eLife: latest articles

Sibling chimerism among microglia in marmosets

rcdelros@broadinstitute.org (Alec Wysoker) — Fri, 14 Aug 2026 00:00:00 +0000

Chimerism happens rarely among most mammals, but is common in marmosets and tamarins, a result of fraternal twin or triplet birth patterns in which in utero connected circulatory systems (through which stem cells transit) lead to persistent blood chimerism (12–80%) throughout life. The presence of Y-chromosome DNA sequences in organs of female marmosets has long suggested that chimerism might also affect these organs. However, a longstanding question is whether this chimerism is driven by blood-derived cells or involves contributions from other cell types. To address this question, we analyzed single-cell RNA-seq data from blood, liver, kidney, and many brain regions across a number of marmosets, using transcribed single-nucleotide polymorphisms (SNPs) to identify cells with the sibling’s genome in various cell types within these tissues. Sibling-derived chimerism in all tissues arose entirely from cells of hematopoietic origin (i.e., myeloid and lymphoid lineages). In brain tissue this was reflected as sibling-derived chimerism among microglia (20–52%) and macrophages (18–64%) but not among other resident cell types (neurons, glia, or ependymal cells). The percentage of microglia that were sibling-derived showed significant variation across brain regions, even within individual animals, likely reflecting distinct responses by genetic-sibling microglia to local recruitment or proliferation cues or, potentially, distinct clonal expansion histories in different brain areas. In the animals and tissues we analyzed, microglial gene expression profiles bore a much stronger relationship to local/host context than to sibling genetic differences. Naturally occurring marmoset chimerism will provide new ways to recognize the effects of genes, mutations, and brain contexts on microglial biology and to distinguish between effects of microglia and other cell types on brain phenotypes.

Cryo-EM structure of the bicarbonate receptor GPR30

awatanabe-tky@umin.ac.jp (Airi Jo-Watanabe) — Fri, 14 Aug 2026 00:00:00 +0000

G-protein-coupled receptor 30 (GPR30) is a bicarbonate receptor that plays a vital role in cellular responses to extracellular pH and ion homeostasis. Despite its significance, the mechanisms by which GPR30 interacts with bicarbonate ions remain elusive. There is no consensus on a drug that targets GPR30, and difficulties in pharmacological analyses have limited biological and drug discovery research on GPR30. Here, we present the cryo-electron microscopy structure of human GPR30 in the presence of bicarbonate ions at 3.15 Å resolution. Our structure reveals unique extracellular pockets and critical residues for bicarbonate binding and activation. Functional assays demonstrate that mutations in these residues impair bicarbonate-induced GPR30 activation, underscoring their importance in receptor function. This study also provides insights into G-protein coupling, highlighting the structural divergence between GPR30 and other G-protein-coupled receptors (GPCRs). Our findings not only advance the understanding of the role of GPR30 in pH homeostasis but also pave the way for the development of high-affinity drugs targeting GPR30 for therapeutic interventions in diseases associated with acid-base imbalance.

Parkinson’s disease-associated PINK1 loss disrupts ensheathing glia and causes dopaminergic neuron synapse loss

roman.praschberger@i-med.ac.at (Ayse Kilic) — Thu, 13 Aug 2026 00:00:00 +0000

Parkinson’s disease (PD) is commonly associated with the loss of dopaminergic neurons in the substantia nigra, but many other cell types are affected even before neuron loss occurs. Recent studies have linked oligodendrocytes to early stages of PD, though their precise role is still unclear. PINK1 is mutated in familial PD, and through unbiased single-cell sequencing of the entire brain of Drosophila Pink1 models, we observed significant gene deregulation in ensheathing glia (EG), cells that share functional similarities with oligodendrocytes. We found that the loss of Pink1 leads to abnormalities in EG, similar to the reactive response of EG seen upon nerve injury. Using cell-type-specific transcriptomics, we identified deregulated genes in EG as potential functional modifiers. Specifically downregulating two trafficking factors in EG, Vps35 and Vps13, also mutated in PD, was sufficient to rescue neuronal function and protect against dopaminergic synapse loss. Our findings demonstrate that Pink1 loss in neurons triggers an injury-like response in EG, and that Pink1 loss in EG, in turn, disrupts neuronal function. Vesicle trafficking components, which may regulate membrane interactions between organelles in EG, seem to play a role in maintaining neuronal health and ultimately preventing dopaminergic synapse loss. Our work highlights the essential role of glial support cells in the pathogenesis of PD and identifies vesicle trafficking within these cells in disease progression.

How to give cells an identity crisis

hollien@biology.utah.edu (Julie Hollien) — Thu, 13 Aug 2026 00:00:00 +0000

The transcription factor CHOP helps cells switch from an emergency stress response to a chronic one, where cells survive but lose some of the functions that define their identity.

Nucleation-dependent propagation of Polycomb modifications emerges during the Drosophila maternal to zygotic transition

shelby.blythe@northwestern.edu (Corinne Croslyn) — Thu, 13 Aug 2026 00:00:00 +0000

During zygotic genome activation in Drosophila, broad domains of Polycomb-modified chromatin are rapidly established across the genome. Here, we investigate the spatial and temporal dynamics by which Polycomb group (PcG) histone modifications, H3K27me3 and H2Aub, emerge during early embryogenesis. Using ChIP-seq and live imaging of CRISPR-engineered GFP-tagged PcG components, we show that PRC2-dependent H3K27me3 accumulates adjacent to a subset of E(z)-bound prospective Polycomb response elements (PREs) beginning in nuclear cycle 14 (NC14), with patterns indicative of nucleation followed by spreading. Surprisingly, PRE-binding factors Pho, Combgap, and GAGA-factor are excluded from interphase nuclei prior to NC10, despite nuclear localization of E(z) throughout early interphases. Loss-of-function studies further demonstrate that GAGA-factor is largely dispensable for PcG domain establishment, whereas the pioneer factor Zelda is required for proper deposition of H3K27me3 and H2Aub at a subset of Polycomb domains. The role of Zelda at Polycomb domains is context-dependent; a subset of targets requires Zelda not for E(z) recruitment, but instead to license an E(z)-loaded PRE to deposit H3K27me3. Our findings support a model where licensing of PcG domains is an initial step in the regulatory processes governing Polycomb-regulated developmental genes.

Five-layer systems analysis of Leishmania stage differentiation reveals an essential role for protein degradation in parasite development

pascale.pescher@pasteur.fr (Anne Boland) — Wed, 12 Aug 2026 00:00:00 +0000

Vector-borne, protist parasites have evolved complex developmental programs to adapt to very distinct host environments. How these important pathogens transition between insect and mammalian stages is only poorly understood. Here, we investigated stage differentiation in Leishmania donovani, a trypanosomatid parasite with constitutive gene transcription, offering a model to study post-transcriptional regulation. Using a five-layer integrative systems analysis (genome to metabolome), we compared hamster-derived amastigotes and culture-derived promastigotes. Genomic adaptation was excluded as a major driver of differentiation, while differential mRNA turnover emerged as a key mechanism of stage-specific gene expression. Transcriptomic and proteomic comparisons revealed a broad dynamic range of protein abundance changes that correlated poorly with mRNA levels. This discrepancy was linked to (i) altered snoRNA expression and rRNA modifications, indicating stage-specific tuning of translation, and (ii) differential protein degradation, supported by proteomics following proteasome inhibition with lactacystin. Lactacystin impaired amastigote-to-promastigote differentiation, highlighting the importance of proteasomal activity. Overall, our analysis links Leishmania development to coordinated post-transcriptional regulatory networks. Our findings provide a powerful new resource for research programs that aim to dissect the emergent properties of regulatory networks and feedback loops underlying Leishmania stage differentiation, serving as a blueprint for other vector-borne pathogens that rely on disease-associated developmental transitions.

Aging-associated increase of GATA4 levels in articular cartilage is linked to impaired regenerative capacity of chondrocytes and osteoarthritis

hal46@pitt.edu (Alyssa Aguglia) — Wed, 12 Aug 2026 00:00:00 +0000

Although the causal association between aging and osteoarthritis (OA) has been documented, our understanding of the underlying mechanism remains incomplete. To define the regulatory molecules governing chondrocyte aging, we performed transcriptomic analysis of young and old human chondrocytes from healthy donors. The data predicted that GATA-binding protein 4 (GATA4) may play a key role in mediating the difference between young and old chondrocytes. Results from immunostaining and western blot showed significantly higher GATA4 levels in old human or mouse chondrocytes when compared to young cells. Moreover, overexpressing GATA4 in young chondrocytes remarkably reduced their cartilage-forming capacity in vitro and induced the upregulation of proinflammatory cytokines. Conversely, suppressing GATA4 expression in old chondrocytes, through either siRNA or a small-molecule inhibitor NSC140905, increased the production of aggrecan and collagen type II, and also decreased levels of matrix-degrading enzymes. In OA mice induced by surgical destabilization of the medial meniscus, intra-articular injection of lentiviral vectors carrying mouse Gata4 resulted in a higher OA severity, synovial inflammation, and pain level when compared to control vectors. Mechanistically, we found that overexpressing GATA4 significantly increased the phosphorylation of SMAD1/5. Our work demonstrates that the aging-associated increase of GATA4 in chondrocytes plays a vital role in OA progression, which may also serve as a target to reduce OA in the older population.

