eLife: latest articles

Growth in early infancy drives optimal brain functional connectivity which predicts cognitive flexibility in later childhood

c.bulgarelli@bbk.ac.uk (Adam T Eggebrecht) — Fri, 05 Jun 2026 00:00:00 +0000

Functional brain network organisation, measured by functional connectivity (FC), reflects key neurodevelopmental processes for healthy development. Early exposure to adversity, for example undernutrition, affects neurodevelopment, observable via disrupted FC, and leads to poorer outcomes from preschool age onwards. We assessed longitudinally the impact of early growth trajectories on developmental FC in a rural Gambian population from age 5–24 months. To investigate how these early trajectories relate to later childhood outcomes, we assessed cognitive flexibility at 3–5 years. We observed that early physical growth before the fifth month of life drove optimal developmental trajectories of FC that in turn predicted cognitive flexibility at pre-school age. In contrast to previously studied developmental populations, this Gambian sample exhibited long-range interhemispheric FC that decreased with age. Our results highlight the measurable effects that poor growth in early infancy has on brain development and the possible subsequent impact on pre-school age cognitive development, underscoring the need for early life interventions throughout global settings of adversity.

The NTR/prodrug revolution: Tools for controlling cell loss and regeneration

mparson1@uci.edu (Gha-Hyun J Kim) — Fri, 05 Jun 2026 00:00:00 +0000

Here, we review the history, advancements, and broad utility of the NTR/prodrug system, and suggest future strategies for developing versatile ablation models. As a chemogenetic tool, the nitroreductase (NTR)/prodrug system enables precise spatiotemporal control over cell ablation. The technology leverages bacterial NTR enzymes (e.g. nfsB) to convert inert prodrugs into cytotoxic agents, thereby allowing researchers to induce targeted cell death. Although the NTR/prodrug approach was first implemented in transgenic mice, it was subsequently adapted to zebrafish, where it has been extensively optimized and applied. Consequently, zebrafish remain the primary focus of this review. Nevertheless, the utility of the NTR/prodrug system has expanded to other important model organisms, including Drosophila, Nematostella, Xenopus, medaka, and rats, enabling detailed studies of tissue damage and regeneration. This review highlights how the NTR system has been deployed to model a spectrum of human diseases, including Parkinson’s disease, retinal degeneration, demyelinating disorders, and kidney disease. These models provide valuable platforms to study pathogenesis in vivo. Furthermore, the precise and controllable nature of NTR ablation makes it an ideal tool for high-throughput chemical and genetic screens aimed at discovering pro-regenerative and protective compounds. The development of NTR2.0, an enzyme variant with over 100-fold greater activity, along with more potent prodrugs such as ronidazole (RNZ), has dramatically broadened experimental possibilities. These improvements permit chronic ablation and long-term disease modeling at well-tolerated drug concentrations. Here, we present some key considerations, including transgenic design for optimal cell-type specificity, calibrating expression levels for desired ablation kinetics, and suitable controls to allow interpretation. These best practices will allow the researcher to develop a precise, reproducible, and versatile platform for either modeling human disease or dissecting regenerative mechanisms.

Quantitative RNA pseudouridine landscape reveals dynamic modification patterns and evolutionary conservation across bacterial species

zhangls@ust.hk (Beifang Lu) — Thu, 04 Jun 2026 00:00:00 +0000

Pseudouridine (Ψ) modifications are the most abundant RNA modifications; however, their distribution and functional significance in bacteria remain largely unexplored compared to eukaryotic systems. In this study, we present the first transcriptome-wide and quantitative mapping of Ψ modifications across five diverse bacterial species (Bacillus cereus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Pseudomonas syringae) at single-base resolution, utilizing the optimized baBID-seq method for bacterial RNA. Our analysis revealed growth phase-dependent dynamics of pseudouridylation in bacterial tRNA and mRNA, particularly in genes enriched in core metabolic pathways. Comparative analysis demonstrated evolutionarily conserved features of Ψ modifications, such as dominant motif contexts, Ψ clustering within operons, etc. Functional analysis indicated Ψ modifications affect bacterial mRNA stability, translation, and interactions with specific RNA-binding proteins in response to changing cellular demands during growth phase transitions. The integrated computational analysis on local RNA architecture was conducted to elucidate the structure-dependent Ψ modifications in bacterial RNA. Furthermore, we developed an integrated deep learning framework, combining LSTM-transformer-GNN-based neural networks (pseU_NN) to capture both RNA sequence and local structure features for effective prediction of Ψ-modified sites. Overall, our study provides valuable insights into the landscapes of bacterial RNA Ψ modifications and establishes a foundation for future mechanistic investigations on bacterial Ψ functions.

Direct MRI of collagen

weiger@biomed.ee.ethz.ch (Emily Louise Baadsvik) — Thu, 04 Jun 2026 00:00:00 +0000

Collagen is the most abundant protein in the human body and has an important role in healthy tissue as well as in a range of prevalent diseases. Medical research and diagnostics, hence, call for means of mapping collagen in vivo. Magnetic resonance imaging (MRI) is a natural candidate for this task, offering full 3D capability and versatile contrast non-invasively. However, collagen has so far been invisible to MRI due to extremely short lifetime of its resonances. Here, we report the direct imaging of collagen in vivo by magnetic resonance on the microsecond scale. The dynamics of resonance signals from collagen were first assessed in samples of bovine tendon and cortical bone. On this basis, imaging was performed at echo times down to 10 microseconds, yielding collagen-specific depiction by echo subtraction. The same approach was then extended for use in vivo, enabling direct collagen imaging of a human forearm. This capability suggests significant promise for biomedical science and clinical use.

HSD17B7 is required for the function of sensory hair cells by regulating cholesterol synthesis

ntuwx@ntu.edu.cn (Dong Liu) — Wed, 03 Jun 2026 00:00:00 +0000

Cholesterol homeostasis is fundamental to cellular function, and its disruption underlies a wide range of human diseases. However, the contribution of cholesterol biosynthesis to auditory physiology remains poorly understood. HSD17B7 (17β-Hydroxysteroid dehydrogenase type 7) catalyzes the conversion of zymosterone to zymosterol, a key step in the post-lanosterol cholesterol biosynthetic pathway. Here, we found that Hsd17b7 is highly enriched in sensory hair cells of zebrafish and mice. The deficiency of Hsd17b7 reduced intracellular cholesterol levels in HEI-OC1 cells and zebrafish hair cells, thereby compromising MET and acoustic startle responses. A heterozygous nonsense variant (c.544G>T; p.E182*) in HSD17B7 was identified in an individual with bilateral profound hearing loss. mRNA of c.544G>T HSD17B7 failed to rescue the impaired MET and acoustic startle response of hsd17b7 mutants. Mechanistically, the mutation decreases mRNA abundance and significantly reduces protein. Moreover, expression of the p.E182* mutation disrupted the interaction between HSD17B7 and the ER retention receptor RER1, leading to aberrant subcellular localization and altered cholesterol distribution, thereby exacerbating HC dysfunction. Together, our findings suggest a conserved and essential role for HSD17B7-mediated cholesterol biosynthesis in sensory hair cell function and identify HSD17B7 as a candidate gene for sensorineural hearing loss.

CO₂-dependent opening of connexin 43 hemichannels

n.e.dale@warwick.ac.uk (Alexander Mascarenhas) — Wed, 03 Jun 2026 00:00:00 +0000

Sequence and structure comparisons between alpha and beta connexins, Cx43 and Cx26, revealed that Cx43 has a motif, the carbamylation motif, that confers CO₂-sensitivity on a subset of beta connexins. By using a fluorescent dye loading assay, whole cell patch clamp recordings and real-time measurement of ATP release via GRAB_ATP, we have demonstrated that Cx43 hemichannels open in a highly CO₂-sensitive manner over the range 20–70 mmHg. Mutational analysis confirms that the equivalent residues to those in Cx26, known to be involved in mediating the effects of CO₂ on gating of hemichannels and gap junction channels, also mediate Cx43 hemichannel gating. These data predict that Cx43 will be partially open at resting physiological levels of PCO₂. In acute mouse hippocampal slices, we have demonstrated a CO₂-dependent enhancement of synaptic transmission that was blocked by the Cx43-selective mimetic peptide Gap26. Our data resolves an inconsistency in the literature between in vivo studies suggesting that Cx43 hemichannels are at least partially open at rest and in vitro studies performed in the absence of HCO₃^-/CO₂ buffering that show Cx43 hemichannels are shut.

Dissecting mechanisms of ligand binding and conformational changes in the glutamine-binding protein

thomas.weikl@mpikg.mpg.de (Alessandra Narducci) — Tue, 02 Jun 2026 00:00:00 +0000

The glutamine-binding protein GlnBP is part of an ATP-binding cassette transporter system in Escherichia coli and uses two well-characterized conformational states, an open ligand-free and a closed-liganded state, to facilitate active amino-acid uptake. Existing literature on its ligand-binding mechanism lacked sufficient evidence to univocally assign the kinetic type of binding mechanism for GlnBP: ligand binding prior to conformational change, that is an induced fit, or the conformational selection, in which the ligand binds the matching conformation from a pre-existing ensemble. Since such mechanistic questions are relevant for our fundamental understanding of how this and other biomacromolecules regulate cellular processes, we here revisit the question for GlnBP. We present a biochemical and biophysical analysis using a combination of calorimetry, single-molecule and surface-plasmon resonance spectroscopy, and molecular dynamics simulations. We found that both apo- and holo-GlnBP show no detectable exchange between open and (semi-)closed conformations on timescales between 100 ns and 10 ms and that ligand binding and conformational changes in GlnBP are correlated. A global analysis of our experimental results suggests that the conformational selection model is only compatible with GlnBP for the extreme scenario of very fast conformational exchange between the open and closed states on timescales <100 ns. In contrast, all data remains compatible with an induced-fit mechanism, where the ligand binds GlnBP prior to conformational rearrangements. Importantly, our work demonstrates that it is an intricate task to identify the type of kinetic binding mechanism and that this requires not only a sufficient set of data, but also an integrative experimental and theoretical framework to address the question. Based on this concept, we propose that various protein systems, for which so far only insufficient kinetic data are available, should be revisited.

Correction: Exosome component 1 cleaves single-stranded DNA and sensitizes human kidney renal clear cell carcinoma cells to poly(ADP-ribose) polymerase inhibitor

Tue, 02 Jun 2026 00:00:00 +0000

Beta-Glucan modulates monocyte plasticity and differentiation capacity to mitigate DSS-induced colitis

jianlin.ren@126.com (Dan Du) — Mon, 01 Jun 2026 00:00:00 +0000

Trained immunity involves the reprogramming of innate immune cells after an initial exposure, resulting in heightened inflammatory responses to subsequent stimuli and enhanced bactericidal capacity during infection. However, this pro-inflammatory state could also exacerbate chronic conditions like inflammatory bowel disease (IBD), which is characterized by persistent inflammation and microbial imbalance. It remains unclear how trained immunity influences IBD pathogenesis and whether it can be harnessed therapeutically. In our study, pretreatment with β-glucan reprogrammed bone marrow hematopoietic progenitors and peripheral monocytes, inducing a profound shift in monocyte plasticity and significantly reducing the severity of dextran sulfate sodium (DSS)-induced colitis. Adoptive transfer of bone marrow or peripheral monocytes from β-glucan-trained mice into naive mice conferred robust protection against colitis, demonstrating that this protective effect is transferable. Trained mice also displayed improved clearance of intestinal bacterial infections. Single-cell RNA sequencing revealed an expansion of reparative Cx3cr1⁺ macrophages derived from Ly6C^hi monocytes, correlating with accelerated colonic epithelial regeneration. Collectively, these findings reveal how β-glucan-induced trained immunity modulates monocyte differentiation to ameliorate experimental colitis, highlighting the potential of harnessing trained immunity as a therapeutic strategy to recalibrate innate immune responses and restore gut homeostasis in IBD, shedding light for future clinical applications.

Distinct evolutionary trajectories of two integration centres, the central complex and mushroom bodies, across Heliconiini butterflies

m.farnworth@bristol.ac.uk (Basil el Jundi) — Mon, 01 Jun 2026 00:00:00 +0000

Neural circuits evolved to produce variable cognitive processes through adaptive mechanisms operating within a background of developmental and functional constraints. Understanding how this conflict is resolved requires a comparative framework encapsulating clear behavioural variation. We leverage Heliconiini butterflies to examine how selection shaped the evolution of the central complex and mushroom bodies, two insect integration centres involved in navigation. The evolution of systematic spatial foraging in Heliconius has led to changes in brain morphology and learning and memory profiles over a short evolutionary timescale. Here, we show that in contrast to massively expanded mushroom bodies, the central complex is strongly conserved in size and general architecture. However, we identify divergences in the expression of a neuropeptide, Allatostatin A, in the noduli, and in the numbers of GABA-ergic ring neurons and their branching in the fan-shaped body, which are essential members of the anterior compass pathway. These differences are rare examples of divergence inside the central complex network matching expectations of where evolutionary adaptability might occur. We conclude that due to the contrasting volumetric conservation of the central complex, and the massive differences in the mushroom bodies, their circuit logics must determine distinct responses to selection associated with divergent foraging behaviours.

Mural cells protect the adult brain from hemorrhage but do not control the blood–brain barrier in developing zebrafish

oguzhan.baltaci@petermac.org (Alison Farley) — Mon, 01 Jun 2026 00:00:00 +0000

The blood–brain barrier (BBB) protects the brain from circulating metabolites and plays central roles in neurological diseases. Endothelial cells (ECs) of the BBB are enwrapped by mural cells including pericytes and vascular smooth muscle cells (vSMCs) that regulate angiogenesis, vessel stability and barrier function. To explore mural cell control of the BBB, we investigated neurovascular phenotypes in zebrafish pdgfrb mutants that lack brain pericytes and vSMCs. As expected, mutants showed an altered cerebrovascular network with mispatterned capillaries. Unexpectedly, mutants displayed no BBB leakage at larval stages of development. This suggests that pericytes and vSMCs are not essential for normal BBB function in developing zebrafish. Instead, we observed juvenile and adult BBB disruption occurring at ‘hotspot’ focal hemorrhages at large vessel aneurysms. ECs at leakage hotspots showed induction of caveolae on abluminal surfaces and structural defects including basement membrane thickening and disruption. Our work suggests that capillary pericytes primarily regulate cerebrovascular patterning in development and vSMCs of major arteries protect from hemorrhage and BBB breakdown in older zebrafish. The fact that young zebrafish have a functional BBB in the absence of mural cells calls for renewed interrogation of mural cell control of the BBB throughout vertebrate evolution.

