Étude de relation structure-activité d’un inhibiteur de l’enzyme PACE4 comme traitement du cancer de la prostate

Le cancer est en tête de file des causes de décès au Canada où l’on estime que près de 30% des décès sont attribuables à cette maladie. Le cancer de la prostate est l’un des types de cancer les plus importants -le plus prévalent chez l’homme- et ses traitements actuels sont invasifs, coûteux ou encore peu efficaces sur le long terme, d’où la nécessité de trouver de nouvelles approches thérapeutiques. Notre équipe a démontré que la proprotéine convertase PACE4 est surexprimée dans les adénocarcinomes prostatiques et qu’elle est essentielle à la progression tumorale. L’inhibition de cette enzyme permettrait donc d’augmenter significativement la durée et qualité de vie des patients. Des études SAR (Structure Activity-Relationship) préalables nous ont permis de concevoir un inhibiteur peptidique (le peptide Multi-Leu) ayant une excellente affinité contre la PACE4 et une efficacité in vivo démontrée sur des modèles de souris xénogreffées. Multi-Leu étant de nature peptidique, il est très susceptible à la dégradation par les protéases endogènes si bien que sa stabilité s’avère insuffisante pour en faire un composé viable dans un contexte clinique. Le présent ouvrage est divisé en deux sections : il sera d’abord question de nos travaux de SAR visant à préserver les paramètres pharmacocinétiques viables de notre tête de série originale tout en améliorant sa stabilité métabolique. Ces travaux ayant démontré à plusieurs reprises des valeurs de Ki de l’ordre du nM en essai enzymatique, mais une faible activité antiproliférative chez les lignées de cellules cancéreuses exprimant PACE4, nous avons étudié l’hypothèse d’une faible perméabilité métabolique via des essais PAMPA et par cycométrie de flux (FACS). Nos efforts nous ont permis d’améliorer significativement le profil pharmacocinétique de notre composé peptidomimétique, nous amenant un pas plus près d’un traitement novateur du cancer de la prostate

RAD-QTL mapping reveals both genome-level parallelism and different genetic architecture underlying the evolution of body shape in Lake Whitefish (Coregonus clupeaformis) species pairs

Parallel changes in body shape may evolve in response to similar environmental conditions, but whether such parallel phenotypic changes share a common genetic basis is still debated. The goal of this study was to assess whether parallel phenotypic changes could be explained by genetic parallelism, multiple genetic routes, or both. We first provide evidence for parallelism in fish shape by using geometric morphometrics among 300 fish representing five species pairs of Lake Whitefish. Using a genetic map comprising 3438 restriction site-associated DNA sequencing single-nucleotide polymorphisms, we then identified quantitative trait loci underlying body shape traits in a backcross family reared in the laboratory. A total of 138 body shape quantitative trait loci were identified in this cross, thus revealing a highly polygenic architecture of body shape in Lake Whitefish. Third, we tested for evidence of genetic parallelism among independent wild populations using both a single-locus method (outlier analysis) and a polygenic approach (analysis of covariation among markers). The single-locus approach provided limited evidence for genetic parallelism. However, the polygenic analysis revealed genetic parallelism for three of the five lakes, which differed from the two other lakes. These results provide evidence for both genetic parallelism and multiple genetic routes underlying parallel phenotypic evolution in fish shape among populations occupying similar ecological niches.Keywords : Adaptive radiation, Parallel evolution, Fish body shape, Geometric morphometrics, Genotyping-by-sequencing

Can ‘Hebb’ Be Distracted? Testing the Susceptibility of Sequence Learning to Auditory Distraction

Sequence learning plays a key role in many daily activities such as language and skills acquisition. The present study sought to assess the nature of the Hebb repetition effect—the enhanced serial recall for a repeated sequence of items compared to random sequences—by examining the vulnerability of this classical sequence-learning phenomenon to auditory distraction. Sound can cause unwanted distraction by either interfering specifically with the processes involved in the focal task (interference-by-process), or by diverting attention away from a focal task (attentional capture). Participants were asked to perform visual serial recall, in which one to-be-remembered sequence was repeated every four trials, while ignoring irrelevant sound. Whereas both changing-state (Experiment 1) and deviant sounds (Experiment 2) disrupted recall performance compared to steady-state sounds, performance for the repeated sequence increased across repetitions at the same rate regardless of the sound condition. Such findings suggest that Hebbian sequence learning is impervious to environmental interference, which provides further evidence that the Hebb repetition effect is an analogue of word-form learning

Radiation Induced Variable Retention Time in Dynamic Random Access Memories

The effect of gamma-ray and neutron radiations on the Variable Retention Time (VRT) phenomenon occurring in Dynamic Random Access Memory (DRAM) is studied. It is shown that both ionizing radiation and non-ionizing radiation induce VRT behaviors in DRAM cells. It demonstrates that both Si/SiO2 interface states and silicon bulk defects can be a source of VRT. It is also highlighted that radiation induced VRT in DRAMs is very similar to radiation induced Dark Current Random Telegraph Signal (DC-RTS) in image sensors. Both phenomena probably share the same origin but high magnitude electric fields seem to play an important role in VRT only. Defect structural fluctuations (without change of charge state) seem to be the root cause of the observed VRT whereas processes involving trapping and emission of charge carriers are unlikely to be a source of VRT. VRT also appears to be the most probable cause of intermittent stuck bits in irradiated DRAMs

A structural equation model of intuitive eating with adolescents / Un modèle d’équation structurelle de l’alimentation intuitive avec des adolescents

Introduction. - The tendency to eat by paying attention and respecting the body’s hunger and satiety cues is called intuitive eating. This eating behavior has been linked to positive health and well-being outcomes. Objective. - The purpose of this study was to test a global model linking intuitive eating with self-esteem, body esteem, media influence and including fear of negative appearance evaluation in adolescents’ boys and girls. Method. - In total, 740 adolescent high school students (51.5% girls; M age = 14, SD = 1.5) completed self-report questionnaires with measures of intuitive eating, body esteem, self-esteem, media influence and fear of negative appearance evaluation. Results. - Structural equation modeling revealed an overall excellent fit for the final four-variable model excluding the fear of negative appearance evaluation variable. Mediation analyses showed an indirect relationship between intuitive eating and body esteem via media influence, for girls but not for boys. Body esteem mediated the relationship between intuitive eating and self-esteem, and this indirect effect was stronger for girls than for boys. Conclusion. - A new model is proposed where intuitive eating is associated with self-esteem through body esteem and media influence. These findings suggest that regulating attitudes and behaviors toward food may be related to higher psychological well-being