eLife: latest articles

ImPaqT, a Golden Gate-based immunological toolkit for zebrafish transgenesis

cronan@mpiib-berlin.mpg.de (Christiane Dimmler) — Wed, 29 Jul 2026 00:00:00 +0000

Transgenic animals play an essential role in many aspects of zebrafish research. Here, we have developed ImPaqT (Immunological Toolkit for PaqCI-based Golden Gate Assembly of Tol2 Transgenes), a new Tol2-based transgenesis system that utilizes Golden Gate assembly to facilitate the production of transgenic zebrafish lines. This system allows for rapid assembly of multiple fragments into a single transgene, facile swapping of individual sequences to generate new transgenes, and an easy cloning workflow to incorporate new genetic elements into the existing kit. Within this framework, we have generated reagents to enable gene expression within different cell types, an array of best-in-class fluorescent proteins to visualize cell populations and transgenes, as well as tools to simplify genetic manipulation, purification, and ablation of targeted cells. Unlike many recombination-based systems, our approach is also expandable, allowing the incorporation of complex designs such as multifragment promoters within the established modular framework of ImPaqT. We have demonstrated the function of our system by generating various transgenic immune reporter lines. While we focused on the immune system as an emerging area of study within zebrafish research, ImPaqT can be broadly adapted to the construction of almost any zebrafish transgene, offering new tools for the zebrafish community.

Behavioral signatures of post-decisional attention in preferential choice

ariel.zylberberg@gmail.com (Ariel Zylberberg) — Tue, 28 Jul 2026 00:00:00 +0000

Attention plays a key role in decision-making by directing limited cognitive resources to relevant information. It has been proposed that attention also biases the decision process, due to a multiplicative interaction between attention and subjective value (e.g., Krajbich et al., 2010). We tested two predictions of models that posit a causal multiplicative effect of attention on decision formation: (i) the last fixation should be more informative about the choice when the overall value of the alternatives is high, and (ii) more attention should be directed to the chosen option when choices conflict with stated preferences than when they do not. Reanalyzing several datasets from a food-choice task, we found no evidence supporting these predictions. An alternative model where attention reflects choices after the decision has completed explains key observations, including the last-fixation bias, the gaze-cascade effect, and the effect of the overall value of the alternatives on response times. However, this model does not fully account for the association between dwell time and choice. We conclude that gaze behavior prior to the choice report likely reflects both decisional and post-decisional processes.

CellCover defines marker gene panels capturing developmental progression in neocortical neural stem cell identity

ccolantu@jhmi.edu (An Wang) — Tue, 28 Jul 2026 00:00:00 +0000

Defining cell classes is central to the analysis of growing single-cell RNA sequencing (scRNA-seq) atlases. Marker genes are most often identified by differential expression (DE) methods that assess genes one at a time, ignoring the redundancy and complementarity revealed when genes are considered jointly. Working with binarized expression data, we instead seek discriminating panels of genes that together are specific to a cell type, framing marker-panel selection as a variant of the minimal set-covering problem in combinatorial optimization. This formulation efficiently searches the vast space of candidate panels, exploits the large cell numbers typical of scRNA-seq, and is robust to zero-inflation. Using blood and brain data, we show that our method, CellCover, reduces gene redundancy and captures cell-class-specific signals distinct from those found by DE. Transfer-learning experiments across mouse, primate, and human data demonstrate that CellCover identifies conserved cell classes in neocortical neurogenesis and tracks developmental progression in progenitors and neurons. Examining outer radial glia markers across mammals, we find that transcriptomic elements of this key cell type likely arose in rodent gliogenic precursors before the full program emerged in the primate lineage.

Excitatory cholecystokinin neurons in the CA3 area regulate the navigation learning and neuroplasticity

fwhuang2@stanford.edu (Abdul Baset) — Tue, 28 Jul 2026 00:00:00 +0000

Hippocampus, a key hub of neural circuits for spatial learning and memory, has attracted tremendous studies. Neuronal information processing in the hippocampus can be regulated by many types of neuropeptides. Cholecystokinin (Cck), the most abundant neuropeptide in the central nervous system that is involved in modulating neuronal functions, such as cognition, memory, and neuroplasticity, is widely expressed in the hippocampus. However, whether local excitatory Cck neurons modulate hippocampal function is still unclear. In this study, we showed that CA1 pyramidal neurons receive projections from excitatory Cck neurons in area CA3 (CA3^Cck neurons) in adult mice. Subsequently, activation of the CA1-projecting CA3^Cck neurons triggers the release of Cck. Then, we found that the activity of CA3^Cck-CA1 neurons supports the hippocampal-dependent tasks. Furthermore, inhibition of CA3^Cck-CA1 projections or knockdown of CA3^Cck gene expression markedly impaired the behavioral tasks and neuroplasticity. Taken together, these results may add to a better understanding of how neuromodulators regulate the neural functions in the central nervous system.

Magnesium isoglycyrrhizinate alleviates alcohol-associated liver disease through targeting HSD11B1

liyan181@smu.edu.cn (Hao Wang) — Tue, 28 Jul 2026 00:00:00 +0000

While magnesium isoglycyrrhizinate (MgIG) is a clinically approved therapy for alcohol-associated liver disease (ALD), its precise molecular targets and mechanisms remain uncharacterized. This study aimed to define MgIG’s hepatoprotective actions in chronic-binge ALD mouse models and ethanol/palmitic acid-exposed AML-12 hepatocytes. Through an integrated strategy encompassing RNA sequencing, molecular docking, and microscale thermophoresis, we discovered that MgIG directly binds to hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) at residue 187, a finding corroborated by molecular dynamics simulations. In vivo, MgIG markedly attenuated alcohol-induced liver injury, evidenced by ameliorated histological damage, reduced hepatic steatosis, and normalized liver-to-body weight ratios. In vitro, it effectively reduced lipid accumulation, inflammation, and apoptosis. Mechanistically, RNA sequencing identified isopentenyl diphosphate delta isomerase 1 (IDI1) as a key downstream effector. Hepatocyte-specific genetic manipulations confirmed that MgIG modulates the SREBP2–IDI1 axis, thereby suppressing lipogenesis, inflammatory responses, and apoptotic pathways. We reveal HSD11B1 as a novel direct molecular target of MgIG and elucidate its therapeutic mechanism through the HSD11B1–SREBP2–IDI1 signaling axis, which profoundly impacts ALD pathogenesis. These findings not only validate MgIG’s clinical utility but also highlight a promising new therapeutic target for ALD.

Correction: The neuropeptide sulfakinin is a peripheral regulator of insect behavioral switch between mating and foraging

Tue, 28 Jul 2026 00:00:00 +0000

Sensory adaptation and pupil-linked arousal support flexible evidence accumulation during perceptual decision making

jigold@pennmedicine.upenn.edu (Joshua I Gold) — Mon, 27 Jul 2026 00:00:00 +0000

Effective decision making in dynamic environments requires flexible evidence accumulation. Although models often express this flexibility as a property of the accumulator, its implementation in the brain may involve adaptive mechanisms operating at other stages of the decision process. We examined two such mechanisms: (1) stimulus-specific sensory adaptation at the level of evidence encoding, and (2) arousal-related neuromodulation, which could, in principle, affect both evidence encoding and accumulation. We measured single-unit activity in the middle temporal (MT) area and pupil-linked arousal while monkeys performed a modified random-dot motion direction-discrimination task in which an adapting stimulus with varied temporal stability preceded a behaviorally relevant test stimulus. The monkeys’ decisions reflected adaptive evidence accumulation that depended on temporal-context stability and corresponded to context-dependent changes in both stimulus-specific sensory adaptation in MT and task-evoked pupil responses. However, adaptation and pupil adjustments were not related to each other. Together, these findings suggest that multiple mechanisms contribute to flexible, context-dependent evidence accumulation, including changes in sensory adaptation that shape evidence encoding and changes in arousal that may shape the accumulation process itself.

Reprogramming of host energy metabolism mediated by the TNF-iNOS-HIF-1α axis plays a key role in host resistance to Plasmodium infection

kelycatarine@gmail.com (Diego Luis Costa) — Mon, 27 Jul 2026 00:00:00 +0000

TNF has a dual effect in Plasmodium infection, bolstering the host's immune defense while also inducing sickness behavior. Here, we confirm that TNF signaling hampers physical activity, food intake, and energy expenditure while enhancing glucose uptake by the liver and spleen, as well as controlling parasitemia in Plasmodium chabaudi (Pc)-infected mice. We also report that TNF is required for expression of inducible nitric oxide synthase (iNOS), stabilization of hypoxia-inducible factor 1α (HIF-1α), expression of glucose transporter GLUT1, and enhanced glycolysis in monocytic cells from Pc-infected mice. Importantly, Pc-infected Nos2^-/-, TNFR1 cKO, and HIF-1a cKO mice show impaired release of TNF and glycolysis in monocytes, along with increased parasitemia and disease tolerance. Altogether, our results indicate that TNF-iNOS-HIF-1α-induced glycolysis in monocytes plays a critical role in host defense and sickness behavior in Pc-infected mice.

An abundant merozoite surface protein of Plasmodium falciparum modulates susceptibility to inhibitory antibodies

danny.wilson@adelaide.edu.au (Danny W Wilson) — Mon, 27 Jul 2026 00:00:00 +0000

Malaria merozoite surface proteins (MSPs) are thought to have important roles in red blood cell (RBC) invasion and their exposure on the parasite surface makes them attractive vaccine candidates. However, their role in invasion has not been directly demonstrated and their biological functions remain unknown. One of the most abundant merozoite surface proteins is PfMSP2, a likely ancestral protein that has been maintained in the Plasmodium falciparum lineage and is a focus of vaccine development. Using CRISPR-Cas9 gene editing, we removed PfMSP2 from two different P. falciparum lines with no impact on parasite replication or phenotype in vitro, demonstrating that it is not essential for RBC invasion. Interestingly, loss of PfMSP2 led to increased inhibitory potency of antibodies targeting other merozoite proteins involved in invasion, particularly PfAMA1. In a solid-phase model, increasing concentrations of PfMSP2 protein reduced binding of different antibodies against PfAMA1 in a dose-dependent manner. These data suggest that PfMSP2 can modulate the susceptibility of merozoites to protective inhibitory antibodies. The results of this study change our understanding of the potential functions of PfMSP2 and establish a new concept in malaria where a surface protein can reduce the protective efficacy of antibodies targeting a different antigen. These findings have important implications for understanding malaria immunity and informing vaccine development.

In-cell cryo-electron tomography reveals differential effects of type I and type II kinase inhibitors on LRRK2 filament formation and microtubule association

aleschziner@ucsd.edu (Andres E Leschziner) — Mon, 27 Jul 2026 00:00:00 +0000

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a leading contributor to developing familial and idiopathic Parkinson’s disease (PD). Most PD-causing LRRK2 mutations increase the kinase activity, leading to increased phosphorylation of Rab GTPases, disrupting vesicular trafficking, cytoskeletal dynamics, and autophagy. Under homeostatic conditions, the bulk of WT and PD-mutant LRRK2 is found in the cellular cytosol. However, exogenously expressed LRRK2 can form microtubule-associated filaments that have been shown to affect molecular transport along microtubules in vitro. While the physiological relevance of microtubule binding has not been established yet, inhibitors being designed and tested as therapeutics have been shown to either promote or prevent filament formation of LRRK2. In this study, we examine the localization and resulting molecular organization of hyperactive LRRK2-I2020T, a common PD mutant, in HEK 293FT cells treated with type I (MLi-2) or type II (GZD-824) kinase inhibitors. Treatment with a type I kinase inhibitor results in extensive LRRK2-I2020T decoration around microtubules and microtubule bundling. Stabilization of LRRK2-I2020T filaments by type I inhibitor treatment allowed us to build a full-length closed-kinase model of LRRK2-I2020T in its cellular environment. Conversely, treatment with a type II inhibitor resulted in minimal microtubule decoration by LRRK2-I2020T compared to type I inhibitor-treated cells. This study provides a structural framework for understanding how type I and type II kinase inhibitors differentially modulate LRRK2 filament formation, demonstrating that type I inhibitor treatment promotes a distinct filament architecture, whereas such assemblies are not observed with type II inhibitors.

Stable excitatory-inhibitory synapse balance despite dynamic turnover

richard.sando@vanderbilt.edu (Cassandra M Smith) — Mon, 27 Jul 2026 00:00:00 +0000

Diverse synaptic connections self-organize into neural circuits during brain development. A balance between excitatory and inhibitory synaptic function is required for information processing by these neural circuits. Despite the importance of this balance, the interplay between excitatory and inhibitory synaptic assembly during circuit establishment remains unclear due to a lack of means to monitor both processes simultaneously. Here, we develop imaging and analysis methods to visualize and track excitatory and inhibitory synapses. By applying these approaches, we find that despite continual dynamics, excitatory and inhibitory synaptic density remain at steady-state levels during synapse maturation. These results indicate balanced excitatory and inhibitory synapse assembly, despite continual synaptic turnover.

Active dendrites enable robust spiking computations despite timing jitter

tsjb2@cam.ac.uk (Michael E Rule) — Mon, 27 Jul 2026 00:00:00 +0000

Dendritic action potentials exhibit long plateaus of many tens of milliseconds, outliving axonal spikes by an order of magnitude. The computational role of these slow events seems at odds with the need to rapidly integrate and relay information throughout large nervous systems. We propose that the timescale of dendritic potentials allows for reliable integration of asynchronous inputs. We develop a physiologically grounded model in which the extended duration of dendritic spikes equips each dendrite with a resettable memory of incoming signals. This provides a tractable model for capturing dendritic nonlinearities observed in experiments and in more complex, detailed models. Using this model, we show that long-lived, nonlinear dendritic plateau potentials allow neurons to spike reliably when confronted with asynchronous input spikes. We demonstrate this model supports non-trivial computations in a network solving an association/discrimination task using sparse spiking that is subject to timing jitter. This demonstrates a computational role for the specific timecourse of dendritic potentials in situations where decisions occur quickly, reliably, and with a low number of spikes. Our results provide empirically testable hypotheses for the role of dendritic action potentials in cortical function, as well as a potential bio-inspired means of realising neuromorphic spiking computations in analog hardware.

Correction: Differential regulation of hair cell actin cytoskeleton mediated by SRF and MRTFB

Mon, 27 Jul 2026 00:00:00 +0000

CROP2, a Retriever–PROPPIN complex mediating protein export from endosomes to the plasma membrane in human cells

andreas.mayer@unil.ch (Andreas Mayer) — Fri, 24 Jul 2026 00:00:00 +0000

Endosomes generate tubulo-vesicular carriers to redistribute proteins between plasma membrane, Golgi, and lysosomes. These transport routes employ distinct combinations of sorting nexins with complexes such as Retromer or Retriever. We now show that, while Retromer associates with the PROPPIN WIPI1 to form the previously described CROP complex, Retriever associates with WIPI2, forming CROP2. WIPI2 integrates into Retriever-dependent coat complexes since it interacts both with the Commander subunit CCDC93 and its cognate sorting nexin SNX17. CROP and CROP2 are exclusive in their physical associations and pathway selective. Whereas CROP2 is required for endosomal exit of Integrin β1, it does not affect CROP-dependent cargos such as EGFR or GLUT1. Vice versa, CROP is not required for Integrin β1 trafficking. WIPI1 and WIPI2 rely on similar molecular features. Their activity depends on the same FSSS motif to integrate into Retromer and Retriever complexes, respectively, and on an amphipathic membrane-inserting α-helix, which conveys membrane fission activity to PROPPINs. This suggests that Retromer and Retriever coats integrate distinct PROPPIN isoforms to promote fission of the respective endosomal carriers formed by them.

