locomotion modulation, indicating that AFD can mediate tactile-dependent behavior independently of its thermosensory apparatus. In contrast, ablating the AFD neuron eliminates tactile-dependent modulation, pointing to an essential role for AFD itself, rather than its sensory dendritic endings. Further, we find tactile-dependent modulation requires the AIB interneuron, which connects AFD to touch circuits via electrical synapses. Removing innexins expressed in AFD and AIB abolishes this modulation, while re-establishing AFD–AIB connections with engineered electrical synapses restores it. Collectively, these findings uncover a previously unrecognized function of AFD beyond thermosensation, highlighting its influence on context-dependent neuroplasticity and behavioral modulation through broader circuit connectivity.

Single-cell lineage tracing identifies hemogenic endothelial cells in the adult mouse bone marrow

jingxinfeng475@gmail.com (Avinash Bhandoola) — Mon, 27 Apr 2026 00:00:00 +0000

During mouse development, hematopoietic stem and progenitor cells (HSPCs) originate from hemogenic endothelial cells (ECs) through a process of endothelial-to-hematopoietic transition. These HSPCs are thought to fully sustain adult hematopoiesis. However, it remains unknown whether adult ECs retain hemogenic potential. Here, we used in vivo genetic lineage tracking at population and single-cell (sc) levels, scRNA sequencing, and bone marrow (BM) transplantation to detect hemogenic ECs in adult mice. We identify and characterize BM-resident, adult Cdh5/VE-Cadherin⁺ ECs that produce hematopoietic cell-progeny in vitro and in mice. These adult hemogenic ECs and their hematopoietic cell progeny give rise to hematopoietic cells following adoptive transfer into adult mice. Furthermore, blood cells generated from adult and developmental ECs comparably home to peripheral tissues, where they similarly contribute to inflammatory responses. Thus, our results identify previously unrecognized BM-derived adult hemogenic ECs that generate HSPC and functional mature blood cells.

Does the brain really know what word is coming next?

rja2163@columbia.edu (Richard J Antonello) — Mon, 27 Apr 2026 00:00:00 +0000

Apparent neural encoding of future words may arise from the statistical structure of language itself, rather than from predictive computations in the brain.

The dual molecular identity of vestibular kinocilia bridges structural and functional traits of primary and motile cilia

amir.tavakolitarghi@nih.gov (Amirrasoul Tavakoli) — Fri, 24 Apr 2026 00:00:00 +0000

Vestibular hair cells (HCs) convert gravitational and head motion cues into neural signals through mechanotransduction, mediated by the hair bundle—a mechanically integrated organelle composed of stereocilia and a kinocilium. The kinocilium, a specialized form of primary cilium, remains incompletely defined in structure, molecular composition, and function. To elucidate its characteristics, we conducted single-cell RNA sequencing of adult vestibular and cochlear HCs, uncovering a selective enrichment of primary and motile cilia-associated genes in vestibular HCs, particularly those related to the axonemal repeat complex. This enrichment of orthologous axoneme-related genes was conserved in zebrafish and human vestibular HCs, indicating a shared molecular architecture. Immunostaining validated the expression of key motile cilia markers in vestibular kinocilia. Moreover, live imaging of bullfrog and mouse HCs from crista ampullaris revealed spontaneous kinociliary motion. Together, these findings define the kinocilium as a unique organelle with molecular features of primary and motile cilia and suggest its previously unknown role as an active, force-generating element within the hair bundle.

The olfactory receptor SNIF-1 mediates foraging for leucine-enriched diets in C. elegans

vsingh001@dundee.ac.uk (Changchun Chen) — Fri, 24 Apr 2026 00:00:00 +0000

Acquisition of essential nutrients through diet is crucial for the survival of animals. Dietary odors might enable animals to forage for nutrient-rich diets. We asked if Caenorhabditis elegans, a bacterivorous nematode, uses olfactory cues to forage for essential amino acid-rich (EAA) diets. Using the native microbiota of C. elegans, we show that worms rely on olfaction to select leucine (EAA)-supplemented bacteria. Using gas chromatography, we find that leucine-supplemented bacteria produce isoamyl alcohol (IAA) odor in the highest abundance. Prior adaptation of worms to IAA diminishes the diet preference of worms. Several wild isolates of C. elegans display robust responses to IAA, emphasizing its ecological relevance. We find that foraging for a leucine-supplemented diet is mediated via the AWC olfactory neurons. Finally, we identify SNIF-1 G protein-coupled receptor in AWC neurons as a receptor for IAA and a mediator of dietary decisions in worms. Our study identifies a receptor-ligand module underpinning foraging behavior in C. elegans.

Teaching early-career researchers how to respond to peer reviewers

e.kalkhoven@umcutrecht.nl (Eric Kalkhoven) — Thu, 23 Apr 2026 00:00:00 +0000

The process of publishing a research article in a scientific journal inevitably involves revising the original version of the article to respond to the concerns raised by peer reviewers. In this article we describe a course module that introduces MSc students at Utrecht University in the Netherlands to this part of the publication process. During the module the students and an invited speaker actively discuss the revision process for a recent article by the speaker. Feedback from students and speakers on the module – which could be readily transferred to other courses in the life and biomedical sciences – has been largely positive.

SMC complex unidirectionally translocates DNA by coupling segment capture with an asymmetric kleisin path

takada@biophys.kyoto-u.ac.jp (Giovanni Bruno Brandani) — Wed, 22 Apr 2026 00:00:00 +0000

SMC (structural maintenance of chromosomes) protein complexes are ring-shaped molecular motors essential for genome folding. Despite recent progress, the detailed molecular mechanism of DNA translocation in concert with the ATP-driven conformational changes of the complex remains to be clarified. In this study, we elucidated the mechanisms of SMC action on DNA using all-atom and coarse-grained molecular dynamics simulations. We first created a near-atomic full-length model of a prokaryotic SMC–kleisin complex based on experimental structures and implemented ATP-dependent conformational changes using a structure-based coarse-grained model. We further incorporated key protein–DNA hydrogen-bond interactions derived from fully atomistic simulations. Extensive simulations of the SMC complex with 800 base pairs of duplex DNA over the ATP cycle observed unidirectional DNA translocation by the SMC complex. The process exhibited a step size of ~200 base pairs, wherein the SMC complex captured a DNA segment of about the same size within the SMC ring in the engaged state, followed by its pumping into the kleisin ring as ATP was hydrolyzed. Analysis of trajectories identified the asymmetric path of the kleisin as a critical factor for the observed unidirectionality.

Multiple functions of cerebello-thalamic neurons in learning and offline consolidation of a motor skill in mice

lena@biologie.ens.fr (Andrés Pablo Varani) — Wed, 22 Apr 2026 00:00:00 +0000

Motor skill learning is a complex and gradual process that involves the cortex and basal ganglia, both crucial for the acquisition and long-term retention of skills. The cerebellum, which rapidly learns to adjust the movement, connects to the motor cortex and the striatum primarily via the ventral and intralaminar thalamus, respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. Using a targeted chemogenetic inhibition that preserves the motor abilities, we found that cerebellar nuclei neurons projecting to the intralaminar thalamus contribute to learning and expression, while cerebellar nuclei neurons projecting to the ventral thalamus contribute to offline consolidation. Asymptotic performance, however, required each type of neurons. Thus, our results show that cerebellar neurons belonging to two parallel cerebello-thalamic pathways play distinct, but complementary, roles functioning on different timescales and both necessary for motor skill learning.

HEB collaborates with TCR signaling to upregulate Id3 and enable γδT17 cell maturation in the fetal thymus

manderso@sri.utoronto.ca (Cornelis Murre) — Wed, 22 Apr 2026 00:00:00 +0000

T cells expressing the γδ T cell receptor (TCR) develop in a stepwise process initiating at the αβ/γδ T cell branch point, followed by maturation and acquisition of effector functions, including the ability to produce interleukin-17 (IL-17) as γδT17 cells. Previous studies linked TCR signal strength and fate choices to the transcriptional regulator HEB (Tcf12) and its antagonist, Id3, but how these factors regulate different stages of γδ T cell development has not been determined. We found that immature fetal γδTCR⁺ cells from conditional Tcf12 knockout (HEB cKO) mice were defective in activating the γδT17 program at an early stage, whereas Id3-deficient (Id3-KO) mice displayed a partial block in γδT17 maturation and a defect in IL-17 production. We also found that HEB cKO mice failed to upregulate Id3 during γδT17 development, whereas HEB overexpression elevated the levels of Id3 in collaboration with TCR signaling. Moreover, Egr2 and HEB were bound to several of the same regulatory sites on the Id3 gene locus in the context of early T cell development. Therefore, our findings reveal an interlinked sequence of events during which HEB and TCR signaling synergize to upregulate Id3, which enables maturation and acquisition of the γδT17 effector program.

A quantitative in vivo CRISPR-imaging platform identifies regulators of hyperplastic and hypertrophic adipose morphology in zebrafish

james.minchin@ed.ac.uk (James Minchin) — Wed, 22 Apr 2026 00:00:00 +0000

Adipose tissues exhibit a remarkable capacity to expand, regress, and remodel in response to energy status. The cellular mechanisms underlying adipose remodelling are central to metabolic health. Hypertrophic remodelling – characterised by the enlargement of existing adipocytes – is associated with insulin resistance, type 2 diabetes, and cardiovascular disease. In contrast, hyperplastic remodelling – in which new adipocytes are generated – is linked to improved metabolic outcomes. Despite its clinical importance, the regulation of hypertrophic and hyperplastic adipose morphology remains poorly understood. Here, we integrate human transcriptomic data with a quantitative CRISPR-imaging platform in zebrafish to identify regulators of adipose morphology. We developed an image-based phenotyping pipeline that captures lipid droplet size, number, and spatial patterning, and applied generalised additive modelling to quantify hyperplastic versus hypertrophic morphology signatures. Using this platform, we conducted an F0 CRISPR screen targeting 25 candidate genes and identified three that induced hypertrophic morphology (txnipa, mmp14b, and foxp1b) and an additional candidate that altered total adiposity (kazna). For functional validation, we generated stable loss-of-function alleles for both zebrafish foxp1 paralogues. Spatial analysis along the anterior-posterior axis revealed that foxp1b mutants display developmental hypertrophy but profoundly blunted adaptive responses to high-fat diet (~68% reduction across all spatial zones), while foxp1a mutants show normal baseline morphology but disrupted spatial patterning of diet-induced hypertrophy. Together, these findings establish a scalable CRISPR-imaging platform for in vivo genetic screening of adipose morphology and reveal distinct roles for Foxp1 paralogues in developmental patterning and adaptive responses to dietary challenge in adipose tissue.

