Biology subjects

Marques, J.

Publications and source records attributed to Marques, J..

12 recordsLinked to original sources

bioRxiv2026

An Eco-Evolutionary Modelling Framework for Mosquito Host Specialisation

Host preference varies widely across mosquitoes, with many species feeding opportunistically on diverse vertebrate hosts, while others show strong fidelity to specific hosts. Anthropophilia, the behavioural preference for feeding on humans, is a defining characteristic of some mosquito species responsible for the transmission of major human diseases, including malaria, dengue, and yellow fever. The evolution of anthropophilia therefore has profound epidemiological implications because increased human biting elevates vectorial capacity and disease transmission potential. However, the ecological and evolutionary mechanisms driving this extreme specialisation have not yet been fully elucidated and remain difficult to unify across laboratory and field studies. Here we present an eco-evolutionary modelling framework that links genetically determined mosquito traits with spatially structured host environments. Our framework integrates innate olfactory sensitivity, blood meal-derived fitness benefits, and spatio-temporal host accessibility. Two complementary indices are introduced: a local specialisation index, capturing short-term ecological feeding strategies, and a co-evolutionary index, capturing long-term genetic coupling between host detection and resource utilisation. Our results demonstrate that host specialisation is not a default evolutionary outcome but an environmentally gated process, which is favoured in resource-poor or temporally varying habitats and strongly filtered by seasonality. The framework yields testable predictions regarding when specialisation emerges, persists, or collapses, with direct implications for predicting vector-borne disease risk in changing environments

evolutionary biology↗

bioRxiv2026

Intestinal bacteria hijack an evolutionarily conserved epithelial repair signal

Apoptosis in the gut triggers an expansion in the Enterobacteriaceae family of bacteria, causing both prolonged tissue injury and delayed repair. However, the mechanisms linking the Enterobacteriaceae bloom and subsequent deleterious tissue response are relatively unknown. Here, we establish purines as a major component of the apoptotic secretome that are consumed by bacteria. Explicitly, we identify hypoxanthine as a critical metabolite that is taken up and metabolised by both pathogenic and commensal species within the Enterobacteriaceae family. Epithelial cells release hypoxanthine into the extracellular space during early stages of apoptosis via the upregulation of equilibrative nucleoside transporters 1/2 (ENT1/2). Critically, beyond simply linking host and microbe, we delineate a connection between the release of hypoxanthine from the dying cell and the ability of the host to repair damaged epithelial tissue. Hypoxanthine is a potent promoter of epithelial cell repair in both gut and skin across the phylogenetic tree including humans, mice, zebrafish, and fruit flies and promotes similar ATP production and cellular proliferation in eukaryotic and microbial recipients. Thus, the preferential utilisation of hypoxanthine by the Enterobacteriaceae directly competes with the host for a core reparative signal.

microbiology↗

bioRxiv2026

A dual-phase enhancer couples progenitor maintenance and pancreatic lineage stability

Enhancers orchestrate transcriptional programs that control organ development and maintain differentiated cell states, yet how individual enhancers integrate developmental and long-term tissue maintenance logic remains poorly understood. Here, we identify a distal enhancer downstream of ptf1a (z3-DpE) as a regulatory node coupling pancreatic development with acinar cell homeostasis in zebrafish. Deletion of z3-DpE reduces ptf1a expression in pancreatic multipotent progenitor cells (MPCs), leading to depletion of the progenitor pool, altered morphogenesis, and premature exocrine differentiation. Transcriptomic analysis reveals broad repression of proliferation- and morphogenesis-related genes, including Notch pathway components essential for progenitor maintenance. After differentiation, loss of z3-DpE contributes to acinar cell loss, expansion of ductal and endocrine compartments, and disrupted pancreatic architecture. Chromatin-accessibility profiling of purified acinar cells reveals that reduced ptf1a activity leads to widespread remodeling of the acinar chromatin landscape, with decreased accessibility at loci associated with acinar identity and developmental programs, and increased accessibility at sites linked to inflammation, epithelial plasticity, and pancreatic cancer susceptibility. Histopathological analysis shows disorganized acinar tissue with increased duct-like structures and mucinous lesions reminiscent of early pancreatic neoplasia. Thus, z3-DpE safeguards acinar identity by sustaining ptf1a expression and a chromatin landscape that restricts fate instability and pathological plasticity. Our findings demonstrate the mechanistic sufficiency of a single enhancer to coordinate progenitor expansion and long-term lineage stabilization, providing a paradigm for how a developmental regulatory element is redeployed to preserve tissue integrity and suppress disease-associated plasticity.