Structural dynamics of IRE1 and its interaction with unfolded peptides

covino@fias.uni-frankfurt.de (Elena Spinetti) — Thu, 23 Jul 2026 00:00:00 +0000

The unfolded protein response (UPR) is a crucial signaling network that preserves endoplasmic reticulum (ER) homeostasis, impacting both health and disease. When ER stress occurs, often due to an accumulation of unfolded proteins in the ER lumen, the UPR initiates a broad cellular program to counteract cytotoxic effects. Inositol-requiring enzyme 1 (IRE1), a conserved ER-bound protein, is a key sensor of ER stress and activator of the UPR. While biochemical studies confirm IRE1’s role in recognizing unfolded polypeptides, high-resolution structures showing direct interactions remain elusive. Consequently, the precise structural mechanism by which IRE1 senses unfolded proteins is debated. In this study, we employed advanced molecular modeling and 137 µs of atomistic molecular dynamics simulations to clarify how IRE1 detects unfolded proteins. Our results demonstrate that IRE1’s luminal domain directly interacts with unfolded peptides and reveal how these interactions can stabilize higher-order oligomers. We provide a detailed molecular characterization of unfolded peptide binding, identifying two distinct binding pockets at the dimer’s center, separate from its central groove. Furthermore, we present high-resolution structures illustrating how BiP associates with IRE1’s oligomerization interface, thus preventing the formation of larger complexes. Our structural model reconciles seemingly contradictory experimental findings, offering a unified perspective on the diverse sensing models proposed. We elucidate the structural dynamics of unfolded protein sensing by IRE1, providing key insights into the initial activation of the UPR.

The population structure of invasive Lantana camara is shaped by its mating system

praveenprakash@ncbs.res.in (P Praveen) — Thu, 23 Jul 2026 00:00:00 +0000

Over the last century, invasive species have emerged as an important driver of global biodiversity loss. Lantana camara is one of the hundred most problematic invasive species globally, yet its genetic diversity patterns remain poorly understood. Previous studies hypothesize that invasive L. camara is a species complex of hybrid origin, though this remains untested. We investigated the population genetic patterns of L. camara by sampling 359 plants representing diverse flower colour variants across 36 locations in India. Analyses of the population structure using 19,008 SNPs revealed a strong genetic structure in India. However, this structure showed little correlation with geography; instead, individuals with similar flower colours clustered together irrespective of location in the structure analysis. Low genetic distance between most of the individuals indicated the absence of multiple species. A high inbreeding coefficient and low proportion of heterozygous sites suggested predominant self-fertilization, confirmed by bagging experiments. Thus, we infer that L. camara exists as homozygous inbred lines formed by self-fertilization, associated with distinct flower colours. These results refute the hypothesis that L. camara is a species complex. Our findings highlight a hitherto unknown role for mating systems in invasive species, furthering our understanding of evolution in invasive species.

Large-scale synthetic data enable digital twins of human excitable cells

ceclancy@ucdavis.edu (Colleen E Clancy) — Thu, 23 Jul 2026 00:00:00 +0000

Individual variability shapes how diseases manifest, how patients respond to therapy and how rare phenotypes arise. Conventional experimental approaches obscure variation by averaging which limits mechanistic insight and predictive accuracy. We present a computational framework that builds digital twins of human-induced pluripotent stem cell-derived cardiomyocytes from a single optimized voltage clamp experiment. The framework depends on massive synthetic datasets comprising simulated cells that span broad ionic and electrophysiological ranges. These synthetic data make it possible to control parameters precisely, explore biological variability comprehensively, and train models beyond the limits of experimental data. A neural network trained on synthetic data then inferred biophysical parameters from experimental recordings from live cells, reproducing distinct electrophysiological features. Our study unites computational modeling, data simulation, and learning to enable scalable, precise, individualized cardiac electrophysiology modeling and can be readily extended to any electrically active cell type.

Functional muscle networks as biomarkers of post-stroke motor impairment and therapeutic responsiveness

david.oreilly166@gmail.com (Andrea Turolla) — Thu, 23 Jul 2026 00:00:00 +0000

Standardised assessment of post-stroke motor impairment and treatment responsiveness remains a major clinical challenge. In this study, we tackle this challenge by applying a novel muscle network analysis framework to human stroke survivors undergoing intensive upper-limb motor training (O’Reilly & Delis, 2024). Our approach revealed distinct patterns of redundant and synergistic muscle interactions, collectively reflecting the diverse biomechanical roles of flexor- and extensor-driven networks. From these patterns, we derived new biomarkers that stratified patients by gross motor impairment severity and therapeutic responsiveness, each associated with unique physiological signatures. Remarkably, we identified a shift from redundancy to synergy in muscle coordination as a hallmark of effective motor recovery—a transformation supported by a more precise quantification of impairment over conventional approaches. These findings offer an in-depth characterisation of post-stroke motor recovery and establish a robust, independent tool for evaluating rehabilitation efficacy. Future research should employ this framework to identify biomarkers of activities- and participation-related functional recovery.

PKMζ-PKCι/λ double-knockout demonstrates atypical PKC is crucial for the persistence of hippocampal LTP and spatial memory

afenton@nyu.edu (Alejandro Grau-Perales) — Wed, 22 Jul 2026 00:00:00 +0000

PKMζ is a persistently active atypical PKC (aPKC) isoform thought to maintain late-phase long-term potentiation (late-LTP) and long-term memory. PKMζ-knockout mice, however, still exhibit hippocampal LTP and spatial memory while lacking neocortical LTP, questioning whether this kinase is fundamental to enduring synaptic potentiation and memory. Tsokas et al. (2016) suggested that the other aPKC, PKCι/λ, may compensate for PKMζ during maintenance in the hippocampus of PKMζ-null mice. In wild-type mice, PKCι/λ drives early-LTP and short-term memory, whereas in PKCι/λ-knockout mice, PKMζ compensates by supporting both early- and late-phase processes. Here, we show that PKCι/λ is persistently upregulated during maintenance in two mouse models: PKMζ-conditional knockout mice, and double-knockout mice carrying both conditional deletion of PKCι/λ and constitutive loss of PKMζ. Because PKCι/λ-gene excision is inducible in the double-knockout line, we could characterize the persistent increase of PKCι/λ in late-LTP prior to its deletion. To examine PKCι/λ function, we induced its deletion in the hippocampus. Whereas mutual compensation preserves LTP when either PKCι/λ or PKMζ alone is knocked out, double-knockout of both PKCι/λ and PKMζ eliminates late-LTP. Double-knockout also abolishes spatial long-term memory without affecting short-term memory. Thus, when PKMζ is absent, PKCι/λ persists to maintain hippocampal late-LTP and long-term memory.

Enteropathogenic Escherichia coli-mediated fast and coordinated Ca^²+ responses regulate NF-κB activation

guy.tranvannhieu@i2bc.paris-saclay.fr (Fangrui Guo) — Wed, 22 Jul 2026 00:00:00 +0000

Enteropathogenic Escherichia coli (EPEC) is a major bacterial enteropathogen causing infectious diarrhea among children in developing countries. Here, we found that EPEC induced isolated Ca²⁺ responses in epithelial cells, triggered by extracellular ATP (eATP). These responses were dependent on type III secretion (T3S) and down-regulated by the bacterial secreted protease EspC, consistent with eATP released by the T3S translocon pore-forming activity in host membranes. By performing high-speed Ca²⁺ imaging, we uncovered that at the onset of infection, low eATP levels triggered Ca²⁺-responses involving the whole cell but showing small amplitude and fast kinetics usually associated with local Ca²⁺ responses. The findings, supported by theoretical modeling, evoke a conceptual shift whereby low amounts of inositol 1, 4, 5-trisphosphate (IP₃) induced by low eATP levels and subsequent moderate Ca²⁺ release enable the fast coordination of IP₃ receptor cluster activation throughout the cell. Importantly, these yet undescribed coordinated fast responses occurred over prolonged time periods and defined a cell state with dampened activation of the pro-inflammatory transcriptional activator NF-kB associated with a decrease in its Ca²⁺-dependent O-linked β-N-acetylglucosamine modification.

Two time scales of adaptation in human learning rates

tom.verguts@ugent.be (Haopeng Chen) — Wed, 22 Jul 2026 00:00:00 +0000

Different situations may require radically different information updating speeds (i.e., learning rates). Some demand fast learning rates while others benefit from using slower ones. To adjust learning rates, decision makers could rely on either global, meta-learned differences between environments, or faster but transient adaptations to locally experienced prediction errors. Here, we introduce a new paradigm that allows researchers to measure and empirically disentangle both forms of adaptation. Participants performed short blocks of trials of a continuous estimation task – fishing for crabs – on six different islands that required different optimal (initial) learning rates. Across two experiments, participants showed fast adaptations in learning rate within a block. Critically, participants also learned global environment-specific learning rates over the time course of the experiment, as evidenced by computational modelling and by the learning rates calculated on the very first trial when revisiting an environment (i.e., unconfounded by transient adaptations). Using representational similarity analyses of fMRI data, we found that differences in voxel pattern responses in the central orbitofrontal cortex (OFC) correlated with differences in these global environment-specific learning rates. Our findings show that humans adapt learning rates at both slow and fast time scales, and that the central OFC may support meta-learning by representing environment-specific task-relevant features such as learning rates.

Reactive oxygen detoxification contributes to Mycobacterium abscessus antibiotic survival

bhpenn@health.ucdavis.edu (Abigail Ray) — Tue, 21 Jul 2026 00:00:00 +0000

When a population of bacteria is exposed to a bactericidal antibiotic, most cells die rapidly. However, a subpopulation of antibiotic-tolerant cells known as ‘persister cells’ can survive for prolonged periods. In addition, antibiotic tolerance can be broadly induced throughout the population by stresses such as nutrient deprivation. However, the pathways required to maintain viability in this setting and how stress induces antibiotic tolerance are both poorly understood. To identify genetic determinants of antibiotic tolerance in mycobacteria, we carried out transposon insertion sequencing (Tn-Seq) screens in Mycobacterium abscessus (Mabs) exposed to bactericidal translation-inhibiting antibiotics. This analysis identified genes essential for the survival of both spontaneous persister cells, as well as for stress-induced tolerance, allowing the first genetic comparison of these states in mycobacteria. Pathway analysis identified multiple genes involved in the detoxification of reactive oxygen species (ROS), including the catalase-peroxidase katG, which contributed to survival in both unstressed and nutrient-starved cells. In addition, we found that endogenous ROS were generated by translation-inhibiting antibiotics, and that hypoxia impaired bacterial killing. KatG specifically contributed to survival following exposure to transcription or translation inhibitors, but not other antibiotic classes tested. Thus, the lethality of some antibiotics is amplified by toxic ROS accumulation, and antibiotic-tolerant cells require detoxification systems in order to remain viable. These findings further demonstrate that antibiotic-induced ROS plays a broad role in mediating antibiotic lethality across diverse organisms.

The adaptive landscapes of three global Escherichia coli transcriptional regulators

caua.westmann@ieu.uzh.ch (Andreas Wagner) — Tue, 21 Jul 2026 00:00:00 +0000

The evolution of gene regulation is a major source of evolutionary adaptation and innovation, particularly when organisms encounter new or changing environments. Central to this process is the emergence of new transcription factor binding sites (TFBSs). Adaptive landscapes provide a powerful framework to study such emergence by linking regulatory DNA sequences to their transcriptional outputs. Although several landscapes have been characterized for DNA, RNA, and proteins, large-scale in vivo adaptive landscapes for bacterial TFBSs remain scarce. Here, we address this gap by experimentally mapping the first comprehensive in vivo regulatory landscapes for three global transcription factors in Escherichia coli: cAMP receptor protein, Fis, and IHF. Using a massively parallel reporter assay, we quantify the regulation strength of more than 30,000 TFBS variants for each factor, and reconstruct their adaptive landscapes. All three landscapes are highly rugged and exhibit pervasive epistasis, with thousands of local peaks distributed broadly across sequence space. This ruggedness contrasts sharply with the much smoother TFBS landscapes of eukaryotes. It suggests greater constraints on the evolution of prokaryotic gene regulation. Nonetheless, evolutionary simulations show that ~10% of evolving populations can reach a peak of strong regulation, a proportion that is significantly greater than in comparable random landscapes. Adaptive evolution starting from the same DNA sequence can attain different high peaks, and some peaks are reached more frequently than others. Together, our results show that de novo adaptive evolution of new gene regulation in bacteria is feasible, but subject to a blend of chance, historical contingency, and evolutionary biases.

Single-cell characterization of anterior segment development in the mouse reveals the cell types, pathways, and signals driving formation of the trabecular meshwork and Schlemm’s canal

rb3132@cumc.columbia.edu (Aakriti Bhandari) — Tue, 21 Jul 2026 00:00:00 +0000

Morphogenesis of the anterior segment (AS) is crucial for healthy ocular physiology and vision, but is only partially understood. The Schlemm’s canal (SC) and trabecular meshwork (TM) are essential drainage tissues within the AS, and their proper development and function are critical for maintaining normal intraocular pressure; abnormalities in either tissue can result in elevated pressure and glaucoma. Here, we use single-cell transcriptomic profiling to provide high-resolution molecular detail of mouse AS development with a particular focus on SC and TM. We report transcriptomes for ~130,000 single cells at key developmental stages from postnatal day 2 (P2) to P60. We provide the first annotation of cell types across these developmental stages and crucial information about dynamic changes in pathways/gene expression. Further, we trace developmental trajectories for TM cell and SC endothelial cell (SEC) subtypes and determine genes and signaling networks driving their specific cell fates. We demonstrate dynamic changes in signaling interactions between SC and the TM cells during their synchronized development. Collectively, our data lay a deep molecular foundation for AS development that will direct understanding of normal ocular physiology, glaucoma, and other AS conditions.

Quantitative computerized analysis demonstrates strongly compartmentalized tissue deformation patterns underlying mammalian heart tube formation

jorgendm@ujaen.es (Jorge N Domínguez) — Tue, 21 Jul 2026 00:00:00 +0000

The quantitative analysis of tissue deformation at cellular resolution remains an important challenge in mammalian organogenesis. Here, we developed a new computational workflow to extract regional and temporal patterns of tissue deformation, and applied it to a collection of live microscopy datasets from mouse cardiogenesis. We devised a method to track tissue deformation directly from time-lapse raw images and experimentally validated the method by comparison with actual cell tracks. We then used a machine-learning approach to temporally and spatially align different specimens and reconstruct a single statistical model of tissue motion, deducing maps of strain, anisotropy, and tissue growth. We also implemented a virtual fate mapping tool that allows tracking any initial position in the cardiac primordium onto the linear heart tube (HT). Our study reveals predominant local cellular coherence during the deformation of the cardiac tissue, whereas strong compartmentalization of tissue deformation patterns transforms the bilateral cardiac primordium into a 3D longitudinal HT. At the future outer curvature of the primitive tube, the ventricular chamber forms by expansion of the tissue in a hemi-barrel shape with two harnessing belts: one that constrains tissue expansion at the arterial pole and one that constrains the expansion at the venous pole. Our study provides a new approach to understanding heart morphogenesis and proposes a new model of primitive HT formation.