Human brain-wide activation of sleep rhythms

jgao@pku.edu.cn (Haiteng Wang) — Wed, 12 Aug 2026 00:00:00 +0000

During sleep, our brain undergoes highly synchronized activity, orchestrated by distinct neural rhythms. Little is known about the associated brain activation during these sleep rhythms, and even less about their functional implications. In this study, we investigated the brain-wide activation underlying human sleep rhythms by employing simultaneous electroencephalography and functional magnetic resonance imaging in 107 participants during nocturnal naps (first half of the night). We identified robust coupling between slow oscillations (SOs) and fast spindles during deep non-rapid eye movement sleep (N2/3 stages), with spindle peaks consistently occurring just before the SO UP-state. This SO-spindle coupling was linked to elevated activation in both the thalamus and hippocampus, alongside increased functional connectivity from the hippocampus to the thalamus and from the thalamus to the medial prefrontal cortex. An open-ended cognitive state decoding analysis suggested that these activations may relate to episodic memory processes, yet were distinct from task-related networks. Together, these findings highlight the thalamus as a key coordinator of hippocampal–cortical communication during sleep and provide new insights into the mechanisms by which synchronized sleep rhythms may support memory consolidation.

Spine nanostructure profiling of cultured neurons from mouse models reveals a schizophrenia-linked role for Ecrg4

shigeo.okabe@riken.jp (Atsu Aiba) — Tue, 11 Aug 2026 00:00:00 +0000

Dendritic spine dysfunction may contribute to the etiology and symptom expression of neuropsychiatric disorders. The intimate relationship between spine morphology and function suggests that decoding disease-related abnormalities from spine morphology can aid in developing synapse-targeted interventions. Here, we describe a population analysis of dendritic spine nanostructure applied to the objective grouping of multiple mouse models of neuropsychiatric disorders. This method has identified two major groups of spine phenotypes linked to schizophrenia and autism spectrum disorder (ASD). An increase in spine subpopulation with small volumes characterized the spines of schizophrenia-associated mouse models, whereas a spine subset with large volumes increased in ASD models. Schizophrenia-associated mouse models showed higher similarity in spine morphology, driven by reduced size and growth of nascent spines. The expression of Ecrg4, a gene encoding small secretory peptides, was increased in schizophrenia-associated mouse models, and functional studies confirmed its critical involvement in impaired spine dynamics and shape. These results suggest that population-level spine analysis provides rich insights into heterogeneous spine pathology, facilitating the identification of new molecular targets related to core synaptic dysfunction.

A dual role for PGLYRP1 in host defense and immune regulation during B. pertussis infection

cskerry@som.umaryland.edu (Ciaran Skerry) — Tue, 11 Aug 2026 00:00:00 +0000

Bordetella pertussis, the etiologic agent of whooping cough, remains a serious public health concern despite widespread vaccination. Improved therapeutics and vaccines are urgently needed. Host recognition of bacterial peptidoglycan (PGN), including B. pertussis extracellular PGN fragment tracheal cytotoxin (TCT) shapes the immune response to infection. Peptidoglycan recognition proteins (PGLYRPs) are a conserved innate immune family that bind bacterial PGN and are primarily known for bactericidal activity in mammals; however, their immune modulatory roles are beginning to gain appreciation. The role of PGLYRPs in mammalian host defenses to Gram-negative pathogens, such as B. pertussis, remains largely unknown. Here, using knockout mice, single-cell and bulk transcriptomics, and functional assays, we identify a dual role for PGLYRP1 in modulating host immune responses to B. pertussis. PGLYRP1 contributes to antibacterial responses and paradoxically dampens inflammatory responses and inhibits bacterial killing later in infection. Mechanistically, PGLYRP1 enhances NOD1 signaling in response to TCT while suppressing NOD2− and triggering receptor expressed on myeloid cells-1 (TREM-1)-mediated inflammatory pathways. TCT-bound PGLYRP1 selectively impairs TREM-1 activation compared to PGNs from other bacteria. These findings demonstrate that B. pertussis co-opts PGLYRP1 to alter immune signaling, revealing a novel immune evasion mechanism with implications for vaccine design and host-directed therapeutics.

In vivo mapping of striatal neurodegeneration in Huntington’s disease with Soma and Neurite Density Imaging

Metzler-BaddeleyC@cardiff.ac.uk (Anne Rosser) — Tue, 11 Aug 2026 00:00:00 +0000

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterised by progressive cognitive and motor decline driven by basal ganglia (BG) atrophy. Clinical trials of novel disease-modifying therapies are ongoing, creating a need for sensitive non-invasive imaging biomarkers. Soma and Neurite Density Imaging (SANDI) is a multi-shell diffusion MRI model that estimates intracellular signal fractions from sphere-shaped soma and shows promise as a marker of neurodegeneration. The objectives of this study were to characterise HD-related microstructural abnormalities in the BG using SANDI and to examine relationships between SANDI and volumetric measurements and motor performance. T1- and diffusion-weighted images (b-values 200–6000 s/mm²) were acquired on a 3T Siemens Connectom scanner (300 mT/m) in 56 individuals with HD and 57 age- and sex-matched controls. HD participants completed Quantitative Motor (Q-Motor) tasks, summarised using principal component analysis. SANDI estimated apparent soma and neurite density, apparent soma size, and extracellular signal fraction. Microstructural and volumetric indices were extracted from bilateral caudate, putamen, pallidum and thalamus regions, compared between groups, and correlated with Q-Motor performance. HD was associated with reduced apparent soma density and increased apparent soma size and extracellular signal fraction in the BG but not the thalami. No group differences were present for apparent neurite density. SANDI metrics correlated with Q-Motor performance and explained up to 63% of striatal atrophy in HD. SANDI indices detected HD-related striatal neurodegeneration, explained atrophy, and correlated with motor impairments, demonstrating its potential as an in vivo biomarker and surrogate clinical outcome measure for HD and other neurodegenerative diseases.

Divergent C. elegans toxin alleles are suppressed by distinct mechanisms

szdralje@gmail.com (Daniel HW Leighton) — Tue, 11 Aug 2026 00:00:00 +0000

Toxin-antidote elements (TAs) are selfish DNA sequences that bias their transmission to the next generation. TAs typically consist of two linked genes: a toxin and an antidote. The toxin kills progeny that do not inherit the TA, while the antidote counteracts the toxin in progeny that inherit the TA. We previously discovered two TAs in Caenorhabditis elegans that follow the canonical TA model of two linked genes: peel-1/zeel-1 and sup-35/pha-1. Here, we report a new TA that exists in three distinct states across the C. elegans population. The canonical TA, which is found in isolates from the Hawaiian Islands, consists of two genes that encode a maternally deposited toxin (TMRL-1) and a zygotically expressed antidote (AMRL-1). The toxin induces larval lethality in embryos that do not inherit the antidote gene. A second version of the TA has lost the toxin gene but retains a partially functional antidote. Most C. elegans isolates, including the standard laboratory strain N2, carry a highly divergent allele of the toxin that has retained its activity, but have lost the antidote through pseudogenization. Multiple lines of evidence suggest that the N2 tmrl-1 allele is likely recognized by piRNAs, leading to MUT-16-dependent 22G small interfering RNA (siRNA) production and post-transcriptional silencing of the transcript. The N2 haplotype represents the first naturally occurring unlinked toxin-antidote system where the toxin is post-transcriptionally suppressed by endogenous small RNA pathways.

Global relationships between body size and urban affinity across more than 30,000 plant and animal species

c.callaghan@ufl.edu (Brittany M Mason) — Tue, 11 Aug 2026 00:00:00 +0000

Urbanization is a major global driver of biodiversity change, with species responses to urban settings ranging from avoidance to exploitation. To better understand these responses, we conducted a global analysis of urban relative affinity inferred from occurrence data across more than 30,000 animal and plant species. Our synthesis showed a consistent pattern across taxa and biogeographic regions: many species are urban avoiders, while few thrive as urban exploiters—a pattern we coin ‘species urbanness distribution’. We then assessed whether body size, an integrative ecological trait fundamental to space use, mobility, metabolism, and environmental sensitivity, showed consistent associations with urban affinity among species and across 371 taxonomic families. Analyses were conducted at the interspecific level and focused primarily on variation among taxonomic families (with an accompanying application to view results available for each family here: https://globalecologyresearchgroup.github.io/Callaghan_et_al-2026-eLife-ShinyApp/). Larger body sizes were generally associated with greater urban affinity in plants compared to animals, though these size-affinity relationships showed considerable variability among families. Our findings highlight the heterogeneous relationship between body size and urban affinity across the tree of life, underscoring the importance of tailored strategies to support urban biodiversity. This research advances ecological understanding of urban filtering and provides a framework for guiding biodiversity-sensitive urban planning amid accelerating global urbanization.