developmental biology↗

bioRxiv2025

JMJD5 regulates metabolism by inhibiting the Arginine Methyltransferase PRMT6

2-Oxoglutarate-dependent dioxygenases (2OGDDs) employ molecular oxygen, 2-oxoglutarate, and ferrous iron to catalyse two-ectron oxidations. This dependency enables some 2OGDD to act as sensors of cellular metabolic states, driving crucial functions when oxygen or metabolic homeostasis is perturbed, including adaptation to low oxygen, epigenetic control of gene transcription, and the reshaping of metabolic pathways. Jumonji-C (JmjC) domain-containing protein 5 (JMJD5), a 2OGDD that regulates epigenetic marks, is essential for DNA damage repair and is a key regulator of cell metabolism. Notably, JMJD5 is often reduced in hepatocellular carcinoma, correlating with poor overall survival. Despite its biological significance, the molecular functions of JMJD5 remain unresolved, and its physiological targets are elusive. Here, we identify and characterise a novel signalling pathway where JMJD5 hydroxylates an arginine residue on the protein ISY1. This modification enables ISY1 to bind to and reduce the activity of Protein Arginine N-methyltransferase 6 (PRMT6). Significantly, the inactivation of PRMT6 rescues the majority of the molecular phenotype driven by JMJD5 loss, establishing the JMJD5-ISY1-PRMT6 pathway as a principal executor of JMJD5s enzymatic function. In a genetically engineered murine liver cancer model, JMJD5 loss suppressed tumour growth and rewired one-carbon, amino acid, and lipid metabolism, recapitulating the network-level changes observed in human HCC cells. This signalling pathway clarifies existing controversies regarding JMJD5s function and identifies PRMT6 as a potential therapeutic target for treating cancers that lack JMJD5.

cell biology↗

bioRxiv2025

Spine-brain dynamics during human defensive threat-reactions

Synchrony between central and autonomic nervous system responses during threat rely on spine-brain interactions. Activation of the parasympathetic autonomic nervous system during acute threat has been linked to optimized action preparation and longer-term stress-resilience. However, it is unclear how this is orchestrated by spine-brain interactions during our widely used models of threat conditioning. Here we used a well-established threat conditioning procedure to test whether freezing-related bradycardia modulates the strength of motor- and sensory-relevant spinal-brain connectivity patterns. Conditioning elicited the expected autonomic and psychophysiological responses, with significant bradycardia and heightened differentiation between conditioned stimuli. Heart rate bradycardia modulated activity in the cingulate cortex and spinal cord, emphasizing their role in freezing. Notably, bradycardia-modulated spinal cord activity during threat was functionally coupled with motor cortex activity, suggesting a preparatory response for defensive actions. Establishing these effects for the first time in humans helps discovery of biomarkers for threat coping-relevant body-brain interactions, essential for clinical evaluations.

neuroscience↗

bioRxiv2024

Uncovering multiscale structure in the variability of larval zebrafish navigation

Animals chain movements into long-lived motor strategies, resulting in variability that ultimately reflects the interplay between internal states and environmental cues. To reveal structure in such variability, we build models that bridges across time scales that enable a quantitative comparison of behavioral phenotypes among individuals. Applied to larval zebrafish exposed to diverse sensory cues, we uncover a hierarchy of long-lived motor strategies, dominated by changes in orientation distinguishing cruising and wandering strategies. Environmental cues induce preferences along these modes at the population level: while fish cruise in the light, they wander in response to aversive (dark) stimuli or in search for prey. Our method enables us to encode the behavioral dynamics of each individual fish in the transitions among coarse-grained motor strategies. By doing so, we uncover a hierarchical structure to the phenotypic variability that corresponds to exploration-exploitation trade-offs. Within a wide range of sensory cues, a major source of variation among fish is driven by prior and immediate exposure to prey that induces exploitation phenotypes. However, a large degree of variability is unexplained by environmental cues, pointing to hidden states that override the sensory context to induce contrasting exploration-exploitation phenotypes. Altogether, our approach extracts the timescales of motor strategies deployed during navigation, exposing undiscovered structure among individuals and pointing to internal states tuned by prior experience.

animal behavior and cognition↗

bioRxiv2024

Antiviral RNA interference targets viral transcripts but not genomes of RNA viruses in Drosophila melanogaster