Interplay between cohesin and TORC1 links chromosome segregation and gene expression to environmental changes

jpaul.javerzat@ibgc.cnrs.fr (Adèle L Marston) — Mon, 01 Jun 2026 00:00:00 +0000

Cohesin is a DNA tethering complex essential for chromosome structure and function. In fission yeast, defects in the cohesin loader Mis4 result in chromosome segregation defects and dysregulated expression of genes near chromosome ends. A genetic screen for suppressors of the thermosensitive growth defect of mis4-G1487D identified several hypomorphic mutants of the Target of Rapamycin Complex 1 (TORC1), a conserved kinase that integrates cellular signals to regulate growth and metabolism through substrate-specific phosphorylation. Here, we demonstrate that the TORC1 pathway modulates cohesin functions in chromosome segregation and gene expression. In the context of compromised cohesin loading, the incidence of chromosome segregation defects was modulated by the growth medium in a TORC1-dependent manner. Pharmacological or genetic downregulation of TORC1 activity restored cohesin binding to its chromosomal sites and improved mitotic chromosome segregation. Notably, reduced TORC1 activity also increased cohesin binding and chromosome transmission fidelity in wild-type cells. These results suggest that environmental cues influence chromosome stability via TORC1. Biochemically, TORC1 co-purified with cohesin and reduced TORC1 activity correlated with decreased phosphorylation of specific residues on Mis4 and cohesin. Mutations in cohesin that mimic the non-phosphorylated state mirrored the effects of TORC1 downregulation, showing that TORC1 is part of the network that controls cohesin phosphorylation to modulate its functions. Finally, we show that the functional interaction between TORC1 and Mis4 extends to the regulation of stress-responsive genes. Our findings reveal a TORC1–cohesin link that may facilitate cellular adaptation to environmental changes. Given that TORC1 inhibitors and calorie restriction extend lifespan in diverse species, this connection raises the intriguing possibility that cohesin-mediated changes in chromosome structure contribute to these effects.

Ubiquitin ligase ITCH regulates life cycle of SARS-CoV-2 virus

jiouw@jhmi.edu (Andrew Pekosz) — Fri, 29 May 2026 00:00:00 +0000

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection poses a major threat to public health, and understanding the mechanism of viral replication and virion release would help identify therapeutic targets and effective drugs for combating the virus. Herein, we identified E3 ubiquitin protein ligase Itchy homolog (ITCH) as a central regulator of SARS-CoV-2 at multiple steps and processes. ITCH enhances the ubiquitination of viral envelope and membrane proteins and mutual interactions of structural proteins, thereby aiding in virion assembly. ITCH-mediated ubiquitination also enhances the interaction of viral proteins to the autophagosome receptor p62, promoting their autophagosome-dependent secretion. Additionally, ITCH disrupts the trafficking of the protease furin and the maturation of cathepsin L, thereby suppressing their activities in cleaving and destabilizing the viral spike protein. Furthermore, ITCH exhibits robust activation during the SARS-CoV-2 replication stage, and SARS-CoV-2 replication is significantly decreased by genetic or pharmacological inhibition of ITCH. These findings provide new insights into the mechanisms of the SARS-CoV-2 life cycle and identify a potential target for developing treatments for the virus-related diseases.

Generative modeling for RNA splicing prediction and design

yosephb@biociphers.org (Anna Tangiyan) — Fri, 29 May 2026 00:00:00 +0000

Alternative splicing (AS) of pre-mRNA plays a crucial role in tissue-specific gene regulation, with disease implications due to splicing defects. Predicting and manipulating AS can therefore uncover new regulatory mechanisms and aid in therapeutic design. We introduce TrASPr+BOS, a generative AI model with Bayesian Optimization for predicting and designing RNA for tissue-specific splicing outcomes. Transformer for Alternative Splicing Prediction (TrASPr) is a multi-transformer model that can handle different types of AS events and generalize to unseen cellular conditions. It then serves as an oracle, generating labeled data to train a Bayesian Optimization for Splicing (BOS) algorithm to design RNA for condition-specific splicing outcomes. We show TrASPr+BOS outperforms existing methods, enhancing tissue-specific AUPRC by up to 1.8-fold and capturing tissue-specific regulatory elements. We validate hundreds of predicted novel tissue-specific splicing variations and confirm new regulatory elements using dCas13. We envision TrASPr+BOS as a light yet accurate method researchers can probe or adopt for specific tasks.

LFA-1 interaction with GBP-130 on Plasmodium falciparum-infected red blood cells mediates NK cell activation and parasite control

dhiraj@icgeb.res.in (Alma Tammour) — Thu, 28 May 2026 00:00:00 +0000

Natural killer (NK) cells contribute to early immunity against Plasmodium falciparum by recognizing and eliminating infected red blood cells (iRBCs), a process mediated in part by the integrin LFA-1. However, the cognate parasite ligand for LFA-1 has remained unknown. Here, we identify glycophorin binding protein-130 (PfGBP-130) as a surface-expressed ligand on iRBCs that binds the I-domain of LFA-1 (LFA-1 αI). Using an LFA-1 αI-Fc fusion protein, we demonstrate stage-specific binding to iRBCs, and LC-MS/MS analysis of immunoprecipitates of αI-Fc bound to iRBC revealed PfGBP-130 as a high-confidence interactor. Recombinant PfGBP-130 binds NK and THP-1 cells in an LFA-1-dependent manner. Co-culture assays show that PfGBP-130 promotes NK cell activation and degranulation and facilitates contact-dependent killing of iRBCs. Neutralizing antibodies against PfGBP-130 significantly impair these responses. Our findings establish PfGBP-130 as the LFA-1 ligand on iRBCs, providing new insight into NK cell-mediated immunity in malaria and identifying a potential target for host-directed interventions.

Chromosome-scale genome assembly of the European common cuttlefish Sepia officinalis

g.laurent@brain.mpg.de (David Hain) — Thu, 28 May 2026 00:00:00 +0000

Coleoid cephalopods, a subclass of mollusks that includes octopuses, cuttlefish, and squid, exhibit sophisticated biological features, such as dynamic and neurally driven camouflage behavior, inter-individual communication, single-lens camera-like eyes, the largest brains among invertebrates, and a distinctive embryonic development. The common cuttlefish Sepia officinalis has served as a model organism in various research fields, spanning biophysics, neurobiology, behavior, evolution, ecology, and biomechanics. More recently, it has become a model to investigate the neural mechanisms underlying cephalopod camouflage, using quantitative behavioral approaches alongside molecular techniques to characterize the identity, evolution, and development of neuronal cell types. Despite significant interest in this animal, a high-quality, annotated genome of this species is still lacking. To address this, we sequenced and assembled a chromosome-scale genome for S. officinalis. Our assembly spans 5.68 billion base pairs and comprises 1n=47 repeat-rich chromosome scaffolds. This was unexpected because the haploid karyotypes of other decapods indicate 46 chromosomes. Detailed comparisons of our data to those from published decapod genome assemblies and to another recent genome assembly of S. officinalis (itself suggesting 1n=49 chromosomes) in fact revealed clear homologies between 46 scaffolds across all the datasets. In-depth comparison of datasets reveals highly repetitive regions at discordant scaffold boundaries and suggests that the true karyotype of S. officinalis is probably 1n=46 chromosomes, a likely ancestral and if true, conserved decapod karyotype. Our results include a comprehensive gene annotation and full-length transcript prediction, which we used to characterize orthologous gene families across mollusks. We identified several large-scale expansions specific to cephalopods, with many genes specific to neural or non-neural tissues of adult S. officinalis. In summary, this genome should provide a valuable resource for future research on the evolution, brain organization, information processing, development, and behavior in this important clade.

Language acquisition in newborns

mpenag@uc.cl (Marcela Peña) — Thu, 28 May 2026 00:00:00 +0000

The ability of newborns to distinguish between different voices helps them to establish verbal memories from a very early age.

Effects of residue substitutions on the cellular abundance of proteins

lindorff@bio.ku.dk (Kresten Lindorff-Larsen) — Thu, 28 May 2026 00:00:00 +0000

Multiplexed assays of variant effects (MAVEs) make it possible to measure the functional impact of all possible single amino acid residue substitutions in a protein in a single experiment. Combination of variant effect data from several such experiments provides the opportunity to conduct large-scale analyses of variant effect scores measured across proteins, but can be complicated by variations in the phenotypes that are probed across experiments. Thus, using variant effect datasets obtained with similar MAVE techniques can help reveal general rules governing the effects of amino acid variation for a single molecular phenotype. In this work, we accordingly combined data from six individual variant abundance by massively parallel sequencing (VAMP-seq) experiments and analysed a total of 31,614 variant effect scores reporting solely on the impact of single amino acid residue substitutions on the cellular abundance of proteins. Using our combined variant effect dataset, we derived and analysed a collection of amino acid substitution matrices describing the average impact on cellular abundance of all residue substitution types in different structural environments. We found that the substitution matrices predict the cellular abundance of protein variants with surprisingly high accuracy when given structural information only in the form of whether a residue is buried or exposed. We thus propose our substitution matrix-based predictions as strong baselines for future abundance model development.

Computational mechanisms for temporal integration in the anterior claustrum

antares0715@gmail.com (Donghyeon Yoon) — Thu, 28 May 2026 00:00:00 +0000

The claustrum, with its extensive reciprocal connections to nearly all cortical regions, has long been hypothesized as a key hub for integrating diverse cognitive, sensory and motor information. However, despite its anatomical connectivity, whether and how it functionally integrates different inputs to generate coherent representations has remained unclear. Here, we developed a recurrent neural network (RNN) trained via supervised learning on behavioral metrics of delayed escape—a behavioral paradigm that requires integration of temporally separated task-relevant signals. A subset of RNN neurons exhibited dynamics similar to those of anterior claustral neurons during this behavior. These neurons formed a recurrent cluster, a structure supported by in vitro stimulation experiments in claustral brain slices. We analyzed the computational properties of this claustrum-like cluster via dimensionality reduction of population activity. The network showed nonlinear integration of temporally distributed inputs and increased synergistic information. Rather than settling into attractors, integrated information was dynamically encoded along continuously evolving neural trajectories. Notably, similar trajectory patterns associated with dynamic integration were observed in claustral recordings, suggesting the model’s biological plausibility. We propose that the anterior claustrum dynamically integrates task-relevant input signals over time and broadcasts the evolving representation to downstream brain regions capable of reading and interpreting it in a context-dependent manner.

A novel RAB5 binding site in human VPS34-CII that is likely the primordial site in eukaryotic evolution

rlw@mrc-lmb.cam.ac.uk (Antoine Nicolas Dessus) — Thu, 28 May 2026 00:00:00 +0000

RAB5-GTP activation of the multiprotein VPS34 complex II (VPS34-CII) is critical for endosomal sorting and maturation, phagocytosis, and receptor downregulation. RAB5-GTP activates VPS34-CII by binding to a helical insertion in the C2 domain of VPS34 on the BECLIN1/UVRAG-containing adaptor arm of the complex. The autophagy complex, VPS34 complex I (VPS34-CI), features a unique ATG14L subunit in place of the VPS34-CII UVRAG subunit, and we found that this distorts the adaptor arm to alter the VPS34 RAB-GTPase binding pocket so that it preferentially binds RAB1-GTP. Surprisingly, our higher-resolution single-particle cryo-EM structure of VPS34-CII showed a second RAB5-GTP binding site on the VPS15 solenoid region. This site (VPS15-RAB5-site) appears to be the primordial RAB5-binding region. A mutant in the helical insertion of the C2 domain of human VPS34 that mimics the Saccharomyces cerevisiae sequence abolishes RAB5 binding to VPS34. Mutation of the VPS15-RAB5-site ortholog in S. cerevisiae VPS15 resulted in defective CPY sorting, loss of colocalisation with the RAB5 ortholog Vps21, and loss of binding to Vps21 in vitro. Evolutionary expansion from one to two RAB5-orthologue binding sites may have increased membrane binding and VPS34-CII activity to adapt to more complex endocytic systems.

High-frequency spike inference with particle Gibbs sampling

g.diana.mail@gmail.com (B Semihcan Sermet) — Wed, 27 May 2026 00:00:00 +0000

Calcium-sensitive fluorescent indicators enable monitoring of spiking activity in large neuronal populations in animal models. Despite the plethora of algorithms developed over the past decades, accurate spike-time inference methods for spike rates exceeding 20 Hz are lacking. More importantly, little attention has been devoted to the quantification of statistical uncertainties in spike time estimation, which is essential for assigning confidence levels to inferred spike patterns. To address these challenges, we introduce (1) a statistical model that accounts for bursting neuronal activity and baseline fluorescence modulation and (2) apply a Monte Carlo strategy (particle Gibbs with ancestor sampling) to estimate the joint posterior distribution of spike times and model parameters. Our method is competitive with state-of-the-art supervised and unsupervised algorithms, as evaluated on the CASCADE benchmark datasets. Analysis of fluorescence transients recorded with the ultrafast genetically encoded calcium indicator GCaMP8f demonstrates that our method can resolve interspike intervals as short as 5 ms. Overall, our study describes a Bayesian inference method for detecting neuronal spiking patterns and quantifying their uncertainty. The use of particle Gibbs samplers enables unbiased estimates of spike times and all model parameters, providing a flexible statistical framework for testing more specific models of calcium indicators.

Hsp70 is phosphorylated in a conserved response to DNA damage and contributes to cell cycle control

Shaeri.Mukherjee@ucsf.edu (Alexandra Wooldredge) — Wed, 27 May 2026 00:00:00 +0000

Hsp70s are essential molecular chaperones that are increasingly recognized to be regulated by post-translational modifications. Here, we show that phosphorylation of a conserved threonine (T495), previously shown to be exploited by a Legionella pneumophila kinase to inhibit Hsp70, occurs endogenously in human cells in response to DNA damage, particularly when base excision repair is overburdened. This modification is cell cycle dependent, and in yeast, phosphomimetic or phosphonull Hsp70 variants disrupt G1/S progression under normal and DNA-damaging conditions. Biochemically, the phosphomimetic T495E mutation locks Hsp70 in an open-like conformation without blocking substrate engagement. Together, our results reveal a conserved mechanism by which dynamic Hsp70 phosphorylation regulates the G1/S transition and delays cell cycle progression during DNA damage, highlighting how pathogen-derived insights can uncover fundamental cell biology principles.