A tool to pulse-label yeast nuclear pore complexes in imaging and biochemical experiments

l.m.veenhoff@rug.nl (Annemiek C Veldsink) — Mon, 10 Aug 2026 00:00:00 +0000

Nuclear pore complexes (NPCs) are key gateways to the nucleus and major organizers of genome architecture. Despite their importance, it is still not fully understood how NPCs are formed and degraded. Tools to track specific NPCs over time or under stress could unlock critical insights into these questions. Here, we demonstrate that a brief pulse of expression of a previously developed nanobody against baker’s yeast nucleoporin Nup84 (Nordeen et al., 2020) enables a robust, rapid, and straightforward method for pulse-labeling NPCs in both imaging and affinity purification experiments. This approach offers an alternative to permanent, yet less rapid, genetic fluorophore- or tag-switching techniques, and provides a powerful tool for studying NPC inheritance and turnover through both microscopy and biochemical methods.

A novel prognostic score based on carbohydrate antigen 125, alpha-fetoprotein and carcinoembryonic antigen for Predicting postoperative prognosis in endometrial cancer: Results from a retrospective cohort study

yangh9@sj-hospital.org (Bo Wang) — Mon, 10 Aug 2026 00:00:00 +0000

Background: Endometrial cancer (EC) is a common gynecological malignancy with increasing incidence. While several serum biomarkers have been studied for EC, their combined prognostic value remains unclear. This study aimed to evaluate the prognostic significance of preoperative serum CA125, CA19-9, CA72-4, CEA, and AFP levels in EC patients and develop a risk score for predicting survival outcomes.

A unifying model of T-cell signaling protein condensates in reconstitution experiments

yadomar@mit.edu (Arup K Chakraborty) — Mon, 10 Aug 2026 00:00:00 +0000

The formation of condensates by the Linker for the Activation of T-cells (LAT) is a key signal gating and amplification step in the T-cell receptor signaling pathway. LAT condensation is challenging to study in-vivo and is therefore often investigated using reconstitution experiments. While these experiments recapitulate key aspects of LAT condensation, they also exhibit some puzzling features. Here, we describe the mechanisms underlying these observations using two complementary models. First, we employ a Smoluchowski aggregation model to show that the delay time before condensation is observed arises from a low effective binding probability between LAT monomers. Second, we propose a field-theoretic model that reproduces all condensate morphologies observed in experiments, showing that they can arise from common underlying dynamics modulated by variations in experimental conditions. This result unifies different experimental observations reported previously. While this article addresses open questions regarding the formation of LAT condensates, our results also provide a common framework for understanding condensation of other multivalent membrane proteins such as EGFR, FGFR2, and nephrin.

Translational reading frame predicts the pathogenicity of C-terminal frameshift deletions in MeCP2

J.Guy@ed.ac.uk (Adrian Bird) — Mon, 10 Aug 2026 00:00:00 +0000

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline stop motif (-PPX) generated by a shift to the +2 reading frame. CTDs that shift to the +1 frame avoid this motif and are benign. Replacing the stop codon of the PPX motif with tryptophan restores MeCP2 expression and rescues RTT-like phenotypes in a CTD mouse model. An adenine base editor efficiently introduces this substitution in cultured cells. These findings define a reliable prognostic distinction between benign and pathogenic CTDs and establish a potential editing strategy for correcting disease-causing CTD mutations.

Evaluating the applicability of replication success metrics in animal-to-human translation: A simulation study

rachel.heyard@uzh.ch (Benjamin Victor Ineichen) — Fri, 07 Aug 2026 00:00:00 +0000

Translation failure, in which promising animal study results cannot be reproduced in human trials, is a challenge in biomedical research. Metrics for replication success are widely used to evaluate reproducibility, that is the extent to which the results of a study agree with those of replication studies. The relevance of these metrics in assessing animal-to-human translation success (or failure) is unclear. We conducted a simulation study to examine whether these metrics can quantify translation success, and how their performance varies under different conditions. Using parameters from a meta-analysis on prenatal amino acid supplementation and maternal blood pressure, we simulated animal and human studies under 648 scenarios, varying effect sizes, heterogeneity, animal sample sizes, and number of pooled animal studies. Nine metrics were assessed, namely the two-trials rule, meta-analysis, replication Bayes factor, unweighted and weighted Edgington’s methods, golden skeptical p-value, and three versions of controlled skeptical p-value. Most metrics, except meta-analysis and replication Bayes factor, controlled false positive rates under no heterogeneity, but became liberal as heterogeneity increased, particularly between human studies. Translation power (i.e. the probability of true positive translation success) was constrained by the weaker evidence of the two findings; for example, small sample size in the animal studies resulted in lower translation power. The metric based on meta-analysis frequently indicated success when either of the species found strong evidence, while skeptical p-values were more conservative. The skeptical p-value that controls overall type-one error and the weighted version of Edgington’s method performed relatively consistently across scenarios. However, no metric was uniformly optimal. Metrics developed for replication studies can inform assessments of translation, but their utility depends on the underlying evidence and assumptions. Using multiple metrics in combination, with attention to their strengths and limitations, is recommended for evaluating the translation of animal findings to human outcomes.

Functional specialization of mPFC-BLA and mPFC-NAc pathways in affective state representation

huilu@gwu.edu (Chen Zeng) — Fri, 07 Aug 2026 00:00:00 +0000

Effective emotional processing, crucial for adaptive behavior, is mediated by the medial prefrontal cortex (mPFC) via connections to the basolateral amygdala (BLA), and nucleus accumbens (NAc), traditionally considered functionally similar in modulating reward and aversion responses. However, the functional specialization of the mPFC→BLA and mPFC→NAc pathways in representing affective states remains unclear. We found that while overall firing patterns appeared consistent across emotional states, deeper analysis revealed distinct variabilities. Specifically, mPFC→BLA neurons, especially ‘center-ON’ neurons, exhibited heightened activity during behaviors classically associated with anxiety-like states, suggesting their involvement in aversive behavioral regulation. Conversely, mPFC→NAc neurons were more active during exploratory and approach-related behaviors, implicating them in the processing of positively valenced behavioral states. Notably, mPFC→NAc neurons showed significant pattern decorrelation during social interactions, suggesting a pivotal role in processing social preference. Additionally, repeated win/loss outcomes in the tube test produced distinct hierarchy-dependent behavioral changes and elevated corticosterone levels in loser mice, supporting the biological relevance of these behaviorally defined states. Together, these findings reveal pathway-specific representations of affect-related behavioral states in mPFC circuits and provide a framework for understanding how prefrontal outputs organize adaptive behavior across environmental contexts.

Using mathematical models to optimise mosquito net distribution

prete@unicamp.br (Carlos A Prete Jr) — Fri, 07 Aug 2026 00:00:00 +0000

Tailoring malaria control interventions to regional transmission dynamics and behavioural characteristics can optimise them in resource-limited settings.

Mood computational mechanisms underlying increased risk behavior in adolescent suicidal patients

hzl_811015@126.com (Bastien Blain) — Fri, 07 Aug 2026 00:00:00 +0000

Suicidal thoughts and behaviors (STB) are among the leading causes of death worldwide. Although previous research has consistently documented elevated risk-taking in individuals with STB and identified mood disturbances as central features of suicidality, the precise cognitive and affective computational mechanisms underlying this increased risky behavior remain poorly understood. Here, 83 adolescent inpatients with affective disorders—including 58 patients with STB (S⁺) and 25 without STB (S⁻)—and 118 age- and sex-matched healthy controls (HC) completed a decision-making task involving choices between certain and gamble options, alongside momentary mood ratings. Behavioral analyses showed that S⁺ exhibited greater risk-taking than both S⁻ and HC. Computational modeling of choice behavior using a prospect-theory framework augmented with value-insensitive approach–avoidance parameters indicated that this increase in risky behavior was specifically driven by an elevated approach parameter in S⁺. In addition, mood-model analyses revealed reduced sensitivity to certain rewards in S⁺ relative to S⁻ and HC. Importantly, these computational signatures predicted suicidal symptom severity and showed generalizability in an independent general-population sample (n = 747). In S⁺, lower mood sensitivity to certain rewards was associated with greater gambling, providing a computational affective account of increased risk-taking in STB. These findings remained robust after adjusting for demographic, clinical, and medication-related variables. Overall, our study identifies cognitive and affective computational mechanisms contributing to elevated risk-taking in STB and highlights their potential relevance for the early identification and prevention of suicidality.

Pathogen-phage geomapping to overcome resistance

camilla.do@bcm.edu (Anthony W Maresso) — Thu, 06 Aug 2026 00:00:00 +0000

The rise of antibiotic resistance has renewed interest in bacteriophages as therapeutic alternatives. However, coevolution of phage and bacteria will naturally give rise to phage-resistant pathogens, complicating phage therapy efforts. A critical bottleneck in the production of phage therapeutics is the discovery of virulent phages against resistant pathogens. Conventional methods for discovery are time-consuming, biased, and laborious, limiting the potential for identifying suitable phage candidates. To overcome these limitations, we combined small-volume environmental sampling with 16 S rRNA sequencing to identify reservoirs where bacterial hosts co-exist with their phage predators. This strategy, which we term geographical phage mapping (geΦmapping), pinpoints ecological ‘hotspots’ for targeted phage hunting. We further developed a portable phage hunting device (ΦHD) that generates highly enriched phage concentrates directly from these reservoirs. By integrating geΦmapping with high-throughput enrichment, we constructed the RΦ library, a diverse collection of novel phages. We captured and isolated 36 new phages targeting extremely resistant organisms across various ESKAPE pathogens when conventional phage hunting and experimental evolution approaches failed.