RNA interference (RNAi) mediated by the small interfering RNA (siRNA) pathway is a major antiviral mechanism in insects. This pathway is triggered when double-stranded RNA (dsRNA) produced during virus replication is recognized by Dicer-2, leading to the formation of virus-derived siRNA duplexes. These siRNAs are loaded onto the programmable nuclease Argonaute-2 (AGO2), with one strand serving as a guide to target and cleave fully complementary sequences of viral RNAs. While siRNAs are generated from viral dsRNA, the specific viral RNA species targeted for silencing during RNA virus replication remains unclear. In this study, we characterized the primary viral RNA targets of the Drosophila siRNA pathway during infections caused by negative and positive RNA viruses, namely Vesicular stomatitis virus (VSV) and Sindbis virus (SINV). Our findings reveal that polyadenylated transcripts of VSV and SINV are the major targets of silencing by the siRNA pathway during infection, likely when they are poised for translation. Consistent with earlier findings, we confirmed that AGO2 copurifies with ribosomes, and this is not affected by virus infection. Therefore, we propose that the inhibition of the replication of RNA viruses in Drosophila results from the silencing of incoming viral transcripts, facilitated by the association of AGO2 with ribosomes. Author SummaryThe small interfering RNA (siRNA) pathway mediates major antiviral immune response in insects, functioning to cleave viral RNA. While this pathway has been extensively studied in the fruit fly Drosophila melanogaster, the specific molecular targets of inhibition by the siRNA pathway have remained unclear. In this study, we aimed to elucidate these targets. Our findings demonstrate that polyadenylated transcripts produced during viral infection are the primary targets of the Drosophila siRNA pathway, in the case of both negative and positive single-stranded RNA viruses. The silencing of these transcripts accounts for the antiviral effect of the siRNA pathway, suggesting that direct targeting of viral RNA genomes is unlikely to occur. We confirmed that Argonaute-2 (AGO2), the core component of the silencing complex, co-purifies with ribosomes and also show that this association is not affected by viral infection. This suggests that AGO2 is in permanent association with ribosomes where it can efficiently scan viral transcripts before they undergo translation by the cellular machinery, thereby preventing viral replication. These results provide valuable insights into the mechanism of gene silencing the siRNA pathway.

immunology↗

bioRxiv2023

ALDH1A3-acetaldehyde re-wires neural crest stem cell and high metabolism states to potentiate melanoma heterogeneity

Cancer cellular heterogeneity and therapy resistance arise substantially from metabolic and transcriptional adaptations, but how these are interconnected is poorly understood. Here, we show that in melanoma, the cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) forms an enzymatic partnership with acetyl-CoA synthetase 2 (ACSS2) in the nucleus to couple high glucose metabolic flux with acetyl-histone H3 modification of neural crest lineage and glucose metabolism genes. Importantly, we show acetaldehyde is a metabolite source for acetyl-histone H3 modification in an ALDH1A3, dependent manner providing a physiologic function for this highly volatile and toxic metabolite. In a zebrafish model of melanoma residual disease, a subpopulation of ALDH1-high cells emerges following BRAF inhibitor treatment and targeting these with an ALDH1 suicide inhibitor, nifuroxazide, delays or prevents BRAF inhibitor drug-resistant relapse. Our work reveals that the ALDH1A3-ACSS2 couple directly coordinates nuclear acetaldehyde-acetyl-CoA metabolism with specific chromatin-based gene regulation and represents a potential therapeutic vulnerability in melanoma. HighlightsO_LIALDH1A3-high melanomas are in a high glucose metabolic flux and neural crest stem cell dual state. C_LIO_LINuclear ALDH1A3 partners with ACSS2 to promote selective acetyl-histone H3. C_LIO_LIAcetaldehyde is an acetyl source for ALDH1A3 dependent histone H3 acetylation. C_LIO_LIALDH1A3 is a master regulator and pharmaceutical target for melanoma heterogeneity. C_LI

cancer biology↗

bioRxiv2022

Resistance to EGFR inhibitors in lung cancer occurs through horizontal transfer and is associated with increased caveolins expression

