Biology subjects

Jaquet, V.

Publications and source records attributed to Jaquet, V..

4 recordsLinked to original sources

bioRxiv2026

Redistribution of codon-optimality effects: measurement strategy alters the division of labor between translation and mRNA decay

Codon optimality promotes efficient translation and, as recent research has shown, also extends mRNA lifetimes. However, how control is distributed between translation and mRNA degradation remains unclear. We show that this relative impact depends strongly on the measurement approach. Using fluorescent protein reporters can underestimate codon-optimality-dependent increases in translation efficiency. Conversely, analyses based on poly(A)-selected RNA overestimate the impact on translation, because stable transcripts undergoing poly(A) shortening are often inefficiently captured, leading to skewed protein-to-mRNA ratios. This technical bias is not offset by the marginal decline in ribosomal association observed as mRNAs age. Estimates based on total RNA measurements redistribute some of the control attributed to translation to mRNA stability, making the contributions comparable for mRNAs with shorter coding sequences. For longer mRNAs, codon optimality increasingly controls elongation speed, with a greater effect on translation efficiency than on degradation. These insights highlight the importance of measurement strategy for accurately quantifying the determinants of mRNA stability and protein synthesis.

biochemistry↗

bioRxiv2026

Otenabant is a Selective Antagonist of Human PIEZO1

Background and purposePIEZO1 mechanosensitive cation channels translate mechanical cues into intracellular Ca2+ and Na+ elevations, enabling cells to respond to physical alterations in their environment. PIEZO1 contributes to red blood cells (RBC) volume homeostasis and gain-of-function PIEZO1 mutations cause hereditary xerocytosis (HX), a rare mostly compensated hemolytic anemia, and aberrant channel activation exacerbates sickling and vascular dysfunction in sickle cell disease. Despite strong genetic and physiological evidence supporting PIEZO1 as a therapeutic target, potent and selective inhibitors are limited, and existing compounds show modest specificity or poorly explored mechanisms. Improved pharmacological tools are needed. Experimental approachWe conducted a high-throughput screen of FDA-approved drugs to identify PIEZO1 inhibitors. Compounds were tested at concentrations of 10 {micro}M in a monocytic cell line, using intracellular Ca2+ elevations evoked by the PIEZO1 agonist Yoda1 as read-out. The inhibitory activity of the best hit was validated and compared to existing PIEZO1 inhibitors using electrophysiological analysis, orthogonal PIEZO1-dependent assays across cell lines and human RBCs. As functional proof, we investigated the impact of three PIEZO1 inhibitors on RBC deformability by ektacytometry, after Yoda1 pre-stimulation. Key resultsThis screen identified Otenabant, a selective Cannabinoid Receptor Type 1 (CB1) antagonist, as a potent PIEZO1 inhibitor. Otenabant dose-dependently inhibited Ca2+ elevations mediated by endogenous or exogenously expressed human PIEZO1, but was ineffective against mouse Piezo1, revealing species-specific channel differences. Otenabant inhibited mechanosensitive currents elicited by shear stress in fibroblasts and by repeated poking in PIEZO1-expressing HEK-293 cells, altering the currents activation and inactivation kinetics, and prevented Yoda1-induced hyperpolarization in RBCs. Otenabant was able to reverse the negative impact of Yoda1 on RBC deformability. Conclusions and implicationsThese findings demonstrate the utility of Yoda-based screening for discovering PIEZO1 antagonists and identify Otenabant as a promising chemical scaffold for developing selective PIEZO1 inhibitors with therapeutic potential.

pharmacology and toxicology↗

bioRxiv2023

The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm

The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput-screening (HTS) assay to measure changes in [Ca2+]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm motility, acrosomal exocytosis (AR), and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiological concentrations. Stanozolol, epiandrosterone, and pregnenolone induced AR similarly to P4, whereas stanozolol and estropipate induced an increase in sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and affect human sperm functions in vitro.

cell biology↗

bioRxiv2018

Navigating in vitro bioactivity data: investigating available resources using model compounds

Modern medicine and an increasingly complex environment contribute to exposure of humans to a large number of chemical compounds, that can potentially be toxic. Although widely used, compound testing in animals has important limitations. In vitro testing provides a promising alternative. However, because of the relative inaccessibility and fragmentation of available data, the in vitro approach largely underperforms its potential. The aim of this study is to investigate how available public online resources (tools and databases) support accessing and distribution of in vitro compound data. We examined 19 public online resources, mapped their features, and evaluated their usability with a set of four model compounds (aspirin, rosiglitazone, valproic acid, and tamoxifen). By investigating compound names and identifiers, we observed extensive variation and inconsistencies in available resources: the synonyms were different, compounds structural identifiers (InChI, InChIKey, SMILES and IUPAC systematic name) underperformed in omics databases, identification of compound related metadata (e.g. concentrations used in the experiments) from omics experiments was complex and none of the available resources clearly distinguished between in vivo and in vitro data. In addition, we estimated accessibility of selected public resources using computational queries. Only a few public resources provided access to compound-related data using semantic web technology. The general quality of experiment annotations created further difficulties in identifying data of interest. Therefore, we identified several standardized ontologies with potential to provide an increased accuracy for extensive data retrieval of in vitro compound data. Furthermore, using the examples of our model compounds, we provide recommendations on the use of ontologies by suggesting specific ontology terms to annotate in vitro experimental data when being published.

pharmacology and toxicology↗