Molecular architecture of the tumor microenvironment caused by BRCA1 and BRCA2 somatic mutations in human lung adenocarcinoma

lgm179496478@163.com (Gang Xu) — Tue, 26 May 2026 00:00:00 +0000

Homologous recombination repair (HRR) deficiency is associated with improved immunotherapy responses in non-small cell lung cancer (NSCLC) patients. The HRR genes BRCA1/2 are key regulators of DNA repair, yet their impact on the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unclear. Using single-cell sequencing and multi-omics data, we characterized BRCA1/2 mutation-associated transcriptional programs, immune cell composition, and functional alterations in T cells, investigating the molecular and immune architecture of BRCA-mutant LUAD patients. BRCA1/2 mutations were associated with increased genomic instability and poor prognosis in LUAD patients, but predicted better clinical outcomes following immune checkpoint blockade (ICB) treatment. BRCA1 mutations correlated with an upregulated type I IFN/IFN-γ signature and CD8⁺ T cell activation. BRCA2 mutations were associated with alveolar/stress/inflammatory responses and enhanced MHC-II antigen presentation, linked to CD4⁺ T cell differentiation. Both alterations coincided with reduced CD28 co-stimulation and CTL activity, hinting at immune evasion. We identified two tissue-resident memory T cell (Trm) subsets as predictors of clinical outcomes and ICB response. BRCA1 mutations were associated with CD8⁺ Trm expansion, whereas BRCA2 mutations were linked to tumor CD4⁺ Trm expansion and peripheral T/NK cell cytotoxicity. Furthermore, a cancer-promoting program activated by BRCA1 mutation was vulnerable to histone deacetylase inhibitors, which inhibited LUAD tumor growth. This study provides a preliminary characterization of the BRCA-mutant TME in LUAD patients, revealing distinct transcriptional and immune patterns that highlight differences in BRCA1/2-associated molecular architecture and offer a framework for improving therapy efficacy in LUAD.

Cognitive simplicity drives collective route improvements in homing pigeons

shoubhik.banerjee001@umb.edu (Albert B Kao) — Tue, 26 May 2026 00:00:00 +0000

Cognitive abilities are central to how animals navigate complex environments. Beyond individual cognition, group living can also enhance navigation by pooling individually acquired information. One way this may be achieved is by following experienced leaders, which requires recognizing expertise within group members. Alternatively, accurate decisions could also emerge without expert opinions, through simpler mechanisms like the ‘wisdom of crowds’ principle that average out individual biases. Consequently, collective navigation strategies range from cognitively complex to simple, and yet, the prevalence or interplay of different collective strategies in nature remains unexplored. In this study, we asked: what is the navigation mechanism, requiring minimal cognitive demands, that is necessary and sufficient to quantitatively replicate the experimental results of a 2017 study on homing pigeons (Columba livia), which showed that sequential chains of bird pairs flying home—similar to a game of telephone—led to shorter homing routes compared to control birds flying individually or in fixed pairs. Our results show that the experimental data aligns closely with the simplest strategy—route averaging. Surprisingly, the complex mechanism of selectively propagating the best flight through social learning offered no additional advantage. We further observed that mixed strategies, although not supported by the experimental data, in theory combined advantages from both averaging and active selection of better routes, resulting in even greater performance. Hence, our results highlight the potential for future research to investigate selective pressures shaping the evolution of cultural learning and trade-offs among different decision mechanisms theoretically available to social animals in nature.

Multi-talker speech comprehension at different temporal scales in listeners with normal and impaired hearing

jixingli@cityu.edu.hk (Jixing Li) — Tue, 26 May 2026 00:00:00 +0000

Comprehending speech requires deciphering a range of linguistic representations, from phonemes to narratives. Prior research suggests that in single-talker scenarios, the neural encoding of linguistic units follows a hierarchy of increasing temporal receptive windows. Shorter temporal units like phonemes and syllables are encoded by lower-level sensory brain regions, whereas longer units such as sentences and paragraphs are processed by higher-level perceptual and cognitive areas. However, the brain’s representation of these linguistic units under challenging listening conditions, such as a cocktail party situation, remains unclear. In this study, we recorded electroencephalogram (EEG) responses from both normal-hearing and hearing-impaired participants as they listened to individual and dual speakers narrating different parts of a story. The inclusion of hearing-impaired listeners allowed us to examine how hierarchically organized linguistic units in competing speech streams affect comprehension abilities. We leveraged a hierarchical language model to extract linguistic information at multiple levels—phoneme, syllable, word, phrase, and sentence—and aligned these model activations with the EEG data. Our findings showed distinct neural responses to dual-speaker speech between the two groups. Specifically, compared to normal-hearing listeners, hearing-impaired listeners exhibited poorer model fits at the acoustic, phoneme, and syllable levels, as well as the sentence levels, but not at the word and phrase levels. These results suggest that hearing-impaired listeners experience disruptions at both shorter and longer temporal scales, while their processing at medium temporal scales remains unaffected.

Inhibitory columnar feedback neurons are involved in motion processing in Drosophila

msilies@uni-mainz.de (Daryl M Gohl) — Tue, 26 May 2026 00:00:00 +0000

Visual motion information is essential to guiding the movements of many animals. The establishment of direction-selective signals, a hallmark of motion detection, is considered a core neural computation and has been characterized extensively in primates, mice, and fruit flies. In flies, the circuits that produce direction-selective signals rely on feedforward visual pathways that connect peripheral visual inputs to the dendrites of the ON and OFF-direction-selective cells. Here, we describe a novel role for feedback inhibition in motion computation. Two GABAergic neurons, C2 and C3, connect to neurons upstream of the direction-selective T4 and T5 cells, and blocking C2 and C3 affects direction selectivity in T4/T5. In the ON pathway, this is likely achieved by C2-mediated suppression of responses in the major T4 input neuron Mi1. Together, C2 and C3 suppress responses to non-preferred stimuli in both T4 and T5. At the behavioral level, feedback inhibition temporally sharpens responses to ON-moving stimuli, enhancing the fly’s ability to discriminate visual stimuli that occur in quick succession. GABAergic inhibitory feedback neurons thus constitute an essential component within the circuitry that computes visual motion.

Hyperactivated glycolysis drives spatially patterned Kupffer cell depletion in MASLD

shanzhao@ynu.edu.cn (Cheng Xie) — Tue, 26 May 2026 00:00:00 +0000

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression is characterized by hepatic inflammation and cell death, yet the mechanisms underlying Kupffer cell (KC) loss remain poorly understood. Here, we sought to elucidate the metabolic basis of KC death during MASLD. Using metabolomics, immunostaining, and flow cytometry, we evaluated metabolic alterations and KC death throughout early MASLD progression. We found that KC death is an early hallmark of MASLD, exhibiting greater susceptibility and a spatial distribution consistent with KC zonation. Moreoever, KCs undergo progressive metabolic reprogramming toward enhanced glucose utilization during MASLD development, which is correlated with KC death. In combination with biochemical agonist, isotope tracing, and primary KC culture, we further demonstrated that augmented glycolytic metabolism directly drives KC death in vitro. Consistently, using Chi3l1-deficient mice, we further demonstrated that increased glucose utilization accelerates KC death in vivo. Together, these findings establish a causal link between glycolytic activation and KC loss during MASLD progression, highlighting glucose metabolic pathways as potential therapeutic targets to preserve KC homeostasis and mitigate MASLD.

Correction: Embryo-derive TNF promotes decidualization via fibroblast activation

Tue, 26 May 2026 00:00:00 +0000

Involuntary feedback responses reflect a representation of partner actions

sethsull@udel.edu (Jan A Calalo) — Fri, 22 May 2026 00:00:00 +0000

We have a remarkable ability to seamlessly and rapidly coordinate actions with others, from double Dutch to dancing. Humans use high-level partner representations to jointly control voluntary actions, while other work shows lower-level involuntary feedback responses to sudden visual perturbations. Yet, it is unknown if a high-level partner representation can be rapidly expressed through lower-level involuntary sensorimotor circuitry. Here, we test the idea that a partner representation influences involuntary visuomotor feedback responses during a cooperative sensorimotor task. Using two experiments and dynamic game theory predictions, we show that involuntary visuomotor feedback responses reflect a partner representation and consideration of a partner’s movement cost (i.e., accuracy and energy). Collectively, our results suggest there is top-down modulation from high-level partner representations to lower-level sensorimotor circuits, enabling fast and flexible feedback responses during jointly coordinated actions.

Isolation of small extracellular vesicles from small volumes of blood plasma using size exclusion chromatography and density gradient ultracentrifugation

kongfang@gmail.com (Andrew SW Wong) — Fri, 22 May 2026 00:00:00 +0000

Small extracellular vesicles (sEVs) are heterogeneous biological vesicles released by cells under both physiological and pathological conditions. Due to their potential as valuable diagnostic and prognostic biomarkers in human blood, there is a pressing need to develop effective methods for isolating high-purity sEVs from the complex milieu of blood plasma, which contains abundant plasma proteins and lipoproteins. Size exclusion chromatography (SEC) and density gradient ultracentrifugation (DGUC) are two commonly employed isolation techniques that have shown promise in addressing this challenge. In this study, we aimed to determine the optimal combination and sequence of SEC and DGUC for isolating sEVs from small plasma volumes, in order to enhance both the efficiency and purity of the resulting isolates. To achieve this, we compared sEV isolation using two combinations: SEC-DGUC and DGUC-SEC, from unit volumes of 500 μL plasma. Both protocols successfully isolated high-purity sEVs; however, the SEC-DGUC combination yielded higher sEV protein and RNA content. We further characterized the isolated sEVs obtained from the SEC-DGUC protocol using flow cytometry and mass spectrometry to assess their quality and purity. In conclusion, the optimized SEC-DGUC protocol is efficient, highly reproducible, and well suited for isolating high-purity sEVs from small blood volumes.

In situ mutational screening and CRISPR interference define apterous cis-regulatory inputs during compartment boundary formation

gusag@mit.edu (Dimitri Bieli) — Fri, 22 May 2026 00:00:00 +0000

The establishment of tissue axes is fundamental during embryonic development. In the Drosophila wing, the anterior/posterior (AP) and the dorsal/ventral (DV) compartment boundaries provide the basic coordinates around which the tissue develops. These boundaries arise as a result of two lineage decisions, the acquisition of posterior fate by the selector gene engrailed (en) and dorsal fate by the selector gene apterous (ap). While the en expression domain is set up during embryogenesis, ap expression begins only during early wing development. Thus, the correct establishment of the ap expression pattern relative to en must be tightly controlled. Here, we functionally investigate the transcriptional inputs integrated by the early ap enhancer (apE) and their requirement for correct boundary formation. Detailed mutational analyses using CRISPR/Cas revealed a role for apE in positioning the DV boundary relative to the AP boundary, with apE mutants often displaying mirror-image anterior wing duplications. We then designed and applied methods to accomplish tissue-specific enhancer disruption via dCas9 expression. This approach allowed us to dissect the spatiotemporal requirement for apE function, clarifying the mechanism by which apE misregulation leads to AP defects. Base-pair-resolution analyses of apE uncovered a single HOX-binding site essential for wing development that, when mutated, led to wingless flies. We demonstrated that the transcription factors Pointed (Pnt), Homothorax (Hth), and Grain (Grn) are required for apE function, and the HOX gene Antennapedia (Antp) contributes to early wing development. Together, our results provide a comprehensive molecular basis of early ap activation and the developmental consequences of its misregulation, shedding light on how compartmental boundaries are set up during development.

Sexual dimorphism in sensorimotor transformation of optic flow

yuri.ogawa@flinders.edu.au (Aika Young) — Fri, 22 May 2026 00:00:00 +0000

Motion vision underpins a wide range of adaptive behaviours essential for individual and species survival. In hoverflies, some visual behaviours are sexually dimorphic, including for example male high-speed pursuit of conspecifics matched by improved optics and faster photoreceptors. Other visual behaviours are sexually monomorphic, with for example similar foraging flight speeds in male and female hoverflies. However, whether the descending neurons responsible for sensorimotor transformation of optic flow are sexually dimorphic is unknown. To address this, we combined morphological analysis with electrophysiology of optic flow sensitive descending neurons and compared neural responses to the behavioural output in tethered hoverflies. We found that while optomotor flight behaviour is largely sexually monomorphic, the underlying neural responses are sexually dimorphic, especially at higher optic flow velocities. Additionally, behavioural responses were noticeably slower than neural responses. Together, our findings uncover a nuanced, sex- and stimulus-dependent sensorimotor transformation, shaped by both neural architecture and behavioural demands.

Developmental constraints mediate the reversal of temperature effects on the autumn phenology of European beech after the summer solstice

dominic.rebindaine@usys.ethz.ch (Constantin M Zohner) — Fri, 22 May 2026 00:00:00 +0000

Accurate projections of temperate tree growing seasons under climate change require representing developmental constraints that determine tree resource allocation. A phenological ‘switch point’ after the summer solstice (21 June) has been proposed, with pre-solstice warming advancing autumn phenology and post-solstice warming delaying it. We propose that this switch is flexible and occurs at the compensatory point between early-season development and late-season temperature effects. We performed trans-solstice climate manipulation experiments on potted European beech (Fagus sylvatica) saplings to test (i) how spring leaf-out timing and June-August temperatures influence end-of-season timing (bud set and leaf senescence) and (ii) whether daytime and nighttime temperatures before and after the solstice have distinct effects. Bud set and senescence were tightly coupled (R²=0.49), with stronger bud responses. Each day of delayed leaf-out postponed bud set by 0.24±0.06 days and senescence by 0.22±0.08 days. July full-day cooling delayed autumn phenology in late-leafing individuals (bud set +4.9±2.6 days; senescence +3.1± 2.8 days) but had a negligible impact on early-leafing trees. August full-day cooling advanced both stages. Pre-solstice daytime cooling had no effect, while post-soltice daytime cooling advanced autumn phenology. Nighttime cooling consistently delayed bud set. These findings support the Solstice-as-Phenology-Switch model and highlight the central role of developmental progression in constraining growing seasons. Faster early-season development – especially under nighttime warming – moves trees past the switch earlier, increasing sensitivity to late-season cooling and thereby triggering earlier autumn phenology. Phenology models should incorporate these developmentally-mediated and diel-specific temperature responses.