Colony demographics shape nest construction in Camponotus fellah ants

ofer.feinerman@weizmann.ac.il (Ehud Fonio) — Wed, 22 Apr 2026 00:00:00 +0000

The ant nest serves as the skeleton of the ant superorganism. Similar to a skeleton, the nest expands as the colony grows and requires repair after catastrophic events. We experimentally compared nest excavation in colonies seeded from a single mated queen and allowed to grow for 6 months to excavation triggered by a catastrophic event in colonies with fixed demographics, where the age of each worker, including the queen, is known. The areas excavated by equal group sizes differed significantly between these conditions: heterogeneous populations in naturally growing colonies as well as cohorts of young ants dig larger areas than old ant cohorts. Moreover, we find that younger ants tend to dig slanted tunnels while older ants dig straight down. This is a novel form of age polyethism, where an ant’s age dictates not only her likelihood to engage in a task but also the way she performs the task. We further present a quantitative model that predicts that under normal growth, digging is predominantly performed by the younger ants, while after a catastrophe, all ants dig to restore lost nest volume. The fact that the nests of naturally growing colonies exhibit slanted tunnels strengthens this prediction. Finally, our results indicate how a colony’s demographic and physical history are sketched into the current structure of its nest.

Clathrin-independent endocytosis and retrograde transport in cancer cells tune immune synapse organization and CD8 T cell response

henri-francois.renard@unamur.be (Alix Buridant) — Wed, 22 Apr 2026 00:00:00 +0000

Endophilin A3-mediated clathrin-independent endocytosis (EndoA3-mediated CIE) contributes to the internalization of immunoglobulin-like proteins, including key immune synapse components. Here, we identify ICAM1 as a novel EndoA3-dependent cargo, alongside ALCAM. We demonstrate that both proteins subsequently follow retromer-dependent retrograde transport to the trans-Golgi network (TGN) in cancer cells. From there, we propose that they undergo polarized redistribution to the plasma membrane, where they contribute to immune synapse formation between cancer cells and cytotoxic CD8 T cells. Disruption of EndoA3 or retromer components significantly affects the response of autologous cytotoxic CD8 T cells, as evidenced by reduced cytokine production and secretion, but increased lytic activity, while proliferation and later activation marker expression remain intact. This is accompanied by diminished ICAM1 density at the immune synapse, where we observe it arriving via polarized vesicular transport, indicating altered synapse organization. Indeed, cancer cells lacking EndoA3-mediated CIE or retromer form enlarged immune synapses that fail to sustain full T cell cytokine secretion, suggesting a compensatory attempt by T cells to overcome the defective synapse, while likely promoting more transient contacts that potentially favor serial killing. Together, these findings reveal that EndoA3-mediated CIE and retrograde transport act in concert in cancer cells to relocate immune synapse components via the Golgi, thereby fine-tuning the balance between cytotoxic T cell cytokine secretion and lytic activity. These insights contribute to a better understanding of the mechanisms governing immune synapse formation and organization, providing a necessary foundation for the long-term identification of new strategies to enhance T cell–mediated anti-tumor immunity.

Modeling the hallucinatory effects of classical psychedelics in terms of replay-dependent plasticity mechanisms

colin.bredenberg@mila.quebec (Blake Richards) — Tue, 21 Apr 2026 00:00:00 +0000

Classical psychedelics induce complex visual hallucinations in humans, generating percepts that are coherent at a low level, but which have surreal, dream-like qualities at a high level. While there are many hypotheses as to how classical psychedelics could induce these effects, there are no concrete mechanistic models that capture the variety of observed effects in humans, while remaining consistent with the known pharmacological effects of classical psychedelics on neural circuits. In this work, we propose the ‘oneirogen hypothesis,’ which posits that the perceptual effects of classical psychedelics are a result of their pharmacological actions inducing neural activity states that truly are more similar to dream-like states. We simulate classical psychedelics’ effects via manipulating neural network models trained on perceptual tasks with the Wake-Sleep algorithm. This established machine learning algorithm leverages two activity phases: a perceptual phase (wake) where sensory inputs are encoded, and a generative phase (dream) where the network internally generates activity consistent with stimulus-evoked responses. We simulate the action of psychedelics by partially shifting the model to the ‘Sleep’ state, which entails a greater influence of top-down connections, in line with the impact of psychedelics on apical dendrites. The effects resulting from this manipulation capture a number of experimentally observed phenomena, including the emergence of hallucinations, increases in stimulus-conditioned variability, and large increases in synaptic plasticity. We further provide a number of testable predictions which could be used to validate or invalidate our oneirogen hypothesis.

Brain-wide mapping of layer-specific functional connectivity in the human cortex at 3T using draining-vein-suppressed fMRI

weitang_chang@med.unc.edu (Kelly S Giovanello) — Tue, 21 Apr 2026 00:00:00 +0000

Layer-dependent functional magnetic resonance imaging (fMRI) is a promising yet challenging approach for investigating layer-specific functional connectivity (FC). Achieving a brain-wide mapping of layer-specific FC requires several technical advancements, including sub-millimeter spatial resolution, sufficient temporal resolution, functional sensitivity, global brain coverage, and high spatial specificity. Although gradient echo (GE)-based echo planar imaging (EPI) is commonly used for rapid fMRI acquisition, it faces significant challenges due to the draining-vein contamination. In this study, we addressed these limitations by integrating velocity-nulling (VN) gradients into a GE-BOLD fMRI sequence to suppress vascular signals from the vessels with fast-flowing velocity. The extravascular contamination from pial veins was mitigated using a GE-EPI sequence at 3T rather than 7T, combined with phase regression methods. Additionally, we incorporated advanced techniques, including simultaneous multi-slice (SMS) acceleration and NOise Reduction with DIstribution Corrected principal component analysis (NORDIC PCA) denoising, to improve temporal resolution, spatial coverage, and signal sensitivity. This resulted in a VN fMRI sequence with 0.9 mm isotropic spatial resolution, a repetition time (TR) of 4 s, and brain-wide coverage. The VN gradient strength was determined based on results from a button-pressing task. Using resting-state data, we validated layer-specific FC through seed-based analyses, identifying distinct connectivity patterns in the superficial and deep layers of the primary motor cortex (M1), with significant inter-layer differences. Further analyses with a seed in the primary sensory cortex (S1) demonstrated the reliability of the method. Brain-wide layer-dependent FC analyses yielded results consistent with prior literature, reinforcing the efficacy of VN fMRI in resolving layer-specific functional connectivity. Given the widespread availability of 3T scanners, this technical advancement has the potential for significant impact across multiple domains of neuroscience research.

Prior cocaine use disrupts identification of hidden states by single units and neural ensembles in orbitofrontal cortex

wenhui.zong@nih.gov (Geoffrey Schoenbaum) — Tue, 21 Apr 2026 00:00:00 +0000

The orbitofrontal cortex (OFC) is critical to identifying task structure and to generalizing appropriately across task states with similar underlying or hidden causes. This capability is at the heart of OFCs proposed role in a network responsible for cognitive mapping, and its loss can explain many deficits associated with OFC damage or inactivation. Substance use disorder is defined by behaviors that share much in common with these deficits, such as an inability to modify learned behaviors in the face of new information about undesired consequences. One explanation for this similarity would be if addictive drugs impacted the ability of OFC to recognize underlying similarities, hidden states, that allow information learned in one setting to be used in another. To explore this possibility, we trained rats to self-administer cocaine and then recorded single-unit activity in lateral OFC as these rats performed in an odor sequence task consisting of unique and shared positions. In well-trained controls, we observed chance decoding of sequence at shared positions and near chance decoding even at unique positions, reflecting the irrelevance of distinguishing these positions in the task. By contrast, in cocaine-experienced rats, decoding remained significantly elevated, particularly at the positions that had superficial sensory differences that were collapsed in controls across learning. These neural differences were accompanied by increases in behavioral variability at these positions. A tensor component analysis showed that this effect of reduced generalization after cocaine use also extended across positions in the sequences. These results show that prior cocaine use disrupts the normal identification of hidden states by OFC.

Antibiotic potentiation and inhibition of cross-resistance in pathogens associated with cystic fibrosis

nikol.kaderabkova@austin.utexas.edu (Alain Filloux) — Tue, 21 Apr 2026 00:00:00 +0000

Critical Gram-negative pathogens, like Pseudomonas, Stenotrophomonas, and Burkholderia, are now resistant to most antibiotics. Complex resistance profiles, together with synergistic interactions between these organisms, increase the likelihood of treatment failure in distinct infection settings, for example in the lungs of cystic fibrosis (CF) patients. Here, we discover that cell envelope protein homeostasis pathways underpin both antibiotic resistance and cross-protection in CF-associated bacteria. We find that inhibition of oxidative protein folding inactivates multiple species-specific resistance proteins. Using this strategy, we sensitize multidrug-resistant Pseudomonas aeruginosa to β-lactam antibiotics and demonstrate promise of new treatment avenues for the recalcitrant emerging pathogen Stenotrophomonas maltophilia. The same approach also inhibits cross-protection between resistant S. maltophilia and susceptible P. aeruginosa, allowing eradication of both commonly co-occurring CF-associated organisms. Our results provide the basis for the development of next-generation strategies that target antibiotic resistance, while also impairing specific interbacterial interactions that enhance the severity of polymicrobial infections.

