Biology subjects

Mercier, J.

Publications and source records attributed to Mercier, J..

6 recordsLinked to original sources

bioRxiv2026

RyR2-Dependent Calcium Leak Drives the Acute Cardiovascular Manifestations of Ciguatera Poisoning: implications for an emerging climate-sensitive cardiotoxic disease

Background: Ciguatera is the most prevalent non-bacterial seafood poisoning worldwide. It results from the consumption of fish contaminated with ciguatoxins (CTXs). Cardiovascular manifestations are frequently reported in affected patients; however, the molecular mechanisms underlying CTX-induced cardiac dysfunction remain poorly understood. Methods: We investigated the effects of purified CTX-1B and CTX-3C on human induced pluripotent stem-cell-derived ventricular cardiomyocytes. Electrophysiology, intracellular calcium cycling and contractility, and cellular structure were assessed. The RyR2 channel activity was studied in planar lipid bilayers, and molecular docking was used to identify a potential CTX-1B interaction site. Consequences on cardiac function were assessed in rats using echocardiography and EKG. Findings: We found that ciguatoxin exposure rapidly increased diastolic intracellular calcium, with severe impacts on the cardiac excitation-contraction coupling, and caused sarcomeric disorganization in human cardiomyocytes. Single-channel recordings indicated that CTX-1B prolonged RyR2 openings at resting cytosolic calcium and altered ATP-dependent gating. These findings are consistent with a state-dependent remodeling of RyR2 gating rather than uniform potentiation. Docking placed CTX-1B within the RyR2 transmembrane region, near ATP-associated regulatory elements. In rats, CTX-1B caused premature atrial contractions, ventricular ectopy, and acute cardiac dysfunction, with impaired relaxation. Interpretation: These findings identify RyR2-dependent calcium leak as a plausible contributor to ciguatoxin cardiotoxicity and extend the established model based on sodium-channel activation and altered sarcolemmal ion handling. Combined disruption of membrane excitability and intracellular calcium release could explain the rapid electrical and mechanical abnormalities associated with ciguatera. As intensive international shipping traffic and the global dispersal of harmful microalgae via ballast water expand exposure risk alongside the international seafood trade, ciguatera should be considered an emerging global cardiovascular hazard.

physiology↗

bioRxiv2026

Vitality capacity preservation through lifelong aerobic exercise: a pathway to healthy ageing

BackgroundThe distinction between healthy and pathological ageing has led to the concept of vitality capacity (VC), which can be understood as the bodys physiological reserve. An individuals VC can be estimated using 12 biomarkers spread across 3 domains: immune and stress response, energy and metabolism and neuromuscular function. Vitality capacity may be preserved by lifelong physical activity. This cross-sectional study aimed to examine the relationship between lifelong aerobic physical activity and VC. MethodsVC of 20 lifelong active and 19 inactive healthy adults aged >55 years was assessed using 12 biomarkers across the three VC domains. Domain-specific z-scores were calculated and averaged to derive a global VC score. Principal component analysis was performed and loadings extracted to estimate domains weight, and multiple correlations were conducted to identify associations among biomarkers, domains and VC scores. ResultsVC was higher in lifelong active participants (+0.2 z-score units, p = 0.006) and correlated with age (r = -0.53, p < 0.001). Neuromuscular domain contributed most to VC variability, and the immune and stress response domain was higher in the active group (+0.4 z-score units, p = 0.001) as energy/metabolism among female participants (+0.5 z-score units, p.adj = 0.006). ConclusionLifelong aerobic physical activity is associated with higher VC in older adults, particularly within the immune and stress response domain. These findings highlight the role of physical activity in preserving the physiological reserve and reinforce the relevance of lifelong aerobic physical activity as a driver of healthy ageing.

physiology↗

bioRxiv2026

In silico evaluation of the effects of temperature on the affinity of the SV2C ligand UCB-1A to SV2 isoforms

Synaptic vesicle glycoproteins 2 (SV2) are integral membrane proteins essential for neurotransmitter release and are implicated in neurological disorders including epilepsy and Parkinsons disease. In the attempt to develop a ligand selective for SV2C, and in collaboration with UCB, UCB-F was identified as a potential candidate. However, the affinity of UCB-F to SV2C was found to be temperature dependent, decreasing by about 10-fold from +4 to 37 degrees. UCB1A was subsequently identified as SV2C ligand displaying in vitro a 100-fold selectivity for SV2C compared with SV2A. In this study we investigated whether the binding of UCB-1A to SV2A and SV2C was affected by the temperature. A combination of experimental binding assay data and molecular dynamics (MD) simulations were used. The binding studies revealed that UCB1A affinity for SV2A decreased significantly at 37 {degrees}C compared with 4 {degrees}C, whereas binding to SV2C remained largely unchanged. MD simulations reproduced these observations, namely that ligand RMSD values at 310 K showed that UCB1A binding fluctuated markedly in the SV2A complex, with many trajectories exceeding the 3.0 [A] stability cutoff, whereas UCB1A remained relatively well-anchored in SV2C under the same conditions. Structural analysis showed that, while UCB1A adopts a conserved binding pose across all isoforms stabilized by {pi}- {pi} stacking and a hydrogen bond with Asp, SV2C possesses a unique stabilizing feature. In SV2C, Tyr298 is less exposed to the solvent and engages in a persistent hydrogen bond with Asparagine, a structural feature that reinforces pocket stability and limits temperature-induced destabilization. This interaction is absent in SV2A, consistent with its greater temperature sensitivity. Together, these findings provide a mechanistic explanation for the experimentally observed temperature independence of UCB1A binding to SV2C. More broadly, the results highlight the importance of incorporating physiologically relevant temperatures into SV2 ligand evaluation and demonstrate how combining experiments with simulations can uncover isoform-specific mechanisms of ligand recognition and stability.