RNA selectively modulates activity of virulent amyloid PSMα3 and host-defense LL-37 via phase separation and aggregation dynamics

meytal.landau@desy.de (Alexander Kai Buell) — Mon, 20 Jul 2026 00:00:00 +0000

Amyloid-forming peptides are increasingly recognized as dynamic regulators at the host–pathogen interface, yet how environmental factors control their assembly and activity remains poorly understood. Here, RNA acts as a concentration-dependent regulator of two sequence-related α-helical peptides with fundamentally different assembly behaviors: the cross-α amyloid-forming Staphylococcus aureus virulence factor PSMα3 and the non-amyloidogenic human host-defense peptide LL-37. RNA drives PSMα3 through distinct assembly states, from liquid-like condensates to fibrillar polymorphs, while preserving cytotoxic and antimicrobial activity over time. In contrast, RNA attenuates LL-37 cytotoxicity toward host cells while maintaining antibacterial activity, consistent with a host-protective immunomodulatory effect. Together with the opposing effects of epigallocatechin gallate, which redirects both peptides into amorphous assemblies, these findings support a mechanistic model in which biological activity is governed by supramolecular architecture, assembly trajectory, and dynamics rather than by monomer abundance or mature fibrils alone. More broadly, our findings identify RNA as an environmental regulator of α-helical peptide assemblies, and establish assembly-state control as a tunable determinant of virulence and host defense.

Neural categorization of visual words of alphabetic and non-alphabetic languages

shan@pku.edu.cn (Guo Zheng) — Mon, 20 Jul 2026 00:00:00 +0000

Languages provide social-category markers that tag people as one or another social group. How does the brain sort words into different language categories as a basis of the social-categorization function of language? The current work addressed this issue by testing neural categorization of visual words of different writing systems in nine studies using electroencephalography, magnetoencephalography, and a repetition suppression paradigm. This work showed that a neural network, including the anterior temporal, insular, orbital frontal, and ventral occipito-temporal cortices in both hemispheres, was engaged in computations of correlation distances between two words to represent intra-language similarity and inter-language difference during categorization of visual words of alphabetic and non-alphabetic languages. These processes occurred as early as 150 ms post-stimulus, recruited within-hemisphere functional connections, operated independently of words’ semantic meanings and pronunciations, and exhibited consistently across individuals with diverse language backgrounds. These findings highlight the neural mechanisms of language-based spontaneous neural categorization of visual words as a basis of the social-categorization function of language.

FMRP regulates neuronal RNA granules containing stalled ribosomes, not where ribosomes stall

wayne.sossin@mcgill.ca (Jewel T-Y Li) — Mon, 20 Jul 2026 00:00:00 +0000

Local protein synthesis is a crucial process that maintains local proteostasis in neurons. A large percentage of mRNAs translated in developing neurons are associated with stalled ribosomes. FMRP, the protein lost in Fragile X syndrome, is highly enriched in RNA granules that contain stalled ribosomes. Previous examination of ribosome-protected fragments (RPFs) from stalled neuronal ribosomes identified sequences that match those found in mRNAs associated with FMRP. To investigate whether FMRP recognition of these sequences is important for determining where ribosomes stall on mRNAs, we examined RPFs isolated from P5 mice of both sexes that lack the FMRP protein. The loss of FMRP had no significant effect on the proteins associated with neuronal stalled ribosomes, on ribosome structure, or the stalling sites (locations where RPFs accumulated). There was a small, but significant decrease in the number of RPFs from mRNAs previously shown to be associated with FMRP by CLIP. Additionally, the number of neuronal RNA granules containing stalled ribosomes, as assayed by ribopuromycylation, decreased. These results suggest a role of FMRP in neuronal RNA granules that contain stalled ribosomes, though loss of FMRP does not influence where ribosomes are stalled or the formation of stalled ribosome.

Cluster size determines internal structure of transcription factories in human cells

gnegro2@ed.ac.uk (Antonio Suma) — Mon, 20 Jul 2026 00:00:00 +0000

Transcription is a fundamental cellular process and the first step of gene expression. In human cells, it depends on the binding to chromatin of various proteins, including RNA polymerases and numerous transcription factors (TFs). Observations indicate that these proteins tend to form macromolecular clusters, known as transcription factories, whose morphology and composition are still debated. While some microscopy experiments have revealed the presence of specialised factories, composed of similar TFs transcribing families of related genes, sequencing experiments suggest instead that mixed clusters may be prevalent, as a panoply of different TFs binds promiscuously to the same chromatin region. The mechanisms underlying the formation of specialised or mixed factories remain elusive. With the aim of finding such mechanisms, here we develop a chromatin polymer model mimicking the chromatin binding-unbinding dynamics of different types of complexes of TFs. Surprisingly, both specialised (i.e. demixed) and mixed clusters spontaneously emerge, and which of the two types forms depends mainly on cluster size. The mechanism promoting mixing is the presence of non-specific interactions between chromatin and proteins, which become increasingly important as clusters become larger. This result, that we observe both in simple polymer models and more realistic ones for human chromosomes, reconciles the apparently contrasting experimental results obtained. Additionally, we show how the introduction of different types of TFs strongly affects the emergence of transcriptional networks, providing a pathway to investigate transcriptional changes following gene editing or naturally occurring mutations.

Paternal over- and under-nutrition programme fetal and placental development in a sex-specific manner in mice

a.watkins@sheffield.ac.uk (A Augusto Coppi) — Mon, 20 Jul 2026 00:00:00 +0000

The association between sub-optimal paternal diet and offspring well-being is becoming established. However, the underlying mechanisms are yet to be fully defined. The aim of this study was to establish the impact of over- and under-nutrition, with or without macronutrient supplementation, on male reproductive fitness and post-fertilisation development. Male C57BL/6J mice were fed either control diet (CD), isocaloric low-protein diet (LPD), high-fat/sugar ‘Western’ diet (WD), or LPD or WD supplemented with methyl donors and carriers (MD-LPD or MD-WD, respectively) for 8 weeks before mating with virgin C57/BL6J females. Placental tissue was collected at embryonic day (E)8.5 to assess early placental (ectoplacental cone) morphology and metabolism and E17.5 for sex-specific transcriptomic profiling. Post-mating, stud male tissues were harvested for the assessment of testicular morphology and gene expression, gut microbiota composition, and metabolic status. WD and MD-WD males displayed increased adiposity, hepatic cholesterol and free fatty acids, and gut microbiota dysbiosis when compared to CD-fed males. In the testes, WD and MD-WD perturbed the expression of genes associated with metabolism and transcription regulation. Additionally, we observed differential expression of multiple genes within the Wnt signalling pathway, central in the regulation of cellular proliferation, migration, survival, and cell fate determination during development. Despite no impact on fundamental male fertility, significant changes in ectoplacental cone metabolism, fetal growth, and placental gene expression were observed in response to specific dietary regimens. Interestingly, while CD male and female placentas displayed 301 genome-wide, sexually dimorphic genes, LPD, MD-LPD, WD, and MD-WD male and female placentas possessed only 13, 0, 14, and 15 sexually dimorphic genes, respectively. Our data show that while sub-optimal paternal diet has minimal impact on male fertility, fetal and placental development are perturbed in a sex-specific manner.

Organization of circuits linking descending input to motor output in the Drosophila Male Adult Nerve Cord connectome

jefferis@mrc-lmb.cam.ac.uk (Andrew S Champion) — Mon, 20 Jul 2026 00:00:00 +0000

In most animals, a small number of descending neurons (DNs) connect the brain to circuits and motor neurons (MNs) in the nerve cord. To understand how brain signals generate behavior, it is critical to understand the organization of the neural pathways linking DNs to MNs. In companion papers, we introduced a densely reconstructed connectome of the Drosophila Male Adult Nerve Cord (MANC; Takemura et al., 2024), including cell types and developmental lineages (Marin et al., 2024), which provides complete connectivity of the ventral nerve cord (VNC) at synaptic resolution. Here, we present a first look at the organization of the networks connecting DNs to MNs. We first proofread and curated all DNs and MNs, then systematically matched their morphology to light microscopy data. We report both broad organizational patterns of the entire network and fine-scale analysis of selected circuits of interest. We discover that direct DN-MN connections are infrequent and identify neuron communities putatively linked to control of different motor systems, including walking, flight steering and power generation, and coordinated action of wings and legs. Our analyses generate hypotheses for future functional experiments and empowers others to investigate these and other circuits of the VNC in richer mechanistic detail.

Serotonergic modulation of motor subspace dynamics drives a sleep-independent quiescent state

ymchai@ustc.edu.cn (Daguang Li) — Mon, 20 Jul 2026 00:00:00 +0000

The dorsal raphe nucleus (DRN) serotonergic (5-HT) system has been implicated in regulating sleep and motor control; however, its specific role remains controversial. In this study, we found that optogenetic activation of DRN 5-HT neurons in larval zebrafish induced a quiescent state and a reduced response to acoustic stimuli. Unlike sleep, the induced quiescent state was not accompanied by a loss of postural control, and nighttime activation of DRN 5-HT neurons led to a subsequent sleep rebound. Whole brain light field imaging combined with demixed principal component analysis (dPCA) revealed distinct neural subspaces related to DRN activation, sound responses, and motor activity. DRN 5-HT activation selectively modulated the motor-related subspace while leaving the sound-evoked subspace unaffected. Unlike DRN activation, sleep induced by mepyramine significantly altered sound-evoked neuronal activity patterns. Further analysis demonstrated that serotonin had a graded effect on the motor subspace, wherein downstream neurons responsible for particular bout types were more significantly influenced. Embedding motor population activity in a curved geometric space revealed that the degree of curvature scales with behavioral suppression across animals, providing a quantitative signature of the quiescent state. Together, these results elucidate that serotonergic modulation promotes behavioral quiescence through selective regulation of motor populations.

Enhanced processivity and collective force production of kinesin-1 at low radial forces

yildiz@berkeley.edu (Ahmet Yildiz) — Mon, 20 Jul 2026 00:00:00 +0000

Kinesin-1 is a robust motor that carries intracellular cargos toward the plus ends of microtubules. However, optical trapping studies reported that kinesin-1 is a slippery motor that quickly detaches from the microtubule, and multiple kinesins are incapable of teaming up to generate large collective forces. This may be due to the vertical (z) forces that the motor experiences in a single bead trapping assay, accelerating the detachment of the motor from a microtubule. Here, we substantially lowered the z-force by using a long DNA handle between the motor and the trapped bead and characterized the motility and force generation of single and multiple human kinesin-1 motors in vitro. Contrary to previous views, we show that kinesin-1 is a robust motor that resists microtubule detachment before it reaches high hindering forces, but it quickly detaches under assisting forces even at low z-forces. We also demonstrate highly efficient collective force generation by multiple kinesin-1 motors. These results provide an explanation for how multiple kinesins team up to perform cellular functions that require higher forces than a single motor can bear.

Serial dependence predicts generalization in perceptual learning

yoram.bonneh@gmail.com (Dov Sagi) — Mon, 20 Jul 2026 00:00:00 +0000

Visual perception is shaped by recent experience, but how these momentary influences accumulate to support long-term learning and generalization remains unclear. Here, we asked whether short-term memory traces, namely attractive serial-dependence effects (SDEs), promote learning generalization. We reanalyzed over 200,000 trials from observers trained on a visual texture-discrimination task under three conditions that differentially modulated generalization. Under certain conditions, SDEs reached further back in time than previously reported and persisted after eight days of practice, despite the non-informative nature of past stimuli. Observers in conditions previously shown to support generalization displayed larger long-range SDEs, and individual SDE magnitude predicted transfer of learning across locations. We propose that SDE is associated with learning flexibility, providing a principled framework for when and why perceptual learning generalizes, which is central to theories of cognitive flexibility. Attractive serial dependence is not an extra mechanism in this model—it is the behavioral footprint of ongoing template plasticity required for flexibility in changing environments.

DuoHexaBody-CD37 induces direct cytotoxic signaling in diffuse large B-cell lymphoma

Annemiek.vanSpriel@radboudumc.nl (Annemiek B van Spriel) — Mon, 20 Jul 2026 00:00:00 +0000

Diffuse large B-cell lymphoma (DLBCL) is a common aggressive form of non-Hodgkin lymphoma. Tetraspanin CD37 is highly expressed on mature B cells and being studied as a therapeutic target for NHL, including DLBCL. DuoHexaBody-CD37 is a biparatopic antibody with an E430G hexamerization-enhancing mutation targeting two non-overlapping CD37 epitopes shown to promote complement-dependent cytotoxicity. However, the impact of DuoHexaBody-CD37 on direct cytotoxic signaling has not yet been studied. Here, we demonstrate that DuoHexaBody-CD37 induces direct cytotoxicity in DLBCL-derived tumor cell lines independent of the subtype. DuoHexaBody-CD37 induced significant CD37 clustering and was retained at the cell surface in contrast to rituximab, which was internalized. Unbiased screening identified the modulation of 26 (phospho)proteins upon DuoHexaBody-CD37 treatment of primary B cells or DLBCL cells. Whereas DLBCL cells predominantly upregulated p-SHP1(Y564) upon DuoHexaBody-CD37 treatment, primary B cells showed significantly increased p-AKT(S473) and MAPK signaling which is linked to cell survival. Studies using CD37-mutants identified the N-terminus to be involved in DuoHexaBody-CD37-induced signaling. Finally, DuoHexaBody-CD37 treatment inhibited cytokine pro-survival signaling in DLBCL cells. These findings provide novel insights into the signaling functions of CD37 upon DuoHexaBody-CD37 treatment, and open up opportunities for developing CD37-targeted immunotherapy in combination with small molecule inhibitors to maximize tumor cell death.

Flexible and high-throughput simultaneous profiling of gene expression and chromatin accessibility in single cells

volker_soltys@eva.mpg.de (Dingwen Su) — Mon, 20 Jul 2026 00:00:00 +0000

Gene regulation underpins development and is an intricate biological process involving transcription, typically at promoters within accessible chromatin. To understand cell-type-specific regulatory networks, the ability to capture both transcription and chromatin accessibility simultaneously is crucial. However, joint measurements are technically challenging and current methodologies still face adoption challenges. Here, we present easySHARE-seq, an improvement on SHARE-seq for the simultaneous measurement of ATAC- and RNA-seq in single cells. We address several limitations of the previous method by improving the barcode and streamlining the protocol. As a result, easySHARE-seq libraries have a usable sequence of up to 300 bp (+200 bp increase), making it suitable for, e.g., investigation of allele-specific signals or variant discovery. Furthermore, easySHARE-seq libraries do not require a dedicated sequencing run thus saving costs. We applied easySHARE-seq to murine liver nuclei and recovered 19,664 nuclei with joint chromatin and expression profiles. By benchmarking against other combinatorial indexing-based techniques, we showed that we can recover over 1.5-fold more transcripts per cell while retaining high scalability and low cost. To showcase our method, we identified cell types, exploited the multiomic measurements to link cis-regulatory elements to their target genes and investigated liver-specific micro-scale changes. We conclude that easySHARE-seq improves upon previous methods and can produce high-quality multiomic datasets. We expect it to be applicable to a wide range of study designs.

