Biology subjects

Smith, E.

Publications and source records attributed to Smith, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Spatiotemporal profiling of T cell repertoires in Lynch syndrome reveals convergent immune responses through neoplastic progression

Surveillance of individuals with Lynch syndrome (LS), who are carriers of heterozygous inactivating mismatch repair (MMR) gene mutations that predispose to colorectal cancer, enables the study of tumour-immune coevolution during tumour initiation. Somatic loss of MMR activity in the LS colon leads to the accrual of cancer driver mutations, and also of neoantigens likely to generate an adaptive immune response. However, the spatial and temporal immune dynamics in colon and peripheral blood are uncharacterised. Here we show that the neoplastic evolution of mismatch repair deficient (MMRd) clones leads to large-scale and sustained reorganisation of the T-cell repertoire in colon and peripheral blood. We performed dense spatiotemporal profiling of T cell receptor (TCR) repertoires from 109 colonic biopsies (11 tumour samples, 98 normal bowel) from seven individuals, with eight matched blood repertoires. We additionally analysed 13 colorectal polyp repertoires from eight participants, 286 cross sectional blood repertoires from 242 participants (198 LS and 44 non-LS) and 52 longitudinal peripheral blood samples from 26 individuals with LS. We detected tumour-associated T cell clones, some of which were widely present in normal bowel tissue and also detectable in peripheral blood. Sequence similarity analysis revealed conserved TCR architectures across tissue compartments and recurrent clustering patterns between patients, that were not present in non-Lynch controls, consistent with convergent MMRd-associated antigen-driven immune selection. We identified systemic signatures associated with local tumour immune activity and revealed evidence of structured repertoire remodelling before overt malignancy. Longitudinal profiling revealed frequent turnover of low-abundance clonotypes, whereas highly abundant clonotypes persisted for several years. Collectively, our data defines the local and circulating TCR landscape associated with colonic neoplasia in LS, and provides a framework for LS blood-based immune monitoring, early interception and biomarker development.

immunology↗

bioRxiv2026

RasGRP1 promotes efficient intestinal tuft cell differentiation

Intestinal stem and progenitor cells balance proliferation and lineage commitment to maintain epithelial homeostasis and adapt to environmental challenges. Tuft cells are a rare chemosensory lineage that rapidly expands in response to the cytokine IL-13 during helminth infection, yet how epithelial progenitor states influence this response remains incompletely understood. Using genetic mouse models, intestinal organoids, and single-cell approaches, we identify the Ras guanine nucleotide exchange factor RasGRP1 as an epithelial-intrinsic promoter of efficient tuft cell differentiation. Rasgrp1 is expressed in rare crypt epithelial cells distinct from Lgr5-positive stem cells. Once cells entered the tuft cell differentiation trajectory, Rasgrp1 deficiency has little impact on tuft cell maturation, including expression of the Pou2f3 tuft cell transcription factor. Instead, RasGRP1 acts at the progenitor stage, where it restrains EGFR-driven proliferation and supports a transcriptionally heterogeneous transit-amplifying state, including a subset of cells expressing Pou2f3, that is largely lost upon Rasgrp1 deficiency. Consistent with this model, EGFR inhibition restores tuft cell numbers in Rasgrp1-deficient organoids and cooperates with IL-13 to enhance tuft cell differentiation. Rasgrp1-deficient mice exhibit delayed tuft cell hyperplasia and inefficient helminth clearance. Conversely, constitutive epithelial RasGRP1 overexpression, uncoupled from its endogenous regulation, drives spontaneous tuft cell hyperplasia and accelerates parasite clearance, but alters the balance of intestinal epithelial lineages. Together, our findings identify RasGRP1 as a cell-intrinsic regulator that restrains progenitor proliferation and promotes responsiveness to IL-13, thereby coupling growth factor signaling, cell cycle control, and immune-driven epithelial lineage specification.

