eLife: latest articles

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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