A quantitative pipeline for whole-mount deep imaging and analysis of multi-layered organoids across scales

leo.guignard@univ-amu.fr (Agathe Rostan) — Fri, 22 May 2026 00:00:00 +0000

Whole-mount 3D imaging at the cellular scale is a powerful tool for exploring complex processes during morphogenesis. In organoids, it allows examining tissue architecture, cell types, and morphology simultaneously in 3D models. However, cell packing in multilayered organoid tissues hinders both deep imaging and quantification of cell-scale processes. To address these challenges, we developed an experimental and computational pipeline to extract properties at scales ranging from cell to tissue. The experimental module is based on two-photon imaging of immunostained organoids. The computational module corrects for optical artifacts, performs accurate 3D nuclei segmentation and reliably quantifies gene expression. We provide the computational module as a user-friendly Python package called Tapenade, along with napari plugins which enable joint data processing and exploration across scales. We demonstrate the pipeline by quantifying 3D spatial patterns of gene expression and nuclear morphology in gastruloids, revealing how local cell deformations and gene co-expression relate to tissue-scale organization. This quantitative pipeline improves our understanding of gastruloid development, and lays the groundwork for a wide range of multi-layered organoids and tumoroids systems

Lipopolysaccharide stimulates dynamic changes in B cell metabolism to promote proliferation

j.s.c.arthur@dundee.ac.uk (Andrew JM Howden) — Thu, 21 May 2026 00:00:00 +0000

Naive B cells exit quiescence and enter a proliferative state upon activation, ultimately differentiating into antibody-secreting or memory B cells. Toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS), can serve as physiological stimuli to initiate this transition. Using quantitative proteomics, we show that TLR4 engagement induces metabolic reprogramming in murine B cells, increasing the expression of amino acid transporters and cholesterol biosynthetic enzymes. The amino acid transporter SLC7A5 is markedly upregulated following LPS stimulation, and conditional deletion of Slc7a5 impairs B cell proliferation, underscoring its essential role in B cell activation. LPS also elevates intracellular cholesterol levels, and inhibition of the rate-limiting enzyme HMG-CoA reductase blocks proliferation. This effect was mediated by a dual requirement for cholesterol metabolism and protein prenylation downstream of HMG-CoA reductase. Notably, this was not unique to TLR4 signalling but is also observed in B cells activated via TLR7, TLR9, CD40, or the B cell receptor. Together, these findings reveal that metabolic rewiring, including amino acid uptake and cholesterol metabolism, is an essential feature of B cell activation and proliferation.

The nucleus accumbens shell regulates hedonic feeding via a rostral hotspot

alinamariuca.marinescu@hest.ethz.ch (Alina-Măriuca Marinescu) — Thu, 21 May 2026 00:00:00 +0000

The medial nucleus accumbens shell (medNAcSh) is a key regulator of hedonic feeding, controlling reward consumption through its projections to downstream structures. Recent studies showed that the primary cellular mediators of these effects are dopamine 1 receptor-positive striatal projection neurons (D1-SPNs). Specifically, D1-SPN activity gets inhibited during reward consumption, and such inhibition is necessary and sufficient to authorize consumption, independent of metabolic need. Anatomically, the medNAcSh spans 1–1.5 mm along the rostro-caudal axis in mice, and previous studies have reported functional gradients along this axis. For instance, pharmacological studies have suggested that rostral rather than caudal medNAcSh regulates appetitive behavior. However, the mechanisms underlying this topographical gradient remain unknown. Here, we hypothesized that D1-SPNs contribute to this gradient by regulating hedonic feeding via a specific hotspot in the rostral medNAcSh. Using calcium monitoring with fiber photometry in mice, we show that rostral medNAcSh D1-SPNs demonstrate inhibitory responses during reward consumption, while caudal D1-SPNs do not. Consistently, optogenetic stimulation of rostral D1-SPNs inhibits consumption, while stimulation of caudal D1-SPNs had minimal effects, confirming the existence of a functional rostro-caudal gradient. Importantly, we observed no differences between rostral and caudal D1-SPNs in their responses to aversive stimuli, suggesting that the D1-SPN gradient is specific to appetitive contexts. To investigate potential molecular correlates of this functional gradient, we leveraged open-source anatomy datasets and performed fluorescent in situ hybridization, identifying Stard5 and Peg10 as markers enriched in the rostral and caudal medNAcSh, respectively. Finally, we developed a novel Stard5-Flp driver line to selectively target the rostral hotspot and demonstrated that Stard5+ neurons recapitulate rostral D1-SPN activity patterns. Together, these findings establish a spatially confined rostral medNAcSh subregion as a critical regulator of reward consumption and introduce Stard5 as a molecular tool for its manipulation, offering new opportunities for intervention in dysregulated eating.

Insights into perceptual learning

zhonglin@nyu.edu (Zhong-Lin Lu) — Thu, 21 May 2026 00:00:00 +0000

A form of short-term memory called serial dependence can predict how effectively perceptual learning transfers to novel visual locations.

Single-cell transcriptomics-informed induced pluripotent stem cells differentiation to tenogenic lineage

Dmitriy.Sheyn@csmc.edu (Angela Papalamprou) — Thu, 21 May 2026 00:00:00 +0000

During vertebrate embryogenesis, axial tendons develop from the paraxial mesoderm and differentiate through specific developmental stages to reach the syndetome stage. While the main roles of signaling pathways in the earlier stages of differentiation have been well established, pathway nuances in syndetome specification from the sclerotome stage have yet to be explored. Here, stepwise differentiation of human induced pluripotent stem cells to the syndetome stage is shown, using chemically defined media and small molecules that were modified based on single-cell RNA-sequencing and pathway analysis. A significant population of branching off-target cells differentiating toward a neural phenotype overexpressing Wnt was identified. Further transcriptomics post-addition of a WNT inhibitor at the somite stage and onwards revealed not only total removal of the neural off-target cells, but also increased syndetome induction efficiency. Fine-tuning tendon differentiation in vitro is essential to address the current challenges in developing a successful cell-based tendon therapy.

Multimodal MRI marker of cognition explains the association between cognition and mental health in the UK Biobank

is.buyanova@gmail.com (Irina Buianova) — Wed, 20 May 2026 00:00:00 +0000

Cognitive dysfunction often co-occurs with psychopathology. Advances in neuroimaging and machine learning have led to neural indicators that predict individual differences in cognition with reasonable performance. We examined whether these indicators explain the relationship between cognition and mental health in the UK Biobank (n>14,000). Using machine learning, we quantified the covariation between cognition and 133 mental health indices and derived neural indicators of cognition from 72 neuroimaging phenotypes across diffusion-weighted MRI (dwMRI), resting-state functional MRI (rsMRI), and structural MRI (sMRI). With commonality analyses, we investigated how much of the cognition–mental health covariation is captured by each indicator and neural indicators combined within and across MRI modalities. The predictive association between mental health and cognition was at r=0.3. Neuroimaging captured 2.1 to 25.8% of the cognition-mental health covariation. Combining phenotypes within modalities improved the explanation to 25.5% for dwMRI, 29.8% for rsMRI, and 31.6% for sMRI, and combining them across modalities enhanced the explanation to 48%. We present an integrated approach to derive multimodal MRI markers of cognition that can be transdiagnostically linked to psychopathology, demonstrating that the predictive ability of neural indicators extends beyond the prediction of cognition itself, enabling us to capture cognition-mental health covariation.

Uncovering the electrical synapse proteome in retinal neurons via in vivo proximity labeling

stetenbo@Central.UH.EDU (Alberto E Pereda) — Wed, 20 May 2026 00:00:00 +0000

Electrical synapses containing Connexin 36 (Cx36) represent the main means for direct electrical communication among neurons in the mammalian nervous system. However, little is known about the protein complexes that constitute these synapses. In the present study, we applied different BioID strategies to screen the interactomes of Connexin 36 and its zebrafish orthologue Cx35.1 in retinal neurons. For in vivo proximity labeling in mice, we took advantage of the Cx36-EGFP strain and expressed a GFP-nanobody-TurboID fusion construct selectively in AII amacrine cells. For in vivo BioID in zebrafish, we generated a transgenic line expressing a Cx35.1-TurboID fusion under control of the Cx35.1 promoter. Both strategies allowed us to capture a plethora of molecules that were associated with electrical synapses and showed a high degree of evolutionary conservation in the proteomes of both species. Besides known interactors of Cx36 such as ZO-1 and ZO-2, we have identified more than 50 new proteins, such as scaffold proteins, adhesion molecules, and regulators of the cytoskeleton. Moreover, we determined the subcellular localization of these proteins in mouse retina and tested potential binding interactions with Cx36. Among these new interactors, we identified signal-induced proliferation associated 1 like 3 (Sipa1l3), a protein that has been implicated in cell junction formation and cell polarity, as a new scaffold of electrical synapses. Interestingly, Sipa1l3 was able to interact with ZO-1, ZO-2, and Cx36, suggesting a pivotal role in electrical synapse function. In summary, our study provides the first detailed view of the electrical synapse proteome in retinal neurons, which is likely to apply to electrical synapses elsewhere.

The multifaceted role of EXOC6A in ciliogenesis

tktang@ibms.sinica.edu.tw (Chien-Ting Wu) — Wed, 20 May 2026 00:00:00 +0000

Ciliogenesis is a highly ordered process that requires membrane trafficking, fusion, and maturation. In this study, we investigated EXOC6A, a component of the exocyst complex known for secretory vesicle trafficking and fusion, and found that it interacts with myosin-Va (Myo-Va) during ciliogenesis. EXOC6A colocalizes with Myo-Va at various stages of ciliogenesis, including preciliary vesicles, ciliary vesicles (CVs), and ciliary sheath membrane during ciliogenesis. We found that EXOC6A vesicles are actively recruited, integrated, and exit from the CVs and the ciliary sheath, implying that EXOC6A vesicles may facilitate continuous cilia membrane remodeling during ciliogenesis. Importantly, EXOC6A knockout impairs ciliogenesis, arresting most cells at the CV stage and preventing recruitment of NPHP and MKS module components to the transition zone. Furthermore, EXOC6A vesicles are transported to the mother centriole via a dynein-, microtubule-, and actin-dependent mechanism. Our results suggest that EXOC6A functions in both early and late stages of ciliogenesis, and is involved in orchestrating vesicle dynamics, cilia membrane remodeling, and formation.

Twelve phosphomimetic mutations induce the assembly of recombinant full-length human tau into paired helical filaments

mg@mrc-lmb.cam.ac.uk (Jane L Wagstaff) — Wed, 20 May 2026 00:00:00 +0000

The assembly of tau into amyloid filaments is associated with more than 20 neurodegenerative diseases, collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of brain-derived tau filaments revealed that specific structures define different diseases, triggering a quest for the development of experimental model systems that replicate the structures of disease. Here, we describe 12 phosphomimetic serine/threonine-to-aspartate mutations in tau, which we term PAD12, that collectively induce the in vitro assembly of full-length three-repeat tau into filaments with the same structure as paired helical filaments extracted from the brains of individuals with Alzheimer’s disease. Solution-state nuclear magnetic resonance spectroscopy suggests that phosphomimetic mutations in the carboxy-terminal domain of tau may facilitate filament formation by disrupting an intramolecular interaction between two IVYK motifs. PAD12 tau can be used for both nucleation-dependent and multiple rounds of seeded assembly in vitro, as well as for the seeding of tau biosensor cells. PAD12 tau can be assembled into paired helical filaments under various shaking conditions, with the resulting filaments being stable for extended periods of time. They can be labelled with fluorophores and biotin. Tau filaments extracted from the brains of individuals with Alzheimer’s disease have been known to be made of hyperphosphorylated and abnormally phosphorylated full-length tau, but it was not known if the presence of this post-translational modification is more than a mere correlation. Our findings suggest that hyperphosphorylation of tau may be sufficient for the formation of the Alzheimer tau fold. PAD12 tau will be a useful tool for the study of molecular mechanisms of neurodegeneration.

MORC2 mediates transcriptional regulation through liquid-liquid phase separation

huangcd@ustc.edu.cn (Chao Wang) — Wed, 20 May 2026 00:00:00 +0000

MORC2 is a chromatin-associated ATPase essential for transcriptional silencing and genome stability, yet the biophysical principles governing its regulatory activity remain elusive. Here, we demonstrate that full-length MORC2 undergoes biomolecular condensation to form dynamic nuclear assemblies, a process fundamentally required for its repressor function. Endogenous MORC2 forms discrete, dynamic condensates in neurons from Morc2a^EGFP chimeric mice, supporting the physiological relevance of these assemblies in vivo. Mechanistically, a 3.1 Å crystal structure of coiled-coil 3 (CC3) identifies a dimeric scaffold that serves as a structural hub, while multivalent ‘sticker’ interactions between an intrinsically disordered region (IDR) and a newly defined IDR-binding domain (IBD) drive condensation. We show that DNA acts as a molecular scaffold that triggers MORC2 condensation, which in turn allosterically stimulates its ATPase activity. Critically, by employing a ‘killswitch’ strategy to decouple assembly from internal fluidity, we reveal that only dynamic MORC2 condensates, not static aggregates or condensation-deficient mutants, can restore transcriptional regulation in MORC2-knockout cells. Furthermore, pathogenic variants linked to CMT2Z and SMA differentially perturb these material properties and enzymatic turnover, providing a mechanistic link between condensate dysregulation and human neuropathies. Together, our findings establish a DNA-templated condensation mechanism for MORC2 and provide a molecular framework for understanding how the material state of chromatin-associated machinery dictates gene regulation and disease pathogenesis.