Orderly mitosis shapes interphase genome architecture

mistelit@mail.nih.gov (Adib Keikhosravi) — Tue, 21 Apr 2026 00:00:00 +0000

Genomes assume a complex 3D architecture in the interphase cell nucleus. Yet the molecular mechanisms that determine global genome architecture are only poorly understood. To identify mechanisms of higher-order genome organization, we performed high-throughput imaging-based CRISPR knockout screens targeting 1064 genes encoding nuclear proteins in multiple human cell lines. We assessed changes in the distribution of centromeres at single-cell resolution as surrogate markers for global genome organization. The screens revealed multiple major regulators of spatial distribution of centromeres, including components of the nucleolus, kinetochore, cohesins, condensins, and the nuclear pore complex. Alterations in centromere distribution required progression through the cell cycle and acute depletion of mitotic factors with distinct functions altered centromere distribution in the subsequent interphase. These results identify molecular determinants of spatial centromere organization, and they show that orderly progression through mitosis shapes interphase genome architecture.

Single-cell co-mapping reveals relationship between chromatin state and gene expression in early zebrafish development

v.bhardwaj@uu.nl (Alberto Griffa) — Tue, 21 Apr 2026 00:00:00 +0000

Establishing a cell type-specific chromatin landscape is crucial for the maintenance of cell identity during embryonic development. However, our knowledge of how this landscape is set during vertebrate embryogenesis has been limited, due to the lack of methods to jointly detect chromatin modifications and gene expression in the same cell. Here we present a multimodal measurement of full-length transcriptome and histone modifications in individual cells during early embryonic development in zebrafish. We show that before the formation of germ layers, the chromatin and transcription states of cells are uncoupled and become progressively connected during gastrulation and somitogenesis. Silencing of developmental genes is achieved by local spreading of repressive chromatin together with cell type-specific demethylation. Combining transcription factor (TF) expression and chromatin states within an interpretable machine learning model, we classify TFs as lineage-specific activators and repressors and identify a subset of TFs that are epigenetically regulated. Altogether, our data resolves the dynamic relationship between chromatin and transcription during early vertebrate development and clarifies how these two layers interact to establish cell identity.

PPIscreenML is a method for structure-based screening of protein-protein interactions using AlphaFold

johnkaranicolas1@gmail.com (Jesse Chen) — Tue, 21 Apr 2026 00:00:00 +0000

Protein-protein interactions underlie nearly all cellular processes. With the advent of protein structure prediction methods such as AlphaFold2 (AF2), models of specific protein pairs can be built extremely accurately in most cases. However, determining the relevance of a given protein pair remains an open question. It is presently unclear how to use best structure-based tools to infer whether a pair of candidate proteins indeed interacts with one another: ideally, one might even use such information to screen among candidate pairings to build up protein interaction networks. Whereas methods for evaluating quality of modeled protein complexes have been co-opted for determining which pairings interact (e.g. pDockQ and iPTM), there have been no rigorously benchmarked methods for this task. Here, we introduce PPIscreenML, a classification model trained to distinguish AF2 models of interacting protein pairs from AF2 models of compelling decoy pairings. We find that PPIscreenML outperforms methods such as pDockQ and iPTM for this task, and further that PPIscreenML exhibits impressive performance when identifying which ligand/receptor pairings engage one another across the structurally conserved tumor necrosis factor superfamily (TNFSF). Analysis of benchmark results using complexes not seen in PPIscreenML development strongly suggests that the model generalizes beyond training data, making it broadly applicable for identifying new protein complexes based on structural models built with AF2.

The robust, high-throughput, and temporally regulated roxCre and loxCre reporting systems for genetic modifications in vivo

kathyolui@cuhk.edu.hk (Bin Zhou) — Mon, 20 Apr 2026 00:00:00 +0000

Cre-loxP technology, a cornerstone in fate mapping and in vivo gene function studies, faces challenges in achieving precise and efficient conditional mutagenesis through inducible systems. This study introduces two innovative genetic tools designed to overcome these limitations. The first, roxCre, enables DreER-mediated Cre release, paving the way for intersectional genetic manipulation that permits increased precision and efficiency. The second, loxCre, facilitates conditional gene targeting by allowing CreER lines to induce Cre expression with significantly enhanced efficiency. These tools incorporate a fluorescent reporter for genetic lineage tracing, simultaneously revealing efficient gene knockout in cells marked by the reporter. These strategies hold great potential for precise and efficient exploration of lineage-specific gene functions, marking a significant advancement in genetic research methodologies.

Dimorphic neural network architecture prioritizes sexual-related behaviors in male Caenorhabditis elegans

heliu@bnu.edu.cn (Chunxiuzi Liu) — Mon, 20 Apr 2026 00:00:00 +0000

Neural network architecture determines its functional output. However, the detailed mechanisms are not well characterized. In this study, we focused on the neural network architectures of male and hermaphrodite Caenorhabditis elegans and the association with sexually dimorphic behaviors. We applied graph theory and computational neuroscience methods to systematically discern the features of these two neural networks. Our findings revealed that a small percentage of sexual-specific neurons exerted dominance throughout the entire male neural network, suggesting males prioritized sexual-related behavior outputs. Based on the structural and dynamical characteristics of two complete neural networks, sub-networks containing sex-specific neurons and their immediate neighbors, or sub-networks exclusively comprising sex-shared neurons, we predicted dimorphic behavioral outcomes for males and hermaphrodites. To verify the prediction, we performed behavioral and calcium imaging experiments and dissected a circuit that is specific for the increased spontaneous local search in males for mate-searching. Our research sheds light on the neural circuits that underlie sexually dimorphic behaviors in C. elegans and provides significant insights into the interconnected relationship between network architecture and functional outcomes at the whole-brain level.

Alpha-band phase modulates perceptual sensitivity by changing internal noise and sensory tuning

apilipen@ucsc.edu (Alexandra McGowan) — Mon, 20 Apr 2026 00:00:00 +0000

Alpha-band neural oscillations (8–13 Hz) are theorized to phasically inhibit visual processing based, in part, on results showing that pre-stimulus alpha phase predicts detection (i.e., hit rates). However, recent failures to replicate and a lack of a mechanistic understanding regarding how alpha impacts detection have called this theory into question. We recorded EEG while six observers (6020 trials each) detected near-threshold Gabor targets embedded in noise. Using signal detection theory (SDT) and reverse correlation, we observed an effect of occipital and frontal pre-stimulus alpha phase on sensitivity (d'), not criterion. Hit and false alarm rates were counterphased, consistent with a reduction in internal noise during optimal alpha phases. Perceptual reports were also more consistent when two identical stimuli were presented during the optimal phase, suggesting a decrease in internal noise rather than signal amplification. Classification images revealed sharper spatial frequency and orientation tuning during the optimal alpha phase, implying that alpha phase shapes sensitivity by modulating sensory tuning towards relevant stimulus features.

How individual vigor shapes human–human physical interaction

dverdel@ic.ac.uk (Bastien Berret) — Mon, 20 Apr 2026 00:00:00 +0000

The speed of voluntary movements varies systematically, with some individuals moving consistently faster than others across different actions. These variations, conceptualized as vigor, reflect a time–effort–accuracy tradeoff in motor planning. How do two mechanically coupled partners with different individual vigors collaborate, e.g. to move a table together? Here, we show that such dyads coordinate goal-directed movements with minimal interaction force, exhibiting a dyadic vigor with similar characteristics as individual vigor. The emerging dyadic motor plan is strongly influenced by the slower partner, whose vigor predicts dyadic vigor, with effects lasting beyond practice. Computational modeling with stochastic optimal control reveals the critical role of partners’ movement timing uncertainty and vigor in shaping coordination, allowing us to predict dyadic movements from individual behavior across diverse conditions. These findings shed light on the mechanisms underlying human collaboration and may be used in applications ranging from physical training and rehabilitation to collaborative robotics for manufacturing.

Structural mechanisms of pump assembly and drug transport in the AcrAB–TolC efflux system

gxf16@tsinghua.org.cn (Jiawei Wang) — Mon, 20 Apr 2026 00:00:00 +0000

Tripartite multidrug efflux pumps that span the cell envelope are essential for antibiotic resistance in Gram-negative bacteria. Here, we report cryo-EM structures of two endogenous efflux complexes from Escherichia coli: a TolC–YbjP subcomplex at 3.56 Å resolution and the complete TolC–YbjP–AcrABZ pump at 3.39 Å. Structural analysis reveals that YbjP, a previously uncharacterized lipoprotein, binds TolC in a 3:3 stoichiometry, bridging the TolC protomers at their equatorial domain. Clear density of the mature YbjP’s N-terminal Cys19 indicates that YbjP is anchored to the outer membrane by an N-terminal lipid moiety. Notably, YbjP remains bound as TolC undergoes AcrA-induced opening, suggesting that this accessory protein accommodates the conformational change. The AcrB trimer simultaneously presents three distinct conformational states (L, T, and O), capturing a complete transport cycle. These high-resolution structures provide insights into the architecture and mechanism of clinically relevant efflux machinery, identifying YbjP as a previously unrecognized structural component that contributes to TolC positioning, and may assist in its membrane localization.

Taking the biology seriously makes models better

a.gil@ucl.ac.uk (Andreas Tiffeau-Mayer) — Mon, 20 Apr 2026 00:00:00 +0000

A new biologically-informed training paradigm enables protein language models to predict affinity maturation trajectories for antibodies.