biochemistry↗

bioRxiv2026

Discovery and characterization of UCB-1A: the first PET radioligand for imaging synaptic vesicle glycoprotein 2C

The synaptic vesicle glycoprotein 2C (SV2C) is a synaptic protein involved in the regulation of dopamine release. It is expressed in striatum, globus pallidus and substantia nigra, regions involved in the regulation of motor function. Genome-wide association studies, animal model and human brain tissue data indicate a strong link between SV2C and Parkinso[n]s disease, suggesting a potential role of SV2C as synaptic marker for Parkinso[n]s disease. We hypothesize that a positron emission tomography (PET) radioligand for SV2C can serve as imaging marker for Parkinso[n]s disease, enabling early diagnosis and assessment of disease progression. This study was therefore designed to develop a PET radioligand for imaging SV2C. UCB-1A was the lead candidate selected from a library of compounds developed by UCB BioPharma. A translational approach was used, including autoradiography and in vitro binding studies with [3H]UCB-1A, and in vivo PET studies with [11C]UCB-1A in non-human primates (NHPs). The KD of [3H]UCB-1A for rat and human SV2C ranged between 6 and 15 nM, with >100-fold selectivity towards SV2A and SV2B. Specific binding of [3H]UCB-1A in rat and NHP brains was observed in substantia nigra, globus pallidus, striatum and brainstem nuclei, consistent with the expression of SV2C, and was decreased in the striatum of 6-hydroxydopamine-lesioned rats and in the putamen of Parkinson donors. UCB-1A was successfully radiolabelled with 11C and PET studies in NHPs demonstrated that [11C]UCB-1A displays suitable pharmacokinetic properties, a brain distribution consistent with the expression of SV2C and is selective for SV2C. [11C]UCB-1A is the first PET radioligand for in vivo imaging of SV2C and a potential synaptic marker for in vivo studies in Parkinso[n]s disease.

neuroscience↗

bioRxiv2021

ContaTester: Fast cross-contamination estimation and identification for large human sequencing cohorts

BackgroundInterest in genomic medicine for human health studies and clinical applications is rapidly increasing. Clinical applications require contamination-free samples to avoid misleading results and provide a sound basis for diagnosis. ResultsHere we present ContaTester, a tool which requires only allele balance information gathered from a VCF file to detect cross-contamination in germline human DNA samples. Based on a regression model of allele balance distribution, ContaTester allows fast checking of contamination levels for single samples or large cohorts (less than two minutes per sample). We demonstrate the efficiency of ContaTester using experimental validations: ContaTester shows similar results to methods requiring alignment data but with a significantly reduced storage footprint and less computation time. Additionally, for contamination levels above 5%, ContaTester can identify contaminants across a cohort, providing important clues for troubleshooting and quality assessment. ConclusionsContaTester estimates contamination levels from VCF files generated from whole genome sequencing normal sample and provides reliable contaminant identification for cohorts or experimental batches.

bioinformatics↗

bioRxiv2017

GROOLS: reactive graph reasoning for genome annotation through biological processes

BackgroundHigh quality functional annotation is essential for understanding the phenotypic consequences encoded in a genome. Despite improvements in bioinformatics methods, millions of sequences in databanks are not assigned reliable functions. The curation of protein functions in the context of biological processes is a way to evaluate and improve their annotation.\n\nResultsWe developed an expert system using paraconsistent logic, named GROOLS (Genomic Rule Object-Oriented Logic System), that evaluates the completeness and the consistency of predicted functions through biological processes like metabolic pathways. Using a generic and hierarchical representation of knowledge, biological processes are modeled in a graph from which observations (i.e. predictions and expectations) are propagated by rules. At the end of the reasoning, conclusions are assigned to biological process components and highlight uncertainties and inconsistencies. Results on 14 microbial organisms are presented.\n\nConclusionsGROOLS software is designed to evaluate the overall accuracy of functional unit and pathway predictions according to organism experimental data like growth phenotypes. It assists biocurators in the functional annotation of proteins by focusing on missing or contradictory observations.

bioinformatics↗