Lineage priming and cell type proportioning depends on the interplay between stochastic and deterministic factors

christopher.thompson@ucl.ac.uk (Catherine Pears) — Tue, 19 May 2026 00:00:00 +0000

Isogenic cells can break symmetry and adopt different fates, even when exposed to a seemingly identical environment. This deeply conserved phenomenon allows unicellular organisms to pre-empt dynamically changing environments and is central to the evolution of multicellularity. It is thought that cells are primed towards different lineages by cell-cell variation, although the underlying mechanisms are poorly understood. To address this, we exploit the tractability of the social amoeba Dictyostelium discoideum, where cell fate choice also does not depend on spatial cues. We develop and test a model to explain quantitative experimental single-cell observations of probabilistic differentiation. The model suggests that cell cycle position affects lineage choice, as previously shown but that stochastic cell-cell variation also plays a key role. Single cell sequencing reveals genes that exhibit cell type-specific expression or genes that affect fate choice exhibit extensive stochastic cell-cell expression variation. Like lineage priming genes in ESCs, they are associated with H3K4 methylation, which when perturbed affects their expression and disrupt fate choice. We suggest the integration of stochastic and deterministic inputs represents an adaptive mechanism to increase developmental robustness against perturbations that affect deterministic signals.

Single-domain antibody inhibitors target the coiled coil arms of the Bacillus subtilis SMC complex

stephan.gruber@unil.ch (Lea M Huber-Hürlimann) — Tue, 19 May 2026 00:00:00 +0000

Synthetic nanobodies—also called sybodies—have proven valuable for stabilizing conformations of purified proteins, advancing structural and functional studies for example of transmembrane proteins. However, their utility in modulating protein function in living cells has remained less well explored. Structural Maintenance of Chromosomes (SMC) complexes facilitate chromosome organization, a fundamental process in all domains of life. In this study, we target the bacterial SMC complex, Smc-ScpAB, in Bacillus subtilis with synthetic nanobodies, aiming to identify key functional regions of the protein complex in a largely unbiased manner. We first isolate sybodies that specifically bind purified Smc-ScpAB and then express them in B. subtilis to select binders capable of disrupting Smc-ScpAB function, leading to chromosome segregation defects and cell death. Mapping and biochemical characterization show that the 14 disruptive sybodies belong to one of three library designs, target the Smc subunit near the same coiled coil arm interface and modulate its ATPase activity in two principal ways, highlighting the mid-region of the Smc coiled coil as critical feature of the SMC-DNA folding process. These findings underscore the potential of sybodies—and, by extension, designed binders—as versatile tools for probing dynamic protein function in living cells.

Two neuropeptides that promote blood feeding in Anopheles stephensi mosquitoes

prashali.bansal@tigs.res.in (Pooja DB) — Tue, 19 May 2026 00:00:00 +0000

Animals routinely need to make decisions about what to eat and when. These decisions are influenced not only by the availability and quality of food but also by the internal state of the animal, which needs to compute and give weights to these different variables before making a choice. Feeding preferences of female mosquitoes exemplify this behavioural plasticity. Both male and female mosquitoes usually feed on carbohydrate-rich sources of nectar or sap but the female also feeds on blood, which is essential for egg development. This blood-appetite is modulated across the female’s reproductive cycle, yet little is known about the factors that bring it about. We show that mated, but not virgin Anopheles stephensi females, a major vector of urban malaria in the Indian subcontinent and West Africa, suppress blood feeding between a blood meal and oviposition. We identify several candidate genes through transcriptomics of blood-deprived and -sated An. stephensi central brains that could modulate this behaviour. We show that short neuropeptide F (sNPF) and RYamide (RYa) act together to promote blood feeding and identify a cluster of cells in the subesophageal zone that expresses sNPF transcripts only in the blood-hungry state. Such females also have more sNPF transcripts in their midguts. Based on these data, we propose a model where increased sNPF levels in the brain and gut promote a state of blood-hunger, which drives feeding behaviour either by sNPF’s action in the two tissues independently or via a communication between them. This occurs in the context of the action of RYa in the brain.

Cell surface localisation of GPI-anchored receptors in Trypanosoma brucei

mc115@cam.ac.uk (Alexander D Cook) — Tue, 19 May 2026 00:00:00 +0000

Trypanosoma brucei, the causal agent of Human and Animal African trypanosomiasis proliferates in the extracellular milieu of mammals. It acquires host macromolecular nutrients by receptor-mediated endocytosis. The best characterised cell surface receptor is for transferrin (TfR), and it has been reported to be preferentially localised in the flagellar pocket domain of the plasma membrane, the sole site of endocytosis. In this location, the TfR may be inaccessible to adaptive immune system effectors. The T. brucei genome encodes ~15 TfR variants, and here we compared two, the first attached to the plasma membrane by a single glycosylphosphatidylinositol (GPI)-anchor and the other by two. Transferrin uptake kinetics were similar and rapid for both. Unexpectedly, initial binding of transferrin occurred over the whole cell surface suggesting the TfR was not localised solely in the flagellar pocket. This localisation was confirmed by immunofluorescence assays and was independent of the number of GPI-anchors. Two other GPI-anchored receptors were investigated to determine whether localisation to the whole cell surface was a general property of GPI-anchored receptors. Haptoglobin-haemoglobin uptake assays and immunofluorescence localisation of complement factor H receptor showed both were also whole cell surface localised. The mechanisms by which trypanosome receptors are protected from antibody-mediated attack are more complex than hiding in a pocket.

Full factorial construction of synthetic microbial communities

alvaro.sanchez@usal.es (Alvaro Sanchez) — Tue, 19 May 2026 00:00:00 +0000

Constructing combinatorially complete species assemblages is often necessary to dissect the complexity of microbial interactions and to find optimal microbial consortia. At the moment, this is accomplished through either painstaking, labor-intensive liquid handling procedures, or through the use of state-of-the-art microfluidic devices. Here, we present a simple, rapid, low-cost, and highly accessible liquid handling methodology for assembling all possible combinations of a library of microbial strains, which can be implemented with basic laboratory equipment. To demonstrate the usefulness of this methodology, we construct a combinatorially complete set of consortia from a library of eight Pseudomonas aeruginosa strains, and empirically measure the community-function landscape of biomass productivity, identify the highest-yield community, and dissect the interactions that lead to its optimal function. This easy-to-implement, inexpensive methodology will make the assembly of combinatorially complete microbial consortia easily accessible for all laboratories.

Cas9⁺ conditionally immortalized neutrophil progenitors as a tool for genome-wide CRISPR screening for neutrophil differentiation and function

sastanley@berkeley.edu (Alex Zilinskas) — Mon, 18 May 2026 00:00:00 +0000

Neutrophils are short-lived cells of the innate immune system that play numerous roles in defense against infection, regulation of immune responses, tissue damage and repair, autoimmunity, and other non-communicable diseases. Understanding neutrophil function at a mechanistic level has been hampered by the difficulty of working with primary neutrophils, which die rapidly upon isolation, and the relative paucity of neutrophil cell lines. Here, we report the creation of a Cas9 +ER-Hoxb8 neutrophil progenitor cell line that enables both forward and reverse genetic analysis of neutrophils. By editing progenitors via transduction with sgRNAs and then withdrawing estrogen, Cas9-edited neutrophils are produced with high efficiency. Importantly, neutrophil differentiation of edited progenitors occurs both in vitro in cell culture and when transferred into murine recipients. To demonstrate the utility of Cas9 +ER-Hoxb8 progenitors for forward genetics, we performed a pooled CRISPR screen to identify factors required for survival during neutrophil differentiation. This screen identified hundreds of genes, including Cebpe, a transcription factor known to be required for neutrophil differentiation from pre-neutrophils to immature neutrophils. Using this progenitor cell line, we confirmed that Cebpe is required for neutrophil differentiation in vivo, validating the utility of this line for studying in vivo phenotypes. The screen also identified all components of the WASH complex as being required for neutrophil differentiation, extending its known role in hematopoietic stem cell differentiation to later stages of neutrophil development. Taken together, this resource enables the analysis of the role of neutrophils in numerous disease states using genetics for the first time.

Rapid riparian ecosystem recovery in low-latitudinal North China following the end-Permian mass extinction

tianlibgeg@cug.edu.cn (Daoliang Chu) — Mon, 18 May 2026 00:00:00 +0000

The greatest mass extinction at the end of the Permian, ca. 252 million years ago, led to a tropical dead zone on land and sea. The speed of recovery of life has been debated, whether fast or slow, and terrestrial ecosystems are much less understood than marine. Here, we show fast reestablishment of riparian ecosystems in low-latitude North China as little as ~2 million years after the end-Permian mass extinction. The initial ichnoassemblages in shallow lacustrine and fluvial facies of late Smithian age are monospecific, devoid of infaunalization, with apparent size reduction. In the following Spathian, relatively complex, multi-level, structured riverain ecosystems had been rebuilt including medium-sized carnivores, plant stems, root traces, increased ichnological complexity, and significantly increased infaunalization. Specifically, burrowing behavior had re-emerged as a key life strategy not only to minimize stressful climatic conditions, but possibly to escape predation.

Identification and classification of ion channels across the tree of life provide functional insights into understudied CALHM channels

wei.lu@northwestern.edu (Kennady Boyd) — Mon, 18 May 2026 00:00:00 +0000

The ion channel (IC) genes encoded in the human genome play fundamental roles in cellular functions and disease, and are one of the largest classes of druggable proteins. However, limited knowledge of the diverse molecular and cellular functions carried out by ICs presents a major bottleneck in developing selective chemical probes for modulating their functions in disease states. The wealth of sequence data available on ICs from diverse organisms provides a valuable source of untapped information for illuminating the unique modes of channel regulation and functional specialization. However, the extensive diversification of IC sequences and the lack of a unified resource present a challenge in effectively using existing data for IC research. Here, we perform integrative mining of available sequence, structure, and functional data on 419 human ICs across disparate sources, including extensive literature mining by leveraging advances in LLMs to annotate and curate the full complement of the ‘channelome’. We employ a well-established orthology inference approach to identify and extend the IC orthologs across diverse organisms to above 48,000. We show that the depth of conservation and taxonomic representation of IC sequences can further be translated to functional similarities by clustering them into functionally relevant groups, which can be used for downstream functional prediction on understudied members. We demonstrate this by delineating co-conserved patterns characteristic of the understudied family of the calcium homeostasis modulator (CALHM) family of ICs. Through mutational analysis of co-conserved residues altered in human diseases and electrophysiological studies, we show that these evolutionarily constrained residues play an important role in channel gating functions. Thus, by providing new tools and resources for performing large comparative analyses on ICs, this study addresses the unique needs of the IC community and provides the groundwork for accelerating the functional characterization of dark channels for therapeutic intervention.

Redirection of SARS-CoV-2 to phagocytes by intranasal sACE2-Fc as a universal decoy confers complete prophylactic protection

llmpoon@hku.hk (Alex WH Chin) — Mon, 18 May 2026 00:00:00 +0000

The rapid evolution of SARS-CoV-2 and other respiratory RNA viruses limits the success of current vaccines and antibody-based therapies. Engineered decoy receptors based on soluble angiotensin-converting enzyme 2 (sACE2) offer promising alternatives but show limited clinical success. This study conducted functional and mechanistic analyses using an optimized sACE2 mutant fused to human IgG1 Fc (B5-D3) as a representative, revealing redirection of virus–decoy complexes from epithelial infection to lysosomal degradation in phagocytes beyond viral neutralization. Intranasal prophylactic delivery of B5-D3 confers complete protection in SARS-CoV-2-infected K18-hACE2 mice, regardless of age. Abrogation of Fc effector functions compromises antiviral protection, indicating that Fc-mediated uptake of virus–decoy complexes is critical. Transcriptomic analysis suggests that B5-D3 induces early immune activation in the lungs of infected mice. Bio-distribution and flow cytometry reveal selective targeting of airway phagocytes. In vitro assays confirm lysosomal degradation of virus–decoy complexes by macrophages without productive infection. These findings reveal a distinct antiviral mechanism via phagocytic clearance, supporting refined regimens for decoy treatments against SARS-CoV-2 and potentially other respiratory viruses.

Circadian control of a sex-specific behavior in Drosophila

srisau@cab.cnea.gov.ar (Diana Lorena Franco) — Mon, 18 May 2026 00:00:00 +0000

An endogenous circadian clock controls many of the behavioral traits of Drosophila melanogaster. This ‘clock’ relies on the activity of interconnected clusters of neurons that harbor the clock machinery. The hierarchy among clusters involved in the control of rest-activity cycles has been extensively studied. Sexually dimorphic behaviors, on the other hand, have received less attention. Even though egg-laying, a female characteristic behavior, has been shown to be rhythmic, it remains largely unexplored possibly due to methodological constraints. The current study provides the first steps towards determining the neural substrates underlying the circadian control of egg-laying. We show that, whereas the lateral ventral neurons (LNvs) and the dorsal neurons (DNs) are dispensable, the lateral dorsal neurons (LNds) are necessary for rhythmic egg-laying. Systematically probing the Drosophila connectome for contacts between circadian clusters and oviposition-related neurons, we found no evidence of direct connections between LNvs or DNs and neurons recruited during oviposition. Conversely, we did find bidirectional connections between two Cryptochrome (Cry) expressing LNd (Cry + LNds) and oviposition-related neurons. Taken together, these results reveal that Cry + LNd neurons have a leading role in the control of the egg-laying rhythm in Drosophila females.

Surging towards a better understanding of ovulation

akauffman@health.ucsd.edu (Alexander S Kauffman) — Mon, 18 May 2026 00:00:00 +0000

The ability to record the real-time activity of specialized neurons in the brains of female mice is providing new insights into the hormonal control of ovulation.

Mapping of in vivo cleavage sites uncovers a major role for yeast RNase III in regulating protein-coding genes

ambro.van.hoof@uth.tmc.edu (Ambro van Hoof) — Mon, 18 May 2026 00:00:00 +0000

A large fraction of newly transcribed RNA is degraded in the nucleus, but nuclear mRNA degradation pathways remain largely understudied. The yeast nuclear endoribonuclease Rnt1 has a well-characterized role in the maturation of many ncRNA precursors. However, the scope and consequence of its function in mRNA degradation pathways are much less defined. Here, we take a whole-transcriptome approach to identify Rnt1 cleavage sites throughout the yeast transcriptome in vivo, at single-nucleotide resolution. We discover previously unknown Rnt1 cleavage sites in many protein-coding regions and find that the sequences and structures necessary for cleavage mirror those required for the cleavage of known targets. We show that the nuclear localization of Rnt1 functions as an additional layer of target selection control, and that cleaved mRNAs are likely exported to the cytoplasm to be degraded by Xrn1. Further, we find that several cleavage products are much more abundant in our degradome sequencing libraries than decapping products, and strikingly, mutations in one Rnt1 target, YDR514C, suppress the growth defect of an RNT1 deletion. Overexpression of YDR514C results in slow growth, further suggesting that Rnt1 may limit the expression of YDR514C to maintain proper cell growth. This study uncovers a broader target range and function for the well-known RNase III enzyme.