cell biology↗

bioRxiv2026

MERFISHEYES: Web-based Visualization and Sharing Platform for Single-cell and Single-molecule Spatial Transcriptomics

Interactive exploration and sharing of hybridization-based spatial transcriptomics datasets remain limited by large file sizes, specialized software, and computationally intensive preprocessing, restricting rapid access to publicly available resources such as the Brain Image Library. Here we present MERFISHEYES (https://merfisheyes.com), a browser-based platform for interactive visualization of single-cell and single-molecule spatial transcriptomics data across commercial and emerging high-throughput platforms. MERFISHEYES enables marker gene exploration, cross-dataset and cross-species comparison, visualization of subcellular RNA localization, and collaborative sharing through browser-accessible links generated directly from drag-and-drop datasets. We use MERFISHEYES to enable browser-based visualization of all 158 spatial transcriptomics datasets in the Brain Image Library and demonstrate its capabilities in handling high-throughput 3D data with genome-scale imputation of gene expression and DNA accessibility. MERFISHEYES provides a scalable framework for rapid exploration, sharing, and collaborative analysis of spatial transcriptomics data.

bioinformatics↗

bioRxiv2026

Mapping and rewiring the MYBPC3 promoter for rescue of haploinsufficiency driven hypertrophic cardiomyopathy

Autosomal dominant loss-of-function variants in the gene MYBPC3 are, collectively, the most common genetic cause of hypertrophic cardiomyopathy (HCM) and are a prototype of haploinsufficient human disease. Typical for haploinsufficiency-associated genes, hundreds of unique loss-of-function pathogenic variants have been reported for MYBPC3 - therapeutic gene editing to correct each of these variants poses major regulatory and logistical hurdles. Upregulating wild-type allele expression could offer a generalizable therapeutic strategy, but the capacity to modulate native MYBPC3 transcription is unknown. Here, we present a variant-agnostic approach to rescue haploinsufficiency by mapping and rationally redesigning the MYBPC3 promoter. Using massively parallel reporter assays (MPRAs) in human induced pluripotent stem cell-derived cardiomyocytes, we performed saturation mutagenesis of the MYBPC3 promoter at single base-pair resolution. This defined a new class of clinically relevant noncoding loss-of-function variants while revealing essential cis-regulatory grammar anchored by key transcription factor binding sites (TFBSs). Furthermore, by systematically screening thousands of variant combinations, modular promoter elements, and heterologous TFBS insertions, we identified synergistic sequence edits that drive robust increases in MYBPC3 expression. Together, our findings improve the clinical interpretation of noncoding variants and establish a scalable blueprint for promoter editing to treat MYBPC3-associated HCM and other haploinsufficient diseases.

molecular biology↗

bioRxiv2026

Nucleotide-binding motifs nucleated folding of the first enzymes

The earliest stages of protein evolution remain a mystery: the nature of the first protein forms, their roles in emergent biological systems, and the forces that shaped them are largely unknown. Here, we combine insights from metabolic modelling, the organization of protein structure space, and protein folding mechanisms to probe the emergence of two ubiquitous cofactor- binding folds: Rossmanns and P-loop NTPases. While both folds are essential for contemporary life, we show that Rossmanns catalyze reactions deeper within the metabolic core and are more central in structure space than P-loop NTPases. Folding mechanism analysis further reveals that, whereas P-loop NTPases may require non-local interactions to fold, Rossmann folding can be nucleated by a structural module at the heart of the fold that contains a nucleotide-binding motif. Because this motif also directly mediates biochemical activity, this result suggests how early proteins may have compactly satisfied both folding and biochemical activity. Our results imply that folding constraints favored early enzymatic forms with compact binding motifs and modest catalytic roles. We conclude that the early emergence of the Rossmann fold reflects the chemical and physical constraints of protein folding, explaining both its profound antiquity and sustained longevity.

biochemistry↗

bioRxiv2026

Bilayer thickness and transmembrane domain dynamics drive directional ER-Golgi traffic via Erv14/cornichon