DNA tensiometer reveals catch-bond detachment kinetics of kinesin-1, -2, and -3

woh1@psu.edu (Crystal R Noell) — Mon, 20 Jul 2026 00:00:00 +0000

Bidirectional cargo transport by kinesin and dynein is essential for cell viability, and defects are linked to neurodegenerative disease. Computational models predict that load-dependent motor detachment strongly determines the outcome of kinesin–dynein tug-of-war, with kinesin-3 and kinesin-2 more load-sensitive than kinesin-1. Yet reconstituted assays show that all three kinesin families compete similarly well against dynein. Previous work demonstrated that vertical forces from optical trapping assays can enhance kinesin-1 dissociation, suggesting that motor behavior may depend strongly on cargo geometry. To measure kinesin detachment and reattachment kinetics under forces applied parallel to the microtubule, we developed a DNA-based tensiometer using an entropic DNA spring linking motors to microtubules. For kinesin-1, –2, and –3, dissociation rates at stall were slower than during unloaded motion, and reattachment kinetics were consistent with a weakly bound slip state preceding detachment. Kinesin-3 behavior further suggested that long KIF1A run lengths arise from multiple short runs connected by diffusive episodes. Stochastic simulations reproduced the measured load-dependent kinetics and enabled direct comparison of transition rates among kinesin families. These results provide insight into how kinesin-1, –2, and –3 transport cargo in complex cellular geometries and compete against dynein during bidirectional transport.

The view tolerance of human identity recognition depends on horizontal face information

valerie.goffaux@uclouvain.be (Alexia Roux-Sibilon) — Mon, 20 Jul 2026 00:00:00 +0000

This study investigates which visual information enables humans to recognize facial identity across different viewpoints, a key unresolved question in vision science. Participants completed an identity recognition task using faces rotated across a range of yaw angles and filtered to retain specific orientation ranges of visual information. Regardless of viewpoint, human performance consistently relied on horizontal facial information. To understand why, we used model observers to assess the identity information physically available in the images. A view-selective model, which matched identities within the same viewpoint, indicated that diagnostic identity cues shift from predominantly horizontal in frontal views to more vertical in profile views. In contrast, a view-tolerant model, which matched identities across different viewpoints, revealed that horizontal information provides the most stable and reliable identity cues across views. Furthermore, horizontal facial information best predicted the average appearance of a face across viewpoints, supporting its role in forming stable identity representations. These findings suggest that view-tolerant face representations are acquired through exposure to the stable statistical properties of faces primarily conveyed by horizontal information. By specifying the spatial information underlying recognition across viewpoints, the study offers valuable empirical constraints for the development of theoretical and computational models of face recognition.

The two faces of JAK-STAT

yingyi_zhang@tju.edu.cn (Qianying Lu) — Thu, 16 Jul 2026 00:00:00 +0000

A signal that can help breast cancer cells grow may also increase immune responses and boost immune therapy.

The effect of physical activity on brain structure and cognitive function in the population-based cohort of LIFE-Adult Study

polona.kalc@med.uni-jena.de (Andrea Zülke) — Wed, 15 Jul 2026 00:00:00 +0000

Physical activity is believed to positively influence brain health and cognition and is considered a modifiable lifestyle factor that may protect against cognitive decline and neurodegeneration. In this observational study, we investigated the cross-sectional and longitudinal effects of self-reported total and moderate-to-vigorous physical activity on cognitive scores on the Trail Making Test (TMT-A and TMT-B), hippocampal volume, and Brain Age Gap Estimate (BrainAGE) in a large population-based cohort from the LIFE-Adult Study (n=2576). Furthermore, we examined the effect of objectively measured physical activity on brain structure in a subgroup with available accelerometry data (n=227). Multiple linear regression analyses did not show any positive effects of self-reported or objectively measured physical activity on hippocampal volume or processing speed and executive function. Longitudinal path analyses suggested a potential for reverse causation, where a higher BrainAGE at baseline was associated with lower physical capacity at follow-up. Additionally, we observed an age-related bias in the self-reporting of physical activity, indicating that older individuals tend to overestimate their level of activity. Future interventions targeting middle-aged adults may be necessary to raise awareness of potential misperception and encourage increased physical activity.

Correction: Control of Arabidopsis shoot stem cell homeostasis by two antagonistic CLE peptide signalling pathways

Tue, 14 Jul 2026 00:00:00 +0000

Linking germline telomere removal to global programmed DNA elimination in Tetrahymena genome differentiation

kazufumi.mochizuki@igh.cnrs.fr (Alix Lemoine) — Tue, 14 Jul 2026 00:00:00 +0000

In the ciliate Tetrahymena, telomeres of the germline micronucleus (MIC) are removed and replaced by de novo telomere addition during somatic macronuclear (MAC) development. In this study, we investigated the kinetics and mechanism of the MIC telomere elimination. Comparison of the MIC and MAC genome sequences indicated that the MIC telomeres are excised from chromosomes as part of larger MIC-limited sequences (MLSs) through chromosomal breakage. We confirmed this using an optimized oligo-FISH protocol and found that their elimination occurs in parallel with other programmed DNA elimination processes. CRISPR-Cas9 disruption of a MLS-associated Chromosome Breakage Sequence (CBS) showed that elimination of the MLS was not blocked but instead led to loss of its adjacent MAC-destined sequence (MDS), suggesting abnormal co-elimination. In biparental crosses of the CBS mutant, however, both MLS and MDS were retained, DNA elimination was broadly disrupted, and no viable progeny were produced. These findings indicate that chromosome breakage at MLS-associated CBSs is essential for the proper separation of MLSs and MDSs, ensuring correct DNA elimination and successful sexual progeny development. We propose that the MIC telomere elimination is subsumed within the broader process of programmed DNA elimination.

The Crunchometer, a low-cost, open-source acoustic analysis of feeding microstructure

ranier@cinvestav.mx (Alam Coss) — Tue, 14 Jul 2026 00:00:00 +0000

Elucidating the neuronal circuits that govern appetite requires precise, high-resolution monitoring of the microstructure of solid food consumption, a need unmet by existing tools, which are either costly or lack the temporal resolution to align feeding events with neuronal activity. To overcome this, we developed the Crunchometer, a low-cost, open-source acoustic system that uses computational algorithms to generate high-resolution feeding ethograms from the sounds produced during solid food consumption. Validation across energy states (hunger/satiety) confirmed its sensitivity to changes in feeding microstructure, and the system reliably detected semaglutide-induced suppression of intake and reduced preference for a high-fat diet. Leveraging its seamless integration with in vivo recordings in freely behaving mice, we paired the Crunchometer with lateral hypothalamus (LH) electrophysiology to identify ‘meal-related’ neurons that track entire meals rather than individual bouts. Calcium imaging further revealed that distinct subsets of LH GABAergic and glutamatergic neurons were tuned to feeding only, to licking only, or to both behaviors. Thus, LH neuronal ensembles differentially encode the consumption of solid food versus liquid sucrose. These findings demonstrate that the Crunchometer is a robust, accessible platform for dissecting the neural correlates of feeding behavior at the resolution of a single bite.

A natural experiment in Kenya reveals durable immunosuppressive effects of early childhood malaria: a longitudinal cohort study

csande@kemri-wellcome.org (Charles J Sande) — Tue, 14 Jul 2026 00:00:00 +0000

In silico design and validation of high-affinity RNA aptamers for SARS-CoV-2 comparable to neutralizing antibodies

wangzhiye1@zju.edu.cn (Damiano Buratto) — Tue, 14 Jul 2026 00:00:00 +0000

Nucleic acid aptamers hold promise for clinical applications, yet understanding their molecular binding mechanisms to target proteins, and efficiently optimizing their binding affinities, remain challenging. Here, we present CAAMO (Computer-Aided Aptamer Modeling and Optimization), which integrates in silico aptamer design with experimental validation to accelerate the development of aptamer-based RNA therapeutics. Starting from the sequence information of a reported RNA aptamer, Ta, for the SARS-CoV-2 spike protein, our CAAMO method first determines its binding mode with the spike protein’s receptor binding domain (RBD) through a multi-strategy computational approach. We then optimize its binding affinity via structure-based rational design. Among the six designed candidates, five were experimentally verified and exhibited enhanced binding affinities compared to the original Ta sequence. Furthermore, we directly compared the binding properties of the RNA aptamers to neutralizing antibodies and found that the designed aptamer Ta^G34C demonstrated a comparable binding affinity to the RBD compared to the representative neutralizing antibodies analyzed in this study. This highlights its potential as an alternative to existing COVID-19 antibodies. Our work provides a robust approach for the efficient design of a relatively large number of high-affinity aptamers with complicated topologies. This approach paves the way for the development of aptamer-based RNA diagnostics and therapeutics.

Understanding the cellular architecture of Huntington’s disease

dorian.pustina@chdifoundation.org (Dorian Pustina) — Tue, 14 Jul 2026 00:00:00 +0000

A new diffusion MRI approach offers a glimpse of the anomalies of cellular architecture underlying basal ganglia degeneration in Huntington’s disease.

Experimental verification of the error minimization theory using non-standard genetic codes constructed in vitro

ichihashi@bio.c.u-tokyo.ac.jp (Norikazu Ichihashi) — Mon, 13 Jul 2026 00:00:00 +0000

All living systems use an almost identical standard genetic code (SGC), in which 20 amino acids are assigned non-randomly. According to the error minimization theory, amino acids are arranged to minimize the mutational effect on protein function, while experimental verification remains limited. Here, we constructed 10 non-standard genetic codes (non-SGCs) in vitro by reassigning three amino acids (Ala, Ser, and Leu) in vacant codons of the minimal genetic code consisting of 21 tRNAs. Most of these non-SGCs have a higher cost of amino acid replacement than the SGC, calculated based on three amino acid properties: polar requirement (PR), molecular volume (MV), and hydropathy index (HI). The protein function of three reporter genes expressed using these non-SGCs decreased similarly when random mutations were introduced into the genes, implying that the effect of mutations was similar across all the non-SGCs tested here. This result provides direct experimental evidence that mutational robustness does not significantly change in individual reporter protein activity within the range of mutational cost tested in this study (Cost_PR: 5.29–5.77, Cost_MV: 1848–2348, and Cost_HI: 3.27–5.10), which covers approximately 18.4% (PR), 37.6% (MV), and 50.8% (HI) of the possible cost range achievable among one million randomly-generated genetic codes.

Heterozygote advantage cannot explain MHC diversity, but MHC diversity can explain heterozygote advantage

jcherry@ncbi.nlm.nih.gov (Joshua L Cherry) — Mon, 13 Jul 2026 00:00:00 +0000

Several theoretical studies have concluded that heterozygote advantage makes at most a minor contribution to MHC diversity. Siljestam and Rueffler (2024) recently presented models in which heterozygote advantage alone can lead to realistically high diversity. Here I argue that heterozygote advantage cannot by itself explain MHC diversity, and that its contribution to diversity is unlikely to be large in most species. I first show that the high diversity reported by Siljestam and Rueffler is so sensitive to parameter values that the underlying phenomenon cannot explain the widespread diversity of MHC genes. I then consider a fundamental problem with explaining MHC diversity by heterozygote advantage alone: selective forces that favored heterozygotes would lead to the evolution of haplotypes having much higher fitness when homozygous, diminishing or eliminating heterozygote advantage. Diversity maintained by another force, however, might bring about adaptation to the more common heterozygous state at the expense of homozygous fitness. Thus, substantial heterozygote advantage may arise as a consequence of MHC diversity.

Cytoplasmic circular dsDNA is a key constituent of stress granules

natalia.demeshkina@nih.gov (Adrian R Ferré-D'Amaré) — Mon, 13 Jul 2026 00:00:00 +0000

Stress granules are large cytoplasmic bodies formed in response to environmental insults by eukaryotic cells. Stress granule formation is key for post-stress recovery, and many diseases and infections are characterized by dysregulation of these membraneless organelles. How specific and non-specific macromolecular interactions drive the formation of stress granules and other large assemblies is an area of active research. Stress granules are comprised of dense, ~200 nm cores, and these are known to contain numerous RNAs and proteins. Now, we have discovered that more than half of the nucleic acid content of stress granule cores is circular, double-stranded DNA. We demonstrate cytologically that these extrachromosomal circular DNAs (eccDNAs) colocalize cytoplasmically with canonical stress granule marker proteins in HEK293T cells, and through CRISPR targeting in budding yeast, that they are required for stress granule formation upon stress. This discovery thus reveals a key function for eccDNA in the eukaryotic stress response.

Human cerebellum and ventral tegmental area interact during extinction of learned fear

enzo.nio@uk-essen.de (Alice Doubliez) — Mon, 13 Jul 2026 00:00:00 +0000

The key elements for fear extinction learning are unexpected omissions of expected aversive events, which are considered to be rewarding. Given its reception of reward information, we tested the hypothesis that the cerebellum contributes to reward-like prediction error processing driving extinction learning via its connections with the ventral tegmental area (VTA). Forty-three young and healthy participants performed a three-day fear conditioning paradigm in a 7T MR scanner. The cerebellum and VTA were active during unexpected omissions of aversive unconditioned stimuli in the initial extinction trials and in other learning phases, in line with the proposed role of prediction-error processing. Increased functional connectivity was observed between the cerebellum and VTA, indicating that they are functionally coupled during fear extinction learning. These results suggest that an interaction between the cerebellum and VTA should be incorporated into the existing model of the fear extinction network.

Anterior cingulate cortex monitors action state and action content in complex associative learning

dw657@drexel.edu (Arron F Hall) — Fri, 10 Jul 2026 00:00:00 +0000

Environmental changes necessitate adaptive responses, and thus the ability to monitor one’s actions and their connection to specific cues and outcomes is crucial for survival. The anterior cingulate cortex (ACC) is implicated in these processes, yet its precise role in action monitoring vs. outcome tracking remains unclear. To investigate this, we developed a novel discrimination–avoidance task for mice, designed with clear temporal separation between actions and outcomes. Our findings show that ACC neurons primarily encode post-action variables over extended periods, reflecting the animal’s preceding actions rather than the outcomes or values of those actions. Specifically, we identified two distinct subpopulations of ACC neurons: one encoding the action state (whether an action was taken) and the other encoding the action content (which action was taken). Importantly, increased post-action ACC activity was associated with better performance in subsequent trials. These findings suggest that the ACC supports complex associative learning through extended signaling of rich action-relevant information, thereby bridging cue, action, and outcome associations.

