Biology subjects

Polack, B.

Publications and source records attributed to Polack, B..

3 recordsLinked to original sources

bioRxiv2024

Transcriptomic plasticity in hybrid schistosomes can contribute to their zoonotic potential

Hybrids between Schistosoma haematobium and S. bovis are linked to both human and animal infections, highlighting the complex interspecies interactions that contribute to the spread of schistosomiasis. Additionally, S. bovis can infect multiple ruminant hosts, facilitating cross- species transmission and increasing the risk of zoonotic outbreaks. In this study, we investigated transcriptomic plasticity as a potential mechanism enabling hybrid schistosomes to adapt to alternative definitive hosts. We focused on two contexts: 1) introgressed S. haematobium x S. bovis hybrids, which demonstrated higher virulence in sheep compared to parental S. bovis, and 2) S. bovis infecting different host species. Our analysis uncovered 366 differentially expressed genes (DEGs), representing 4% of the total protein-coding genes, between introgressed hybrids and parental S. bovis in sheep. We also identified transcriptomic changes in S. bovis across different mammalian hosts (hamster and sheep), with around 30% of the total genes differentially expressed, demonstrating that S. bovis parasites display a high transcriptomic plasticity, allowing them to infect different definitive hosts. Shared enriched biological processes during introgression and host change include nuclear-transcribed mRNA catabolic processes, inner mitochondrial membrane organization, microtubule-based movement, response to endoplasmic reticulum stress, and sensory perception. These findings suggest that transcriptomic plasticity in S. bovis and hybrid worms enhance their ability to adapt and infect diverse host species, potentially increasing their zoonotic potential. This raises concerns for schistosomiasis epidemiology, as this plasticity could expand the parasites transmission capacity and complicate control efforts.

evolutionary biology↗

bioRxiv2022

Rationally designed Gla-domainless FXa as TFPI bait in hemophilia

Gla-domainless factor Xa (GD-FXa) was proposed as a trap to the endogenous anticoagulant Tissue Factor Pathway Inhibitor (TFPI) to restore thrombin generation in hemophilia. Using computational chemistry and experimental approaches, we previously showed that S195A GD-FXa also binds TFPI and restores ex vivo coagulation in hemophilia plasmas. To design a GD-FXa variant with improved anti-TFPI activity and identify suitable sites for mutagenesis, we performed molecular dynamics simulations. The calculations identified residues R150FXa and K96FXa as cold-spots of interaction between GD-FXa and the K2 domain of TFPI. In the three-dimensional model, both residues are facing TFPI hydrophobic residues and are thus potential candidates for mutagenesis into hydrophobic residues to favor an improved protein-protein interaction. Catalytically inactive GD-FXa variants containing the S195A mutation and additional mutations as K96Y, R150I, R150G and R150F were produced to experimentally confirm these computational hypotheses. Among these mutants, the R150FFXA showed increased affinity for TFPI as theoretically predicted, and was also more effective than S195A GD-FXa in restoring coagulation in FVIII deficient plasmas. Moreover, the R150 mutants lost interaction with antithrombin, which is favorable to extend their half-life.

bioengineering↗

bioRxiv2018

Aggregates dramatically alter fibrin ultrastructure.

Among the many factors influencing fibrin formation and structure (concentration, temperature, composition, pH,...), it has been suggested that the polydispersity of fibrinogen may play an important role. We propose here a detailed investigation of the influence of this parameter on fibrin multiscale structure.\n\nTwo commercial fibrinogen preparations were used, a monodisperse and a polydisperse one. First, the respective compositions of both fibrinogen preparations were thoroughly determined by measuring the FXIII, fibronectin, ,{beta} and {gamma} intact-chains contents, the{gamma}/{gamma} chains ratio, the N-glycosylation and the post-translational modifications. Slight variations between the composition of the two fibrinogen preparations were found which are much smaller than the compositional variations necessary to alter significantly fibrin multiscale structure as observed in the literature. Conversely, MALLS coupled SEC and DLS measurements showed that the polydisperse preparation contains significant amounts of aggregates while the other preparation is essentially monodisperse.\n\nThe multiscale structure of the fibrins produced from those two fibrinogen preparations was determined by using X-ray scattering, spectrophotometry, and confocal microscopy. Results show that fibers from the monodisperse fibrinogen present a crystalline longitudinal and lateral structure and form a needle-like network. The internal structure of fibers produced from the polydisperse fibrinogen looks amorphous with star-like branching nodes. The multiscale structure of mixtures between the two preparations shows a smooth evolution, demonstrating that the quantity of aggregates is a major determining factor for fibrin multiscale structure. Indeed, the effect of a few percent in mass of aggregates is larger than any other effect due to compositional differences under the same reaction conditions. Finally we propose a mechanistic interpretation of our results which points at a direct role of the aggregates during polymerization which disrupt the ideal ordering of monomers inside fibrin protofibrils and fibers.

biophysics↗