PTEN restrains SHH medulloblastoma growth through cell autonomous and nonautonomous mechanisms

joynera@mskcc.org (Alexandra L Joyner) — Fri, 17 Apr 2026 00:00:00 +0000

A third of patients with the pediatric cerebellar tumor Medulloblastoma (MB) have mutations that activate Sonic hedgehog (SHH) signaling (SHH-MB subgroup). The contribution of secondary mutations to tumor severity, however, is not clear. PTEN mutations are enriched in the SHH-1 subtype that has the lowest survival rate. Widespread heterozygous loss of Pten in two SHH-MB mouse models increases penetrance and accelerates onset of differentiated tumors. We delineated cellular and transcriptional changes that accelerate tumor growth and cause differentiation using a sporadic SHH-MB mouse model expressing oncogenic SmoM2 in rare cerebellar granule cell precursors (GCPs) and scRNA-seq analysis. Homozygous but not heterozygous sporadic loss of Pten resulted in rapid acceleration of tumor growth and end-stage disease by 40 days, compared to ~25% survival in control SmoM2 mice at 100 days. Heterozygous PTEN mutations, therefore, should negatively impact disease outcome primarily with germline mutations. Loss of Pten in normal or SmoM2-expressing GCPs increased proliferation and enhanced progenitor state initially, but by 12 days Pten mutant SmoM2 tumors were highly differentiated due to increased survival of non-proliferating GCPs. Furthermore, macrophage infiltration and cytotoxicity appeared reduced in differentiated regions of tumors lacking Pten, indicating cell nonautonomous changes could also contribute to accelerated tumor growth.

Modality-agnostic decoding of vision and language from fMRI

mitja.nikolaus@posteo.de (Isabelle Berry) — Fri, 17 Apr 2026 00:00:00 +0000

Humans perform tasks involving the manipulation of inputs regardless of how these signals are perceived by the brain, thanks to representations that are invariant to the stimulus modality. In this paper, we present modality-agnostic decoders that leverage such modality-invariant representations to predict which stimulus a subject is seeing, irrespective of the modality in which the stimulus is presented. Training these modality-agnostic decoders is made possible thanks to our new large-scale fMRI dataset SemReps-8K, released publicly along with this paper. It comprises six subjects watching both images and short text descriptions of such images, as well as the conditions during which the subjects were imagining visual scenes. We find that modality-agnostic decoders can perform as well as modality-specific decoders and even outperform them when decoding captions and mental imagery. Furthermore, a searchlight analysis revealed that large areas of the brain contain modality-invariant representations. Such areas are also particularly suitable for decoding visual scenes from the mental imagery condition.

Cdhr1a and pcdh15b may link photoreceptor outer segments with calyceal processes revealing a potential mechanism for cone-rod dystrophy

jakub.famulski@uky.edu (Jakub K Famulski) — Fri, 17 Apr 2026 00:00:00 +0000

Cone-rod dystrophy (CRD) is a macular degeneration disorder characterized by initial cone cell degeneration. Mutations in CDHR1, a photoreceptor-specific cadherin, have been found to be associated with the incidence of CRD. While studying the function of CDHR1, we observed that the localization of the zebrafish homologue, cdhr1a, resembles that of calyceal process (CPs). When co-labeling CPs using pcdh15b, we observed that cdhr1a, in the outer segment (OS), juxtaposes with pcdh15b, found in the CP. Similar localization patterns were detected in human, macaque, xenopus, ducks, gerbil, and mouse. Using immunoprecipitation and K652 cell aggregation assays, we demonstrate that pcdh15b and cdhr1a can interact and thus potentially link the OS and CP. To analyze the consequences of OS-CP interactions in CRD, we established a cdhr1a mutant line (cdhr1a^fs*146). Homozygous cdhr1a^fs*146 mutants exhibit minor cone OS defects starting at 15 dpf and severe OS disruption and cell loss by 3 months. Shortening of CPs coincided with cone OS defects which were significantly exacerbated when combined with the loss of pcdh15b. Rod OS defects were mild and delayed until 3–6 months. In conclusion, we propose that cdhr1a and pcdh15b function to link cone OSs with CPs and maintain OS integrity.

Correction: Autologous P63+ lung progenitor cell transplantation in idiopathic pulmonary fibrosis: a phase 1 clinical trial

Fri, 17 Apr 2026 00:00:00 +0000

Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle

jayanthag@imcb.a-star.edu.sg (Christopher G Sobey) — Fri, 17 Apr 2026 00:00:00 +0000

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16 hr daily fasting regimen (IF16) over 4 months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

Single-mRNA imaging and modeling reveal coupled translation initiation and elongation rates

cedric.gobet@epfl.ch (Cédric Gobet) — Fri, 17 Apr 2026 00:00:00 +0000

mRNA translation involves multiple regulatory steps, but how translation elongation influences protein output remains unclear. Using SunTag live-cell imaging and mathematical modeling, we quantified translation dynamics in single mRNAs across diverse coding sequences. Our Totally Asymmetric Exclusion Process (TASEP)-based Hidden Markov Model revealed a strong coordination between initiation and elongation rates, resulting in consistently low ribosome density (≤12% occupancy) across all reporters. This coupling persisted under pharmacological inhibition of the elongation factor eIF5A, where proportional decreases in both initiation and elongation rates maintained homeostatic ribosome density. In contrast, eIF5A knockout cells exhibited a significant decrease in ribosome density, suggesting altered coordination. Together, these results highlight a dynamical coupling of initiation and elongation rates at the single-mRNA level, preventing ribosome crowding and maintaining translational homeostasis in mammalian cells.

Fragmentation and aggregation of cyanobacterial colonies

y.z.sinzato@uva.nl (Jef Huisman) — Fri, 17 Apr 2026 00:00:00 +0000

Fluid flow has a major effect on the aggregation and fragmentation of bacterial colonies. Yet, a generic framework to understand and predict how hydrodynamics affects colony size remains elusive. This study investigates how fluid flow affects the formation and maintenance of large colonial structures in cyanobacteria, using an experimental technique that precisely controls hydrodynamic conditions. We performed experiments on laboratory cultures and lake samples of the cyanobacterium Microcystis, while their colony size distribution was measured simultaneously by direct microscopic imaging. We demonstrate that extracellular polymeric substances (EPS)-embedded cells formed by cell division exhibit significant mechanical resistance to shear forces. However, at elevated hydrodynamic stress levels (exceeding those typically generated by surface wind mixing), these colonies experience fragmentation through an erosion process. We also show that single cells can aggregate into small colonies due to fluid flow. However, the structural integrity of these flow-induced colonies is weaker than that of colonies formed by cell division. We provide a mathematical analysis to support the experiments and demonstrate that a population model with two categories of colonies describes the measured size distributions. Our results shed light on the specific conditions wherein flow-induced fragmentation and aggregation of cyanobacteria are decisive and indicate that colony formation under natural conditions is mainly driven by cell division, although flow-induced aggregation could play a role in dense bloom events. These findings can be used to improve prediction models and mitigation strategies for toxic cyanobacterial blooms and also offer potential applications in other areas, such as algal biotechnology or medical settings where the dynamics of biological aggregates play a significant role.

Geomagnetic and visual cues guide seasonal migratory orientation in the nocturnal fall armyworm, the world’s most invasive insect

hugao@njau.edu.cn (Bo-Ya Gao) — Thu, 16 Apr 2026 00:00:00 +0000

The mechanisms guiding nocturnal insect migration remain poorly understood. Although many species are thought to use the geomagnetic field, the sensory basis of magnetic orientation in insects has yet to be clarified. We developed an indoor experimental system to investigate the integration of geomagnetic and visual cues in the seasonal orientation of a globally distributed pest moth, the fall armyworm (Spodoptera frugiperda), a highly invasive species which in the past decade has colonized almost all potentially habitable regions of the globe. Our results demonstrate that fall armyworms require both geomagnetic and visual cues for accurate migratory orientation, with visual cues being indispensable for magnetic orientation. When visual and geomagnetic cues are placed in conflict, moths become disoriented, although not immediately, indicating that sensory recognition of the conflict requires time to process. We also show that the absence of visual cues leads to a significant loss of flight stability, which likely explains the disruption in orientation. Our findings highlight that visual cues are critical for stable magnetic orientation in the fall armyworm, offering a basis for future investigations of visual-magnetic integration in noctuid migrants.

Heat shock factor regulation of antimicrobial peptides expression suggests a conserved defense mechanism induced by febrile temperature in arthropods

lsshjg@mail.sysu.edu.cn (Bang Xiao) — Thu, 16 Apr 2026 00:00:00 +0000

Temperature is a critical factor influencing the outbreak and progression of viral diseases in organisms. Febrile temperatures have been shown to enhance immune competence and reduce viral replication in various species. However, the underlying mechanisms remain largely unknown. In this study, we investigate the molecular mechanisms by which elevated temperatures confer resistance to viral infections, focusing on the role of heat shock factor 1 (HSF1) in regulating antimicrobial effectors rather than the traditional target genes molecular chaperones. Using shrimp Litopenaeus vannamei as a model, we demonstrate that febrile temperatures induce HSF1, which in turn upregulates antimicrobial peptides (AMPs) that target viral envelope proteins and inhibit viral replication. Importantly, this is the first to show that HSF1 directly binds to the heat shock element (HSE) motifs of AMPs both in shrimp and Drosophila S2 cells, suggesting this may be a conserved regulatory mechanism in arthropods. Additionally, our findings highlight the role of HSF1 beyond the classical heat shock response, revealing its critical function in modulating innate immunity. These insights provide new avenues for managing viral infections in aquaculture and other settings by leveraging environmental temperature control.