Heterotypic interfacial tension between oncogenic and wild-type populations forms the mechanical basis of tissue-specific oncogenesis in epithelia

medhavi@iisc.ac.in (Akshar Rao) — Thu, 06 Aug 2026 00:00:00 +0000

Why does the same oncogenic mutation drive tumor formation in some tissues but not in others? While cancer driver mutations are well documented, their tissue-specific effects remain largely attributed to genetic factors, leaving the biophysical aspects underexplored. Here, we demonstrate that mechanical interactions between newly transformed and wild-type cells are critical in determining survival and growth of HRas^V12 mutants in human mammary and bronchial epithelia, producing contrasting outcomes in the two tissues. In mammary epithelium, isolated mutants are extruded – typical of epithelial defense against cancer – while mutant groups become spatially confined in kinetically arrested, jammed clusters, marked by an actomyosin belt at the interface. In contrast, bronchial epithelium permits persistent spreading of the mutants, which form long protrusions regardless of colony size. Furthermore, oncogenic clusters in the two tissues exhibit distinct biophysical properties, including variations in cell shapes, intracellular pressure, cell-cell tension, and cellular motility. Using a cell shape-tension coupled bi-disperse vertex model, we reveal that interfacial tension at mutant-wild-type boundaries dictates whether mutants are eliminated, restrained, or expanded. Additionally, modulating the heterotypic interfacial tension alters mutant cluster fates. Together, our findings uncover a mechanical basis for tissue-specific oncogenesis by highlighting how interfacial mechanics between mutants and wild-type populations regulate tumor initiation and progression.

Correction: The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution

Thu, 06 Aug 2026 00:00:00 +0000

Nanoscopy reveals heparan sulfate clusters as docking sites for SARS-CoV-2 attachment and entry

jyewdell@nih.gov (Albert J Jin) — Thu, 06 Aug 2026 00:00:00 +0000

Virus entry is thought to involve binding a unique receptor for cell attachment and cytosolic entry. For SARS-CoV-2 underlying the COVID-19 pandemic, angiotensin-converting enzyme 2 (ACE2) is widely considered the receptor for cell-surface attachment and subsequent cell entry. Using advanced light microscopy to resolve individual virions and receptors, we found instead that heparan sulfate (HS), not ACE2, mediates SARS-CoV-2 cell-surface attachment, and subsequent endocytosis. ACE2 functions only downstream of HS to enable viral genome expression. Instead of binding single HS molecules that electrostatically interact with viral surface proteins weakly, SARS-CoV-2 binds clusters of ~6–137 HS molecules projecting 60–410 nm above the plasma membrane. These tall, HS-rich clusters, present at about one per 6 μm², act as docking sites for viral attachment. Blocking HS binding with the clinically used HS-binding agent pixantrone strongly inhibited an authentic pathogen, the SARS-CoV-2 Omicron JN.1 subvariant, from attaching to and infecting human airway cells. This work establishes a revised entry paradigm in which HS clusters mediate SARS-CoV-2 attachment and endocytosis, with ACE2 acting downstream, thereby identifying HS interactions as a key anti-COVID-19 strategy. This paradigm and its therapeutic implications may apply broadly beyond COVID-19 because, analogous to SARS-CoV-2, HS binds many other viruses but is only considered an attachment regulator.

Brainstem neurons coordinate the bladder and urethral sphincter for urination

jiahb@sibet.ac.cn (Chunhui Yuan) — Thu, 06 Aug 2026 00:00:00 +0000

Urination, a vital and conserved process of emptying urine from the urinary bladder in mammals, requires precise coordination between the bladder and external urethral sphincter (EUS) that is tightly controlled by a complex neural network. However, the specific subpopulation of neurons that accounts for such coordination remains unidentified, limiting the development of target-specific therapies for certain urination disorders, for example, detrusor–sphincter dyssynergia. Here, we find that cells expressing estrogen receptor 1 (ESR1⁺) in the pontine micturition center (PMC) initiate voiding when activated and suspend ongoing voiding when suppressed, each at 100% reliability. Transection of the pelvic nerve does not impair PMC^ESR1+ neurons’ control of the EUS via the pudendal nerve, whereas transection of the pudendal nerve does not impair their control of the bladder via the pelvic nerve. Anatomically, PMC^ESR1+ neurons consist of three distinct spinal-projection-based subpopulations: one targeting the sacral parasympathetic nucleus, one innervating the dorsal gray commissure, and a third that projects to both regions, thereby enforcing the coordination of bladder contraction and sphincter relaxation in a rigid temporal sequence. Thus, we identify a cell type in the brainstem that controls the bladder–urethra coordination for urination.

The cistrome response to hypoxia in human umbilical vein endothelial cells

bass@bio.fsu.edu (Ayush Singh) — Thu, 06 Aug 2026 00:00:00 +0000

Hypoxic stress triggers transcriptional signaling mainly through hypoxia-inducible transcription factors (HIFs), which bind hypoxia response elements (HREs) in gene regulatory regions. However, only a small proportion (~1%) of known HREs are occupied by HIFs during hypoxia, suggesting the involvement of additional hypoxia-responsive factors. To address this gap, we utilized MNase-defined cistrome Occupancy Analysis sequencing (MOA-seq), with the term cistrome referring to all genomic regions where transcription factors and other trans-acting regulators are bound to cis-acting elements across the genome for a particular cell type or treatment. This MNase-based assay enables genome-wide, high-resolution (<30 bp) identification of transcription factor (TF) occupancy footprints embedded within larger regions, most of which were previously annotated as open or accessible chromatin. Applying this in situ cistrome mapping to fixed nuclei from endothelial cells under normoxia or hypoxia (1, 3, or 24 hr) revealed thousands of hypoxia-responsive genomic sites with dynamic TF footprints. The affected genes were enriched in canonical hypoxia-induced pathways, such as angiogenesis. Motif analysis identified over 100 candidate TFs potentially mediating these multifaceted genomic responses. By grouping hypoxia-modified occupancy signals across the hypoxia exposure times, we clustered differentially occupied MOA sites into defined 10 distinct TF kinetic clusters, half of which were associated with HIF1A. HIF1A-proximal binding sites suggested co-activators, while non-HIF1A clusters pointed to additional TFs that may have HIF1A-independent roles. This analysis provides insight into how multiple TF networks coordinate hypoxia responses and highlights the power of cistrome profiling to deepen our understanding of the complex genomic response to low oxygen conditions.

LRRK2 regulates synaptic function through modulation of actin cytoskeletal dynamics

Beccano-KellyD@cardiff.ac.uk (Adriano Lama) — Thu, 06 Aug 2026 00:00:00 +0000

Parkinson’s disease (PD) is a multisystemic disorder that manifests through motor and non-motor symptoms. Motor dysfunction results from the degeneration of dopamine-producing neurons in the substantia nigra pars compacta. Increasing evidence suggests that synapse dysfunction precedes neuronal loss by years. Still, early synaptic alterations in PD remain poorly understood. Here, we integrate literature meta-analysis and multi-omics with biochemical, imaging, and electrophysiological measurements in Lrrk2 mouse models and human iPSC-derived neurons lacking LRRK2. We demonstrate that brain-derived neurotrophic factor (BDNF) activates LRRK2 in differentiated SH-SY5Y cells and primary mouse neurons, reshaping the LRRK2 interactome toward a network of actin cytoskeleton-related proteins. Gene-ontology analyses of both literature-curated LRRK2 interactors and phospho-proteome from striatal tissues with elevated LRRK2 activity highlight synapse-actin remodeling as major affected pathways. We further observed that loss of LRRK2 impairs BDNF signaling and alters postsynaptic density architecture. Young Lrrk2 knockout mice display structural alterations in dendritic protrusions, a phenotype that normalizes with age. In human iPSC-derived neurons, LRRK2 knockout affects maturation and BDNF-dependent regulation of spontaneous synaptic activity. Taken together, our study discloses a critical role of LRRK2 in BDNF-dependent synaptic modulation and identifies the synaptic actin cytoskeleton as a convergent site of LRRK2-associated pathophysiological processes in PD.