Drug-induced changes in connectivity to midbrain dopamine cells revealed by rabies monosynaptic tracing

kbeier@uci.edu (Cindy M Yamamoto) — Fri, 15 May 2026 00:00:00 +0000

Addictive drugs cause long-lasting changes in connectivity from inputs onto ventral tegmental area dopamine cells (VTA^DA) that contribute to drug-induced behavioral adaptations. However, it is not known which inputs are altered. Here, we used a rabies virus (RABV)-based mapping strategy to quantify RABV-labeled inputs to VTA cells after a single exposure to one of a variety of misused drugs – cocaine, amphetamine, methamphetamine, morphine, and nicotine – and compared the relative global input labeling across conditions. We observed that all tested addictive drugs elicited similar input changes onto VTA^DA cells, in particular onto DA cells projecting to the lateral shell of the nucleus accumbens and amygdala. In addition, repeated administration of ketamine/xylazine to induce anesthesia induces a change in inputs to VTA^DA cells that is similar to but different from those elicited by a single exposure to addictive drugs, suggesting that caution should be taken when using ketamine/xylazine-based anesthesia in rodents when assessing motivated behaviors. Furthermore, comparison of viral tracing data to an atlas of gene expression in the adult mouse brain showed that the basal expression patterns of several gene classes, especially calcium channels, were highly correlated with the extent of both addictive drug- or ketamine/xylazine-induced changes in RABV-labeled inputs to VTA^DA cells. Reducing expression levels of the voltage-gated calcium channel Cacna1e in cells in the nucleus accumbens lateral shell reduced RABV-mediated input labeling of these cells into VTA^DA cells. These results directly link genes controlling cellular excitability and the extent of input labeling by RABV.

Adrenomedullin restores the human cortical interneurons migration defects induced by hypoxia

apasca@stanford.edu (Alyssa Puno) — Fri, 15 May 2026 00:00:00 +0000

Extremely preterm birth (at <28 postconceptional weeks) leads to brain injury and represents the leading cause of childhood-onset neuropsychiatric diseases. No effective therapeutics exist to reduce the incidence and severity of brain injury of prematurity. Hypoxic events are the most important environmental factor, along with inflammation. Among other developmental processes, the second half of in utero fetal development coincides with the migration of cortical interneurons from the ganglionic eminences into the cortex; this process is thus prone to disruptions following extremely preterm birth. To date, no studies have directly investigated the migration of human cortical inhibitory neurons under hypoxic conditions. Using multi-day confocal live imaging in human forebrain assembloids (hFA) derived from human-induced pluripotent stem cells (hiPSCs) and ex vivo developing human brain tissue, we found a substantial reduction in the migration of hypoxic interneurons. Using transcriptomics, we identified adrenomedullin (ADM) as the gene with the highest fold change increase in expression. Based on previous literature about the protective role of supplemental ADM for other injuries, here, we demonstrated that addition of exogenous ADM to the hypoxic media restores the migration defects of interneurons. Lastly, we showed that one of the mechanisms of protection by ADM is through the activation of the cAMP/PKA pathway and subsequent pCREB-dependent rescued expression of a subset of GABA receptors, which are known to promote migration. Overall, in this manuscript, we provide the first direct evidence for hypoxia-induced deficits in the migration of human cortical interneurons and identify ADM as a possible target for therapeutic development.

Stranded short nascent strand sequencing reveals the topology of DNA replication origins in Trypanosoma brucei

slavica.stanojcic@umontpellier.fr (Bridlin Barckmann) — Fri, 15 May 2026 00:00:00 +0000

The universal features that define genomic regions acting as replication origins remain unclear. In this study, we mapped a set of origins in Trypanosoma brucei using stranded short nascent strand sequencing methods. Our results showed that DNA replication predominantly initiates in intergenic regions between poly(dA)- and poly(dT)-enriched sequences. G4 structures were detected in the vicinity of some origins and were embedded in poly(dA)-enriched sequences in a strand-specific manner: G4s on the plus strand were located upstream while those on the minus strand were located downstream of the centre. The origins' centres were found to be areas of low nucleosome occupancy, surrounded by regions of high nucleosome occupancy. Furthermore, our results demonstrate that 90% of replication origins overlap with a minor proportion of the previously reported RNA: DNA hybrids. These findings shed new light on the sequence and structural features that define the topology of replication origins in T. brucei. To further characterise replication dynamics at the single-molecule level, we employed DNA combing analysis.

Bilateral equalization of synaptic output in olfactory glomeruli of Xenopus tadpoles

allobet@ub.edu (Artur Llobet) — Fri, 15 May 2026 00:00:00 +0000

Odorants stimulate olfactory sensory neurons (OSNs) to create a bilateral sensory map defined by a set of glomeruli present in the left and right olfactory bulbs. Using Xenopus tropicalis tadpoles, we challenged the notion that glomerular activation is exclusively determined ipsilaterally. Glomerular responses evoked by unilateral stimulation were potentiated following transection of the contralateral olfactory nerve. The gain of function was observed as early as 2 hr after injury and faded away with a time constant of 4 days. Potentiation was mediated by the presence of larger and faster calcium transients driving glutamate release from OSN axon terminals. The cause was the reduction of the tonic presynaptic inhibition exerted by dopamine D₂ receptors. Inflammatory mediators generated by injury were not involved. These findings reveal the presence of a bilateral modulation of glomerular output driven by dopamine that compensates for imbalances in the number of operative OSNs present in the two olfactory epithelia. Considering that the constant turnover of OSNs is an evolutionarily conserved feature of the olfactory system and determines the innervation of glomeruli, the compensatory mechanism described here may represent a general property of the vertebrate olfactory system to establish an odor map.

Tumors mimic the niche to inhibit neighboring stem cell differentiation

swzhao@nankai.edu.cn (Chang Sun) — Fri, 15 May 2026 00:00:00 +0000

Although it is well established that stem cells maintain tissue homeostasis while tumors disrupt it, the mechanisms by which tumors influence the development of nearby stem cells remain poorly understood. Using Drosophila ovaries as a model system, here we discovered that bam or bgcn mutant germline tumors inhibit the differentiation of neighboring wild-type germline stem cells (GSCs). Mechanistically, these tumor cells mimic the stem cell niche by secreting the bone morphogenetic protein (BMP) ligands Dpp and Gbb, but at reduced levels, resulting in moderate BMP signaling activation in adjacent GSCs. Such BMP signaling activation is sufficient to repress bam transcription, thereby blocking GSC differentiation. To our knowledge, this is the first example that tumors can functionally mimic a stem cell niche to inhibit the differentiation of neighboring wild-type stem cells. Similar regulatory paradigms may operate in mammalian tissues, including humans, during tumorigenesis.

The role of ATP synthase subunit e (ATP5I) in mediating the metabolic and antiproliferative effects of metformin in cancer cells

sp.gravel@umontreal.ca (Ana Maria Duman) — Fri, 15 May 2026 00:00:00 +0000

Here, we identify the subunit e of F₁F₀-ATP synthase (ATP5I) as a target of metformin, a first-in-class antidiabetic biguanide. ATP5I maintains the stability of F₁F₀-ATP synthase dimers, which is crucial for shaping cristae morphology. We demonstrate that ATP5I interacts with a biguanide analogue in vitro, and disabling its expression by CRISPR–Cas9 in pancreatic cancer cells leads to the same phenotype as biguanide-treated cells, including mitochondrial morphology alterations, reduction of the NAD⁺/NADH ratio, inhibition of oxidative phosphorylation (OXPHOS), rescue of respiration by uncouplers, and a compensatory increase in glycolysis. Notably, metformin disrupts F₁F₀-ATP synthase oligomerization, leading to the accumulation of vestigial assembly intermediates in pancreatic and osteosarcoma cancer cells, a phenotype also observed upon ATP5I inactivation in pancreatic cancer cells. Moreover, ATP5I knockout (KO) cells exhibit resistance to the antiproliferative effects of biguanides, but reintroduction of ATP5I rescues the metabolic and antiproliferative effects of metformin and phenformin. Finally, a genome-wide CRISPR screening in NALM-6 lymphoma cells revealed that metformin-treated cells exhibit genetic interaction profiles similar to those observed with the F₁F₀-ATP synthase inhibitor oligomycin, but not with the complex I inhibitor rotenone. This provides unbiased support for the relevance of the newly proposed target.

Effort produces after-effects costly for others but valued for self

zhengya1982@gmail.com (Rumeng Tang) — Thu, 14 May 2026 00:00:00 +0000

Engaging in prosocial behavior requires effort, yet people are often averse to exerting effort for others’ benefit. However, it remains unclear how effort exertion affects subsequent reward evaluation during prosocial acts. Here, we combined high-temporal-resolution electroencephalography with a paradigm that independently manipulated physical effort and monetary reward for self and others to elucidate the neural mechanisms underlying the reward after-effect of prosocial effort expenditure. We found dissociable reward after-effects for self-benefiting and other-benefiting effort. For self-benefiting rewards, the reward positivity (RewP) increased with effort demand, suggesting an effort-enhancement effect. In contrast, for other-benefiting rewards, the RewP decreased as effort increased, demonstrating an effort-discounting effect. Critically, this dissociation was contingent upon high reward magnitude and modulated by individual differences in effort discounting, yet remained distinct from performance evaluation. Our findings reveal distinct neural computations for self- and other-benefiting efforts, offering new insights into how prior effort expenditure shapes reward evaluation during prosocial behavior.

Subregional activity in the dentate gyrus is amplified during elevated cognitive demands

a-contractor@northwestern.edu (Anis Contractor) — Thu, 14 May 2026 00:00:00 +0000

Neural activity in the dentate gyrus (DG) supports the detection and discrimination of novelty, context, and patterns. Granule cell activation differs between the supra- and infrapyramidal blades across hippocampal-dependent tasks, yet how excitatory dynamics shape this blade-specific bias under varying cognitive demands remains unclear. Here, we combined an automated touchscreen pattern separation task in mice with temporally controlled tagging of active neurons to determine how increasing cognitive demand influences spatial activity patterns in the DG. As task difficulty increased, activation became progressively biased toward the suprapyramidal blade and was accompanied by structured distributions of active mature granule cells (mGCs) along both the radial and transverse axes. Selective inhibition of mGCs did not alter these spatial patterns, but profoundly impaired performance, as mice were no longer able to discriminate between closely spaced locations. In contrast, chemogenetic inhibition of adult-born dentate granule cells (abDGCs) beyond a critical maturation window impaired performance under high-demand conditions, increased overall mGC activity, and disrupted blade-specific organization even in animals that successfully completed the task. These findings demonstrate that high cognitive demand recruits spatially organized mGC activity and support a modulatory role for abDGCs in shaping dentate circuit dynamics.

A meta-analysis suggests that TMS targeting the hippocampal network selectively improves episodic memory

joelvoss@uchicago.edu (Arantzazu San Agustin) — Thu, 14 May 2026 00:00:00 +0000

Episodic memory is critically dependent on the hippocampal network and is frequently impaired in many clinical disorders. Recent findings highlight Hippocampal Indirectly Targeted Stimulation (HITS) as a promising, network-guided non-invasive transcranial magnetic stimulation (TMS) procedure to enhance episodic memory performance. Here, we report the first comprehensive meta-analysis of HITS effects on episodic memory, encompassing both healthy individuals and clinical populations. HITS using parieto-occipital network targets robustly improved episodic memory, with effects selective for episodic memory versus other non-memory cognitive domains. Efficacy was significantly greater when memory performance was assessed using memory tasks sensitive to recollection, which is strongly linked to hippocampal network function, compared to recognition or other types of episodic memory tasks. Efficacy was also significantly greater when HITS was delivered before the memory tasks were administered versus in the period between study and test phases of tasks. No serious adverse events were reported. These findings establish HITS as a robust approach for episodic memory enhancement, suggesting potential for clinical translation in memory disorders. Selectivity of effects for episodic memory generally and for recollection-format tests in particular indicates cognitive and mechanistic specificity, supporting the potential for targeted and selective neuromodulation of hippocampal networks and their associated functions.

Identification of the regulatory elements and protein substrates of lysine acetoacetylation

yzheng@uga.edu (Bhoj Kumar) — Thu, 14 May 2026 00:00:00 +0000

Short-chain fatty acylations establish connections between cell metabolism and regulatory pathways. Lysine acetoacetylation (Kacac) was recently identified as a new histone mark. However, regulatory elements, substrate proteins, and epigenetic functions of Kacac are not yet fully understood, hindering further in-depth understanding of acetoacetate-modulated (patho)physiological processes. Here, we created a chemo-immunological approach for reliable detection of Kacac, and demonstrated that acetoacetate serves as the primary precursor for histone Kacac. We report the enzymatic addition of the Kacac mark by the acyltransferases GCN5, p300, and PCAF, and its removal by the deacetylase HDAC3. Furthermore, we establish acetoacetyl-CoA synthetase as a key regulator of cellular Kacac levels. A comprehensive proteomic analysis has identified 139 Kacac sites on 85 human proteins. Bioinformatics analysis of Kacac substrates and RNA sequencing data reveal the broad impacts of Kacac on multifaceted cellular processes. These findings unveil pivotal regulatory mechanisms for the acetoacetate-mediated Kacac pathway, opening a new avenue for further investigation into ketone body functions in various pathophysiological states.