Global transcription factors analyses reveal hierarchy and synergism of regulatory networks and master virulence regulators in Pseudomonas aeruginosa

xindeng@cityu.edu.hk (Beifang Lu) — Thu, 16 Apr 2026 00:00:00 +0000

The transcription factor (TF) regulatory network in Pseudomonas aeruginosa is complex and involves multiple regulators that respond to various environmental signals and physiological cues by regulating gene expression. However, the biological functions of at least half of its 373 putative TFs remain uncharacterised. Herein, chromatin immunoprecipitation sequencing (ChIP-seq) was used to investigate the binding sites of 172 TFs in the P. aeruginosa PAO1 strain. The results revealed 81,009 significant binding peaks in the genome, more than half of which were located in the promoter regions. To further decode the diverse regulatory relationships among TFs, a hierarchical network was assembled into three levels: top, middle, and bottom. Thirteen ternary regulatory motifs revealed flexible relationships among TFs in small hubs, and a comprehensive co-association atlas was established, showing the enrichment of seven core associated clusters. Twenty-four TFs were identified as the master regulators of virulence-related pathways. The pan-genome analysis revealed the conservation and evolution of TFs in P. aeruginosa complex and other species. A web-based database combining existing and new data from ChIP-seq and the high-throughput systematic evolution of ligands by exponential enrichment was established for searching TF-binding sites. This study provides important insights into the pathogenic mechanisms of P. aeruginosa and related bacteria and is expected to contribute to the development of effective therapies for infectious diseases caused by this pathogen.

A lipoprotein partner for the Escherichia coli outer membrane protein TolC

bfl20@cam.ac.uk (Andrzej Harris) — Wed, 15 Apr 2026 00:00:00 +0000

The outer membrane protein TolC from Escherichia coli belongs to an extensive superfamily whose members are found throughout the didermal, Gram-negative bacterial lineages. The protein serves as an activated exit duct in multi-drug efflux pumps and protein secretion machinery. Many TolC homologues bear a lipid modification on the N-terminus that embeds into the inner leaflet of the outer membrane and appears to have been a conserved feature; however, the moiety is absent entirely in the E. coli TolC. We have discovered that the E. coli lipoprotein YbjP interacts extensively with the periplasmic surface of TolC and its N-terminal lipid moiety is embedded in the membrane, mimicking the intramolecular and modification-membrane interactions seen in TolC homologues. Here, we present cryo-EM structures of the MacA-MacB-TolC and AcrA-AcrB-TolC tripartite pumps complexed to YbjP. Although the association occurs spontaneously both in vitro and in vivo, the YbjP-TolC interaction is not required for efflux activity under standard laboratory conditions. YbjP may contribute to stabilising the orientation and distribution of TolC in the outer membrane, as well as the expression of transporters for tryptophan and cyclic peptide toxins.

TAD boundaries and gene activity are uncoupled

mistelit@mail.nih.gov (Adib Keikhosravi) — Wed, 15 Apr 2026 00:00:00 +0000

Topologically associating domains (TADs) are prominent features of genome organization. A proposed function of TADs is to contribute to gene regulation by promoting chromatin interactions within a TAD and by suppressing interactions between TADs. Here, we directly probe the structure-function relationship of TADs by simultaneously assessing the behavior of TAD boundaries and gene activity at the single-cell and -allele level using high-throughput imaging. We find that while TAD boundaries pair more frequently than non-boundary regions, these interactions are infrequent and are uncorrelated with transcriptional activity of genes within the TAD. Similarly, acute global transcriptional inhibition or gene-specific activation does not alter TAD boundary proximity. Furthermore, while loss of the cohesin component RAD21 alters gene activity, disruption of TAD boundaries by depletion of the architectural chromatin protein CTCF is insufficient to alter expression of genes within the TAD. These results suggest that TAD boundary architecture and gene activity are largely uncoupled.

Heterogeneity of Sonic Hedgehog response dynamics and fate specification in single neural progenitors

fx220@cam.ac.uk (Andrea R Tentner) — Wed, 15 Apr 2026 00:00:00 +0000

During neural tube patterning, a gradient of Sonic hedgehog (Shh) signaling specifies ventral progenitor fates. The cellular response to Shh is processed through a genetic regulatory network (GRN) to specify distinct fate decisions. This process integrates Shh response level, duration, and other inputs and is affected by noise in signaling and cell position. How reliably the Shh response profile predicts the fate choice of a single cell remains unclear. Here, we use live imaging to track neural progenitors in developing zebrafish and quantify both Shh and fate reporters in single cells over time. We found that there is significant heterogeneity between Shh response and fate choice in single cells. We quantitatively modeled reporter intensities to obtain single-cell response levels over time and systematically evaluated their correlation with cell fate specification. Motor neuron progenitors (pMNs) exhibit a high degree of variability in their Shh responses, which is particularly prominent in the posterior neural tube where the Shh response dynamics are similar to those of the more ventrally fated lateral floor plate cells (LFPs). Our results highlight the precision limit of morphogen-interpretation GRNs in small and dynamic target cell fields.

A stress-activated neuronal ensemble in the supramammillary nucleus produces anxiety-like behavior in male mice

jhan2012@snnu.edu.cn (Jing Han) — Wed, 15 Apr 2026 00:00:00 +0000

Anxiety is a prevalent negative emotional state induced by stress; however, the neural mechanism underlying anxiety is still largely unknown. We used acute and chronic stress to induce anxiety and test anxiety-like behavior; immunostaining, multichannel extracellular electrophysiological recording, and Ca²⁺ imaging to evaluate neuronal activity; and virus-based neuronal tracing to label circuits and manipulate circuitry activity. Here, we identified a hypothalamic region, the supramammillary nucleus (SuM), that plays an important role in anxiety-like behavior. We then characterized a small ensemble of stress-activated neurons (SANs) that are recruited by stress. These SANs respond specifically to stress, and their activation robustly increases anxiety-like behavior in male mice. We also found that ventral subiculum (vSub)-SuM projections, but not dorsal subiculum (dSub)-SuM projections, encode anxiety-like behavior and that inhibition of these vSub-SuM projections has an antianxiety effect. These results indicate that the reactivation of stress-activated supramammillary cells and relevant neural circuits is an important neural process underlying anxiety-like behavior.

Hidden folds reveal brain organization

jurgen.germann@uhn.ca (Jürgen Germann) — Wed, 15 Apr 2026 00:00:00 +0000

Previously underappreciated folds in the cerebral cortex provide insight into how its structure varies across individuals.

New idtracker.ai rethinks multi-animal tracking as a representation learning problem to increase accuracy and reduce tracking time

gonzalo.polavieja@neuro.fchampalimaud.org (Gonzalo de Polavieja) — Wed, 15 Apr 2026 00:00:00 +0000

idTracker and idtracker.ai approach multi-animal tracking from video as an image classification problem. For this classification, both rely on segments of video where all animals are visible to extract images and their identity labels. When these segments are too short, tracking can become slow and inaccurate and, if they are absent, tracking is impossible. Here, we introduce a new idtracker.ai that reframes multi-animal tracking as a representation learning problem rather than a classification task. Specifically, we apply contrastive learning to image pairs that, based on video structure, are known to belong to the same or different identities. This approach maps animal images into a representation space where they cluster by animal identity. As a result, the new idtracker.ai eliminates the need for video segments with all animals visible, is more accurate, and tracks up to 700 times faster.

Epigenetics and chromatin structure regulate var2csa expression and the placental-binding phenotype in Plasmodium falciparum

karine.leroch@ucr.edu (Hannes Hoppe) — Wed, 15 Apr 2026 00:00:00 +0000

Plasmodium falciparum is responsible for what appears to be a never-ending public health issue in the developing world. With repeated infections, a gradual semi-immunity to severe malaria can be acquired, but this is disrupted when women become pregnant as the parasite cytoadheres in the placenta to prevent splenic clearance. This change in tissue tropism is due to specific transcription of the antigenically variable adhesin VAR2CSA. To better understand the molecular mechanisms activating var2csa and antigenic variation overall, we used a combination of phenotypic and systems biology assays. We first established phenotypically homogenous populations of VAR2CSA-expressing and placenta-binding parasites that were shown to exclusively transcribe var2csa while all other var genes remained silenced. We also confirmed that the transcriptional activation was strongly associated with distinct depletion of repressive H3K9me3 marks. Further, we used chromatin conformation capture as a high-resolution approach to determine interchromosomal interactions and established that transcriptional activation is linked to a small yet significant repositioning of var2csa relative to heterochromatic telomeric clusters. Lastly, we demonstrated that occupancy of 5-methylcytosine was present in all var genes but independent of transcriptional repression and switching. All together, these findings provide insights at high resolution into the potential role of 5-methylcytosine in P. falciparum and increase our understanding of the mechanisms regulating antigenic variation at the epigenetics and chromatin structure level.

Endogenous precision of the number sense

arthurpc@fas.harvard.edu (Arthur Prat-Carrabin) — Wed, 15 Apr 2026 00:00:00 +0000

The behavioral variability in psychophysical experiments and the stochasticity of sensory neurons have revealed the inherent imprecision in the brain’s representations of environmental variables. Numerosity studies yield similar results, pointing to an imprecise ‘number sense’ in the brain. If the imprecision in representations reflects an optimal allocation of limited cognitive resources, as suggested by efficient-coding models, then it should depend on the context in which representations are elicited. Through an estimation task and a discrimination task, both involving numerosities, we show that the scale of subjects’ imprecision increases, but sublinearly, with the width of the prior distribution from which numbers are sampled. This sublinear relation is notably different in the two tasks. The double dependence of the imprecision — both on the prior and on the task — is consistent with the optimization of a tradeoff between the expected reward, different for each task, and a resource cost of the encoding neurons’ activity. Comparing the two tasks allows us to clarify the form of the resource constraint. Our results suggest that perceptual noise is endogenously determined, and that the precision of percepts varies both with the context in which they are elicited and with the observer’s objective.