Directionality of protein traffic during secretion is driven by sorting receptors that bind cargo in one compartment and release them in another. Erv14/cornichon family receptors mediate delivery from the endoplasmic reticulum (ER) to the Golgi. Erv14 traffics its client, Mid2, via a conserved interface formed by two transmembrane helices (TMHs). Molecular dynamics simulations of Erv14-Mid2 suggest that Erv14 TMHs undergo dynamic movement in response to both client binding and lipid bilayer thickness. Interaction between charged residues that flank the TMHs of Mid2 and Erv14 couple client binding to stabilization of the Erv14 export signal and thus engagement with the COPII coat. We term this mechanism Helix Engagement Induced Signal-mediated Traffic (HEIST) and suggest it as a general mechanism where changes in membrane biophysical properties drive directional transport.

cell biology↗

bioRxiv2026

Tumor-specific Kinase Motif Enrichment Analysis Identifies Personalized Therapeutic Cancer Targets

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are an uncommon and poorly understood malignancy with low mutational burden, lacking well-defined oncogenic drivers. GEP-NET mortality frequently results from extensive hepatic metastases. Accordingly, we interrogated phosphoproteomic data from GEP-NET liver metastases and patient-matched uninvolved liver to identify tumor-specific signaling and targetable tumor vulnerabilities using Kinase Motif Enrichment Analysis (KMEA), a new tool leveraging the recent Kinase Library compendium of the substrate motif specificity for nearly the entire human kinome. KMEA identified patient tumor-specific upregulation of mTOR or casein kinase 2 (CK2) activity that would be undiscoverable by standard personalized genomic and transcriptomic approaches. Striking concordance was observed between KMEA predictions for specific tumors, and their sensitivity to inhibitors of mTOR or CK2 using patient tumor-derived organoids. These findings reveal potential clinically-actionable protein kinases hyperactivated in GEP-NETs, and more broadly indicate a general method for personalized cancer treatment using phosphoproteomics and KMEA-derived kinase activity signatures.

cancer biology↗

bioRxiv2026

Ontological Analysis of Brain Proteostasis Highlights the Sex-Dependent Trajectory of ApoE Isoform-Specific Regulation

Apolipoprotein E (ApoE) is the strongest genetic predictor of Alzheimers disease (AD) risk, with ApoE4 increasing and ApoE2 decreasing risk relative to ApoE3. Using a global LC-MS proteomic approach, we integrated protein abundance and kinetics in Human-APOE knock-in mice for young (3-month) and aged (18-month) cohorts to quantify the changes in steady-state proteostasis. By mapping 6,052 identified proteins and 3,986 associated turnover rates into ontological groups, we observed that vesicle trafficking and mitochondrial dysregulation occur as early as 3 months in ApoE4 mice accompanied by hyperactive metabolism that eventually reduces with age. In contrast, young and old ApoE2 mice retain similar signatures to ApoE3 mice in metabolic, mitochondrial, cellular regulation, and membrane trafficking ontologies. We found that females had more isoform-induced ontological changes relative to ApoE3, providing insight into sex-dependent vulnerabilities. Our global proteomic approach for ApoE proteostasis crucially unifies independent literature observations while providing turnover kinetics to uncover the underlying mechanism behind abundance changes. Data are available via ProteomeXchange with identifier PXD079261. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/735293v1_ufig2.gif" ALT="Figure 1000"> View larger version (45K): org.highwire.dtl.DTLVardef@28ebfforg.highwire.dtl.DTLVardef@9dc6f2org.highwire.dtl.DTLVardef@704577org.highwire.dtl.DTLVardef@e0b0e2_HPS_FORMAT_FIGEXP M_FIG C_FIG O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/735293v1_ufig1.gif" ALT="Figure 1001"> View larger version (48K): org.highwire.dtl.DTLVardef@17d0474org.highwire.dtl.DTLVardef@af771borg.highwire.dtl.DTLVardef@1b49f67org.highwire.dtl.DTLVardef@14d3aa2_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Sociality changes Gene Essentiality

