Biology subjects

Gouveia, M.

Publications and source records attributed to Gouveia, M..

4 recordsLinked to original sources

bioRxiv2026

Concentration limits and localization of hydrogen peroxide in the extracellular space of solid tissues

H2O2 released to the extracellular space (ECS) regulates diverse physiological processes, yet its concentrations and spatial distribution in tissues remain poorly defined. This uncertainty hampers mechanistic understanding of redox signaling. Here, we used reaction-diffusion modeling to estimate extracellular H2O2 concentrations and transport ranges in various scenarios. Idealized analytical models were combined with numerical models incorporating localized NADPH oxidase (NOX) clusters, ECS microstructure, membrane permeability, and the thioredoxin- and GSH-dependent clearance systems. Using maximal neutrophil and NOX superoxide/H2O2 release rates, we obtained upper bounds for extracellular H2O2. Adjacent to isolated average-sized, fully active NOX2 clusters H2O2 peaked at ~540 nM at adhesion cell-cell separations, and decreased radially over ~50-100 nm. At the receptor cell surface, peak concentration decreased inversely with intercellular separation, to <5 nM at 1 m separation. Radial decrease here, for this wide separation, was over ~2.5 m. Even the former maximal extracellular concentrations induce just a minimal, highly localized oxidation of the intracellular Prdx, Trx and GSH pools. In turn, maximally activated neutrophils carry ~2000 such NOX2 clusters, inducing 10s of M peak ECS H2O2 concentrations. These cause extensive Prdx and Trx oxidation near the exposed membranes. However, the GSH-dependent system still sustains a strong transmembrane gradient if the permeation barrier remains intact, and ECS H2O2 concentrations decay to sub-M within a few m of the source cell. Extracellular H2O2 concentrations scaled linearly with source flux in all the examined conditions. These results establish stringent constraints on autocrine, juxtacrine and next-cell paracrine H2O2 signaling.

systems biology↗

bioRxiv2026

Common germline polymorphisms and somatic cancer mutations exhibit non-random positional overlap across the human genome

Germline and somatic mutations have traditionally been studied independently because they arise in distinct biological contexts and are shaped by different selective pressures. Despite these differences, both originate from the same molecular processes of DNA damage, replication error, and DNA repair. Yet this separation has limited the opportunity of investigation of genomic loci recurrently mutated across both mutational landscapes. Identifying such mutational co-occurrences may provide unique insights into the principles governing recurrent mutation. Here, we show that common germline polymorphisms and cancer-associated somatic SNVs recur at identical genomic positions across the human genome, sharing the same nucleotide substitutions more frequently than expected by chance. This recurrence persists within coding regions, is only minimally explained by the canonical hotspot contexts evaluated here (CpG islands and microsatellites), and is associated with a mutational signature profile enriched for the ubiquitous clock-like SBS5 signature together with DNA repair-associated signatures. Importantly, this overlap pattern is not shared across other germline variation: rare (AF<1%) and clinically classified variants exhibit significantly less overlap than expected. Together, these findings support the existence of intrinsically vulnerable genomic loci and provide a framework for investigating the mechanisms underlying recurrent mutation.

bioinformatics↗

bioRxiv2022

Unappreciated Subcontinental Admixture in Europeans and European Americans: Implications for Genetic Epidemiology Studies

European-ancestry populations are recognized as stratified but not as admixed, implying that residual confounding by locus-specific ancestry can affect studies of association, polygenic adaptation, and polygenic risk scores. We integrated individual-level genome-wide data from ~19,000 European-ancestry individuals across 79 European populations and five European American cohorts. We generated a new reference panel that captures ancestral diversity missed by both the 1000 Genomes and Human Genome Diversity Projects. Both Europeans and European-Americans are admixed at subcontinental level, with admixture dates differing among subgroups of European Americans. After adjustment for both genome-wide and locus-specific ancestry, associations between a highly differentiated variant in LCT (rs4988235) and height or LDL-cholesterol were confirmed to be false positives whereas the association between LCT and body mass index was genuine. We provide formal evidence of subcontinental admixture in individuals with European ancestry, which, if not properly accounted for, can produce spurious results in genetic epidemiology studies.

evolutionary biology↗

bioRxiv2020

Cortical stiffness of keratinocytes measured by lateral indentation with optical tweezers

Keratin intermediate filaments are the principal structural element of epithelial cells. Their importance in providing bulk cellular stiffness is well recognized, but their role in the mechanics of cell cortex is less understood. In this study, we therefore compared the cortical stiffness of three keratinocyte lines: primary wild type cells (NHEK2), immortalized wild type cells (NEB1) and immortalized mutant cells (KEB7). The cortical stiffness was measured by lateral indentation of cells with AOD-steered optical tweezers without employing any moving mechanical elements. The method was validated on fixed cells and Cytochalasin-D treated cells to ensure that the observed variations in stiffness within a single cell line were not a consequence of low measurement precision. The measurements of the cortical stiffness showed that primary wild type cells were significantly stiffer than immortalized wild type cells, which was also detected in previous studies of bulk elasticity. In addition, a small difference between the mutant and the wild type cells was detected, showing that mutation of keratin impacts also the cell cortex. Thus, our results indicate that the role of keratins in cortical stiffness is not negligible and call for further investigation of the mechanical interactions between keratins and elements of the cell cortex.

biophysics↗