Kinesin-1 conformational dynamics are controlled by a cargo-sensitive TPR switch

jj.phillips@exeter.ac.uk (Christiane Schaffitzel) — Tue, 14 Apr 2026 00:00:00 +0000

Kinesin-1 is a dynamic heterotetrameric assembly of two heavy and two light chains (KHC and KLC) that mediates microtubule-based intracellular transport of many different cargoes. The complex adopts a compact, autoinhibited state that is activated by cargo-adaptor proteins containing specific short linear peptide motifs (SLiMs). These motifs interact with the tetratricopeptide repeat (TPR) domains of the KLCs. The mechanism coupling SLiM recognition to activation-associated conformational changes in the complex is unknown. Here, we combine protein design, computational modelling, biophysical analysis, and electron microscopy to examine the structural and mechanistic consequences of SLiM binding to the KLC-TPR domain within the complete heterotetrameric holoenzyme. We show that coiled coil 1 (CC1) of the KHC docks KLC TPR domains in the autoinhibited complex, forming the ‘shoulder’ feature observed in electron microscopy. Disrupting this interaction or binding an activating SLiM dislocates the TPR shoulder, freeing the motor domains and promoting transition between its closed, inactive, and open states. Opening the kinesin-1 complex facilitates binding to the microtubule-associated kinesin-1 cofactor, microtubule-associated protein 7 (MAP7). Therefore, cargo-mediated dislocation of the TPR shoulder serves as a key initial step in kinesin-1 activation, allosterically linking cargo binding to motor dynamics.

Synaptotagmin 1 and Synaptotagmin 7 promote MR1-mediated presentation of Mycobacterium tuberculosis antigens

karamooz@ohsu.edu (Andrew J Olive) — Tue, 14 Apr 2026 00:00:00 +0000

Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that can be sensed by T cells, which are essential for the control of infection. In comparison to viral infections, Mtb antigens are relatively limited and hence, challenging to sample. Specialized antigen presentation pathways enable the presentation of such scarce antigens to CD8⁺ T cells, which are, thus, uniquely poised to survey intracellular environments. A subset of CD8⁺ T cells prevalent in the airways, known as mucosal-associated invariant T (MAIT) cells, can be activated through the presentation of Mtb antigens via the major histocompatibility complex class I-related protein 1 (MR1) molecule. Prior work demonstrates that endosomal calcium signaling is critical for MR1-mediated presentation of Mtb-derived antigens. Here, we show that the calcium-sensing trafficking proteins Synaptotagmin (Syt) 1 and Syt7 specifically promote MAIT cell activation in response to Mtb-infected cells. In bronchial epithelial cells, Syt1 and Syt7 localize to late endo-lysosomes and MR1 vesicles. Loss of Syt1 and Syt7 results in enlarged MR1 vesicles and an increased number of MR1 vesicles in close proximity to Mtb-containing vacuoles during infection. This study identifies a specialized pathway in which Syt1 and Syt7 facilitate the translocation of MR1 from Mtb-containing vacuoles, potentially to the cell surface for antigen presentation.

Fear conditioning biases olfactory sensory neuron frequencies across generations

bjm2174@columbia.edu (Alexis Kim) — Tue, 14 Apr 2026 00:00:00 +0000

The main olfactory epithelium initiates the process of odor encoding. Recent studies have demonstrated intergenerationally inherited changes in the olfactory system in response to fear conditioning, resulting in increases in olfactory sensory neuron frequencies and altered responses to odors. We investigated changes in the cellular composition of the olfactory epithelium in response to an aversive stimulus. Here, we achieve volumetric cellular resolution to demonstrate that olfactory fear conditioning increases the number of odor-encoding neurons in mice that experience odor-shock conditioning (F0), as well as their unconditioned offspring (F1). We demonstrate that the increase in F0 is due, in part, to the biasing of the stem cell layer of the main olfactory epithelium. A detailed analysis of F1 behavior revealed subtle odor-specific differences between the offspring of unconditioned and conditioned parents, despite the absence of an active aversion to the conditioned odor. Thus, we reveal intergenerational regulation of olfactory epithelium composition in response to olfactory fear conditioning, providing insight into the heritability of acquired phenotypes.

Enhanced bacterial chemotaxis in confined microchannels occurs at lane widths matching circular swimming radius

zhchi@ustc.edu.cn (Caijuan Yue) — Tue, 14 Apr 2026 00:00:00 +0000

Understanding bacterial behavior in confined environments is helpful for elucidating microbial ecology and developing strategies to manage bacterial infections. While extensive research has focused on bacterial motility on surfaces and in porous media, chemotaxis in confined spaces remains poorly understood. Here, we investigate the chemotaxis of Escherichia coli within microfluidic lanes under a linear concentration gradient of L-aspartate. We demonstrate that E. coli exhibits significantly enhanced chemotaxis in lanes with sidewalls compared to open surfaces. We attribute this phenomenon primarily to the intrinsic chiral clockwise circular motion of surface-swimming bacteria and the subsequent alignment effect upon collision with the sidewalls. By varying lane widths, we identify that an 8 μm width—approximating the radius of bacterial circular swimming on surfaces—maximizes chemotactic drift velocity. These results are supported by both experimental observations and stochastic simulations, establishing a clear proportional relationship between optimal lane width and the radius of bacterial circular swimming. Further geometric analysis provides an intuitive understanding of this phenomenon. Our results may offer insights into bacterial navigation in complex biological environments such as host tissues and biofilms, providing a preliminary step toward exploring microbial ecology in confined habitats and potential strategies for controlling bacterial infections.

Adaptive variation in avian eggshell gas conductance and structure across elevational gradients?

docampo@princeton.edu (Carlos Daniel Cadena) — Tue, 14 Apr 2026 00:00:00 +0000

Many tropical bird species have restricted elevational distributions, potentially limited by how environmental conditions affect physiological processes. While some studies have examined adult physiology across elevations, relatively little attention has been given to the structure and function of eggshells despite their critical role in regulating gas exchange during the vulnerable embryonic stage. At high elevations, dry air is expected to increase water loss from the egg, and natural selection may favor lower gas conductance to reduce desiccation risk. Structural variation in eggshells, such as increased shell thickness or reduced pore size and density, could serve as a mechanism to regulate gas diffusion. To test for adaptive variation in eggshell traits along elevational gradients, we measured water vapor conductance and used scanning electron microscopy (SEM) to examine eggshell structure in 197 bird species from the Andes. We found that water vapor conductance declined at high elevations across avian communities. However, structural changes in eggshells varied among bird families and did not vary in a predictable way with elevation, suggesting no relationship or divergent adaptive responses to shared selective pressures, particularly in shell thickness, pore density, and pore size. We propose that examining functional and structural eggshell traits can offer insight into species’ elevational limits and inform predictions about their responses to climate change.

Revealing global stoichiometry conservation architecture in cells from Raman spectral patterns

kenichiro_kamei@cell.c.u-tokyo.ac.jp (Hidenori Nakaoka) — Tue, 14 Apr 2026 00:00:00 +0000

Cells can adapt to various environments by changing their biomolecular profiles while maintaining physiological homeostasis. What organizational principles in cells enable the simultaneous realization of adaptability and homeostasis? To address this question, we measure Raman scattering light from Escherichia coli cells under diverse conditions, whose spectral patterns convey their comprehensive molecular composition. We reveal that dimension-reduced Raman spectra can predict condition-dependent proteome profiles. Quantitative analysis of the Raman-proteome correspondence characterizes a low-dimensional hierarchical stoichiometry-conserving proteome structure. The network centrality of each gene in the stoichiometry conservation relations correlates with its essentiality and evolutionary conservation, and these correlations are preserved from bacteria to human cells. Furthermore, stoichiometry-conserving core components obey growth law and ensure homeostasis across conditions, whereas peripheral stoichiometry-conserving components enable adaptation to specific conditions. Mathematical analysis reveals that the stoichiometrically constrained architecture is reflected in major changes in Raman spectral patterns. These results uncover coordination of global stoichiometric balance in cells and demonstrate that vibrational spectroscopy can decipher such biological constraints beyond statistical or machine-learning inference of cellular states.

Active regulation of the epidermal growth factor receptor by the membrane bilayer

binz@mit.edu (Bin Zhang) — Tue, 14 Apr 2026 00:00:00 +0000

Cell surface receptors transmit information across the plasma membrane to connect the extracellular environment to intracellular function. While the structures and interactions of the receptors have been long established as mediators of signaling, increasing evidence suggests that the membrane itself plays an active role in both suppressing and enhancing signaling. Identifying and investigating this contribution has been challenging owing to the complex composition of the plasma membrane. We used cell-free expression to incorporate the epidermal growth factor receptor (EGFR) into nanodiscs with defined membrane compositions and characterized ligand-induced transmembrane conformational response and interactions with signaling partners using single-molecule and ensemble fluorescence assays. We observed that both the transmembrane conformational response and interactions with signaling partners are strongly lipid dependent, consistent with previous observations of electrostatic interactions between the anionic lipids and conserved basic residues near the membrane adjacent domain. Strikingly, the active conformation of EGFR and high levels of ATP binding were maintained regardless of ligand binding with high anionic lipid content typical of cancer cells, where EGFR signaling is enhanced. In contrast, the conformational response was suppressed in the presence of cholesterol, providing a mechanism for its known inhibitory effect on EGFR signaling. Our findings introduce a model of EGFR signaling in which the lipid environment can override ligand control, providing a biophysical basis for both robust EGFR activity in healthy cells and aberrant activity under pathological conditions. The membrane-adjacent protein sequence, likely responsible for the lipid dependence, is conserved among receptor tyrosine kinases, suggesting that active regulation by the plasma membrane may be a general feature of this important class of proteins.

Cocaine disrupts hidden states in the brain

rkeiflin@ucsb.edu (Margo Le) — Mon, 13 Apr 2026 00:00:00 +0000

Cocaine use disrupts the encoding of abstract states in the orbitofrontal cortex.