Correction: Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue

Thu, 09 Jul 2026 00:00:00 +0000

Theta beta ratio in attention deficit hyperactivity disorder using a multiverse analysis

Dawid.strzelczyk@uzh.ch (Andrea Vetsch) — Thu, 09 Jul 2026 00:00:00 +0000

Attention deficit hyperactivity disorder (ADHD) affects 5–7% of children worldwide, yet diagnosis continues to rely on clinical-behavioral assessments. The theta/beta ratio (TBR) derived from electroencephalography (EEG) has long been proposed as a complementary neurobiological marker of ADHD based on reports of elevated TBR in affected children. However, accumulating evidence has raised concerns about the robustness and generalizability of these findings, pointing to a strong sensitivity to methodological choices. Here, we used multiverse analyses to systematically quantify how researcher degrees of freedom shape conclusions about associations between TBR and ADHD. Across two large, independent datasets (Healthy brain network: N=1499; validation sample: N=381), we evaluated 576 theoretically plausible analytical specifications, varying recording conditions, reference scheme, frequency band definitions, treatment of aperiodic (1/f) activity, regions of interest, sample inclusion criteria, and covariate specifications. Across the multiverse, we found that group differences in TBR were highly contingent on analytical choices, with no evidence for robust main effects of diagnosis, indicating no reliable differences between healthy controls, ADHD-inattentive, and ADHD-combined subtypes. Instead, significant effects emerged primarily as interactions with age and individual alpha frequency (IAF), particularly when TBR was derived from aperiodic-uncorrected power or from the aperiodic signal itself. These interaction patterns replicated across both independent samples and were observed using both categorical and dimensional definitions of ADHD. Together, these findings indicate that previously reported TBR effects are largely driven by variability in aperiodic activity and IAF rather than genuine differences in oscillatory theta-beta dynamics. Our results challenge the interpretation of TBR as a reliable standalone biomarker for ADHD and underscore the importance of multiverse approaches for evaluating candidate neurobiological markers in heterogeneous clinical populations.

Correction: Asymmetrical diversification of the receptor-ligand interaction controlling self-incompatibility in Arabidopsis

Thu, 09 Jul 2026 00:00:00 +0000

How attention simplifies mental representations for planning

j.castanheira@ucl.ac.uk (Christina Chang He) — Thu, 09 Jul 2026 00:00:00 +0000

Human planning is efficient – it frugally deploys limited cognitive resources to accomplish difficult tasks – and flexible – adapting to novel problems and environments. Computational approaches suggest that people construct simplified mental representations of their environment, balancing the complexity of a task representation with its utility. These models imply a nested optimisation in which planning shapes perception and perception shapes planning – but the perceptual and attentional mechanisms governing how this interaction unfolds remain unknown. Here, we harness virtual maze navigation to characterise how spatial attention controls which aspects of a task representation enter subjective awareness and are available for planning. We find that spatial proximity governs which aspects of a maze are available for planning and that when task-relevant information follows natural (lateralised) contours of attention, people can more easily construct simplified and useful maze representations. This influence of attention varies considerably across individuals, explaining differences in people’s task representations and behaviour. Inspired by the ‘spotlight of attention’ analogy, we incorporate the effects of visuospatial attention into existing computational accounts of value-guided construal. Together, our work bridges computational perspectives on perception and decision-making to better understand how individuals represent their environments in aid of planning.

Kinematic signatures in reaching movements during spaceflight provide evidence that humans underestimate body mass in microgravity

wei.kunlin@pku.edu.cn (Bo Wang) — Thu, 09 Jul 2026 00:00:00 +0000

Astronauts consistently exhibit slower movements in microgravity, even during tasks requiring rapid responses. The sensorimotor mechanisms underlying this general slowing remain debated. Two hypotheses have been proposed: either the sensorimotor system adopts a conservative control strategy for safety and postural stability, or the system underestimates body mass due to reduced inputs from proprioceptive receptors. To dissociate these opinions, we studied 12 taikonauts aboard the China Space Station performing a classical hand-reaching task. Compared to their pre-flight performance and to an age-matched control group, participants showed increased movement durations and altered kinematic profiles in microgravity. Model-based analyses of motor control parameters revealed that these changes stemmed from reduced initial force generation in the feedforward control phase followed by compensatory feedback-based corrections. These findings provide support for the body mass underestimation hypothesis while being inconsistent with the strategic slowing hypothesis. Importantly, the sensory estimate of bodily property in microgravity is biased but immune from sensorimotor adaptation, calling for an extension of existing theories of motor learning.

The targeted cytosolic degradation of class I histone deacetylases is essential for efficient alphaherpesvirus replication

zenglei2021918@163.com (Bei-Bei Chu) — Thu, 09 Jul 2026 00:00:00 +0000

Viral infection triggers a robust DNA damage response (DDR), reshaping the host chromatin landscape to facilitate viral replication. Here, we uncover a novel mechanism by which alphaherpesviruses exploit the DDR pathway. We demonstrated that herpes simplex virus 1 (HSV-1) and pseudorabies virus (PRV) induced selective degradation of class I histone deacetylases (HDAC1/2), leading to histone hyperacetylation and subsequent DDR activation. Strikingly, viral infection promoted nuclear export of HDAC1/2, followed by MDM2-mediated K63-linked polyubiquitination and proteasomal degradation in the cytoplasm. Pharmacological inhibition of either DDR signaling or HDAC1/2 nuclear export significantly affected viral replication in vitro and in vivo. Our findings reveal a unique viral strategy to hijack host epigenetic regulation for efficient replication, and identify potential therapeutic targets for alphaherpesvirus infections.

The microtubule-binding protein EML3 is required for mammalian embryonic growth and cerebral cortical development, and Eml3 null mice are a model of cobblestone brain malformation

isabelle.carrier@mail.mcgill.ca (Albert M Berghuis) — Thu, 09 Jul 2026 00:00:00 +0000

The cerebral cortex is a multi-layered structure generated through the migration of neural precursors from their birthplace in the ventricular zone to their destination within the cortical plate. Neuronal migration defects are responsible for many human pathologies collectively called neuronal migration disorders, which include subcortical band heterotopia and cobblestone brain (COB) malformation. One example of a protein involved in a neuronal migration disorder is the echinoderm microtubule-associated protein-like 1 (EML1) protein, one of six members of the mammalian EML family. Absence of EML1 protein results in subcortical band heterotopia in mice and humans. Here, we report that the absence of the paralogous protein EML3 leads to delayed embryonic development and small size, and a COB-like phenotype with neuronal ectopias in the dorsal telencephalon. We found that EML3 is expressed in the neuroepithelium and meningeal mesenchyme when those tissues participate in pial basement membrane (PBM) formation. Transmission electron microscopy demonstrated that the extracellular matrix of the PBM is structurally abnormal in Eml3 null mice when the first radially migrating neurons arrive. The reduced structural integrity of the PBM leads to focal over-migration of neurons into the subarachnoid space. These findings strengthen the link between the EML protein family and cortical neuronal migration defects by identifying Eml3 as the first EML family member whose absence leads to over-migration of neuroblasts. Moreover, we report the first COB-like phenotype with PBM structural defects when a single microtubule-associated protein is deleted.

Comparing the outputs of intramural and extramural grants funded by National Institutes of Health

bihutchins@wisc.edu (B Ian Hutchins) — Thu, 09 Jul 2026 00:00:00 +0000

Funding agencies use a variety of mechanisms to fund research. The National Institutes of Health in the United States, for example, employs scientists to perform research at its own laboratories (intramural research), and it also awards grants to pay for research at external institutions such as universities (extramural research). Here, using data from 1594 intramural grants and 97,054 extramural grants funded between 2009 and 2019, we compare the scholarly outputs from these two funding mechanisms in terms of number of publications, Relative Citation Ratio, and clinical metrics. We find that extramural awards are more cost-effective for producing outputs commonly used for academic evaluation, such as publications and citations (per dollar), while intramural awards are more cost-effective for generating research that influences future clinical work, more closely in line with the agency’s health goals. These findings provide evidence that institutional incentives associated with different funding mechanisms drive their comparative strengths.

Inferring variant-specific effective reproduction numbers from combined case and sequencing data

marlinfiggins@gmail.com (Marlin D Figgins) — Thu, 09 Jul 2026 00:00:00 +0000

Accurately estimating relative transmission rates of SARS-CoV-2 variants remains a scientific and public health priority. Recent studies have used the sample proportions of different variants from genetic sequence data to describe variant frequency dynamics and relative transmission rates, but frequencies alone cannot capture the rich epidemiological behavior of SARS-CoV-2. Here, we extend methods for inferring the effective reproduction number of an epidemic using confirmed case data to jointly estimate variant-specific effective reproduction numbers and frequencies of co-circulating variants using cases and sequences across states in the United States from January 2021 to March 2022. Our method can be used to infer structured relationships between effective reproduction numbers across time series, allowing us to estimate fixed variant-specific growth advantages. We use this model to estimate the effective reproduction number of SARS-CoV-2 variants of concern and variants of interest in the United States, and to estimate consistent growth advantages of particular variants across different locations.

Disentangling cephalopod chromatophores motor units with computer vision

g.laurent@brain.mpg.de (Dominic A Evans) — Wed, 08 Jul 2026 00:00:00 +0000

Cephalopod chromatophores are skin pigment organs enabling rapid, neurally controlled camouflage, yet the organization of their motor control remains poorly understood. Previously, we developed CHROMAS, a computer-vision pipeline for high-resolution analysis of chromatophore dynamics (Ukrow et al., 2025). Here, we apply it to investigate motor control and innervation in Euprymna berryi and Sepia officinalis. By segmenting chromatophores into radial slices and analyzing anisotropic deformations, we used dimensionality reduction and source separation to estimate the number and spatial influence of motor neurons controlling individual chromatophores and groups thereof. On average, four independent components were detected per chromatophore, each forming contiguous petal-shaped domains. Clustering thousands of components revealed motor units spanning multiple chromatophores, most involving fewer than 14, with diverse geometries ranging from compact local groups to elongated or fragmented structures; chromatophore pairs were co-innervated more often than expected by chance. Expansion was consistently faster and more stereotyped than relaxation, consistent with active contraction and passive recoil. These results show that chromatophores are not uniform pixels but contrast elements fractionable into sub-territories coordinated across neighbors. This geometry of neural control enables the generation of ‘virtual chromatophores’, that is, functional groupings of adjacent chromatophore territories that act as single units, as well as that of noise in the distribution of pixel shapes.

Celldetective, an AI-enhanced image analysis tool for unraveling dynamic cell interactions

remy.torro@gmail.com (Beatriz Díaz-Bello) — Wed, 08 Jul 2026 00:00:00 +0000

Analysis of multimodal and multidimensional data capturing dynamic interactions between diverse cell populations is a current challenge in bioimaging, especially in the context of immunology and immunotherapy research. Here, we introduce Celldetective, an open-source Python-based software tool designed for high-performance end-to-end analysis of image-based in vitro immune and immunotherapy assays. Celldetective is purpose-built for multicondition, 2D multi-channel time-lapse microscopy of mixed cell populations. Although it is optimised for the needs of immunology assays, it is nevertheless broadly applicable to any biological system involving interacting cell populations. The software seamlessly integrates AI-based segmentation, tracking, and automated single-cell event detection, all within an intuitive graphical interface that supports interactive visualisation, annotation, and training options. We showcase its capabilities with original datasets of single immune effector cell interactions with an activating surface mediated by bispecific antibodies and pairwise interactions in antibody-dependent cell cytotoxicity events.

Cribriform plate microenvironment assembles a suppressive myeloid network during EAE-induced neuroinflammation

zfabry@wisc.edu (Andy Madrid) — Wed, 08 Jul 2026 00:00:00 +0000

During neuroinflammation, CD11c⁺CD11b⁺ myeloid cells accumulate at the cribriform plate, a key cerebrospinal fluid and antigen outflow site in mice. At this site, podoplanin-expressing cells, including lymphatic vessels and meningeal layers, expand to create a distinct drainage microenvironment. In this study, we sought to characterize myeloid cells, which populate this region, using a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis. Utilizing a combination of immunohistochemistry, flow cytometry, and scRNAseq, we report that macrophages and dendritic cells from this region display unique expressional signatures related to tolerance, cell death, and reduced inflammatory profile. Together, this data supports that myeloid retention at the cribriform plate and olfactory bulb meninges promotes a local immunosuppressive environment.

Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity

thayerm@ohsu.edu (Athanasios E Vouzas) — Wed, 08 Jul 2026 00:00:00 +0000

Autosomal monoallelic gene expression and asynchronous replication between alleles are established features of imprinted genes and genes regulated by allelic exclusion. Inactivation/Stability Centers (I/SCs) are recently described autosomal loci that exhibit epigenetic regulation of allelic expression and replication timing, with differences that can be comparable to those observed between the active and inactive X chromosomes . Here, we characterize >100 autosomal loci with allele-specific epigenetic regulation of replication timing and gene expression, defining them as I/SCs. I/SCs are approximately 1 Mbb in size and can contain both protein-coding and noncoding genes. In different single-cell derived clones, these genes may be expressed from a single allele, the opposite allele, both alleles, or not expressed at all. This stochastic, yet mitotically stable, pattern indicates that the choice of which allele is expressed is independent of parent of origin and independent of the expression status of the other allele. Similarly, alleles within I/SCs show varying replication timing, either earlier or later, that is also independent of the other allele. Additionally, we identify syntenic loci in the mouse genome that display epigenetic regulation of allelic replication timing, highlighting the genomic organization and conservation of I/SC-associated regulation between human and mouse genomes. The allele-restricted regulation described here creates extensive cellular mosaicism through a stable epigenetic mechanism. This mosaicism impacts numerous dosage-sensitive genes associated with human diseases such as Alzheimer, Parkinson, epilepsy, deafness, and impaired intellectual development.

Lenacapavir-induced lattice hyperstabilization is central to HIV-1 capsid failure at the nuclear pore complex and in the cytoplasm

gavoth@uchicago.edu (Arpa Hudait) — Wed, 08 Jul 2026 00:00:00 +0000

Lenacapavir (LEN) is the first human immunodeficiency virus type 1 (HIV-1) capsid inhibitor approved for clinical use in humans. It inhibits multiple steps of the viral life cycle; however, the molecular details of the effect of LEN on capsid structure and the mechanistic steps of the inhibition are not understood. Recent studies show that intact cone-shaped capsids and capsids with LEN-induced breaks can dock at nuclear pore complexes (NPCs), but only intact capsids enter the nucleus. In this work, we combined large-scale coarse-grained molecular dynamics simulations and live-cell imaging to investigate the stepwise mechanism of docking of LEN-treated capsids into the NPC. Capsids bound to substoichiometric concentrations of LEN can reach the NPC central channel. As the capsid advances to the nuclear end, lattice defects are formed at the pentamer-hexamer interface – primarily at the narrower end – leading to pentamer dissociation. Dissociation of pentamers is detrimental to capsid integrity, leading to both rupture of the narrow end and destabilization of the hexamer-hexamer interface. Structural analysis of LEN-capsid complexes in our simulations demonstrates heterogeneous hyperstabilization and loss of the essential pliability of the capsid protein lattice. Live-cell imaging of HIV-1 cores labeled with two different fluorescent markers showed that LEN-treated ruptured capsids were docked at the NPC but were not imported into the nucleus. We conclude that LEN contributes to the loss of capsid elasticity and integrity, inhibiting HIV-1 nuclear entry and replication. Our findings demonstrate that altering viral material properties can be an effective strategy for designing human antiviral drugs.