Resistance to treatment is a major clinical problem and a major cause of cancer-related deaths. Understanding the biological basis of resistance acquisition is of utmost importance to improve the clinical management of cancer patients. NGS analysis of human lung cancer (LC) tumors from patients that relapsed after treatment with EGFR-tyrosine kinase inhibitors (TKI), revealed that the p.T790M resistance mutation is not present in all the relapsing tumor cells, suggesting that LC cells can become resistant even if not carrying the p.T790M mutation. Using in vitro treatments with conditioned medium (CM) and in vivo co-inoculation experiments, we show that LC cells sensitive to EGFR-TKIs (S cells) acquire resistance faster when treated with CM from LC cells resistant to EGFR-TKIs (R cells) or when co-inoculated with R cells in opposite flanks of the same animal. Importantly, we show that acquisition of resistance is not due to the emergence of subpopulations of cancer cells with new resistance mutations. Using transcriptomics, we show that acquisition of resistance is associated with upregulation of genes involved in endocytosis, namely caveolins CAV1 and CAV2. These findings were validated in human clinical samples, where an increase in CAV1 and CAV2 expression was associated with tumor relapse after treatment with EGFR-TKIs. Our results suggest that acquisition of resistance to targeted therapies results from the combined effect of selection of cells harboring specific resistance mutations and horizontal transfer of the resistance phenotype. These findings may pave the way to bring intercellular communication into the realm of cancer treatment. One Sentence SummaryResistance to EGFR inhibitors is transferred horizontally between lung cancer cells and is associated with gain of expression of caveolins.

cancer biology↗

bioRxiv2020

Arterial blood contrast (ABC) enabled by magnetization transfer (MT): a novel MRI technique for enhancing the measurement of brain activation changes

Functional brain imaging in humans is almost exclusively performed using blood oxygenation level dependent (BOLD) contrast. This typically requires a period of tens of milliseconds after excitation of the spin system to achieve maximum contrast, leading to inefficient use of acquisition time, reduced image quality, and inhomogeneous sensitivity throughout the cortex. We utilise magnetisation transfer to suppress the signal differentially from grey matter relative to blood so that the local increase in blood volume associated with brain activation (mainly occurring in the arterioles and capillaries) will increase the measured signal. Arterial blood contrast (ABC) is additive to the residual BOLD effect, but will have its maximum value at the time of excitation. We measured brain activation using combined ABC and residual BOLD contrast at different times post-excitation and compared this to BOLD data acquired under otherwise identical conditions. We conclude that using ABC and measuring shortly after excitation gives comparable sensitivity to standard BOLD but will provide greater efficiency, spatial specificity, improved image quality, and lower inter-subject variability. ABC offers new perspectives for performing functional MRI.

neuroscience↗

bioRxiv2020

Cis-regulatory similarities in the zebrafish and human pancreas uncover potential disease-related enhancers

Introductory paragraphThe pancreas is a central organ for human diseases that have a dramatic societal burden, such as pancreatic cancer and diabetes1,2. Non-coding cis-regulatory elements (CREs) of DNA control gene expression3,4, being required for proper pancreas function. Most disease-associated alleles5,6 are non-coding, often overlapping with CREs5, suggesting that alterations in these regulatory sequences contribute to human pancreatic diseases by impairing gene expression. However, functional testing of CREs in vivo is not fully explored. Here we analysed histone modifications, transcription, chromatin accessibility and interactions, to identify zebrafish pancreas CREs and their human functional equivalents, uncovering disease-associated sequences across species. We found a human pancreatic enhancer whose deletion impairs the tumour suppressor gene ARID1A expression, conferring a potential tumour suppressor role to this non-coding sequence. Additionally, we identified a zebrafish ptf1a distal enhancer which deletion generates pancreatic agenesis, demonstrating the causality of this condition in humans7 and the interspecies functional equivalency of enhancers.

genomics↗

bioRxiv2019

Fungal effector Jsi1 hijacks plant JA/ET signaling through Topless

Ustilago maydis (U. maydis) is the causal agent of maize smut disease. During the colonization process, the fungus secretes effector proteins which suppress immune responses and redirect the host-metabolism in favor of the pathogen. Here we describe a novel strategy by which U. maydis induces plant jasmonate/ethylene (JA/ET) hormone signaling and thereby biotrophic susceptibility. The U. maydis effector Jasmonate/Ethylene signaling inducer 1 (Jsi1) possesses an ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motif, DLNxxP, which interacts with the second WD40 domain of the conserved plant co-repressor family Topless/Topless related (TPL/TPR). Jsi1 interaction with TPL/TPRs leads to derepression of the ethylene response factor (ERF) branch of the JA/ET signaling pathway, supporting biotrophic susceptibility. Jsi1 likely activates the ERF branch by interfering with the binding of endogenous DLNxxP motif-containing ERF transcription factors to TPL/TPR proteins. The identification of effector proteins possessing a DLNxxP motif in different fungal species with biotrophic and hemibiotrophic lifestyles together with the validation of the interaction between such effectors from Magnaporthe oryzae (M. oryzae), Sporisorium scitamineum (S. scitamineum), and S. reilianum with TPL proteins indicates the convergent evolution of effectors for modulating the TPL/TPR co-repressor hub.

plant biology↗