Transposon insertion sequencing (Tn-seq) has become a powerful tool for assigning gene fitness and essentiality in bacteria, and has recently been extended to bacteriophages. A core but rarely examined assumption of these screens is that fitness is measured in an asocial environment, where each mutant succeeds or fails on its own. Yet many genes act socially: their products can be shared among neighbors, allowing defective mutants to be complemented in trans. In phages multiple genotypes routinely coinfect the same cell. Here we show that social interactions distort gene essentiality. Using paired quorum-sensing microarray and Tn-seq data from Pseudomonas aeruginosa, we find that quorum-sensing-regulated genes are over-represented among genes scored as non-essential, confirming that social genes are under-reported as essential. We then build a stochastic, agent-based model of phage Tn-seq across an MOI gradient, assigning each gene an intrinsic fitness effect and a complementation fraction. Complementable ("social") genes rise in frequency as MOI increases, masking their true fitness cost, whereas non-complementable ("private") genes, do not. Partitioning genes by life-cycle stage and applying a two-round high-then-low-MOI design, further separates gene functions by life cycle stage. We argue that deliberate MOI manipulation turns a confound into a tool, enabling systematic classification of phage sociality.

evolutionary biology↗

bioRxiv2026

Pharmacological profiling of brain activity in zebrafish

Background and PurposeEpilepsy is a neurological condition characterized by recurring seizures and neuronal hyperexcitability. Cell-based high-throughput screening applications have been essential for drug development and discovering novel biological processes. However, cell-based screens do not provide information on how drug-targeted pathways are integrated into a whole animal. Our objective was to develop and evaluate a screening application using zebrafish larvae to identify signalling mechanisms that modulate neural activity. Experimental ApproachWe developed an in vivo automated high-content screening assay using zebrafish larvae expressing the calcium sensor CaMPARI (calcium-modulated photoactivatable ratiometric integrator) in neurons. This assay can quantify neural activity of multiple individual larvae per well in a 96-well format. We quantified neural activity in 8725 individual larvae, in response to 1292 different drugs to identify molecules that protect against convulsant-induced neuronal hyperexcitability. Key ResultsThe assay was effective at identifying drugs that target diverse neurotransmitter signalling systems. While some commonly used anti-convulsants (e.g. phenytoin, carbamazepine, valproic acid) had poor activity in the assay, Kv7 potassium channel activators were consistently effective (ICA-069673, ICA-27243, ICA-110381, retigabine, and ML213). Many compounds approved for treatment of other conditions, including amitriptyline (depression), cyclobenzaprine (muscle spasm), clomipramine (obsessive-compulsive disorder) and ganaxolone (seizures), also strongly suppressed excitability in the assay. Conclusion and ImplicationsNeuronal CaMPARI expression in zebrafish larvae is a powerful tool for plate-based compound library screening to identify drugs that suppress hyperexcitability in vivo. Bullet Point SummaryO_ST_ABSWhat is already knownC_ST_ABSO_LICaMPARI is an integrative Ca2+ sensor that can be used to identify active neurons. C_LIO_LIKv7 activators (retigabine, ML213, and ICA-069673) are effective at reducing convulsant-induced (4-AP) neuronal hyperexcitability. C_LI What this study addsO_LIAn automated in vivo high-content drug screening assay to quantify neural activity. C_LIO_LIA series of drug targets that influence convulsant-induced hyperexcitability. C_LI Clinical significanceO_LIOur new tool will help identify novel compounds and signalling mechanisms that could be pursued as therapeutic targets for diseases involving electrical hyperexcitability. C_LI

pharmacology and toxicology↗

bioRxiv2026

Understanding the emergence of the influenza A/H3N2 K subclade in its historical and evolutionary context