Visual working memory guides attention rhythmically in humans

ljcps@gzhu.edu.cn (Jiachen Lu) — Wed, 08 Jul 2026 00:00:00 +0000

How does internal representation held in visual working memory (VWM), known as the attentional template, guide attention in humans? A longstanding debate concerns whether only one (Single-Item-Template theory) or multiple (Multiple-Item-Template theory) items serve as attentional templates simultaneously. Here, we propose a Rhythmic-Item-Template hypothesis, successfully reconciling these seemingly contradictory theories. Using the classical VWM-guided attention task with human participants, we found that two VWM items alternately dominate behavioral guidance in theta-rhythmic (4–8 Hz), with anti-correlated activation states in time, and more importantly, this rhythmic oscillation was not driven by the retro-cue processing. Neural recordings revealed that occipital alpha oscillation (8–14 Hz) governed item-specific prioritization, and its amplitude closely tracked subjects’ behavioral guidance, while frontal theta-oscillations phase-led and coupled with occipital alpha oscillations during the item transition. Our Rhythmic-Item-Template results not only resolve previous Single-Item-Template versus Multiple-Item-Template debate but also advance our understanding of how distributed brain rhythms coordinate flexible resource allocation in multi-item memory systems.

Dynamic assembly of malate dehydrogenase–citrate synthase multienzyme complex in the mitochondria

tobata2@unl.edu (Connor Pedersen) — Wed, 08 Jul 2026 00:00:00 +0000

The tricarboxylic acid (TCA) cycle enzymes malate dehydrogenase (MDH1) and citrate synthase (CIT1) form a multienzyme complex, referred to as a metabolon, that channels intermediate oxaloacetate between their reaction centers. Given that the MDH1–CIT1 metabolon enhances pathway reactions in vitro, its dynamic assembly is hypothesized to contribute to TCA cycle regulation in response to cellular metabolic demands. Here, we demonstrated that yeast mitochondrial MDH1 and CIT1 dissociated when aerobic respiration was suppressed by the Crabtree effect and associated when the respiratory activity was enhanced by acetate. Pharmacological TCA cycle inhibition dissociated the complex, whereas electron transport chain inhibition enhanced the interaction. The multienzyme complex assembly was related to the mitochondrial matrix acidification and oxidation, as well as cellular levels of malate, fumarate, and citrate. These factors significantly affected the MDH1–CIT1 complex affinity in vitro. Especially, variations in buffer pH within the physiological pH range between 6.0 and 7.0 in the mitochondrial matrix significantly impacted the MDH1–CIT1 affinity. These results demonstrate the dynamic association and dissociation of the MDH1–CIT1 metabolon and its relationship with respiratory activity, supporting metabolon dynamics as an integral factor in metabolic regulation governed by multiple factors such as mitochondrial pH and metabolite levels.

Medial prefrontal cortex encodes but is not required to generate goal-directed actions under threat

mcastro@uchc.edu (Ji Zhou) — Wed, 08 Jul 2026 00:00:00 +0000

Adaptive behavior under threat requires deciding when to act and when to withhold action to avoid harm, often under conditions where movement, arousal, and task demand covary. Medial prefrontal cortex (mPFC) activity is widely associated with such control, yet it remains unclear whether this activity reflects causal action generation or broader evaluative processes shaped by behavioral state. Here, we combined fiber photometry, single-cell calcium imaging, mixed-effects modeling, and optogenetic inhibition to examine how GABAergic neurons in mouse mPFC represent cues, actions, and outcomes during a series of learned avoidance tasks of increasing complexity that promote cautious responding. By explicitly controlling for baseline activity and movement, we show that much apparent task-related activity in mPFC reflects movement and cue-evoked signals that are also present in a control cortical region, the visual cortex. mPFC GABAergic neurons showed little encoding of simple avoidance contingencies but broadly encoded punished outcomes. A small subset of neurons with strong movement sensitivity encoded more demanding avoidance contingencies requiring selection between action generation and deferment. For equivalent avoidance actions, distinct neuronal populations preferentially encoded either cue onset or the action. Despite this encoding, optogenetic inhibition of mPFC had minimal effects on the learning or performance of the different contingencies. These findings reveal a dissociation between neural encoding and causal necessity, indicating that mPFC GABAergic activity primarily reflects evaluative and contextual aspects of cautious avoidance behavior rather than direct control of action execution.

Proteomic composition and mutual assembly of the C2a projection in vertebrate motile cilia

623056@sdnu.edu.cn (Chunyu Liu) — Wed, 08 Jul 2026 00:00:00 +0000

The central apparatus of motile cilia, consisting of central microtubules and various protein projections, is essential for dictating the ciliary movement. Although three proteins (FAP65, FAP147, and FAP70) have been localized to the C2a projection in Chlamydomonas reinhardtii, the full protein composition and functional roles of the vertebrate C2a remain inadequately defined. Here, we use three knockout mouse models corresponding to their respective homologs (Ccdc108, Mycbpap, and Cfap70) to systematically investigate their functions in vertebrates. Notably, all three knockout strains exhibit distinct phenotypes related to primary ciliary dyskinesia (PCD), including hydrocephalus and sinusitis. The ciliary incorporation of CCDC108, MYCBPAP, and CFAP70 is essential for one another’s stability, with the loss of any single component triggering C2a collapse, which destabilizes the central pair microtubules, and ultimately alters the ciliary movement pattern. Furthermore, we significantly expand the vertebrate C2a proteome by identifying ARMC3 and MYCBP as additional C2a components. Collectively, our findings illuminate the proteomic composition and strict physiological requirements of the vertebrate C2a projection, providing new insights into the molecular pathogenesis of PCD.

Canonical and phosphoribosyl ubiquitination coordinate to stabilize a proteinaceous structure surrounding the Legionella-containing vacuole

Shaeri.Mukherjee@ucsf.edu (Adriana Steinbach) — Wed, 08 Jul 2026 00:00:00 +0000

Legionella pneumophila (L.p.), an intracellular bacterial pathogen, hijacks the ubiquitin signaling network of its eukaryotic host cells to establish infection. Two families of L.p. secreted ubiquitin ligases are instrumental in the maturation of the Legionella-containing vacuole (LCV): the SidC/SdcA family, which catalyzes canonical ubiquitination, and the SidE family, which bypasses the E1-E2-E3 enzymatic cascade and directly conjugates ubiquitin to a target through a phosphoribosyl (PR) linkage. Here, we demonstrate that the coordinated activities of these two effector families generate a hyperstable, ubiquitin-rich structure surrounding the LCV. We propose a model in which an initial wave of SidC/SdcA-mediated canonical ubiquitination around the LCV is further modified by SidE family-driven PR-ubiquitination, resulting in a detergent-resistant ‘cloud’. The ‘cloud’ is transient, breaking down as infection progresses, suggesting that L.p. reshapes the properties of the proteinaceous shell surrounding the vacuole to meet changing needs throughout its intracellular lifecycle. This unusual structure likely stabilizes and protects the LCV, shielding it from host defense mechanisms during early infection. Our findings reveal cellular consequences of effector interplay during infection and provide a foundation for future studies into the structure and function of the proteinaceous ‘cloud’ surrounding the LCV.

Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis

marcia_haigis@hms.harvard.edu (Arlene H Sharpe) — Wed, 08 Jul 2026 00:00:00 +0000

Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4⁺ T cells. We demonstrate that asparagine depletion at different time points after CD4⁺ T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4⁺ T cell differentiation reduces cytokine production in multiple CD4⁺ T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4⁺ T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.

TGF-β drives the conversion of conventional NK cells into uterine tissue-resident NK cells to support murine pregnancy

yokoyama@wustl.edu (D Michael Nelson) — Wed, 08 Jul 2026 00:00:00 +0000

Tissue microenvironments shape lymphocyte differentiation to align immune function with local physiological demands. Uterine natural killer (NK) cells are critical for reproductive success, yet the molecular cues in the uterus that instruct their specialized identities remain incompletely understood. Here, we identify a TGF-β-dependent differentiation pathway by which circulating conventional NK cells convert into uterine tissue-resident NK cells during murine pregnancy. Loss of TGF-β receptor II expression in Ncr1-expressing cells disrupted this conversion, markedly reducing tissue-resident NK cells in the gravid uterus. Impaired TGF-β-driven uterine tissue-resident NK cell differentiation during murine pregnancy led to abnormal spiral artery remodeling and increased fetal resorption rates at mid-gestation, ultimately reducing litter sizes at birth. Collectively, these findings define TGF-β as a pivotal driver of tissue-resident NK cell differentiation in the gravid uterus and establish a mechanistic framework through which the uterine microenvironment programs NK cell identity to meet the physiological demands of gestation.

Impacts of DNA methylation on H2A.Z deposition and nucleosome stability

funabih@rockefeller.edu (Hide A Konishi) — Tue, 07 Jul 2026 00:00:00 +0000

The histone variant H2A.Z and DNA methylation are enriched at mutually exclusive genomic segments, though its mechanistic bases remain unclear. Here, we examine DNA methylation’s influence on the intrinsic stability of the H2A.Z nucleosome and chaperone-mediated H2A.Z deposition. Cryo-EM and endonuclease analyses suggest that DNA methylation subtly increases the openness and accessibility of the H2A.Z nucleosome on satellite II-derived DNA sequences. In transcriptionally silent Xenopus egg extracts, H2A.Z preferentially associates with unmethylated DNA though a substantial proportion of H2A.Z is recruited to methylated DNA. Preferential H2A.Z deposition to unmethylated DNA depends on the SRCAP complex, whose DNA binding is suppressed by methylation, while an SRCAP-independent and DNA methylation-insensitive mechanism for H2A.Z deposition also exists. Altogether, we propose that SRCAP drives the biased association of H2A.Z to unmethylated DNA, while additional mechanisms, potentially taking advantage of the subtle DNA methylation-induced physical effects, further assist the exclusion of H2A.Z from methylated DNA.

Multiple event segmentation mechanisms in the human brain

n.tan@wustl.edu (Jeffrey M Zacks) — Tue, 07 Jul 2026 00:00:00 +0000

The human brain segments continuous experience into discrete events, with theoretical accounts proposing two distinct mechanisms: creating boundaries at points of high prediction error (mismatch between expected and observed information) and high prediction uncertainty (reduced precision in predictions). Using fMRI and computational modeling, we investigated the neural correlates of error-driven and uncertainty-driven boundaries. We developed computational models that generate boundaries based on prediction error or prediction uncertainty, and examined how both types of boundaries, and human-identified boundaries, related to fMRI pattern shifts and evoked responses. Multivariate analysis revealed a specific temporal sequence of neural pattern changes around human boundaries: early pattern shifts in anterior temporal regions (–11.9 s), followed by shifts in parietal areas (–4.5 s), and subsequent whole-brain pattern stabilization (+11.8 s). The core of this dynamic response was associated with both error-driven and uncertainty-driven boundaries. Critically, both error- and uncertainty-driven boundaries were associated with unique pattern shifts. Error-driven boundaries were associated with early pattern shifts in ventrolateral prefrontal areas, followed by pattern stabilization in prefrontal and temporal areas. Uncertainty-driven boundaries were linked to shifts in parietal regions within the dorsal attention network, with minimal subsequent stabilization. In addition, within the core regions responsive to both types of boundaries, the timing differed significantly. These findings provide evidence for two overlapping brain networks that maintain and update representations of the environment, controlled by two distinct prediction quality signals: prediction error and prediction uncertainty.

Continuous developmental changes in word recognition and language learning across early childhood

mcfrank@stanford.edu (Adrian Steffan) — Tue, 07 Jul 2026 00:00:00 +0000

Being a fluent language user involves recognizing words as they unfold in time. How does this skill develop over the course of early childhood? And how does facility in word recognition relate to the growth of vocabulary knowledge? We address these questions using data from Peekbank, an open database of experiments measuring children’s eye movements during early word recognition. In an observational study of 26 datasets from over 2500 children ages 6 months to 6 years, we show that word recognition becomes faster, more accurate, and less variable across development, consistent with a process of skill learning. Factor analysis reveals covariation of word recognition speed and accuracy with children’s vocabulary size in cross-sectional analysis. Further, across a range of longitudinal models, speed, accuracy, and vocabulary were coupled. Children with overall faster word recognition tended to show faster vocabulary growth, though developmental growth in word recognition skill was not specifically associated with growth in vocabulary. Together, these findings support the view that word recognition is a skill that develops gradually across early childhood and that this skill is deeply intertwined with early language learning.

Pervasive relaxed selection on spermatogenesis genes coincident with the evolution of polygyny in gorillas

denard@arizona.edu (David Enard) — Tue, 07 Jul 2026 00:00:00 +0000

Gorillas have a polygynous social system in which the highest-ranking male has almost exclusive access to females and sires most of the offspring in the troop. Such behavior results in a dramatic reduction of sperm competition, which is ultimately associated with numerous traits that cause low efficacy of gorilla spermatogenesis. However, the molecular basis behind the remarkable erosion of the gorilla male reproductive system remains unknown. Here, we explored the genetic implications of the polygynous social system in gorillas by testing for altered selection intensity across 13,310 orthologous protein-coding genes from 261 Eutherian mammals. We identified 578 genes with relaxed purifying selection in the gorilla lineage, compared with only 96 that were positively selected. Genes under relaxed purifying selection in gorillas have accumulated numerous deleterious amino acid substitutions; their expression is biased towards male germ cells, and they are enriched in functions related to meiosis and sperm biology. We tested the role of gorilla relaxed genes previously not implicated in male reproductive function using the Drosophila model system and identified 41 novel spermatogenesis genes required for normal fertility. Furthermore, by exploring exome/genome sequencing data of infertile men with severe spermatogenic impairment, we found that the human orthologs of the gorilla relaxed genes are enriched for loss-of-function variants in infertile men. These data provide compelling evidence that reduced sperm competition in gorillas is associated with relaxed purifying selection on genes related to male reproductive function. The accumulation of deleterious mutations in these genes likely provides the mechanistic basis behind the low efficacy of gorilla spermatogenesis and uncovers new candidate genes for human male infertility.