Individuality across environmental context in Drosophila melanogaster

mathias.wernet@fu-berlin.de (Cara Knief) — Mon, 13 Apr 2026 00:00:00 +0000

Animal behavior is individually variable, and this variability is often consistent over time, a phenomenon called individuality or personality when multiple traits are involved. However, most studies test individuality in only one environment, even though behavior is known to be context-dependent. Analogous to the human ‘person-situation debate,’ we asked whether and to what extent behavioral individuality persists across changing environmental situations in Drosophila melanogaster. Using established and new behavioral assays, we examined three individual traits, namely exploration, attention, and anxiety, across varying environmental contexts, including temperature, visual cues, and arena shape, in both walking and flying flies. We found that individuality is strongly context-dependent, but even under substantial environmental changes, at least one behavioral trait retained individual-specific variation. Different environmental features did not affect individuality equally; instead, they formed a hierarchy in their influence on behavioral consistency. This hierarchy was supported by generalized linear modeling and hierarchical linear mixed-model analysis. Our results show that, as in humans, individuality in flies persists across different situations, although less strongly than across repeated tests in the same context. These findings establish Drosophila as a model for dissecting the developmental, neural, and genetic mechanisms underlying consistent individual differences in behavior across variable environments.

Audiovisual cues must be predictable and win-paired to drive risky choice

brett.hathaway@nih.gov (Angela Langdon) — Mon, 13 Apr 2026 00:00:00 +0000

Risky or maladaptive decision making is thought to be central to the etiology of both drug and gambling addiction. Salient audiovisual cues paired with rewarding outcomes, such as the jackpot sound on a win, can enhance disadvantageous, risky choice in both rats and humans, yet it is unclear which aspects of the cue-reward contingencies drive this effect. Here, we implemented six variants of the rat gambling task (rGT), in which animals can maximize their total sugar pellet profits by avoiding options paired with higher per-trial gains but disproportionately longer and more frequent time-out penalties. When audiovisual cues were delivered concurrently with wins and scaled in salience with reward size, significantly more rats preferred the risky options as compared to the uncued rGT. Similar results were observed when the relationship between reward size and cue complexity was inverted and when cues were delivered concurrently with all outcomes. Conversely, risky choice did not increase when cues occurred randomly on 50% of trials, and decision making actually improved when cues were coincident with losses alone. As such, cues do not increase risky choice by simply elevating arousal or amplifying the difference between wins and losses. It is instead important that the cues are reliably associated with wins; presenting the cues on losing outcomes as well as wins does not diminish their ability to drive risky choice. Computational analyses indicate reductions in the impact of losses on decision making in all rGT variants in which win-paired cues increased risky choice. These results may help us understand how sensory stimulation can increase the addictive nature of gambling and gaming products.

Principles of gamma synchrony predict figure–ground perception in texture stimuli

mario.senden@maastrichtuniversity.nl (Mario Senden) — Fri, 10 Apr 2026 00:00:00 +0000

Gamma synchrony is ubiquitous in visual cortex, but whether it contributes to perceptual grouping remains contentious based on observations that gamma frequency is not consistent across stimulus features and that gamma synchrony depends on distances between image elements. These stimulus dependencies have been argued to challenge the idea that the visual system groups image elements by synchronizing the neural assemblies that encode them. Here, we argue instead that these dependencies may shape synchrony in perceptually meaningful ways. Indeed, according to the theory of weakly coupled oscillators (TWCO), synchrony-based grouping mechanisms require stimulus dependence. Synchronization among coupled oscillators depends on frequency dissimilarity and coupling strength, which in early visual cortex relate to local feature dissimilarity and physical distance, respectively. We manipulated these factors in a texture segregation experiment wherein human observers identified the orientation of a figure defined by reduced contrast heterogeneity compared to the background. Human performance followed TWCO predictions both qualitatively and quantitatively, as formalized in a computational model. Moreover, we found that when enriched with a Hebbian learning rule, our model also predicted human learning effects: Increases in model gamma synchrony due to perceptual learning predicted improvements in texture segregation across sessions. Taken together, our data suggest that the stimulus-dependence of gamma synchrony captures local image statistics and is linked to the stimulus-dependence of texture segregation, and that the effect of visual experience on gamma synchrony provides a viable perceptual learning mechanism for training-induced improvements in texture segregation. Our results suggest that gamma synchrony with its inherent stimulus dependencies can provide a plausible mechanistic basis for perceptual grouping and visual scene segmentation.

Translational control in the spinal cord regulates gene expression and pain hypersensitivity in the chronic phase of neuropathic pain

arkady.khoutorsky@mcgill.ca (Arkady Khoutorsky) — Fri, 10 Apr 2026 00:00:00 +0000

Sensitization of spinal nociceptive circuits plays a crucial role in neuropathic pain. This sensitization depends on new gene expression that is primarily regulated via transcriptional and translational control mechanisms. The relative roles of these mechanisms in regulating gene expression in the clinically relevant chronic phase of neuropathic pain are not well understood. Here, we show that, in mice, changes in gene expression in the spinal cord during the chronic phase of neuropathic pain are substantially regulated at the translational level. Downregulating spinal translation at the chronic phase alleviated pain hypersensitivity. Cell type-specific profiling revealed that spinal inhibitory and excitatory neurons exhibited substantial changes in translation after peripheral nerve injury. Notably, increasing translation selectively in all inhibitory neurons or parvalbumin-positive (PV⁺) interneurons, but not excitatory neurons, promoted mechanical pain hypersensitivity. Furthermore, increasing translation in PV⁺ neurons decreased their intrinsic excitability and spiking activity. Conversely, reducing translation in spinal PV⁺ neurons prevented the nerve injury-induced decrease in excitability but did not alleviate mechanical hypersensitivity. Together, these findings advance our understanding of translational control mechanisms in the spinal cord during neuropathic pain and highlight their cell type- and phase-specific contributions to gene expression and pain hypersensitivity.

Loss of ZNRF3/RNF43 unleashes EGFR in cancer

fy2111@nyu.edu (Amy T Ku) — Fri, 10 Apr 2026 00:00:00 +0000

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the protein most negatively correlated with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of ZNRF3/RNF43 stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data suggest ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptors, uncovering a novel mechanism underlying the frequent co-activation of EGFR and WNT signaling in development and cancer.

Contrasting roles for IKK-regulated inflammatory signalling pathways for development and maintenance of type 1 and adaptive γδ T cells

icarvalho@virtus-rr.com (Benedict Seddon) — Fri, 10 Apr 2026 00:00:00 +0000

The inhibitor of kappa-B kinase (IKK) complex is a critical regulator of cell death and inflammatory signalling in multiple cell types. Phosphorylation of IκB proteins by IKK results in their degradation and consequent activation of NF-κB transcription factors. RIPK1, a critical cell death regulator, is also a direct target of IKK kinase activity, thereby repressing its cell death activity. In αβ T cells, the RIPK1 kinase activity of IKK is critical for normal thymic development while mature αβ T cells require IKK for both activation of NF-κB dependent survival programmes and repression of RIPK1. γδ T cells play a unique and versatile role in host immunity with specific effector functions that enable them to act as early responders in immune defence. The role of IKK-regulated pathways in their development and survival is not known. Here, we dissect the function of IKK and downstream pathways for normal γδ T cell homeostasis. We find that IKK is critical to establish replete γδ T cell populations, but that mechanism varys between different subsets. Type 1 γδ T cells require IKK-dependent NF-κB activation for their generation, while IKK is redundant for development of adaptive γδ T cells. Instead, IKK-dependent NF-κB activation is required for their long-term survival. We also find evidence that IKK repression of RIPK1 is required for survival of peripheral but not thymic γδ T cells. Ablation of CASPASE8 did not rescue γδ T cells in the absence of IKK but rather revealed a potent sensitivity of all γδ subsets to necroptosis, which was rescued by kinase-dead RIPK1. Overall, we reveal critical requirements for IKK-regulated inflammatory pathways by γδ T cells that contrast with those of αβ T cells, and between different subsets, highlighting the complexity of the regulation of these pathways in the adaptive immune system.

Stimulus dependencies—rather than next-word prediction—can explain pre-onset brain encoding in naturalistic listening designs

ines.schoenmann@gmail.com (Floris P de Lange) — Fri, 10 Apr 2026 00:00:00 +0000

The human brain is thought to constantly predict future words during language processing. Recently, a new approach emerged that aims to capture neural prediction directly by using vector representations of words (embeddings) to predict brain activity prior to word onset. Two findings have been proposed as hallmarks of neural next-word prediction: (i) significant encoding prior to word onset and (ii) its modulation by word predictability. However, natural language is rife with temporal correlations, where upcoming words share statistical information with preceding ones. This raises a critical question: Do these hallmarks emerge from the brain actively predicting future content, or might they be equally well explained by the regression model exploiting these inherent stimulus dependencies? To distinguish between these alternatives, we applied the same encoding analysis to passive control systems, i.e., representational systems that encode the stimulus but cannot predict upcoming words. We show that both hallmarks emerge in two such control systems, namely in word embeddings themselves and in speech acoustics. We further show that proposed methods to correct for these dependencies are insufficient, as the effects persist even after such corrections. Together, these results suggest that pre-onset prediction of brain activity might reflect dependencies in natural language rather than predictive computations. This questions the extent to which this new encoding-based method can be used to study prediction in the brain.