Endometrial cells with high ALDH activity contribute to uterine development and regeneration

dmonsiva@bcm.edu (Anna Catherine Unser) — Thu, 06 Aug 2026 00:00:00 +0000

Adult stem cells are thought to drive the regenerative potential of the endometrium and contribute to the pathogenesis of endometriosis; however, their identity and defining features remain to be characterized. Here, we used in vivo and in vitro approaches to demonstrate that cells with high aldehyde dehydrogenase 1 activity (ALDH^HI cells) were long-lived progenitors in the endometrium with a higher organoid formation capacity, long-term passaging potential, and stemness gene signatures. Using lineage tracing with an Aldh1a1^creERT2/+; Rosa26^LSL-tdTomato reporter mouse, Aldh1a1⁺ epithelial cells expanded during postnatal development, Aldh1a1⁺ stromal cells expanded during estrous cycling, and both populations of Aldh1a1⁺ cells were present during postpartum repair. In response to ovariectomy or exogenous estradiol, we found that ALDH1A1⁺ cells localized to glandular crypts of the endometrium or throughout the luminal epithelium, respectively, indicating that their spatial localization is hormone-sensitive. Functionally, we found that selective ablation of ALDH1A1⁺ cells in Aldh1a1^creERT2/+; Rosa26^LSL-DTR mice decreased endometrial gland number and FOXA2 expression. These findings were recapitulated in the human endometrium, where endometrial epithelial organoids with high ALDH activity (ALDH^HI cells) showed a higher organoid formation capacity than ALDH^LO cells and displayed unique transcriptomes with fewer luminal-like ciliated cells. Overall, our studies indicate that ALDH1A1⁺ cells are hormone-sensitive adult stem cells in the endometrium with regenerative potential that are critical for endometrial development and function.

Microenvironmental arginine restriction sensitizes pancreatic cancers to polyunsaturated fatty acids by suppression of lipid synthesis

amuir@uchicago.edu (Alexander Muir) — Wed, 05 Aug 2026 00:00:00 +0000

Nutrient limitation is a characteristic feature of poorly perfused tumors. In contrast to well-perfused tissues, nutrient deficits in tumors impose metabolic constraints on cancer cells. The metabolic constraints created by the tumor microenvironment can lead to vulnerabilities in cancers. Identifying the metabolic constraints of the tumor microenvironment and the vulnerabilities that arise in cancers can provide new insight into tumor biology and identify promising anti-neoplastic targets. To identify how the microenvironment constrains the metabolism of pancreatic tumors, we challenged pancreatic cancer cells with microenvironmental nutrient levels and analyzed changes in cellular metabolism. We found that arginine limitation in pancreatic tumors perturbs saturated and monounsaturated fatty acid synthesis by suppressing the lipogenic transcription factor SREBP1, in part via activation of the amino acid sensor GCN2. Synthesis of these fatty acids is critical for maintaining a balance of saturated, monounsaturated, and polyunsaturated fatty acids (PUFAs) in cellular membranes. Because of microenvironmental constraints on fatty acid synthesis, pancreatic cancer cells and tumors are unable to maintain lipid homeostasis when exposed to PUFAs, leading to cell death by ferroptosis. In sum, arginine restriction in the tumor microenvironment constrains lipid metabolism in pancreatic cancers, which renders these tumors vulnerable to polyunsaturated-enriched fats.

An updated view of glucose pathways in cyanobacteria

bb1gafej@uco.es (José Manuel García-Fernández) — Wed, 05 Aug 2026 00:00:00 +0000

Contrary to previous belief, the cyanobacterium Synechocystis lacks the Entner-Doudoroff pathway for glucose metabolism.

Apparent cooperativity between human CMV virions introduces errors in conventional methods of calculating multiplicity of infection

brent.ryckman@mso.umt.edu (Brent Ryckman) — Wed, 05 Aug 2026 00:00:00 +0000

Whether infection of cells by individual virions occurs randomly, or if there is some form(s) of competition or cooperativity between individual virions, remains largely unknown for most virus–cell associations. Here, we studied cooperativity/competition for three different strains of human cytomegalovirus (HCMV) on two different cell types (fibroblasts and epithelial cells). By titrating viral inocula concentrations in small steps over several orders of magnitude, and by using flow cytometry to precisely measure the frequency of infected cells, we found that for most virus–cell associations, the frequency of cell infection increases faster than linear with an increasing inoculum concentration, indicating cooperativity between individual infecting virions. Mathematical modeling suggests that this apparent cooperativity cannot be explained by heterogeneity in either the infectivity of the individual virions or the resistance of individual cells to infection, or by simple aggregation/clumping of viral particles. Stochastic simulations of two additional alternative models that allow for (1) reduction in cell resistance to infection when exposed to multiple virions, or (2) compensation in infectivity of poorly infectious virions when coinfecting cells with more infectious virions, resulted in apparent viral cooperativity. Analysis of other published datasets suggests the presence of apparent viral cooperativity for HIV and vaccinia virus, infecting CRFK or HeLa cells, respectively, but not for tobacco mosaic virus forming plaques on plant leaves. We thus (1) propose a methodology to rigorously evaluate apparent cooperativity of viruses infecting target cells, and (2) demonstrate that knowing the degree of virus cooperativity for any given virus–cell combination is important for an accurate quantification of multiplicity of infection.

Efficient and reproducible pipelines for spike sorting large-scale electrophysiology data

alessio.buccino@alleninstitute.org (Alessio Paolo Buccino) — Wed, 05 Aug 2026 00:00:00 +0000

The scale of in vivo electrophysiology has expanded in recent years, with simultaneous recordings across thousands of electrodes now becoming routine. These advances have enabled a wide range of discoveries, but they also impose substantial computational demands. Spike sorting, the procedure that extracts spikes from extracellular voltage measurements, remains a major bottleneck: a dataset collected in a few hours can take days to spike sort on a single machine, and the field lacks rigorous validation of the many spike sorting algorithms and preprocessing steps that are in use. Advancing the speed and accuracy of spike sorting is essential to fully realize the potential of large-scale electrophysiology. Here, we present an end-to-end spike sorting pipeline that leverages parallelization to scale to large datasets. The same workflow can run reproducibly on individual workstations, high-performance computing clusters, or cloud environments, with computing resources tailored to each processing step to reduce costs and execution times. In addition, we introduce a benchmarking pipeline, also optimized for parallel processing, that enables systematic comparison of multiple sorting pipelines. Using this framework, we show that Kilosort4, a widely used spike sorting algorithm, outperforms Kilosort2.5. We also show that 7× lossy compression, which substantially reduces the cost of data storage, has minimal impact on spike sorting performance. Together, these pipelines address the urgent need for scalable and transparent spike sorting of electrophysiology data, preparing the field for the coming flood of multi-thousand-channel experiments.

Boosting hyperalignment performance with age-specific templates

james.v.haxby@dartmouth.edu (James V Haxby) — Wed, 05 Aug 2026 00:00:00 +0000

Hyperalignment aligns individual brain activity and functional connectivity patterns to a common, high-dimensional model space, resolving idiosyncrasies in functional–anatomical correspondence and revealing shared information encoded in fine-grained spatial patterns. Given that the brain undergoes significant developmental and functional changes over the lifespan, certain features in brain functional organization may be more prominent in certain age groups than others. In this study, we examined whether age-specific functional templates, compared with a canonical template, could enhance alignment accuracy across diverse age groups. We used the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) dataset (18–87 years old) to build age-specific templates and tested their performance in young and old brains in both the Cam-CAN dataset and the Dallas Lifespan Brain Study dataset (20–90 years old). We found the congruent age-specific template outperforms the incongruent template for various analyses, including inter-subject correlation of hyperaligned connectivity profiles and predictions of individualized connectomes and brain responses to the movie. The results are consistent across both datasets. This work enhances our understanding of age-related differences in brain function, highlights the benefits of age-specific templates to refine hyperalignment model performance, and may contribute to the development of age-sensitive diagnostic tools and interventions for neurological disorders.

High-throughput quantification of population dynamics using luminescence

science@maltemuetter.ch (Daniel C Angst) — Wed, 05 Aug 2026 00:00:00 +0000

Bacterial population decline at antibiotic concentrations above the minimum inhibitory concentration (MIC) remains poorly characterized. This is because colony-forming units (CFU), the standard method to quantify inhibition, are slow, labor-intensive, and costly. Luminescence assays are widely used to quantify population dynamics at subinhibitory concentrations, yet their limitations and reliability at high concentrations remain underexplored. Here, we compared luminescence- and CFU-based rates in Escherichia coli across 20 antimicrobials. In our experiments, luminescence- and CFU-based rates did not differ significantly for half of them. For the other half, CFU-based decline rates were consistently higher. The estimates differed for two main reasons: First, because light intensity tracks biomass more closely than population size, luminescence declined more slowly than the population when bacteria filamented. Second, CFU-based estimates indicated a steeper decline when treatment reduced the number of colonies formed per plated bacterium. This can result from changes in clustering behavior, physiological changes that impair culturability, or antimicrobial carryover. Thus, the suitability of luminescence to quantify bacterial decline depends on the physiological effects of the antimicrobial and whether the quantity of interest is cell number or biomass. Within these limitations, luminescence can serve as an efficient, high-throughput alternative for quantifying bacterial dynamics at super-MIC concentrations.