Characterisation of cold-selective lamina I spinal projection neurons in the mouse

Andrew.Todd@glasgow.ac.uk (Aimi N Razlan) — Wed, 13 May 2026 00:00:00 +0000

Skin cooling is detected by primary afferents that express the Trpm8 channel, but how this information is conveyed to the brain remains poorly understood. We have previously identified a population of lamina I projection neurons belonging to the anterolateral system (ALS) that receive numerous contacts from Trpm8-expressing primary afferents. Here, using a semi-intact somatosensory preparation, we provide evidence that these cells correspond to the cold-selective ALS neurons identified in previous physiological studies. We also confirm the presence of synapses from Trpm8 afferents onto these cells at the ultrastructural level and with optogenetics. Based on our previous transcriptomic findings, we identify calbindin as a molecular marker, and show that this can be used to target the cold-selective ALS neurons for anterograde tracing studies. We provide evidence that they project to brain regions that have been implicated in thermosensation: the rostralmost part of the lateral parabrachial area, the caudal part of the periaqueductal grey matter, and the posterior triangular and ventral posterolateral nuclei of the thalamus. Our findings provide important insights into the organisation of neuronal circuits that underlie thermoregulation and the perception of cold stimuli applied to the skin.

The long non-coding RNA Dreg1 is required for optimal ILC2 development

ajith.vasanthakumar@petermac.org (Adelynn Tang) — Wed, 13 May 2026 00:00:00 +0000

Gata3 is an essential transcription factor for the development of several distinct immune cell lineages such as T cells, natural killer (NK) cells, and innate lymphoid cells (ILCs). As such, the levels and timing of Gata3 expression are critical for directing lineage fate decisions. The Gata3 locus has a complex and dynamic distal regulatory enhancer landscape. Recently, we identified a non-coding RNA, Dreg1, located immediately upstream of the classic +280 kb T/NK cell enhancer (Tce1). To test its function, we excised the Dreg1 locus in mice and observed a selective reduction of group 2 ILCs (ILC2) across multiple tissues, but mature T, NK, and other ILC lineages remained unchanged. In bone marrow, common innate lymphoid cell progenitors (ILCPs) increased while ILC2 progenitors (ILC2P) decreased, with a modest reduction of Gata3 in upstream progenitors consistent with an early developmental bottleneck. Chromatin profiling showed the Dreg1 locus is accessible in early lymphoid progenitors and became decorated with H3K27ac in ILCP in a Tcf1-dependent manner. Furthermore, Tcf1-deficient cells did not express Dreg1 and showed alterations in the epigenetic landscape of the Dreg1 locus. Finally, we discovered that potential homologues of Dreg1 harboured in a syntenic enhancer of GATA3 are also highly expressed in human ILC2. Taken together, we conclude that Dreg1 is a Tcf1-dependent non-coding RNA critical for fine tuning the high level of Gata3 required for the optimal development of the ILC2 lineage.

Locus coeruleus modulation of prefrontal dynamics during attentional switching in mice

hongdian@ucr.edu (Hongdian Yang) — Wed, 13 May 2026 00:00:00 +0000

Behavioral flexibility, the ability to adjust behavioral strategies in response to changing environmental contingencies and internal demands, is fundamental to cognitive functions. Despite a large body of pharmacology and lesion studies, the precise neurophysiological mechanisms that underlie behavioral flexibility are still under active investigations. This work is aimed to determine the role of a brainstem-to-prefrontal cortex circuit in flexible rule switching. We trained mice to perform a set-shifting task in which they learned to switch attention to distinguish complex sensory cues. Using chemogenetic inhibition, we selectively targeted genetically defined locus coeruleus (LC) neurons or their input to the medial prefrontal cortex (mPFC). We revealed that suppressing either the LC or its mPFC projections severely impaired switching behavior, establishing the critical role of the LC-mPFC circuit in supporting attentional switching. To uncover the neurophysiological substrates of the behavioral deficits, we paired endoscopic calcium imaging of the mPFC with chemogenetic inhibition of the LC in task-performing mice. We found that mPFC prominently responded to attentional switching and that LC inhibition not only enhanced the engagement of mPFC neurons but also broadened single-neuron tuning in the task. At the population level, LC inhibition disrupted mPFC dynamic changes and impaired the encoding capacity for switching. Our results highlight the profound impact of the ascending LC input on modulating prefrontal dynamics and provide new insights into the cellular and circuit-level mechanisms that support behavioral flexibility.

Dissociable neural substrates of integration and segregation in exogenous attention

xhe@bournemouth.ac.uk (Ai-Su Li) — Wed, 13 May 2026 00:00:00 +0000

The integration-segregation theory proposes that early facilitation and later inhibition (i.e. inhibition of return [IOR]) in exogenous attention arises from the competition between cue-target event integration and segregation. Although widely supported behaviorally, the theory lacked direct neural evidence. Here, we used event-related functional magnetic resonance imaging (fMRI) in human participants with an optimized cue-target paradigm to test this account. Cued targets elicited stronger activation in the frontoparietal attention networks, including the bilateral frontal eye field (FEF), intraparietal sulcus (IPS), right temporoparietal junction (TPJ), and left dorsal anterior cingulate cortex (dACC), consistent with the notion of attentional demand of reactivating the cue-initiated representations for integration. In contrast, uncued targets engaged the medial temporal cortex, particularly the bilateral parahippocampal gyrus (PHG) and superior temporal gyrus (STG), reflecting the segregation processes associated with new object-file creation and novelty encoding. These dissociable activations provide the first direct neuroimaging evidence for the integration-segregation theory. Moreover, we observed neural interactions between IOR and cognitive conflict, suggesting a potential modulation of conflict processing by attentional orienting. Taken together, these findings provide new insights into exogenous attention by clarifying the neural underpinnings of integration and segregation and uncovering the interaction between spatial orienting and conflict processing.

Examining the role of lipids in hearing

Angela.Ballesteros@nih.gov (Angela Ballesteros) — Wed, 13 May 2026 00:00:00 +0000

The asymmetry of lipid membranes is tightly regulated in eukaryotic cells, and auditory hair cells are no exception.

An altered cell-specific subcellular distribution of translesion synthesis DNA polymerase kappa (POLK) in aging mouse neurons

amp7167@psu.edu (Anirban Paul) — Wed, 13 May 2026 00:00:00 +0000

Genomic stability is critical for cellular function; however, in the central nervous system, highly metabolically active differentiated neurons are challenged to maintain their genome over the organismal lifespan without replication. DNA damage in neurons increases with chronological age and accelerates in neurodegenerative disorders, resulting in cellular and systemic dysregulation. Distinct DNA damage response strategies have evolved with a host of polymerases. The Y-family translesion synthesis (TLS) polymerases are well known for bypassing and repairing damaged DNA in dividing cells. However, their expression, dynamics, and role, if any, in enduring postmitotic differentiated neurons of the brain are completely unknown. We show through systematic longitudinal studies for the first time that DNA polymerase kappa (POLK), a member of the Y-family polymerases, is highly expressed in mouse neurons. With chronological age, there is a progressive and significant reduction of nuclear POLK with a concomitant accumulation in the cytoplasm that is predictive of brain tissue age. The reduction of nuclear POLK in old brains is congruent with an increase in DNA damage markers. The nuclear POLK colocalizes with damaged sites and DNA repair proteins. The cytoplasmic POLK accumulates with stress granules and endo/lysosomal markers. Nuclear POLK expression is significantly higher in GABAergic interneurons (INs) compared to excitatory pyramidal neurons and lowest in non-neurons, possibly reflective of the inherent biological differences such as firing rates and neuronal activity. INs associated with microglia have significantly higher levels of cytoplasmic POLK in old age. Finally, we show that neuronal activity itself can lead to an increase in nuclear POLK levels and a reduction of the cytoplasmic fraction. Our findings open a new avenue in understanding how different classes of postmitotic neurons deploy TLS polymerase(s) to maintain their genomic integrity over time, which will help design strategies for longevity, healthspan, and prevention of neurodegeneration.

Drosophila ryanodine receptor gene triggers functional and developmental muscle properties and could be used to assess the impact of human RYR1 mutations

christophe.jagla@uca.fr (Catherine Sarret) — Wed, 13 May 2026 00:00:00 +0000

The ryanodine receptor (RYR) genes encode evolutionarily conserved calcium release channels involved in a wide range of calcium-dependent biological processes. Here, we show that the sole Drosophila RYR gene (dRyR) functions in differentiated somatic and cardiac muscle as well as in developing embryonic myotubes. In the larval body wall muscles, dRyR protein localizes at the SR membranes, and dRyR knockdown adversely affects muscle contractility, suggesting its conserved role in calcium-triggered E-C coupling. After dRyR attenuation, sarcomere, and mitochondrial patterns are severely impaired, showing dRyR involvement in structural muscle properties. However, dRyR is also prominently expressed and functionally required in growing embryonic muscles. dRyR loss of function leads to myotube growth defects and thin myofiber phenotypes, while its overexpression induces myofiber splitting. Given the structural and functional conservation of dRyR, we used Drosophila to test the impact of one human RYR1 variant of unknown significance (VUS). Larvae carrying p.Met4881Ile RYR1 VUS showed impaired mobility and altered structural muscle properties reminiscent of those seen in dRyR knockdown, thus indicating it is likely pathogenic. Overall, we show that Drosophila dRyR plays a conserved role in setting muscle contractility and structural muscle features. Our findings underline the still under-investigated role of dRyR as a promyogenic factor and provide a first example of the impact assessment of a human RYR1 VUS in Drosophila.

Modeling flexible behavior with remapping-based hippocampal sequence learning

yito@nips.ac.jp (Taro Toyoizumi) — Wed, 13 May 2026 00:00:00 +0000

Animals flexibly change their behavior depending on context. It is reported that the hippocampus is one of the most prominent regions for contextual behaviors, and its sequential activity shows context dependency. However, how such context-dependent sequential activity is established through reorganization of neuronal activity (remapping) remains unclear. To better understand the formation of hippocampal activity and its contribution to context-dependent flexible behavior, we present a novel biologically plausible reinforcement learning model. In this model, Context selector promotes the formation of context-dependent sequential activity and allows for flexible switching of behavior in multiple contexts. This model reproduces a variety of findings from neural activity, optogenetic inactivation, human fMRI, and clinical research. Furthermore, our model predicts that imbalances in the ratio between sensory and contextual representations in Context selector account for schizophrenia and autism spectrum disorder-like behaviors.

A context-free model of savings in motor learning

pgribble@uwo.ca (Jonathan A Michaels) — Wed, 13 May 2026 00:00:00 +0000

Learning to adapt voluntary movements to an external perturbation, whether mechanical or visual, is faster during a second encounter than during the first. The mechanisms underlying this phenomenon, known as savings, remain unclear. Recent studies propose that the high dimensionality of neural control enables the retention of learning traces that may facilitate savings. To test this idea, we used MotorNet, a framework for training recurrent neural networks (RNNs) to control biomechanical models of the human upper limb. RNNs were trained to perform reaching movements with a velocity-dependent force field (FF) and without (NF) in the sequence NF1 (baseline), FF1 (adaptation), NF2 (washout), and FF2 (re-adaptation). RNNs showed behaviural signatures of savings in the absence of any explicit contextual input signalling the presence or absence of the FF. Savings was more robust in RNNs with larger numbers of units. We identified a component of RNN activity associated with savings—a shift in preparatory activity that persisted even after washout. Displacing this preparatory activity in the direction of the shift enhanced savings, whereas perturbations in the opposite direction reduced or eliminated savings. These findings suggest a potential neural basis for motor memory retention underlying savings that is reliant on the high dimensionality of neural circuits for control, and is independent of cognitive or strategic learning.

Intravital calcium imaging of meningeal macrophages reveals niche-specific dynamics and aberrant responses to brain hyperexcitability

dlevy1@bidmc.harvard.edu (Anna Gutterman) — Wed, 13 May 2026 00:00:00 +0000

The meninges, which envelop and protect the brain, host a dense network of resident macrophages with diverse roles in regulating homeostasis and neuroinflammation. Despite their importance, we have a limited understanding of their behavior in vivo. Many dynamic cellular functions of macrophages involve intracellular Ca²⁺ signaling. However, virtually nothing is known about the spatiotemporal Ca²⁺ dynamics of meningeal macrophages in vivo. We developed a chronic intravital two-photon imaging approach and related computational analysis tools to interrogate meningeal macrophage Ca²⁺ dynamics, at subcellular resolution, in a novel Pf4-Cre:Ai162 conditional GCaMP6s reporter mouse model. Using imaging in awake mice, we characterized Ca²⁺ activity in meningeal macrophages at steady state and in response to cortical spreading depolarization (CSD), an aberrant pro-inflammatory brain hyperexcitability event implicated in migraine, traumatic brain injury, and stroke. In homeostatic meninges, macrophages in the dural perivascular niche exhibited several Ca²⁺ dynamic features, including event duration and signal frequency spectrum, distinct from those localized to the interstitial, non-perivascular niche. Simultaneous tracking of macrophage Ca²⁺ dynamics and local vasomotion revealed a subset of dural perivascular macrophages whose activity was coupled to locomotion-driven diameter fluctuations of their associated vessels. Most perivascular and non-perivascular meningeal macrophages displayed propagating intracellular Ca²⁺ activity and synchronized intercellular Ca²⁺ elevations, potentially driven by extrinsic factors. In response to CSD, the majority of perivascular and non-perivascular meningeal macrophages showed a persistent decrease in Ca²⁺ activity, while a smaller subset displayed Ca²⁺ elevations. Mechanistically, calcitonin gene-related peptide receptor signaling mediated the increase but not the decrease in CSD-mediated Ca²⁺ signaling. Collectively, our results highlight a previously unknown diversity of Ca²⁺ dynamics in meningeal macrophages at steady state and in response to an aberrant brain hyperexcitability event linked to neuroinflammation.

Physiological febrile heat stress increases cytoadhesion through increased protein trafficking of Plasmodium falciparum surface proteins into the red blood cell

moritz.treeck@gimm.pt (David Anaguano) — Wed, 13 May 2026 00:00:00 +0000

Fever is a hallmark of malaria. Several studies have linked febrile temperatures to reduced parasite viability, but also to increased cytoadhesion, a key driver of pathology. However, different mechanisms have been proposed to cause changes in cytoadhesion and parasite sensitivity to heat. Here, we demonstrate that exposure of Plasmodium falciparum-infected red blood cells (iRBCs) to physiologically relevant febrile heat stress (39 °C), derived from patient data, enhances cytoadhesion through increased trafficking of the major virulence factor PfEMP1 to the iRBC surface. This phenomenon is not limited to PfEMP1 and common laboratory strains, as it extends to the surface nutrient channel PSAC in four clinical isolates of diverse geographic origin. The increased surface protein display occurs without changes in overall protein expression or parasite developmental progression. Using phosphoproteomics and proximity labelling, we find that elevated temperature also increases trafficking and phosphorylation of exported proteins into the RBC. Enhanced export is likely reliant on the presence of a transmembrane domain as shown by NanoLuc reporter assays. Collectively, our results indicate that febrile temperatures commonly experienced during infection can accelerate protein export, likely at the parasitophorous vacuole. This enhanced export following heat stress is relevant because increased cytoadhesion could influence disease severity through earlier iRBC sequestration and elevated bound parasite mass.

