Biology subjects

Sousa, V.

Publications and source records attributed to Sousa, V..

5 recordsLinked to original sources

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

Unexpected changes in reproductive barriers between incipient species after experimental evolution in sympatry

Hybridization is generally considered a temporary phenomenon, but it is actually widespread and may last for large time periods between species that stably coexist. Here, to test whether evolving with a closely-related species modifies or maintains partial reproductive isolation, we performed experimental evolution in artificial sympatry vs. allopatry with two closely-related colour forms of spider mites (Tetranychus urticae) that exhibit an asymmetrical pattern of pre-mating isolation despite almost complete post-zygotic isolation. We assessed whether evolutionary changes occurred in traits associated to (i) pre-mating isolation, (ii) post-mating pre-zygotic and early post-zygotic isolation, and (iii) late post-zygotic isolation. Our results revealed that reinforcement did not occur even under forced long-term sympatric evolution. Instead, the strength of some reproductive barriers decreased (e.g., premating isolation and fertilization failure), and some trait changes indicated convergence rather than divergence between species (e.g., mating propensity, latency to copulation). In fact, both types of males showed the same decreased preference for red-form females across generations in sympatry. In line with this, traits underlying fertilization success evolved in the same direction and with similar amplitude in heterotypic crosses and in their homotypic control, as the offspring sex ratio of green-form females decreased in sympatry irrespective of the male they mated with. Finally, other changes in reproductive barriers resulted from trait correlations (e.g., decreased zygote mortality but increased juvenile mortality). Hence, despite very high costs of hybridization, responses occurring following evolution in sympatry were unrelated to selection directly associated to hybridization, but rather the by-product of other evolutionary forces, with cascading consequences for reproductive barriers. In particular, these results support the underappreciated hypothesis that within-species sexual interactions can constrain population diver-gence, or even drive trait convergence between species, thereby playing a role in the maintenance of partial reproductive isolation.

evolutionary biology↗

bioRxiv2024

Direct inhibitors of InhA with efficacy similar or superior to isoniazid in novel drug regimens for tuberculosis

Isoniazid is an important first-line medicine to treat tuberculosis (TB). Isoniazid resistance increases the risk of poor treatment outcomes and development of multidrug resistance, and is driven primarily by mutations involving katG, encoding the pro-drug activating enzyme, rather than its validated target, InhA. The chemical tractability of InhA has fostered efforts to discover direct inhibitors of InhA (DIIs). During the past five years, successful target engagement and in vivo efficacy have been demonstrated by diverse DIIs. In this study, we bridge the gap in understanding the potential contribution of DIIs to novel combination regimens and demonstrate a clear distinction of DIIs, like GSK693 and the newly described GSK138, from isoniazid, based on activity against clinical isolates and contribution to novel drug regimens. The results presented increase the understanding of DII mechanism of action and provide further impetus to continue exploiting InhA as a promising target for TB drug development.

pharmacology and toxicology↗

bioRxiv2019

Model-based Assessments of Differential Introgression and Linked Natural Selection During Divergence and Speciation

Demographic changes such as fluctuating population size and differential introgression can mask the effects of natural selection, and affect rates of genome evolution, local adaptation, reproductive isolation, and eventual speciation. Besides identifying differentially introgressing genes (and genomic regions) that are \"labeled\" to be retroactively causal to adaptive evolution and speciation, there is significant impetus to understand, and perhaps estimate the underlying demography that affects current genomic diversity. Using model-based likelihood methods to directly estimate, and decouple the effects of differential intogression and demography across genomic loci offers an ideal solution to detect differential introgression, and population demography and build hypotheses around its underlying evolutionary processes. We describe a computationally efficient parallelized implementation of mixture-model based isolation with migration (IM) analyses to assign loci to classes based on their shared coalescent histories (population sizes, or migration rates). We apply this method to several genomic data sets (great apes - chimpanzees and bonobos, Anopheles mosquitoes, threespine sticklebacks, Mullerian mimics of Heliconius butterflies, mice, European rabbits, and fruitflies), that have been previously characterized (perhaps erroneously) using genome-wide scans of differentiation. We show that we cannot reject a model of differential introgression, or linked selection across a majority of species analyzed, with two species showing the combined effects of differential introgression and linked natural selection across multiple, non-independent genomic loci.

evolutionary biology↗

bioRxiv2018

The population history of northeastern Siberia since the Pleistocene

Far northeastern Siberia has been occupied by humans for more than 40 thousand years. Yet, owing to a scarcity of early archaeological sites and human remains, its population history and relationship to ancient and modern populations across Eurasia and the Americas are poorly understood. Here, we analyze 34 ancient genome sequences, including two from fragmented milk teeth found at the ~31.6 thousand-year-old (kya) Yana RHS site, the earliest and northernmost Pleistocene human remains found. These genomes reveal complex patterns of past population admixture and replacement events throughout northeastern Siberia, with evidence for at least three large-scale human migrations into the region. The first inhabitants, a previously unknown population of \"Ancient North Siberians\" (ANS), represented by Yana RHS, diverged ~38 kya from Western Eurasians, soon after the latter split from East Asians. Between 20 and 11 kya, the ANS population was largely replaced by peoples with ancestry related to present-day East Asians, giving rise to ancestral Native Americans and \"Ancient Paleosiberians\" (AP), represented by a 9.8 kya skeleton from Kolyma River. AP are closely related to the Siberian ancestors of Native Americans, and ancestral to contemporary communities such as Koryaks and Itelmen. Paleoclimatic modelling shows evidence for a refuge during the last glacial maximum (LGM) in southeastern Beringia, suggesting Beringia as a possible location for the admixture forming both ancestral Native Americans and AP. Between 11 and 4 kya, AP were in turn largely replaced by another group of peoples with ancestry from East Asia, the \"Neosiberians\" from which many contemporary Siberians derive. We detect gene flow events in both directions across the Bering Strait during this time, influencing the genetic composition of Inuit, as well as Na Dene-speaking Northern Native Americans, whose Siberian-related ancestry components is closely related to AP. Our analyses reveal that the population history of northeastern Siberia was highly dynamic throughout the Late Pleistocene and Holocene. The pattern observed in northeastern Siberia, with earlier, once widespread populations being replaced by distinct peoples, seems to have taken place across northern Eurasia, as far west as Scandinavia.

genomics↗