GTPase-activating protein DLC1 spatio-temporally regulates Rho signaling

olivier.pertz@unibe.ch (Giliane Rochat) — Fri, 10 Apr 2026 00:00:00 +0000

Emerging evidence suggests that Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) bind to the cytoskeleton or focal adhesions (FAs), controlling spatio-temporal Rho GTPase activity through feedback mechanisms. We explore such feedback in the Rho-specific GAP Deleted in Liver Cancer 1 (DLC1), which binds to FAs through mechanosensitive interactions. Using a FRET biosensor, we show that DLC1 loss of function leads to globally increased Rho activity and contractility in fibroblasts. Although Rho activity appears macroscopically steady, individual molecules undergo ‘signaling flux’—a dynamic cycle of activation and deactivation. To measure this flux, we built a genetic circuit that enables both optogenetic activation of Rho and simultaneous readout of Rho activity. In cells at mechanical steady state, this reveals that DLC1 globally controls the rate of Rho deactivation, both at FAs and at the plasma membrane. Transient induction of local contractility, however, shows DLC1 associating with and dissociating from FAs during their reinforcement and relaxation, which might provide local positive feedback on Rho activity for robust FA disassembly. Together, our results indicate that DLC1 regulates Rho activity both globally at steady state and locally at FAs under tension, highlighting the complexity of spatio-temporal Rho GTPase signaling.

Specialisation of meiotic kinetochores revealed through a synthetic spindle assembly checkpoint strategy

adele.marston@ed.ac.uk (Adèle L Marston) — Thu, 09 Apr 2026 00:00:00 +0000

Meiosis creates haploid gametes through two sequential M phases. While many studies have focused on meiosis I, the molecular events which drive and define meiosis II are largely unknown. Here, we report a novel cell synchronisation strategy which allows for collection of budding yeast Saccharomyces cerevisiae cells arrested at metaphase I or metaphase II, enabling better characterisation of meiosis II events. The method relies on chemically-inducible dimerisation of ectopic copies of spindle assembly checkpoint (SAC) proteins Mps1 and Spc105. Using this synthetic SAC (SynSAC) approach, we found that the SAC response is weaker in metaphase I compared to metaphase II and that the PP1 binding site within Spc105 contributes to restraining the MI SAC response. Furthermore, we demonstrate the utility of the SynSAC approach by analysing the composition and phosphorylation of kinetochores from metaphase I and metaphase II. This revealed an increase in the abundance of outer kinetochore proteins in meiotic metaphase I and reduced phosphorylation on metaphase II kinetochore proteins. Overall, we present the SynSAC method as a valuable tool for analysis of both meiotic metaphases.

Challenges in replay detection by TDLM in post-encoding resting state

simon.kern@zi-mannheim.de (Gordon B Feld) — Thu, 09 Apr 2026 00:00:00 +0000

Using temporally delayed linear modeling (TDLM) and magnetoencephalography (MEG), we investigated whether items associated with an underlying graph structure are replayed during a post-learning resting state. In these same data, we previously provided evidence for replay during online (non-rest) memory retrieval. Despite successful decoding of brain activity during a localizer task, and contrary to predictions, we found no evidence for replay during a post-learning resting state. To better understand this, we performed a hybrid simulation analysis in which we inserted synthetic replay events into a control resting state recorded prior to the actual experiment. This simulation revealed that replay detection using our current pipeline requires an extremely high replay density to reach significance (>1 replay sequence per second, with ‘replay’ defined as a sequence of reactivations within a certain time lag). Furthermore, when scaling the number of replay events with a behavioral measure, we were unable to induce a strong correlation between sequenceness and this measure. We infer that even if replay was present at plausible rates in our resting state dataset, we would lack statistical power to detect it with TDLM. Finally, contrasting our novel hybrid simulation to existing purely synthetic simulations indicated that the latter approaches overestimate the sensitivity of TDLM. We discuss approaches that might optimize the analytic methodology, including identifying boundary conditions under which TDLM can be expected to detect replay. We conclude that solving these methodological constraints will be crucial for optimizing the non-invasive measurement of human replay using MEG.

The dominance of large-scale phase dynamics in human cortex, from delta to gamma

david.murray.alexander@gmail.com (David M Alexander) — Thu, 09 Apr 2026 00:00:00 +0000

The organization of the phase of electrical activity in the cortex is critical to inter-site communication, but the balance of this communication across large-scale (>8 cm), macroscopic (>1 cm), and mesoscopic (1 cm to 1 mm) ranges is an open question. The spatial frequencies (i.e. the spatial scales) of cortical waves have been characterized in the gray matter for micro- and mesoscopic scales of cortex and show decreasing spatial power with increasing spatial frequency. This research, however, has been limited by the size of the measurement array, thus excluding large-scale traveling waves. Obversely, poor spatial resolution of extracranial measurements prevents incontrovertible large-scale estimates of spatial power. We estimate the spatial frequency spectrum of phase dynamics in order to quantify the uncertain large-scale range, utilizing stereotactic electroencephalogram to measure local-field potentials within the gray matter. We take advantage of the large extent of spatial coverage of the cortical sheet, and irregular sampling is offset by use of linear algebra techniques. We find the spatial power of the phase is highest at the lowest spatial frequencies (longest wavelengths), consistent with the power spectra ranges for micro- and meso-scale dynamics, but here shown up to the size of the measurement array (up to 8–16 cm). This result arises across a wide range of temporal frequencies, from the delta band (1–3 Hz) through to the high gamma range (60–100 Hz).

Probing metazoan polyphosphate biology using Drosophila reveals novel and conserved polyP functions

rashna@cdfd.org.in (Deepa Balasubramanian) — Wed, 08 Apr 2026 00:00:00 +0000

Polyphosphate (polyP) exists in all life forms; however, its biological functions in metazoans are understudied. Here, we explored Drosophila, to our knowledge, as the first genetic model to explore polyP biology in metazoans. We established biochemical and in situ methods to detect, quantify, and visualise polyP in Drosophila. We then engineered a FLYX system to deplete polyP in subcellular compartments in a tissue-specific manner. Using these tools, we demonstrated a spatiotemporal and subcellular compartment-specific regulation of polyP levels in various developmental stages and tissue types. We discovered that polyP is crucial for Drosophila hemolymph clotting and proper developmental timing, consistent with an evolutionarily conserved role as exogenous polyP also accelerates mammalian blood clotting. Furthermore, the transcriptomics analysis of polyP-depleted larvae demonstrates the impact of polyP on several cellular processes, including translation. These observations underscore the utility of the toolkit we developed to discover previously unknown polyP functions in metazoans.

Fitness drivers of division of labor in vertebrates

igaru.13@gmail.com (Dustin R Rubenstein) — Wed, 08 Apr 2026 00:00:00 +0000

Although division of labor as a means to increase productivity is a common feature in animal social groups, most previous studies have focused almost exclusively on eusocial insects with extreme task partitioning. Empirical evidence of division of labor in vertebrates is scarce, largely because we lack a theoretical framework to explore the conditions under which division of labor is likely to evolve in cooperatively breeding systems where helpers remain capable of breeding throughout their lifetime. By explicitly considering alternative helping tasks with varying fitness costs, we model how individual decisions on task specialization may influence the emergence of division of labor under both direct and indirect fitness benefits. Surprisingly, we find that direct survival benefits of living in larger groups are the primary force driving the evolution of cooperation to enhance group productivity, and that indirect fitness benefits derived from related group members are only a non-essential facilitator of more stable forms of division of labor in cooperative breeders. In addition, we find that division of labor in vertebrates is favored by harsh environments. Ultimately, our model not only makes key predictions that are consistent with existing empirical data, but also proposes novel avenues for new empirical work in vertebrate and invertebrate systems alike.

Identification and comparison of orthologous cell types from primate embryoid bodies shows limits of marker gene transferability

enard@bio.lmu.de (Anita Térmeg) — Wed, 08 Apr 2026 00:00:00 +0000

The identification of cell types remains a major challenge. Even after a decade of single-cell RNA sequencing (scRNA-seq), reasonable cell type annotations almost always include manual non-automated steps. The identification of orthologous cell types across species complicates matters even more, but at the same time strengthens the confidence in the assignment. Here, we generate and analyze a dataset consisting of embryoid bodies (EBs) derived from induced pluripotent stem cells (iPSCs) of four primate species: humans, orangutans, cynomolgus, and rhesus macaques. This kind of data includes a continuum of developmental cell types, multiple batch effects (i.e. species and individuals) and uneven cell type compositions and hence poses many challenges. We developed a semi-automated computational pipeline combining classification and marker-based cluster annotation to identify orthologous cell types across primates. This approach enabled the investigation of cross-species conservation of gene expression. Consistent with previous studies, our data confirm that broadly expressed genes are more conserved than cell type-specific genes, raising the question of how conserved, inherently cell type-specific, marker genes are. Our analyses reveal that human marker genes are less effective in macaques and vice versa, highlighting the limited transferability of markers across species. Overall, our study advances the identification of orthologous cell types across species, provides a well-curated cell type reference for future in vitro studies and informs the transferability of marker genes across species.

Neuropeptidergic circuit modulation of developmental sleep in Drosophila

ken1ishi2@gmail.com (Chikayo Hemmi) — Wed, 08 Apr 2026 00:00:00 +0000

Sleep–wakefulness regulation dynamically evolves along development in a wide range of organisms. While the mechanism regulating sleep in adults is relatively well understood, little is known about its counterpart in early developmental stages. Here, we report a neuropeptidergic circuitry that modulates sleep in developing Drosophila larvae. Through an unbiased screen, we identified the neuropeptide Hugin and its receptor PK2-R1 as critical regulators of larval sleep. Our genetic and behavioral data suggest that HugPC neurons secrete Hugin peptides to activate insulin-producing cells (IPCs), which express a Hugin receptor PK2-R1. IPCs, in turn, release insulin-like peptides (Dilps) to regulate sleep. We further show that the Hugin/PK2-R1 axis is dispensable for adult sleep. Our findings thus reveal the neuromodulatory circuit that regulates developmental sleep in larvae and highlight differential impacts of the same modulatory axis on early-life sleep and adult sleep.