Heritability of movie-evoked brain activity and connectivity

david.gruskin@columbia.edu (Daniel J Vieira) — Tue, 04 Aug 2026 00:00:00 +0000

The neural bases of sensory processing are conserved across people but no two individuals experience the same stimulus in exactly the same way. Recent work has established that the idiosyncratic nature of subjective experience is underpinned by individual variability in brain responses to sensory information. However, the fundamental origins of this individual variability have yet to be systematically investigated. Here, we establish a genetic basis for individual differences in sensory processing by quantifying (1) the heritability of high-dimensional brain responses to movies and (2) the extent to which this heritability is grounded in lower-level aspects of brain function. Specifically, we leverage 7T fMRI data collected from a twin sample to first show that movie-evoked brain activity is heritable across the cortex, and that this heritability is greater for information encoded in lower temporal frequencies, especially in more associative cortical areas. Next, we use hyperalignment to decompose this heritability into genetic similarity in where vs. how sensory information is processed. We also show that the heritability of brain activity patterns can be partially explained by the heritability of the neural timescale, a one-dimensional measure of local circuit functioning. Finally, we generalize our findings by illustrating a similar pattern of results for the heritability of movie-evoked functional connectivity. These results demonstrate that brain responses to complex stimuli are heritable, and that this heritability is due, in part, to genetic control over stable aspects of brain function.

Proteome dynamics reveal Leiomodin 1 as a key regulator of myogenic differentiation

julia.vonmaltzahn@b-tu.de (Alberto Minetti) — Tue, 04 Aug 2026 00:00:00 +0000

During myogenic differentiation, the cellular architecture and proteome of muscle stem cells and myoblasts undergo extensive remodeling. These processes are partially understood and display alterations in disease and aging, resulting in impaired regeneration. Here, we used mass spectrometry to quantify the temporal dynamics of over 6000 proteins during myogenic differentiation. We identified the actin nucleator leiomodin 1 (LMOD1) among a restricted subset of cytoskeletal proteins increasing in abundance during early myogenic differentiation. LMOD1 is expressed by muscle stem cells in vivo and displays increased abundance during skeletal muscle regeneration in mice, particularly during early stages, suggesting its importance in myotube formation. Notably, LMOD1 knockdown in primary myoblasts and during regeneration severely affects differentiation, while its overexpression accelerates and improves myotube initiation. This suggests LMOD1 is a critical component regulating myogenic differentiation. Mechanistically, we show that LMOD1 physically and functionally interacts with the deacetylase sirtuin1 (SIRT1), a regulator of myogenic differentiation. We demonstrate that LMOD1 influences SIRT1 localization and the expression of its target genes. Consistently, depletion or pharmacological inhibition of SIRT1 partially rescues the differentiation impairment observed after LMOD1 knockdown. Our work identifies LMOD1 as a new regulator that might be targeted to improve muscle regeneration in aging and disease.

Pupil size reveals the perceptual quality and effortless nature of synesthesia

c.strauch@uu.nl (Casper Leenaars) — Tue, 04 Aug 2026 00:00:00 +0000

Synesthesia describes cross-over processes that can generate ‘extra’ conscious percepts, such as seeing additional color when reading numbers. While existing research focuses on the mechanisms and effects of synesthetic associations, it often overlooks its most distinctive feature: unique sensory phenomenology. Here, we introduce pupillometry as an objective physiological measure of synesthetic color phenomenology. Across 16 grapheme-color synesthetes and two matched control groups, pupil responses tracked the brightness of synesthetic colors under constant physical visual input, scaling with self-reported strength. Synesthetic colors elicited pupil dynamics comparable to real colors, dissociating synesthetes from non-synesthetes. These responses emerged too rapidly to reflect imagery and scaled with reported color brightness, revealing cross-over caused genuine perceptual processing. Controls required to generate color associations showed greater effort-linked pupil dilation than synesthetes or controls who did not report colors, providing evidence for the effortless nature of synesthesia. Synesthesia thus provides a tractable human model for studying physiologically measurable phenomenology.

Deletion of neuroligins from astrocytes does not detectably alter synapse numbers or astrocyte cytoarchitecture by maturity

samgolf@uab.edu (George Nakahara) — Tue, 04 Aug 2026 00:00:00 +0000

Astrocytes perform multifarious roles in the formation, regulation, and function of synapses in the brain, but the mechanisms involved are incompletely understood. Interestingly, astrocytes abundantly express neuroligins, postsynaptic adhesion molecules that function as synaptic organizers by binding to presynaptic neurexins. Here, we examined the function of neuroligins in astrocytes with a rigorous genetic approach that uses the conditional deletion of all major neuroligins (Nlgn1–3) in astrocytes in vivo in mice and complemented this approach by a genetic deletion of neuroligins in glial cells that are co-cultured with human neurons. Our results show that early postnatal deletion of neuroligins from astrocytes in vivo has no detectable effect on cortical or hippocampal excitatory or inhibitory synapses, and does not alter the cytoarchitecture of astrocytes when evaluated in young adult mice. Moreover, deletion of astrocytic neuroligins in co-cultures of human neurons produced no detectable consequences for the formation and function of synapses. Thus, astrocytic neuroligins are unlikely to fundamentally shape synapse formation or astrocyte morphogenesis, but likely perform other important roles that remain to be discovered.

Methylation clocks fail to generalize across genetically admixed individuals

tony@capralab.org (Anthony J Griswold) — Tue, 04 Aug 2026 00:00:00 +0000

Epigenetic aging clocks based on DNA methylation patterns across the genome have emerged as a potential biomarker for risk of age-related diseases, like Alzheimer’s disease (AD), and environmental and social stressors. However, methylation clocks have not been comprehensively validated in genetically diverse individuals. Here, we evaluate a set of first-, second-, and third-generation methylation clocks in 621 AD patients and matched controls from African American, Hispanic, and White cohorts. The clocks are less accurate at predicting age in genetically admixed cohorts compared to the White cohort, especially for those with substantial African ancestry. This decreased accuracy holds in >2500 individuals of European and African ancestry from three additional datasets. The clocks also fail to consistently identify age acceleration in admixed AD cases compared to controls. To explore potential causes for the lack of generalization of the clocks, we intersected clock CpGs with methylation, germline genetic variants, and methylation QTL (meQTL) data from global populations. We find differential methylation between African and European ancestry individuals is common for clock CpGs. Genetic variants rarely disrupt clock CpGs between populations, but a substantial fraction of clock CpGs have meQTL with significantly higher frequencies in African genetic ancestries. Our results demonstrate that methylation clocks often fail to predict age and AD risk when applied across populations and suggest avenues for improving their portability by considering differences in genetic and epigenetic patterns across human populations.

In-situ glial cell-surface proteomics identifies pro-longevity factors in Drosophila

hongjie.li@bcm.edu (Amogh Varanasi) — Tue, 04 Aug 2026 00:00:00 +0000

Much focus has shifted towards understanding how glial dysfunction contributes to age-related neurodegeneration due to the critical roles glial cells play in maintaining brain health. Cell-cell interactions, which are largely mediated by cell-surface proteins, control many critical aspects of development and physiology; as such, dysregulation of glial cell-surface proteins is hypothesized to play an important role in age-related neurodegeneration. However, it remains technically difficult to profile glial cell-surface proteins in intact brains. Here, we applied an in-situ cell-surface proteomic profiling method to glial cells from intact fly brains. Applying this platform to young and old flies, we identified candidate genes predicted to be involved in brain aging. Through a genetic screen, we identified one surface protein, DIP-β, which is down-regulated in old flies and can increase fly lifespan when overexpressed in adult glial cells. We performed whole-head single-nucleus RNA-seq and revealed that DIP-β overexpression mainly impacts glial and fat cells. We also found that glial DIP-β overexpression was associated with improved cell-cell communication. Our study is the first to apply in-situ cell-surface proteomics to glial cells in Drosophila, and to identify DIP-β as a potential glial regulator of brain aging.

Analysis of cancer mutations introduced into the Drosophila melanogaster Notch negative regulatory region uncovers a diversity of regulatory outcomes

martin.baron@manchester.ac.uk (Hideyuki Shimizu) — Tue, 04 Aug 2026 00:00:00 +0000

Activating mutations of Notch are drivers of the blood cell cancer, T-ALL, and some solid tumours. The negative regulatory region (NRR) of the extracellular domain (ECD) and the PEST region of the intracellular domain (ICD) are mutation hot spots which can act synergistically in T-ALL. The NRR, comprised of a heterodimerisation domain (HD) and three Lin12/Notch repeats (LNR A-C), masks the S2 cleavage site, normally only exposed following ligand binding and cleaved as the first step that ultimately leads to ICD release. Drosophila mutants have played a key role in analysing Notch structure/function, but there have been few mutational studies of the NRR. Here, we expressed, in S2 cells, over 20 cancer mutations located in the HD, LNR and LNR/HD interface, introduced into Drosophila Notch. Mutations in the HD domain core did not activate, likely due to absence in Drosophila of an S1 cleavage within the HD required for mammalian Notch activity. In contrast, mutations in the LNR/HD interface behaved similarly to T-ALL, activating constitutively with no further ligand induction and were synergistic with PEST deletion. Mutations of surface-exposed residues of LNR-C also activated constitutively but remained inducible both by ligand and by an intracellular endocytic regulator, Deltex, and were not synergistic with PEST deletions. These mutations caused elevated Notch levels and decreased turnover, suggesting a novel regulatory mechanism. Our results, therefore, uncover a variety of outcomes arising from perturbations of the NRR and will facilitate the establishment of Drosophila cancer models and the development of mutant-specific approaches to effective therapies.

