Biology subjects

Alves, I.

Publications and source records attributed to Alves, I..

5 recordsLinked to original sources

bioRxiv2026

Uncovering a Sex-Specific cAMP Landscape in Vascular Smooth Muscle

The second messenger, cyclic adenosine monophosphate (cAMP), plays a crucial role in regulating cellular function, including in vascular smooth muscle (VSM). While extensive research has focused on the compartmentalization of cAMP signaling in various cell types, the influence of biological sex on distinct cAMP pools and their functional implications in the VSM remains largely unexplored. To address this knowledge gap, we employed a multiscale experimental approach spanning targeted cAMP biosensors, wire myography, live-cell calcium imaging, proximity ligation assays, and in vivo ultrasound imaging. Our findings reveal a sex-specific distribution of cAMP signaling domains, with the cAMP pool selectively present in the SR of females but not males in the VSM. Ovariectomy abolished this sexual dimorphism, with SR cAMP pools disappearing in ovx females, mirroring the pattern observed in male cells. Males and ovx female VSM exhibited a significantly stronger RyR-PDE3/PDE4 association than sham females, suggesting that ovarian hormone-dependent sequestration of phosphodiesterases away from the SR licenses cAMP signaling in this compartment in female cells. Functionally, this sexually dimorphic cAMP compartmentalization correlates with smaller Ca2+ spark amplitude, reduced isoproterenol-induced relaxation, and higher pulse wave velocity in male and ovx compared to female VSM/vessels/mice. Together, these findings establish biological sex as a fundamental determinant of subcellular cAMP organization in VSM, with implications for understanding sex differences in vascular function and cardiovascular disease.

cell biology↗

bioRxiv2023

Membrane lipid poly-unsaturation selectively affects ligand induced dopamine D2 receptor internalization

The brain is highly enriched in poly-unsaturated fatty acids (PUFAs) and their deficiency has been associated with several neuropsychiatric disorders. Here, we demonstrate that the Dopamine receptor D2 (D2R), a class A G protein coupled receptor (GPCR) which is a main target of antipsychotics, displays unique sensitivity to membrane PUFA composition. We found that membrane enrichment with either of two distinct PUFAs significantly impairs agonist-induced D2R endocytosis in HEK-293 cells and cortical neurons. This treatment does not affect clathrin-mediated endocytosis or the internalization of several other GPCRs. Moreover, we show that D2R clustering at endocytic pits is not affected, but that recruitment of {beta}-arrestin2 is strongly impaired and endocytic vesicle formation is slowed down. Finally, mutation of key residues in intracellular loop 2 abolishes the sensitivity of D2R endocytosis to PUFA enrichment. We conclude that D2R trafficking is uniquely dependent on membrane PUFAs, which could influence its role in the control of brain function and behavior.

cell biology↗

bioRxiv2022

Genetic population structure across Brittany and the downstream Loire basin provides new insights on the demographic history of Western Europe

European genetic ancestry originates from three main ancestral populations - Western hunter-gatherers, early European farmers and Yamnaya Eurasian herders - whose edges geographically met in present-day France. Despite its central role to our understanding of how the ancestral populations interacted and gave rise to modern population structure, the population history of France has remained largely understudied. Here, we analysed the high-coverage whole-genome sequences and genome-wide genotype profiles of respectively 856 and 3,234 present-day individuals from the northern half of France, and merged them with publicly available present-day and ancient Europe-wide genotype datasets. We also explored, for the first time, the whole-genome sequences of six mediaeval individuals (300-1100 CE) from Western France to gain insights into the genetic impact of what is commonly known as the Migration Period in Europe. We found extensive fine-scale population structure across Brittany and the downstream Loire basin, emphasising the need for investigating local populations to better understand the distribution of rare and putatively deleterious variants across space. Overall, we observed an increased population differentiation between the northern and southern sides of the river Loire, which are characterised by different proportions of steppe vs. Neolithic-related ancestry. Samples from Western Brittany carry the largest levels of steppe ancestry and show high levels of allele sharing with individuals associated with the Bell Beaker complex, levels that are only comparable with those found in populations lying on the northwestern edges of Europe. Together, our results imply that present-day individuals from Western Brittany retain substantial legacy of the genetic changes that occurred in Northwestern Europe following the arrival of the Bell Beaker people c. 2500 BCE. Such genetic legacy may explain the sharing of disease-related alleles with other present-day populations from Western Britain and Ireland.

genetics↗

bioRxiv2022

Impact of membrane lipid polyunsaturation on dopamine D2 receptor ligand binding and signaling

The heterogenous and dynamic constitution of the membrane fine-tunes signal transduction. In particular, the polyunsaturated fatty acid (PUFA) tails of phospholipids influence the biophysical properties of the membrane, production of second messengers, or membrane partitioning. Few evidence mostly originating from studies of rhodopsin suggest that PUFAs directly modulate the conformational dynamic of transmembrane proteins. However, whether such properties translate to other G protein-coupled receptors remains unclear. We focused on the dopamine D2 receptor (D2R), a main target of antipsychotics. Membrane enrichment in n-3, but not n-6, PUFAs potentiates ligand binding. Molecular dynamics simulations show that the D2R preferentially interacts with n-3 over n-6 PUFAs. Furthermore, even though this mildly affects signalling in heterologous systems, in vivo n-3 PUFA deficiency blunts the effects of D2R ligands. These results suggest that n-3 PUFAs act as allosteric modulators of the D2R and provide a putative mechanism for their potentiating effect on antipsychotic efficacy.

cell biology↗

bioRxiv2019

The Genetic History of France

The study of the genetic structure of different countries within Europe has provided significant insights into their demographic history and their actual stratification. Although France occupies a particular location at the end of the European peninsula and at the crossroads of migration routes, few population genetic studies have been conducted so far with genome-wide data. In this study, we analyzed SNP-chip genetic data from 2 184 individuals born in France who were enrolled in two independent population cohorts. Using FineStructure, six different genetic clusters of individuals were found that were very consistent between the two cohorts. These clusters match extremely well the geography and overlap with historical and linguistic divisions of France. By modeling the relationship between genetics and geography using EEMS software, we were able to detect gene flow barriers that are similar in the two cohorts and corresponds to major French rivers or mountains. Estimations of effective population sizes using IBDNe program also revealed very similar patterns in both cohorts with a rapid increase of effective population sizes over the last 150 generations similar to what was observed in other European countries. A marked bottleneck is also consistently seen in the two datasets starting in the fourteenth century when the Black Death raged in Europe. In conclusion, by performing the first exhaustive study of the genetic structure of France, we fill a gap in the genetic studies in Europe that would be useful to medical geneticists but also historians and archeologists.

genetics↗