Functional imaging of nine distinct neuronal populations under a miniscope in freely behaving animals

mary.phillips@zeiss.com (Mary L Phillips) — Tue, 12 May 2026 00:00:00 +0000

Head-mounted miniscopes have enabled functional fluorescence imaging in freely moving animals. However, current technology is limited to recording at most two spectrally distinct fluorophores, severely restricting the number of identifiable cell types. Here, we introduce multiplexed neuronal imaging (Neuroplex), a pipeline combining miniscope Ca²⁺ recordings with in vivo multiplexed confocal spectral imaging to distinguish nine projection-defined neuronal subtypes through the same GRIN lens. By co-registering defined neurons with fluorophore-specific spectral fingerprints via linear unmixing, we link projection-defined identities to behaviorally relevant neuronal activity. This approach overcomes spectral constraints of miniscopes, enabling circuit-level dissection of behavior in single animals.

Endogenous corazonin signaling modulates the post-mating switch in behavior and physiology in females of the brown planthopper and Drosophila

wusf@njau.edu.cn (Congfen Gao) — Tue, 12 May 2026 00:00:00 +0000

Mating in insects typically triggers a post-mating response (PMR) in females, characterized by reduced receptivity to re-mating and increased oviposition, which ensures numerous and viable offspring and male paternity. This PMR is induced by male seminal factors, such as sex peptide in Drosophila melanogaster, as well as intrinsic female signaling components. The latter signaling remains poorly understood in most insects, including the devastating rice pest, the brown planthopper (BPH) Nilaparvata lugens. Here, we show that the neuropeptide corazonin (CRZ) and its receptor (CrzR) are critical for the PMR in female BPHs. Peptide injection, RNAi knockdown, and CRISPR/Cas9 mutagenesis confirm that intact CRZ signaling reduces re-mating frequency and increases ovulation in mated BPH females. The CrzR is highly expressed in the female reproductive tract, and CrzR knockdown phenocopies CRZ diminishment. Importantly, female CRZ/CrzR signaling is required for male seminal factors, such as the peptide maccessin, to induce the PMR; with disrupted CrzR signaling, injection of seminal fluid or maccessin fails to reduce female receptivity. Notably, CRZ is not produced in male accessory glands (MAGs) of BPHs and thus not transferred during copulation. We furthermore demonstrate that also in D. melanogaster disrupted CRZ signaling increases female re-mating and reduces oviposition, while CRZ injection suppresses virgin receptivity and increases oviposition. Finally, we detected no CRZ in the MAG of D. melanogaster, supporting its role as an endogenous signal in the female PMR also in this species. In summary, our findings reveal a conserved role of endogenous CRZ signaling in regulating the female PMR and demonstrate that female CRZ signaling and male-derived signals cooperate to induce post-mating transitions in BPHs and D. melanogaster. CRZ is a paralog of the peptide gonadotropin-releasing hormone, known to regulate reproduction in vertebrates, including humans, suggesting evolutionary conservation of an ancient function.

Science under threat around the world

debat.humberto@inta.gob.ar (Humberto J Debat) — Tue, 12 May 2026 00:00:00 +0000

Politicians are reducing public funding for science and dismantling scientific institutions for ideological reasons in Argentina and the United States. It appeared as if something similar could happen in the Netherlands, but the collapse of a coalition government led to a reprieve. How should the scientific community respond to such crises?

Drift in individual behavioral phenotype as a strategy for unpredictable worlds

rtmaloney@coloradocollege.edu (Athena Q Ye) — Tue, 12 May 2026 00:00:00 +0000

Individuals, even with matched genetics and environment, show substantial phenotypic variability. This variability may be part of a bet-hedging strategy, where populations express a range of phenotypes to ensure survival in unpredictable environments. In addition, phenotypic variability between individuals (‘bet-hedging’), individuals also show variability in their phenotype across time, even absent external cues. There are few evolutionary theories that explain random shifts in phenotype across an animal's life, which we term drift in individual phenotype. We use individuality in locomotor handedness in Drosophila melanogaster to characterize both bet-hedging and drift. We use a continuous circling assay to show that handedness spontaneously changes over timescales ranging from seconds to the lifespan of a fly. We compare the amount of drift and bet-hedging across a number of different fly strains and show independent strain-specific differences in bet-hedging and drift. We show manipulation of serotonin changes the rate of drift, indicating a potential circuit substrate controlling drift. We then develop a theoretical framework for assessing the adaptive value of drift, demonstrating that drift may be adaptive for populations subject to selection pressures that fluctuate on timescales similar to the lifespan of an animal. We apply our model to real-world environmental signals and find patterns of fluctuations that favor random drift in behavioral phenotype, suggesting that drift may be adaptive under some real-world conditions. These results demonstrate that drift plays a role in driving variability in a population and may serve an adaptive role distinct from population-level bet-hedging.

HIV-1 envelope glycoprotein modulates CXCR4 clustering and dynamics on the T cell membrane

mmellado@cnb.csic.es (Adriana Quijada-Freire) — Tue, 12 May 2026 00:00:00 +0000

HIV-1 entry into susceptible cells requires the dynamic interaction of its envelope (Env) glycoprotein with the host cell receptor CD4 and a co-receptor, either CCR5 or CXCR4. While the core molecular mechanisms driving Env-receptor interactions and subsequent membrane fusion are well characterized, the precise nanoscale spatial reorganization of these co-receptors at the viral binding site remains poorly defined. In this study, we employed single-particle tracking total internal reflection fluorescence (SPT-TIRF) microscopy to quantitatively analyze nanoscale organizational changes of CXCR4 on the surface of human CD4⁺ T cells following binding by X4-tropic HIV-1. Our data reveal that both recombinant X4-gp120 and virus-like particles expressing physiological levels of X4 Env proteins (gp120 and gp41) promote CXCR4 clustering, a phenomenon linked to cell infection. Furthermore, these ligands induced oligomerization of CXCR4^R334X, a naturally occurring mutant associated with WHIM syndrome that supports HIV-1 infection, but fails to oligomerize in response to CXCL12. Our findings establish a link between CXCR4 clustering and HIV-1 infection, enhancing our understanding of the initial events in viral attachment and entry. These results further suggest that HIV-1 depends on a specific spatial arrangement of co-receptors, distinct from that induced by their natural chemokine ligands, highlighting the critical role of cell-surface receptor spatial organization in dictating cellular function.

Cortical motor activity modulates respiration and reduces apnoea in neonates

caroline.hartley@paediatrics.ox.ac.uk (Caroline Hartley) — Tue, 12 May 2026 00:00:00 +0000

Respiration is governed by a widespread network of cortical and subcortical structures. This complex communication between the brain and lungs is altered in pathological conditions. Apnoea – the cessation of respiration – is a common condition in infants, particularly those born prematurely. Apnoea in infants is believed to relate to immaturity of brainstem respiratory centres; involvement of the cortex in respiration in infants has yet to be explored. We investigated if there was any evidence for cortical coupling with respiration in newborn humans and whether it relates to apnoea. Using simultaneous electroencephalography (EEG) and impedance pneumography, we investigated interactions between cortical and respiratory activity (known as cortico-respiratory coupling) using phase-amplitude coupling. We show that cortico-respiratory coupling is present in premature and term newborns (104 recordings from 68 infants; 34.5±2.6 weeks postmenstrual age), identifying an interplay between breathing phase and EEG amplitude. We further shed light on the biological meaning by revealing that the strongest coupling occurs during inspiration and that cortical activity precedes respiration, with coupling strongest over frontocentral regions. Whilst our study was limited in spatial resolution, and determining causality is challenging, we believe these findings support the notion that the cortico-respiratory coupling observed here constitutes communication between cortical motor areas and lung effectors. Moreover, we show that cortico-respiratory coupling is negatively correlated with the rate of apnoea, revealing novel insight into this common and potentially life-threatening neonatal pathology.

Regime shift detection and neurocomputational substrates for under and overreactions to change

raccoon65.y@nycu.edu.tw (George Wu) — Mon, 11 May 2026 00:00:00 +0000

The world constantly changes, with the underlying state of the world shifting from one regime to another. The ability to detect a regime shift, such as the onset of a pandemic or the end of a recession, significantly impacts individual decisions, as well as governmental policies. However, determining whether a regime has changed is usually not obvious, as signals are noisy and reflective of the volatility of the environment. We designed an fMRI paradigm that examines a stylized regime-shift detection task. Human participants showed systematic overreaction and underreaction: Overreaction was most commonly seen when signals were noisy, but when environments were stable and change is possible but unlikely. By contrast, underreaction was observed when signals were precise but when environments were unstable and hence change was more likely. These behavioral signatures are consistent with the system-neglect computational hypothesis, which posits that sensitivity or lack thereof to system parameters (noise and volatility) is central to these behavioral biases. Guided by this computational framework, we found that individual subjects’ sensitivity to system parameters was represented by two distinct brain networks. Whereas a frontoparietal network selectively represented individuals’ sensitivity to signal noise but not environment volatility, the ventromedial prefrontal cortex (vmPFC) showed the opposite pattern. Further, these two networks were involved in different aspects of regime-shift computations: while vmPFC correlated with subjects’ beliefs about change, the frontoparietal network represented the strength of evidence in favor of regime shifts. Together, these results suggest that regime-shift detection recruits belief-updating and evidence-evaluation networks and that under- and overreactions arise from how sensitive these networks are to the system parameters.

Recombination shapes the diversification of the wtf meiotic drivers

gongzhen@nnu.edu.cn (Guan-Zhu Han) — Mon, 11 May 2026 00:00:00 +0000

Meiotic drivers are selfish genetic elements that distort fair segregation. The wtf genes are poison-antidote meiotic drivers that are experiencing rapid diversification in fission yeasts. However, gene duplication alone is insufficient to drive the diversification of wtf genes, given the poison encoded by a newly duplicated wtf gene can be detoxified by the antidote encoded by the original wtf gene. Here, we analyze the evolution of wtf genes across 21 strains of Schizosaccharomyces pombe. Knocking out each of 25 wtf genes in S. pombe strain 972h- separately does not attenuate the yeast growth, indicating that the wtf genes might be largely neutral to their carriers in asexual life cycle. Interestingly, wtf genes underwent recurrent and intricate recombination. As proof of principle, we generate a novel meiotic driver through artificial recombination between wtf drivers, and its encoded poison cannot be detoxified by the antidotes encoded by their parental wtf genes but can be detoxified by its own antidote. Therefore, we propose that recombination can generate new meiotic drivers and thus shape the diversification of the wtf drivers.

Adult-neurogenesis allows for representational stability and flexibility in early olfactory system

Krishnan_Padmanabhan@urmc.rochester.edu (Krishnan Padmanabhan) — Mon, 11 May 2026 00:00:00 +0000

In the olfactory system, adult-neurogenesis results in the continuous reorganization of synaptic connections and network architecture throughout the animal’s life. This poses a critical challenge: How does the olfactory system maintain stable representations of odors amidst this ongoing circuit instability? Utilizing a detailed spiking network model of early olfactory circuits, we uncovered dual roles for adult-neurogenesis: one that both supports representational stability to faithfully encode odor information, and also one that facilitates plasticity to allow for learning and adaptation. In the main olfactory bulb, adult-neurogenesis affects neural codes in individual mitral and tufted cells but preserves odor representations at the neuronal population level. By contrast, in the olfactory piriform cortex (PCx), both individual cell responses and overall population dynamics undergo progressive changes due to adult-neurogenesis. This leads to representational drift, a gradual alteration in stimulus-evoked activity patterns. Both processes are dynamic and depend on experience such that repeated exposure to specific odors reduces the drift due to adult-neurogenesis; thus, when the odor environment is stable over the course of adult-neurogenesis, it is spike-timing-dependent plasticity that leads representations to remain stable in the PCx; when those olfactory environments change, adult-neurogenesis allows cortical representations to track environmental change. Whereas perceptual stability and plasticity due to learning are often thought of as two distinct, often contradictory processes in neuronal coding, we find that adult-neurogenesis serves as a shared mechanism for both. In this regard, the quixotic presence of adult-neurogenesis in the mammalian olfactory bulb that has been the focus of considerable investigation in chemosensory neuroscience may be the mechanistic underpinning behind an array of complex computations.

Cross-modal interaction of human alpha activity does not reflect inhibition of early sensory processing in a frequency-tagging study using EEG and MEG

marion.brickwedde@charite.de (Ali Mazaheri) — Mon, 11 May 2026 00:00:00 +0000

Selective attention involves prioritising relevant sensory input while suppressing irrelevant stimuli. It has been proposed that oscillatory alpha-band activity (~10 Hz) aids this process by functionally inhibiting early sensory regions. However, recent studies have challenged this notion. Our EEG and MEG studies aimed to investigate whether human alpha oscillations serve as a 'gatekeeper' for downstream signal transmission. We first observed these effects in an EEG study and then replicated them using MEG, which allowed us to localise the sources. We employed a cross-modal paradigm where visual cues indicated whether upcoming targets required visual or auditory discrimination. To assess inhibition, we utilised frequency-tagging, simultaneously flickering the fixation cross at 36 Hz and playing amplitude-modulated white noise at 40 Hz during the cue-to-target interval. Consistent with prior research, we observed an increase in posterior alpha activity following cues signalling auditory targets. However, remarkably, both visual and auditory frequency-tagged responses amplified in anticipation of auditory targets, correlating with alpha activity amplitude. Our findings suggest that when attention shifts to auditory processing, the visual stream remains responsive and is not hindered by occipital alpha activity. This implies that alpha modulation does not solely regulate 'gain control' in early visual areas but rather orchestrates signal transmission to later stages of the processing stream.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.