Thalamo-accumbal circuit adaptations following extended oxycodone abstinence

alonsocy@umn.edu (Elena Chartoff) — Tue, 04 Aug 2026 00:00:00 +0000

Opioid use disorder is characterized by compulsive drug seeking and heightened relapse vulnerability following abstinence, a phenomenon known as incubation of craving. Although preclinical data suggest similar behavioral expression of opioid use between sexes, conclusive evidence on sex differences in craving and relapse across abstinence periods remains lacking. Here, we investigated the effects of abstinence from oxycodone self-administration on neurotransmission in the paraventricular thalamus (PVT) to nucleus accumbens shell (NAcSh) pathway in male and female rats. Using optogenetics and ex vivo electrophysiology, we assessed synaptic strength, glutamate release probability, and intrinsic excitability of NAcSh medium spiny neurons (MSNs) following 1 (acute) or 14 (prolonged) days of forced abstinence. No sex differences were observed in oxycodone self-administration or somatic withdrawal. However, females exhibited greater cue-induced relapse after prolonged but not acute abstinence. Prolonged abstinence produced comparable increases in PVT-NAcSh synaptic strength and presynaptic glutamate release probability in both sexes, while inhibitory transmission and MSN excitability were largely unaltered. The dissociation between comparable circuit-level plasticity and sex-specific relapse vulnerability suggests that PVT-NAcSh strengthening represents a shared neuroadaptation to oxycodone abstinence, while mechanisms driving heightened relapse in females likely involve additional circuit elements that remain to be identified.

Niche exclusion of a lung pathogen in mice with designed probiotic communities

collette2@llnl.gov (Adam P Arkin) — Tue, 04 Aug 2026 00:00:00 +0000

For years, the airway microbiota have been theorized to be gatekeepers of respiratory health, as pathogens entering the airway make contact with resident microbes prior to or coincident with their interaction with host cells. Thus, modification of the native airway community may serve as a means of altering the local environment in favor of health. In this work, we hypothesize that synthetic bacterial communities introduced into the airway can serve as prophylactic countermeasures against infection by Burkholderia thailandensis in mice. We demonstrate that understanding of antagonistic interactions between a pathogen and airway microbiota in vitro can guide identification of probiotics with protective capabilities in vivo. Specifically, we show that niche overlap between the probiotic and pathogen is indicative of probiotic performance in vivo. This work serves as a foundation for the rational design of probiotic communities for protection against and treatment of respiratory infections.

Concurrent category-selective neural activity across the ventral occipito-temporal cortex supports a non-hierarchical view of human visual recognition

bruno.rossion@univ-lorraine.fr (Bruno Rossion) — Tue, 04 Aug 2026 00:00:00 +0000

Visual recognition is a fundamental human brain function, supported by a network of regions in the ventral occipito-temporal cortex (VOTC). This network is thought to be organized hierarchically, with definite processing stages increasing in invariance and time-course from posterior to anterior cortical regions. Here, we provide a stringent test of this view by measuring category-selective neural activity to natural images of faces across the VOTC with electrophysiological intracerebral recordings in a large human sample (N=140; >11,000 recording sites). Face-selective high frequency broadband (30–160 Hz) neural activity is distributed across the VOTC, with right-hemispheric dominance and regional peaks of activity. Crucially, while a progressive increase in degree of category-selectivity is found along the postero-anterior axis, neural activity occurs largely concurrently (~100 ms onset – ~450 ms offset) across all VOTC regions. These observations challenge the standard hierarchical view of neural organization of visual object recognition in the human association cortex, supporting alternative models of this key brain function.

Gene dosage imbalance disrupts systemic metabolism in the Dp16 Down syndrome mouse model

gwwong@jhmi.edu (Christy M Nguyen) — Mon, 03 Aug 2026 00:00:00 +0000

Gene dosage imbalance resulting from an extra copy of human chromosome 21 (Hsa21) contributes to numerous clinical features in Down syndrome (DS). While dysregulated metabolism has long been noted in DS, the underlying cause is poorly understood and vastly understudied. To fill this critical knowledge gap, we conducted a comprehensive metabolic analysis of Dp(16)1Yey/+mice (abbreviated Dp16), a segmental duplication model carrying ~58% of the triplicated Hsa21 gene orthologs. Our multi-tissue transcriptomic analyses reveal shared and sex-specific increases in expression dosage of the triplicated genes in white and brown adipose tissues, liver, skeletal muscle, and hypothalamus. Despite sexual dimorphism in body weight, body temperature, food intake, and physical activity, Dp16 males and females share striking core phenotypes of pronounced insulin resistance, glucose intolerance, impaired lipid clearance, and dyslipidemia. Functional assessments, combined with biochemical, transcriptomic, and metabolomic analyses reveal tissue signatures of immune activation and a pro-inflammatory state, ER and oxidative stress, fibrosis, impaired glucose and fatty acid catabolism, altered lipid and bile acid profiles, and reduced mitochondrial respiratory capacity in Dp16 mice. These concerted changes disrupt homeostatic mechanisms that underpin metabolic health, contributing to systemic metabolic dysfunction. An obesogenic diet further exacerbates insulin resistance in Dp16 males and females despite divergent weight gain. The collective phenotypes broadly reflect the metabolic profile of DS. Our extensive molecular, biochemical, and physiological data provide an essential foundation for genetic dissection of dosage-sensitive genes affecting glucose and lipid metabolism, and for testing therapeutic strategies to improve metabolic outcomes in DS.

Correction: cxcl18b-defined transitional state-specific nitric oxide drives injury-induced Müller glia cell-cycle re-entry in the zebrafish retina

Mon, 03 Aug 2026 00:00:00 +0000

Following your heart as it takes shape

nicole.dubois@mssm.edu (Alexandra Trouilloud) — Fri, 31 Jul 2026 00:00:00 +0000

A novel computational pipeline reveals patterns of tissue movement and growth in early heart formation and advances virtual modeling of development.

ATP-driven conformational dynamics reveal hidden intermediates in a heterodimeric ABC transporter

tampe@em.uni-frankfurt.de (Christoph Nocker) — Fri, 31 Jul 2026 00:00:00 +0000

ATP-binding cassette (ABC) transporters are essential molecular machines whose conformational dynamics have largely been inferred from ensemble-averaged measurements. Resolving dynamic heterogeneity and transient intermediates, however, requires single-molecule approaches. Here, we use single-molecule Förster resonance energy transfer (smFRET) to resolve ATP-driven conformational dynamics of the heterodimeric type IV ABC transporter TmrAB, a functional homolog of the human antigen transporter TAP, at the level of individual molecules. Fluorophores positioned at the nucleotide-binding domains and periplasmic gate were validated by accessible-volume simulations, fluorescence lifetimes, and ensemble FRET, demonstrating that these reporters reliably track conformational transitions. Single-molecule analysis distinguishes ATP-free and ATP-bound states and quantifies ATP-dependent population shifts from nucleotide-free to physiological ATP concentrations. Kinetic analysis further reveals an unexpectedly long ATP-bound dwell time of ~300 ms. Using complementary stabilization strategies, we directly resolve a previously hidden outward-facing open state that is kinetically masked under turnover conditions. These results provide the first single-molecule characterization of TmrAB and establish a quantitative single-molecule framework for dissecting ATP-coupled conformational dynamics in heterodimeric ABC transporters.

Repurposed small molecule toxin inhibitors neutralise a diversity of venoms from the Neotropical viperid snake genus Bothrops

rachel.clare@edgehill.ac.uk (Adam Westhorpe) — Fri, 31 Jul 2026 00:00:00 +0000

Snakebite globally claims more than 100,000 lives per year and results in morbidity for 400,000 survivors. Current treatment uses antibody-based antivenoms which are constrained by their efficacy, safety, and cost. In this study we evaluated the efficacy of previously described repurposed drugs against viperid snakes of the medically important Bothrops genus. Despite variable toxin representation and bioactivity across this central and south American genus, we found that the lead inhibitors targeting metalloproteinases (marimastat and DMPS) and phospholipases (varespladib) demonstrated pan-species neutralisation in enzymatic assays, whilst nafamostat (serine protease inhibitor) had variable activity. The metalloproteinase inhibitors protected against the procoagulant and haemorrhagic effects of several venoms in phenotypic assays. Collectively these findings demonstrate that repurposed drugs may be of great value as early interventions for the treatment of bothropic envenoming in the Neotropics and thus provide a strong rationale for their progression into future preclinical and clinical evaluation for snakebite indication.