Profiling of terminating ribosomes reveals translational control at stop codons

sq38@cornell.edu (Leiming Dong) — Tue, 07 Jul 2026 00:00:00 +0000

Accurate termination of protein synthesis is paramount for the integrity of the cellular proteome, yet the dynamics and fidelity of ribosome termination remain poorly understood. Here, we establish a profiling strategy to capture terminating ribosomes in mammalian cells and reveal a substantial heterogeneity in ribosome pausing at individual stop codons. We identify a sequence motif upstream of the stop codon that promotes termination pausing, a finding supported by massively parallel reporter assays. Unexpectedly, reduced termination pausing increases the likelihood of stop codon slippage, giving rise to proteins with heterogeneous C-terminal extensions. Mechanistically, we show that sequence-dependent termination pausing is consistent with post-decoding mRNA scanning by the 3′ end of 18 S rRNA. We further uncover tissue-specific patterns of termination pausing that correlate with the stoichiometry of Rps26, which potentially modulates mRNA:rRNA interactions. Together, these results suggest termination pausing as a distinct translational signature shaped by mRNA sequence contexts, ribosome heterogeneity, and cell type-specific translational control.

Optimised genome editing for precise DNA insertion and substitution using prime editors in zebrafish

s.scholpp@exeter.ac.uk (Amir Khan) — Tue, 07 Jul 2026 00:00:00 +0000

CRISPR/Cas9-mediated genome editing has rapidly become a popular tool for studying gene functions and generating genetically modified organisms. However, using this system, stochastic integration of random insertions and deletions restricts precise genome manipulation. Advanced CRISPR/Cas9 technologies using Prime Editors (PEs), Cas9 proteins fused with reverse transcriptase, enable programmed integration of short DNA modifications into the genome. However, its application in precise genome editing in animal models is challenging. Here, we utilise a nickase- and a nuclease-based PE to perform programmed short DNA substitutions and insertions at various loci in the zebrafish genome. Whereas nickase-based PE2 mediated a higher ratio of precise prime edits to the total edits, nuclease-based PEn was more efficient for short DNA modifications, achieving up to 27.3% precise insertion. To further evaluate our approach, we inserted a nuclear localisation signal into a reporter transgene to incorporate longer fragments by prime editing. These gene modifications were transmitted to the next generation. We show that PE-mediated prime editing can efficiently manipulate genome information in zebrafish without using exogenous donor DNA.

Development of auditory and spontaneous movement responses to music over the first postnatal year

trinh.nguyen@iit.it (Atesh Koul) — Tue, 07 Jul 2026 00:00:00 +0000

Humans across cultures not only share the ability to recognise music but also respond to it through movement. While the sensory encoding of music is well-studied, when and how infants naturally start moving to music is largely unexplored. This study simultaneously investigates infants’ neural (auditory) responses and spontaneous movements to music during the first postnatal year. Neural activity (EEG) and body kinematics (markerless pose estimation) were recorded from 79 infants (aged 3, 6, and 12 months) listening to refrains of children’s music, along with shuffled, high-pitched, and low-pitched versions of the same songs. Neural data revealed that, across all ages, infants exhibit enhanced auditory responses to music compared to shuffled music, indicating that auditory encoding of music emerges early in development. Movement data revealed a different outcome. While coarse auditory-motor coupling is present at all ages, more complex structured movement patterns emerge in response to music only by 12 months. Notably, no age group demonstrated evidence of coordinated movements to music. Additionally, enhanced auditory responses to high vs low pitch were only evident at 6 months, while infants’ movements were better predicted by high-pitched compared to low-pitched music at all ages. This study provides initial insights into how the developing brain gradually transforms music into spontaneous movements of increasing complexity.

Arrayed single-gene perturbations identify drivers of human anterior neural tube closure

roya_huang@berkeley.edu (Chudi Abraham-Igwe) — Tue, 07 Jul 2026 00:00:00 +0000

Genetic studies of human embryonic morphogenesis are constrained by ethical and practical challenges, restricting insights into developmental mechanisms and disorders. Human pluripotent stem cell (hPSC)-derived organoids provide a powerful alternative for the study of embryonic morphogenesis. However, screening for genetic drivers of morphogenesis in vitro has been infeasible due to organoid variability and the high costs of performing scaled tissue-wide single-gene perturbations. By overcoming both these limitations, we developed a platform that integrates reproducible organoid morphogenesis with uniform single-gene perturbations, enabling high-throughput arrayed CRISPR interference screening in hPSC-derived organoids. To demonstrate the power of this platform, we screened 77 transcription factors in an organoid model of anterior neurulation to identify ZIC2, SOX11, and ZNF521 as essential regulators of neural tube closure. We discovered that ZIC2 and SOX11 are required for closure, while ZNF521 prevents ectopic closure points. Single-cell transcriptomic analysis of perturbed organoids revealed co-regulated gene targets of ZIC2 and SOX11 and an opposing role for ZNF521, suggesting that these transcription factors jointly govern a gene regulatory program driving neural tube closure in the anterior forebrain region. Our single-gene perturbation platform enables high-throughput genetic screening of in vitro models of human embryonic morphogenesis.

Ligand-dependent enhancer activation indirectly modulates non-target promoters in a chromatin domain

aprotim@tifrh.res.in (Aprotim Mazumder) — Tue, 07 Jul 2026 00:00:00 +0000

Transcription activation of genes by estrogen is driven by enhancers, which are often located within the same topologically associating domain (TAD) as non-targeted promoters. We investigated how acute enhancer-driven activation affects neighbouring non-target genes within the same TAD. Using single-molecule RNA FISH (smFISH), we tracked the transcription of TFF1 (enhancer-target gene) and TFF3 (non-target gene) during estrogen stimulation. We observed mutually exclusive expression patterns: TFF1 expression peaked at 1 hr, while TFF3 reached its peak at 3 hr after TFF1 activation had diminished. Chromatin looping data indicated that the enhancer loops with the TFF1 gene but not TFF3, suggesting that TFF3 upregulation is not due to direct enhancer-promoter interactions. CRISPR deletion of the enhancer affected TFF1 transcription more acutely than TFF3. 1,6-hexanediol (HD) exposure suggested that the TFF1 enhancer:promoter undergoes a potential ERα-mediated condensate formation, which sequesters the transcriptional machinery and inhibits TFF3 expression. As estrogen signaling fades at 3 hr, TFF1 expression declines while TFF3 expression increases. Our findings reveal that enhancer-driven activation can indirectly repress neighboring genes within the same TAD, highlighting a dynamic shift in gene expression as signaling progresses.

Mechanistic insights into transcriptional regulation of ARHGAP36 expression identify a factor predictive of neuroblastoma survival

olehmann@ualberta.ca (Armin M Gamper) — Mon, 06 Jul 2026 00:00:00 +0000

Cancer repeatedly exploits attributes fundamental for morphogenesis to advance malignancy and metastasis. This is illustrated by lineage-specific transcription factors that regulate neural crest migration, representing frequent drivers of malignancy. One such example is the forkhead transcription factor FOXC1, where gain of function is a feature of diverse cancers that is associated with an unfavorable prognosis. Using RNA-, ChIP-sequencing and CRISPR interference, we show that Foxc1 binds a locus in a region of closed chromatin to induce expression of Arhgap36, a tissue-specific inhibitor of protein kinase A. Because PKA is a core Hedgehog (Hh) pathway inhibitor, Foxc1’s induction of Arhgap36 expression increases Hh activity. The function of Sufu, a PKA substrate, and a second essential Hh pathway inhibitor, is likewise impaired. The resulting increased Hh pathway output is resistant to pharmacological inhibition of Smoothened, a phenotype of more aggressive cancers. The Foxc1–Arhgap36 relationship identified in murine cells was further evaluated in neuroblastoma, a neural crest-derived pediatric malignancy. This demonstrated in a cohort of 1348 patients that high levels of ARHGAP36 are predictive of improved 5-year survival. Accordingly, this study has identified as a novel transcription factor which enhances ARHGAP36 expression, one that induces Hh activity in multiple tissues during development. It also establishes a model by which increased levels of FOXC1 via ARHGAP36 and PKA inhibition dysregulate multiple facets of Hh signaling and provides evidence demonstrating relevance to a common neural-crest-derived malignancy.

Lipid packing contributes to the confinement of caveolae to the plasma membrane

richard.lundmark@umu.se (Aleksei Kabedev) — Mon, 06 Jul 2026 00:00:00 +0000

Lipid packing is a fundamental characteristic of bilayer membranes. Yet, we lack detailed mechanistic understanding of how lipid packing directly affects membrane-associated cellular processes. Here, we address this by focusing on caveolae, small Ω-shaped invaginations of the plasma membrane, which serve as key regulators of cellular lipid sorting and mechano-responses. In addition to caveolae coat proteins, the lipid membrane is a core component of caveolae that critically impacts their biogenesis, morphology, and stability. We show that the small compound Dyngo-4a adsorbs and inserts into the membrane, resulting in a dramatic dynamin-independent inhibition of caveola dynamics. Analysis of model membranes in combination with molecular dynamics simulations revealed that a substantial amount of Dyngo-4a was inserted and positioned at the level of cholesterol in the bilayer, affecting lipid order in a cholesterol-dependent manner. Dyngo-4a treatment resulted in decreased lipid packing of the plasma membrane. This prevented caveolae internalization and lateral diffusion without affecting their morphology, associated proteins, or the overall cell stiffness. Artificially increasing plasma membrane cholesterol levels was found to counteract the block in caveola dynamics caused by Dyngo-4a. Therefore, we propose that the outer leaflet lipid packing of cholesterol in the plasma membrane critically contributes to the confinement of caveolae to the plasma membrane.

SqueakPose Studio, an end-to-end platform for pose estimation and real-time edge-AI deployment

david.haggerty@nih.gov (Caleb Browning Darden) — Mon, 06 Jul 2026 00:00:00 +0000

Accurate pose estimation underpins quantitative analysis of behavior, yet many deep learning-based tracking tools remain optimized for offline workflows that rely on fragmented software pipelines, workstation-grade GPUs, or external middleware to enable real-time deployment. Here, we present an integrated software-hardware ecosystem for pose estimation that spans dataset creation, model training, offline analysis, and real-time deployment on embedded edge-computing devices. SqueakPose Studio provides a software suite for whole-frame, deep learning-based pose estimation that unifies dataset creation, manual and model-assisted labeling, model training, validation, and large-scale offline inference. The system leverages modern object-detection architectures to enable efficient end-to-end training and inference without patch-based sampling or multistage post-processing, and supports execution on CPUs, GPUs, and Apple Silicon. For experimental settings requiring continuous recording and synchronized data acquisition, SqueakView enables real-time model deployment, video capture, and sensor logging on embedded edge-computing hardware, while MouseHouse provides a compact, modular enclosure designed for home cage-based experiments that integrates embedded GPU compute, microcontroller-based timing, and peripheral I/O. A shared data format and deterministic timing architecture ensure consistency across offline analysis and real-time deployment. Together, SqueakPose Studio, SqueakView, and MouseHouse provide a unified platform for pose estimation that supports both conventional offline analysis and embedded, real-time experimentation, without reliance on workstation-grade hardware or external middleware.

A coma pattern-based autofocusing method resolves bacterial cold shock response at single-cell level

shuqiang.huang@siat.ac.cn (Jinjuan Wang) — Mon, 06 Jul 2026 00:00:00 +0000

Imaging-based single-cell physiological profiling holds great potential for uncovering fundamental bacterial cold shock response (CSR) mechanisms, but its application is impeded by severe focus drift during rapid temperature downshifts required for CSR induction. Here, we introduce LUNA (Locking Under Nanoscale Accuracy), an innovative autofocusing method that leverages the coma pattern of detection light to characterize focus drift. LUNA improves the focusing precision down to 3 nm and extends the focusing range to at least 40 times the objective depth of focus. These advancements enable us to investigate the complete dynamics of bacterial single-cell CSR, revealing continuous cellular growth and division. We resolve a three-phase adaptation process characterized by distinct growth deceleration dynamics, and show that bacterial cells maintain robust size regulation and coordinate uniform adaptation to cold shock through synchronized growth and elapsed cycles. Notably, a model based on scattering theory reconciles the paradox between the growth lag of batch culture and continuous single-cell growth. These findings fundamentally transform our understanding of bacterial CSR and highlight LUNA’s excellent potential for expanding state-of-the-art research in biology.

Activity-dependent CO₂ production in the axon triggers opening of Connexin32 in the Schwann cell paranode

n.e.dale@warwick.ac.uk (Amol Bhandare) — Mon, 06 Jul 2026 00:00:00 +0000

Loss of function mutations of Cx32, which is expressed in Schwann cells, cause X-linked Charcot-Marie-Tooth disease, a slowly progressive peripheral neuropathy. Action potential propagation causes Cx32 hemichannels in the Schwann cell paranode to open. As Cx32 hemichannels are directly sensitive to CO₂, we have tested whether CO₂ produced in the axon, as a consequence of the energetic demands of action potential propagation, might gate Cx32 hemichannels. Using isolated sciatic nerve from the mouse, we found that the critical components required for intercellular CO₂ signaling are present (nodal mitochondria, the source of CO₂; a CO₂-permeable aquaporin, AQP1; paranodal Cx32; and carbonic anhydrase). We have used a membrane impermeant fluorescent dye, FITC, to demonstrate the opening of Cx32 in Schwann cells in response to an external CO₂ stimulus or during action potential propagation in the isolated nerve. Pharmacological manipulations of AQP1 or carbonic anhydrase activity altered Cx32 gating during action potential firing. Expression of a modified Cx32 subunit, Cx32^DN, that coassembles with Cx32^WT, revealed that the activity-dependent dye loading of Schwann cells depended upon CO₂ binding to Cx32. CO₂ can, therefore, mediate neuron-to-glia signaling via connexins. CO₂ permeable aquaporins and carbonic anhydrase are key components of this signaling mechanism.

TopoMetry systematically learns and evaluates the latent geometry of single-cell data

david.oliveira@dpag.ox.ac.uk (Ana I Domingos) — Fri, 03 Jul 2026 00:00:00 +0000

Reconstructing and investigating the geometry underlying data is a fundamental task in single-cell analysis, yet no unified framework exists for learning, evaluating, and diagnosing representations that faithfully preserve it. We present TopoMetry, a geometry-aware framework that learns intrinsic coordinate systems directly from the data and refines them into high-fidelity spectral scaffolds. These scaffolds capture both local neighborhoods and global structures, supporting downstream analyses such as clustering and visualization. In benchmarks across diverse single-cell datasets, TopoMetry preserved geometry more reliably than standard workflows and revealed biological signals otherwise obscured, including unexpected transcriptional diversity among T cells and links between RNA-defined subpopulations, and clonal expansion. The full analysis can be executed with a single line of code to generate a comprehensive report, making the framework both powerful and accessible. Beyond individual findings, TopoMetry warrants a shift of focus from static two-dimensional projections to the systematic learning and evaluation of geometry itself, enabling more accurate exploration of cellular diversity.