The emergence in 2025/26 of the influenza A/H3N2 K substrain (H3N2/K) was the cause of significant public health concern. This genetically divergent virus was assessed to have a strongly decreased reactivity to contemporary vaccine strains. Respectively prolonged and early influenza seasons in the Southern and Northern Hemispheres contributed to concerns about vaccine efficacy. Here we retrospectively assessed the genetic and antigenic properties of this virus, combining epidemiological surveillance data, computational antigenic analysis, and serological data using samples from a well-stratified UK cohort. In contrast to initial indications, we found that despite the genetic distinctiveness of H3N2/K the virus had undergone limited antigenic change, suggesting that its emergence was instead the result of selection for non-antigenic properties. We confirmed previous results showing that contemporary vaccines produced an enhanced neutralising response to H3N2/K but, in a stratified serological analysis, showed that responses to the J and K substrains were age-dependent, largely driven by patterns of vaccination. Our results have implications for antigenic surveillance and for public communication strategies in future influenza seasons.

evolutionary biology↗

bioRxiv2026

Comprehensive interaction profiling and machine learning prediction of bacteriophage infectivity across clinically diverse Pseudomonas aeruginosa

The rise of antibiotic-resistant bacterial infections has driven renewed interest in bacteriophage therapy, where viruses that specifically kill bacteria are used as targeted antimicrobials. Pseudomonas aeruginosa, a WHO critical-priority pathogen that causes severe infections in hospitalized and immunocompromised patients, presents a major challenge for phage therapy because of its extraordinary genetic diversity. Phages effective against one bacterial strain often fail against others, and existing cross-resistance-profiling approaches require iterative empirical testing of each new patient isolate. To establish a genome-based framework for rapid phage-isolate matching, we assembled a collection of 95 genomically diverse P. aeruginosa phages representing 20 genera and tested each against 99 genetically diverse clinical isolates, generating 9,405 infection outcome measurements. Bacterial O-antigen serotype emerged as the dominant determinant of strain susceptibility, while defense systems, anti-defense systems, and prophage burden contributed smaller strain-specific effects. The full curated multivariate model explained 47% of strain-susceptibility variance. Machine-learning models integrating these features and pangenome-derived gene clusters reached a per-strain AUROC of 0.86. In an in vivo proof-of-concept test against a single held-out strain, the ML-designed cocktail produced a [~]12-fold greater median CFU reduction than the expert-designed cocktail (q = 0.045), with both cocktails substantially reducing burden relative to the untreated control ([~]113-fold for ML, [~]9-fold for CG; both q < 10{square}3). SHAP analysis of the model identified bacterial surface-architecture genes (LPS biosynthesis, outer membrane proteins, type IV pili) as the dominant predictors, with defense-system content modulating which specific phages succeed against a strain rather than uniformly damping susceptibility. Together, these results establish a genome-based framework for predicting phage susceptibility in genetically diverse clinical isolates.

microbiology↗

bioRxiv2026

Comparative benchmarking of single-cell transcriptomes and immune repertoires across technologies

Immune receptor profiling enables tracking of individual T or B cell clones across time and tissues, providing insight into immune responses, cancer, and autoimmunity. When combined with single-cell transcriptomics, it links clonotype identity to cellular function, revealing the diversity and dynamics of immune cell populations. This study presents a head-to-head benchmarking comparison of two single-cell immune profiling technologies: droplet-based microfluidics from 10x Genomics (10x) and combinatorial barcoding from Parse Biosciences (Parse). Using matched human samples from PBMCs, the analysis evaluates performance across transcriptomic and T cell immune receptor features to assess data quality, reproducibility, and chain-specific recovery. The findings provide a framework for interpreting single-cell immune profiling platforms and emphasize the importance of accounting for technology-specific biases in bioinformatic analyses.

bioinformatics↗

bioRxiv2026

Comprehensive profiling reveals Sialyl-Tn upregulation and prognostic value in prostate cancer