Comprehensive characterization of human color discrimination thresholds

fh862@sas.upenn.edu (Alex H Williams) — Fri, 31 Jul 2026 00:00:00 +0000

Color discrimination thresholds—the smallest detectable color differences—provide a benchmark for models of color vision, enable quantitative evaluation of eye diseases, and inform the design of display technologies. Despite their importance, a comprehensive characterization of these thresholds has long been considered intractable due to the psychophysical curse of dimensionality. Here, we address this challenge using a novel semiparametric Wishart process psychophysical model (WPPM), which leverages the feature that the internal noise limiting color discrimination varies smoothly across stimulus space. The model was fit to data collected with a nonparametric adaptive trial-placement procedure, enabling efficient stimulus selection. Together, through the combination of adaptive trial placement and post hoc WPPM fitting, we achieved a comprehensive characterization of color discrimination in the isoluminant plane with only ∼6000 trials per participant (N = 8). Once fit, the WPPM allows readouts of discrimination performance for any stimulus pair. We validated these readouts against 25 probe psychometric functions, measured with an additional 6000 trials per participant held out from model fitting. In conclusion, our study provides a foundational dataset for color vision, and our approach generalizes beyond color to any domain in which the internal noise limiting performance varies smoothly across stimulus space, offering a powerful and efficient method for comprehensively characterizing various perceptual discrimination thresholds.

Benchmarking biochemical networks generated by large language models

jsaucerman@virginia.edu (B Adam Bates) — Fri, 31 Jul 2026 00:00:00 +0000

Computational models of biochemical networks provide frameworks for predicting how molecular cues guide cell decisions. These models are typically limited by the time-intensive manual curation required to extract network mechanisms from incomplete literature. Here, we test whether general-purpose large language models (LLMs) can generate accurate models of signaling and metabolic networks. We find that general-purpose LLMs generate 24–65% of the reactions of literature-curated signaling networks for cardiomyocyte hypertrophy, myofibroblast activation, and mechanosignaling. Further, logic-based models based on these networks predict responses to perturbations with accuracies of 6–33%. In the context of metabolic modeling, LLMs are able to generate 64–91% of the reactions within the core Escherichia coli metabolic network and demonstrate highly variable accuracies in predicting substrate utilization. Current general-purpose LLMs generate biochemical networks with moderate accuracy, and this study provides a pipeline and benchmarks to guide future improvements.

Decoupling AMPK from fatty acid synthesis allows maintenance of fitness late in life

jon.houseley@babraham.ac.uk (Dorottya Horkai) — Fri, 31 Jul 2026 00:00:00 +0000

Although lifespan has long been the focus of ageing research, preventing functional decline late in life is a more pressing societal need. Here, we investigate the basis of senescence and declining fitness during replicative ageing in budding yeast, and describe a metabolic perturbation that preserves late-life fitness even on an unrestricted glucose diet. We show that senescence can be prevented by constitutive activation of AMPK, though only for approximately half the ageing population, and use genetic and functional assays to link this heterogeneous response with differences in cytosolic acetyl coenzyme A (Acetyl-CoA) metabolism. In one class of ageing cell, AMPK activity maintains fitness late in life through pathways that transport cytosolic Acetyl-CoA into mitochondria, but AMPK also inhibits fatty acid synthesis which leads to lipid starvation in the other class of ageing cell. Therefore, AMPK activity has both positive and negative effects, but we show that constitutive AMPK activity uncoupled from fatty acid synthesis inhibition (the A2A mutant) suppresses senescence and maintains fitness in both classes of ageing cell. Our findings support a model in which lipid starvation and excess Acetyl-CoA availability are major drivers of senescence in replicatively aged wild-type yeast. This work shows that ageing is not intrinsically associated with declining fitness, at least in yeast, and that re-engineering highly conserved metabolic pathways allows fitness to be preserved very late in life.

Dichotomy between extracellular signatures of active dendritic chemical synapses and gap junctions

rishi@iisc.ac.in (Richa Sirmaur) — Thu, 30 Jul 2026 00:00:00 +0000

Local field potentials (LFPs) are compound signals that represent the dynamic flow of information across the brain, which have been historically associated with chemical synaptic inputs. How do gap junctional inputs onto active compartments shape LFPs? We developed a methodology to record extracellular potentials associated with different patterns of gap junctional inputs onto conductance-based models. We found that synchronous inputs through chemical synapses yielded a negative deflection in proximal extracellular electrodes whereas those onto gap junctions manifested a positive deflection. Importantly, we observed extracellular dipoles only when inputs arrived through chemical synapses but not with gap junctions. Remarkably, hyperpolarization-activation cyclic nucleotide-gated channels, which typically conduct inward currents, mediated outward currents triggered by the fast voltage transition caused by synchronous inputs. With rhythmic inputs at different frequencies arriving through gap junctions, we found strong suppression of LFP power at higher frequencies as well as frequency-dependent differences in the spike phase associated with the LFP when compared to respective chemical synaptic counterparts. All observed differences in LFP were mediated by the relative dominance of synaptic currents vs. voltage-driven transmembrane currents with chemical synapses vs. gap junctions, respectively. Our analyses unveil a hitherto unknown role for active dendritic gap junctions in shaping extracellular potentials.

Neural correlates of perceptual consciousness from within: A narrative review of human intracranial research

nathan.faivre@univ-grenoble-alpes.fr (Alexis Robin) — Thu, 30 Jul 2026 00:00:00 +0000

Despite many years of research, the quest to identify neural correlates of perceptual consciousness (NCC) remains unresolved. One major obstacle lies in methodological limitations: most studies rely on non-invasive neural measures with limited spatial or temporal resolution, making it difficult to disentangle proper NCCs from concurrent cognitive processes. Additionally, the relatively low sensitivity of non-invasive neural measures limits the interpretation of null findings in studies targeting proper NCCs. In this review, we discuss how human intracranial recordings can advance the search for NCCs by offering high spatiotemporal resolution, improved signal sensitivity, and broad cortical and subcortical coverage. We review studies that have examined NCCs at the level of single neurons and populations of neurons, and evaluate their implications on the debates between cognitive and sensory theories of consciousness. Finally, we highlight the limits of current intracranial human recordings and propose future directions based on emerging technologies and novel experimental paradigms.

The titin N2A-MARP signalosome constrains muscle longitudinal hypertrophy in response to stretch

coeno@arizona.edu (Coen Ottenheijm) — Thu, 30 Jul 2026 00:00:00 +0000

Titin-based mechanosensing is a key driver of trophic signaling in muscle, yet the downstream pathways linking titin sensing to muscle remodeling remain poorly understood. To investigate these signaling mechanisms, we utilized unilateral diaphragm denervation (UDD), an in vivo model that induces titin-stiffness-dependent hypertrophy via mechanical stretch. Using UDD in rats and mice, we characterized the longitudinal hypertrophic response and distinguished stretch-induced signaling from denervation effects by performing global transcriptomic and proteomic analyses following UDD and bilateral diaphragm denervation (BDD) in rats. Our findings identified upregulation of titin-associated muscle ankyrin repeat proteins (MARPs). Subsequent phosphorylation enrichment mass spectrometry in mouse diaphragm highlighted the involvement of the N2A-element. UDD in MARP knockout (KO) mice resulted in enhanced longitudinal hypertrophy, with Western blot analysis revealing activation of the mTOR pathway. Furthermore, pharmacological inhibition of mTORC1 with rapamycin suppressed longitudinal hypertrophy, demonstrating that mTOR signaling regulates titin-mediated hypertrophic growth in a MARP-dependent manner. These findings establish MARPs as key modulators of titin-based mechanotransduction and highlight mTORC1 as a central regulator of longitudinal muscle hypertrophy.

Acute opioid responses are modulated by dynamic interactions of Oprm1 and Fgf12

labwilliams@gmail.com (Alexander S Hatoum) — Wed, 29 Jul 2026 00:00:00 +0000

We generated time-series data for 105 morphine- and naloxone-related traits across ~700 BXD mice (64 diverse strains for both sexes) for 3 hr after a single morphine injection. Variations in responses were mapped using genome sequencing-based genotypes. The locomotor responses to morphine mapped to the µ opioid receptor gene (Oprm1) on chromosome (Chr) 10 with a peak linkage of 12.4 (–logp). The B allele inherited from C57BL/6J was associated with up to 60% higher activity. This effect climaxed at 75 min but was exhausted by 160 min. A second major modulator of locomotion emerged after approximately 100 min. This locus was located on Chr 16 with peak linkage of 10.6 in females and included one compelling candidate, fibroblast growth factor 12 (Fgf12). A strong and transient epistatic interaction existed between the Oprm1 and Fgf12 loci during a short time window (45–75 min). In heterogeneous stock rats, we demonstrated that Oprm1 and Fgf12 were co-expressed in one subtype of Drd1⁺ medium spiny neuron. A Bayesian network analysis supported an Oprm1-to-Fgf12 network that involves a MAP kinase cascade that modulates FGF12 phosphorylation and locomotor activation. OPRM1 and FGF12 networks in human genome-wide association study (GWAS) data highlight enrichment of signals associated with substance use disorder. This study represents the first demonstration of a time-dependent epistatic interaction modulating drug response in mammals and the first linkage of Fgf12 to opioid-induced behavior.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.