Neural activity profiles reveal overlapping, intermingled subpopulations spanning area borders in mouse sensorimotor cortex

mattkaufman@uchicago.edu (Harrison Grier) — Fri, 03 Jul 2026 00:00:00 +0000

Cortical control of movement is a distributed computation spanning multiple densely interconnected regions. Although we have rich anatomical atlases and a coarse understanding of how function maps to areas and subregions, we lack a detailed account of how behaviorally relevant activity is organized across the cortical sheet. Here, we trained head-fixed mice to perform a 15-target reach-to-grasp task while we performed cellular-resolution, two-photon calcium imaging across five regions of sensorimotor cortex (>39,000 layer 2/3 neurons). We characterized each neuron’s trial-averaged peri-event activity with interpretable metrics and mapped these response properties across areas, revealing large-scale spatial structure. Neuronal response profiles often shifted abruptly at anatomical borders: motor areas showed sharper tuning and more linear relationships with target location, whereas somatosensory areas displayed more heterogeneous response patterns. Neural response properties also differed according to somatotopic representation. Nonlinear dimensionality reduction of the neural feature matrix revealed that areas varied in their average response profiles, but that areas did not have well-separated feature distributions; instead, each area contained subpopulations. Neurons in each subpopulation had characteristic response profiles and were distributed across multiple cortical areas. The spatial distributions of the subpopulations overlapped, with neurons from different subpopulations salt-and-pepper intermingled in the overlap zones. Together, these results describe novel activity structure across sensorimotor cortex and identify several distinct but spatially overlapping subpopulations with characteristic activity patterns during reach-to-grasp behavior.

Non-canonical amino acid incorporation enables minimally disruptive labeling of stress granule and TDP-43 proteinopathy

jiouw@jhu.edu (Hao Chen) — Fri, 03 Jul 2026 00:00:00 +0000

We report a minimally disruptive labeling strategy for stress granule protein, G3BP Stress Granule Assembly Factor 1 (G3BP1), and ALS-linked protein, TAR DNA-binding protein 43 (TDP-43), using the fluorescent non-canonical amino acid Anap. By integrating the genetic code expansion (GCE) with rational site selection, we achieved precise incorporation of Anap that preserves protein structure and function. In live cells and neurons, Anap labeling faithfully recapitulated localization, stress-induced dynamics, and recovery behavior, outperforming conventional fluorescent tags, and enabling physiologically relevant visualization of protein pathobiology.

Navigating the path: Advice to physician-scientists on choosing a clinical specialty

christopher.williams@vanderbilt.edu (Ali Zarrinpar) — Fri, 03 Jul 2026 00:00:00 +0000

Choosing a clinical specialty is a critical decision for physician-scientist trainees, influencing both clinical practice and research trajectory. This article provides a structured approach to specialty selection, emphasizing the importance of aligning clinical interests with long-term research goals, evaluating training pathways, and considering lifestyle implications. Physician-scientists, including MD-PhD and other dual-degree graduates, as well as MD graduates with research-intensive training, often pursue specialties with established research pathways. We outline key decision-making factors, including mentorship, clinical exposure, research commitment, and financial sustainability. Additionally, we compare research track and categorical residency pathways, detailing differences in training structure, funding opportunities, and career outcomes. The article explores the evolving role of physician-scientists across career stages, from residency through senior faculty leadership, highlighting strategies to maintain research engagement while balancing clinical responsibilities. By critically evaluating these factors and leveraging mentorship and institutional support, physician-scientists can make informed decisions that align with their aspirations, ensuring a fulfilling and impactful career in both medicine and research.

Analysis of dendritic input currents during place field dynamics

ujfalussy.balazs@koki.hu (Balazs B Ujfalussy) — Fri, 03 Jul 2026 00:00:00 +0000

Neuronal activity is driven by the complex interplay between various membrane currents, often located in distinct domains of the spatially extended dendritic tree. How the effect of these currents propagates to the soma and contributes to neuronal output under in vivo conditions is not fully understood. Here, we develop a new method to measure and visualize the contributions of individual membrane currents to the somatic response in spatially extended biophysical model neurons. Our approach relies on the iterative decomposition of the axial current flowing between neighbouring compartments in proportion to the underlying membrane currents measured in the model. We apply this method to visualize the inputs driving hippocampal place cell activity. Our method provides a compact and intuitive description of the various dendritic events underlying subthreshold activity, spiking, or burst firing. By contrasting the dendritic input currents preceding spiking and bursting, we demonstrate that both could occur at highly variable input levels to proximal dendrites (basal and oblique), and that strong distal inputs facilitate, rather than control, the generation of complex spike bursts. Our method opens a novel window onto single-neuron computations that will help to design better models and to interpret the results of in vivo imaging experiments.

The exquisite mechanics of a tsetse bite

aacosta3@nd.edu (Álvaro Acosta-Serrano) — Thu, 02 Jul 2026 00:00:00 +0000

Specialized anatomical structures in the mouth and feet of tsetse flies help them feed on blood from a variety of hosts.

Pink1-mediated mitophagy in the endothelium releases proteins encoded by mitochondrial DNA and activates neutrophil responses during inflammation

jalees@uic.edu (Chinnaswamy Tiruppathi) — Wed, 01 Jul 2026 00:00:00 +0000

Eukaryotic mitochondria are characterized by several features that represent vestiges of their prokaryotic ancestry. One such feature is the N-terminal formylation of proteins encoded by mitochondrial DNA that undergo translation by mitochondrial ribosomes. N-formylated proteins are also released by bacteria and trigger activation of immune cells such as neutrophils. Growing evidence indicates that circulating levels of mitochondrial formyl proteins are elevated in the serum of patients with excessive inflammatory responses. However, the mechanisms by which they are released into circulation are not known. In this study, we have identified vascular endothelial cells as a source of Pink1-dependent release of mitochondrial formyl proteins in response to inflammatory mediators. Mechanistically, the mitophagy mediator Pink1 is stabilized by inflammatory activation of endothelial cells, promoting mitophagy and mitochondrial formyl peptide release both in mice and primary human endothelial cells. Using nanoparticle delivery of Pink1-targeting sgRNA in mice expressing endothelial-specific Cas9, we developed a mouse model in which Pink1 is specifically depleted in the endothelium. Deletion of endothelial Pink1 decreased circulating formyl peptide levels, lowered lung neutrophil infiltration and reduced mortality in mice. We thus propose that endothelial cells upregulate pro-inflammatory mitophagy in response to inflammation, leading to the release of mitochondrial formyl peptides and detrimental neutrophil recruitment into the lung.

Distinct involvements of the subthalamic nucleus subpopulations in reward-biased decision-making in monkeys

lding@pennmedicine.upenn.edu (Joshua I Gold) — Wed, 01 Jul 2026 00:00:00 +0000

The subthalamic nucleus (STN) is a part of the indirect and hyperdirect pathways in the basal ganglia (BG) and has been implicated in movement control, impulsivity, and decision-making. We recently demonstrated that, for perceptual decisions, the STN includes at least three subpopulations of neurons with different decision-related activity patterns (Branam et al., 2024). Here, we show that, for decisions that require both perceptual and reward-based processing, many STN neurons are sensitive to both sensory evidence and reward expectations. Within a drift-diffusion framework, three STN subpopulations show different relationships to model components reflecting the formation of the decision variable, dynamics of the decision bound, and non-decision-related processes. Many STN neurons also represent quantities related to decision evaluation, including choice accuracy and reward expectation. These results help to further delineate the multiple roles that STN plays in forming and evaluating complex decisions that combine multiple sources of information.

Restraint of melanoma progression by cells in the local skin environment

richard.white@ludwig.ox.ac.uk (Emily Montal) — Tue, 30 Jun 2026 00:00:00 +0000

Keratinocytes, the dominant cell type in the melanoma microenvironment during tumor initiation, exhibit diverse effects on melanoma progression. Using a zebrafish model of melanoma and human cell co-cultures, we observed that keratinocytes undergo an epithelial-mesenchymal transition (EMT)-like transformation in the presence of melanoma, reminiscent of their behavior during wound healing. Surprisingly, overexpression of the EMT-transcription factor Twist in keratinocytes led to improved overall survival in zebrafish melanoma models, despite no change in tumor initiation rates. This survival benefit was attributed to reduced melanoma invasion, as confirmed by human cell co-culture assays. Single-cell RNA-sequencing revealed a unique melanoma cell cluster in the Twist-overexpressing condition, exhibiting a more differentiated, less invasive phenotype. Further analysis nominated homotypic jam3b–jam3b and pgrn–sort1a interactions between Twist-overexpressing keratinocytes and melanoma cells as potential mediators of the invasive restraint. Our findings suggest that EMT in the tumor microenvironment may paradoxically limit melanoma invasion through altered cell–cell interactions.

Brawn before bite in endemic Asian eutherian mammals after the end-Cretaceous extinction

zjt@berkeley.edu (Qian Li) — Tue, 30 Jun 2026 00:00:00 +0000

The first 10 million years (Myr) following the Cretaceous-Paleogene (K-Pg) mass extinction marked a period of global greenhouse conditions and dramatic rise of placental mammals. Because ~80% of known terrestrial sections capturing post-K-Pg mammal recovery come from North America, a substantial knowledge gap exists in the tempo and mode of recovery in Asia, where only 3% of global sites are located and most contain species found nowhere else. We show that isolated Paleocene eutherian assemblages from China (1) exhibited high mean tooth size and disparity early in the Paleocene, (2) shifted in their dental shape in parallel with regional and global environmental changes later in the Paleocene, and (3) achieved maximum dental shape-performance covariation near the end of the first 10 Myr post-K-Pg. This ‘brawn before bite’ transformation, coupled with prolonged dental shape versus performance variability, favors a scenario whereby many living orders of eutherian mammals were borne out of phenotypically and functionally plastic ancestral assemblages, including those in tropical South China, during the Paleocene.

Experimental evolution to thermal stress indicates climate resilience in a cosmopolitan arthropod

sjyou@fafu.edu.cn (Fengluan Yao) — Tue, 30 Jun 2026 00:00:00 +0000

Adaptive evolution enables species to survive and thrive under changing environmental conditions. In the face of accelerating global climate change, thermal stress represents a major challenge to the persistence of terrestrial arthropods. Understanding the genetic mechanisms underlying thermal adaptation is therefore critical for predicting species’ evolutionary potential and future success. Here, we combine experimental evolution, phenotypic assays, and multi-omics analyses to investigate the adaptive responses of the diamondback moth (Plutella xylostella), a globally destructive pest of cruciferous crops, to contrasting thermal environments. Populations evolved under hot (32 °C/27 °C) and cold (15 °C/10 °C) regimes exhibited distinct life history and fitness traits relative to those maintained under favorable conditions (26 °C). The hot strain showed accelerated development, higher fecundity, and increased survival under extreme heat, while the cold strain exhibited lower supercooling and freezing points, indicating enhanced cold hardiness. Integrated transcriptomic and metabolomic analyses revealed extensive transcriptional reprogramming and convergent metabolic adjustments, notably a reduction in lipid metabolism to conserve energy under thermal stress. Crucially, non-synonymous mutations in PxSODC enhance superoxide scavenging efficiency, enabling effective oxidative stress management at lower gene expression levels. Furthermore, we identified epigenetic regulation via DNA methylation as a key mediator of this thermal tolerance. Together, these coordinated mutational, epigenetic, and metabolic insights highlight this arthropod’s capacity for global dispersal and likely persistence under climate change, establishing a framework for understanding equivalent effects in other species.

Retrosplenial cortex enables context-dependent goal-directed sensorimotor transformation

pol.bechvilaseca@epfl.ch (Anthony Renard) — Mon, 29 Jun 2026 00:00:00 +0000

The ability to dynamically adjust a behavioral response to a stimulus depending on context is of critical importance for animals. To investigate the neural basis supporting context-dependent sensory processing, we developed a behavioral task in which mice changed their response to a single whisker deflection according to a continuously present contextual cue. Through unbiased optogenetic inactivation mapping, we found that neuronal activity in sensory and motor cortices contributed to task execution and, interestingly, we uncovered an unexpected role of the retrosplenial cortex (RSC) for contextual integration. Widefield calcium imaging revealed that the RSC was the first dorsal cortical area to show context discrimination in response to whisker stimulation, followed by the whisker motor cortex. Finally, we combined optogenetic inactivation with calcium imaging to define causal context-dependent changes in sensorimotor processing. Our cortex-wide mapping experiments thus begin to define key cortical nodes for context-dependent sensorimotor transformation and highlight an important contribution of RSC.

Direct contact between iPSC-derived macrophages and hepatocytes drives reciprocal acquisition of Kupffer cell identity and hepatocyte maturation

phsyuh@nus.edu.sg (Christopher Zhe Wei Lee) — Mon, 29 Jun 2026 00:00:00 +0000

As the resident tissue macrophage of the liver, Kupffer cells (KCs) play an important role in homeostasis and tissue support. However, current in vitro liver models often ignore the contribution of these KCs towards the proper response and function of the tissue. This is especially relevant when we consider the implications of immune-mediated drug injuries. To address this issue, we developed an isogenic co-culture system utilising iPSC-derived macrophages (iMacs) and hepatocytes (iHeps). Directly co-culturing iHeps with iMacs improved the differentiation and maturation of the iHeps, with significant downregulation of fetal hepatocyte markers as well as upregulation of cytochrome genes. Furthermore, the co-culture also imparted stronger KC identity to the iMacs in a contact-dependent manner, with iMacs cultured in iHep conditioned media alone showing weaker expression of key KC markers. Finally, challenging the iHep-iMac co-culture system with seven paradigm hepatotoxic compounds showed dose-dependent cytokine response in the five compounds associated with immune-mediated liver injuries while no significant changes were observed in the two compounds with no reported immune-dependent complications. This effect was also not recapitulated when the co-culture was instead performed with human peripheral blood monocyte-derived macrophages, suggesting that iMacs are essential for liver toxicity response. Taken together, our study shows not only the importance of macrophages in tissue systems, but also that the source of macrophages is critical to the development of accurate in vitro human models.

Correlates of protection against African swine fever virus identified by a systems immunology approach

artur.summerfield@unibe.ch (Artur Summerfield) — Mon, 29 Jun 2026 00:00:00 +0000

African swine fever virus (ASFV) causes a fatal hemorrhagic disease in domestic pigs and wild boars, which poses severe threats to the global pork industry. Despite the promise of live attenuated vaccines (LAVs), their narrow margin between efficacy and residual virulence presents major safety challenges. This study bridges a critical knowledge gap in ASF vaccinology by identifying innate and adaptive correlates of protection. This was achieved by using an established model with two groups of pigs differing in baseline immunological status (farm and specific pathogen-free [SPF]). The animals were immunized with an attenuated ASFV strain and subsequently challenged with a related, highly virulent genotype II strain. By applying a systems immunology approach, we correlated kinetic data, including serum cytokines, blood transcription modules (BTMs), T-cell responses, and antibody levels, with clinical outcomes to track protective and detrimental immune responses to the virus over time. Key innate correlates of protection included early and sustained IFN-α response, activation of antigen presentation BTMs, and controlled IL-8 levels during immunization. Lower baseline immune activation observed in SPF pigs in steady state was linked to increased protection. Adaptive correlates encompassed cell cycle, plasma cell, and T-cell BTM responses lasting until day 15 post-immunization. Consequently, an effective response from ASFV-specific T_h cells prior to challenge indicated protection. After the challenge, an early IFN-α response, along with low levels of pro-inflammatory cytokines and a strong induction of memory T_h and T_c cells, correlated with improved clinical outcomes. The model highlights the critical role of host-specific factors in vaccine efficacy and provides a valuable framework for optimizing ASFV vaccine design while distinguishing between protective and detrimental immune responses.