Prostate cancer is a common cancer in males and there is an urgent unmet clinical need to identify new therapies for advanced disease. Aberrant glycosylation is common in prostate cancer and plays a functional role in disease progression. The sialyl-Tn antigen (sTn) has been widely studied in cancer, yet its involvement in prostate cancer remains relatively unexplored. Here, we utilise a novel anti-sTn antibody (L2A5) to comprehensively monitor sTn expression levels in clinical prostate cancer tissues encompassing normal, benign, primary, metastatic castrate-resistant prostate cancer (CRPC), and patient-derived xenografts (PDXs). We show that while sTn is detected at low or negligible levels in normal prostate tissues, it is expressed in 44% of prostate tumours, and prostate cancer patients with high sTn levels have significantly poorer survival times. Analysis of metastatic therapy resistant prostate-derived tumours growing in liver and bone, shows sTn is expressed in 37.5% of cases. Furthermore, we show sTn is expressed in nearly half of PDXs tested, supporting the use of PDX models as tools for testing anti-sTn therapeutic strategies. These findings identify sTn as potential prognostic biomarker and therapeutic target in prostate cancer and lay the groundwork for the development of sTn-targeted precision therapies for advanced disease.

cancer biology↗

bioRxiv2026

Transcription Factor Subtype Governs Response and Resistance to DLL3-Directed T-Cell Engagement in Small Cell Lung Cancer

Although small cell lung cancer (SCLC) comprises transcription factor (TF)-defined molecular subtypes (ASCL1, NEUROD1, POU2F3), the extent to which these subtypes predict response to clinically effective therapy in patients--and whether therapy can select for subtype switching--remains unknown. The recent approval of the DLL3xCD3 bispecific T-cell engager tarlatamab represents one of the first meaningful advances in relapsed small cell lung cancer (SCLC) in decades, yet responses remain heterogeneous and resistance is inevitable. Here, we inferred SCLC gene expression from circulating chromatin in prospectively collected patient plasma (46 patients; 167 samples), enabling interrogation of response and acquired resistance to tarlatamab. Parallel development of the first immunocompetent syngeneic mouse model to study tarlatamab response and resistance enabled functional validation. Across species, findings converged on a central principle: TF subtype governs both initial response and acquired resistance. Therapeutic response was significantly associated with ASCL1-subtype tumors, whereas NEUROD1-subtype tumors exhibited inferior responses and POU2F3-subtype tumors were uniformly resistant, consistent with DLL3 being a direct ASCL1 transcriptional target and most highly expressed in ASCL1-positive tumors. Strikingly, one mode of acquired resistance revealed therapeutic selection for a NEUROD1-high state with concomitant DLL3 downregulation. Other resistant tumors exhibited enrichment of regulatory and exhausted T-cell programs, highlighting tarlatamabs dual-targeting mechanism of action. Together, these results reveal that tarlatamab exerts selective pressure against ASCL1-driven lineages, facilitating resistance through loss of an antigen intrinsically linked to that state. These findings underscore the clinical relevance of TF-defined molecular subtypes in human SCLC. More broadly, they highlight the power of integrating longitudinal in vivo plasma transcriptional profiling from patient plasma with functional mouse modeling to uncover clinical and biological mechanisms of response and resistance to cell-surface-targeted therapies.

cancer biology↗

bioRxiv2026

Biosensor Cell Array Reveals Temporal GABA Secretion Dynamics from Pancreatic Islets

Pancreatic beta cells have the unique function of synthesizing and secreting high amounts of the inhibitory neurotransmitter {gamma}-aminobutyric acid (GABA). The mechanism of GABA secretion, whether vesicular or channel-mediated, is debated. Our study reveals surprising temporal complexity in the pattern of islet GABA secretion. We used insulin secretion modulators to demonstrate that GABA release is not directly correlated with insulin secretion. VGAT reporter mice also showed that beta cells do not express the requisite vesicular GABA transporter (VGAT) for vesicular GABA release. Instead, GABA is secreted from the cytosol in pulses by the LRRC8A/D isoform of the volume regulatory anion channel (VRAC). We further demonstrate the dynamic coordination of GABA release with calcium influx in beta cells and dependence on beta cell depolarization. These results suggest a model where GABA is released during the peaks of beta cell calcium oscillations to provide feedback which strengthens and reinforces the oscillation waveform.

physiology↗

bioRxiv2026

Structural Basis for Dual Peptidoglycan Hydrolysis by an E. faecium Minhovirus Tail Spike Lysin

Bacteriophages rely on breaching the bacterial cell wall as the first step of infection. We characterise ORF11, a putative tail-spike lysin from the 19 kbp Minhovirus SHEF14, a podovirus infecting Enterococcus faecium. Bioinformatic analyses indicate that ORF11 comprises four domains: a predicted glycosyl hydrolase (D1) a cysteine, histidine-dependent amidohydrolases/peptidases (CHAP, D4), separated by a helical linker (D2) and a CHAP-like domain (D3). This modular organisation is conserved among Enterococcus minhoviruses but differs markedly from analogous proteins in Copernicusvirus phage and related staphylococcal phage. ORF11 2.1 [A] crystal structure reveals an unusual dimeric assembly. The predicted glycosyl hydrolase and CHAP peptidase domains occupy opposite ends of the protein, bridged by the two other domains positioned at the dimer interface. Biochemical assays using recombinant ORF11 and LC-MS/MS confirmed dual peptidoglycan-degrading activity. ORF11 functions as both an N-acetylglucosaminidase and a D, D-endopeptidase, cleaving the bond between the D-alanine in position-4 and the D-aspartate residue at the end of the side chain. Together, these results provide the first structural description of a podovirus tail-spike lysin and demonstrate its bifunctional enzymatic activity. This dual action likely facilitates initial surface recognition and localised peptidoglycan degradation during infection of E. faecium, offering new insights into how minimal-genome phage target this clinically significant antimicrobial-resistant pathogen.

biochemistry↗

bioRxiv2026

Individual Differences in Dopaminergic Modulation of Exploration-Exploitation Behaviour

Dopamine (DA) has been implicated in exploration-exploitation behaviour, i.e., exploring novel, potentially better options vs. exploiting known, previously rewarding options. Impairments in this trade-off occur in psychiatric disorders involving DAergic dysfunction, including addiction and schizophrenia. Pharmacological studies revealed a contribution of DA to exploration, but inconsistent findings suggest that interindividual variability in baseline DA may modulate effects. To address this, we investigated the effects of the DA precursor L-DOPA on exploration-exploitation during reinforcement learning in a sample of N = 75 healthy participants (n = 32 women), following a randomised, double-blind, placebo-controlled, pre-registered design (https://osf.io/p2r7u). We assessed whether putative baseline DA markers, including spontaneous eye blink rate, working memory (WM) capacity, and impulsivity, modulated drug effects and probed visual fixation patterns and pupil dilation as markers of exploration. L-DOPA had no overall effect on computational model parameters of random exploration, directed exploration or choice perseveration. WM capacity moderated drug effects on random exploration, with stronger effects at higher WM capacity. Remaining DA proxies showed no credible effects. Pooling the data from male participants with that from an earlier male-only study (Chakroun et al., 2020; total N = 74), L-DOPA increased uncertainty-dependent value weighting and perseveration strength, while decreasing habit updating, indicating a stronger tendency to repeat previous choices and slower decay of their influence over time. No credible drug effects were observed in female participants. Pupil dilation was tonically increased under L-DOPA and scaled with exploration behaviour and prediction error, confirming that pupillometry can index exploration-exploitation dynamics. Visual exploration patterns reflected uncertainty-driven sampling, but were unaffected by L-DOPA. Taken together, results suggest that DAergic modulation of exploration and perseveration behaviour may be contingent on cognitive capacity and sex, rather than exerting uniform effects across individuals.

neuroscience↗