Contribution de l’éthique théologique du caractère à l’accompagnement pastoral des jeunes adultes

Ce projet doctoral cherche à élaborer une approche éthique d’accompagnement des jeunes adultes (20-35 ans) en milieu pastoral. Prenant son point de départ dans la méthode praxéologique, il déploie une observation de la pratique d’un certain type d’accompagnement pastoral, puis réfléchit sur des traits de la jeunesse actuelle, surtout québécoise. Bien que cherchant à affirmer leur autonomie, les jeunes qui consultent ponctuellement un prêtre cherchent souvent des réponses à leurs dilemmes moraux. La thèse s’inspire des théoéthiciens nord-américains, Stanley Hauerwas et Craig Dykstra pour dépasser la préoccupation du « quoi faire ». En effet, ces auteurs principaux de la thèse se centrent sur la personne, la réalisation de son soi et le type d’homme ou de femme qu’elle veut être. L’accent est donc mis sur l’être, la totalité de la personne, et non seulement sur le faire. Une surenchère de l’importance du « faire » et de l’« action » renvoie à la fois à notre société post-technologique, centrée sur la productivité de la personne et à une morale catholique prescriptive. Néanmoins, l’éthique du caractère propose un chemin de conversion de la question de savoir « quoi faire » dans celle de savoir « comment vivre ». Sur le plan théologique, elle recentre et réinterprète des aspects essentiels du christianisme, soit les récits, la tradition comme histoire, communauté et imagination. Cette approche revitalise le paysage éthique et le style d’accompagnement pastoral auprès des jeunes adultes. En tant que prêtre catholique souvent consulté par des gens de cette catégorie d’âge (20-35 ans), notre projet de thèse se veut inspirateur d’une nouvelle pratique d’accompagnement éthico-pastoral.This doctoral project aims to develop an ethical approach of accompaniment of young adults (20-35 years) in pastoral milieu. Adopting its starting point in the "praxeologic" method, it observes first a certain type of practice in pastoral accompaniment, and then reflects upon some features of young of present times, especially young Quebecers. Although looking for affirmation of their freedom, the young who punctually seek advice from a priest, are often in search of answers to their moral dilemma. It draws on American theologians and moralists, Stanley Hauerwas and Craig Dykstra in order to surpass the concern about "what to do". In effect, these principal authors of the thesis focus on the person, the realization of his self and the type of man or woman he/she wants to be. The emphasis is then put on the issue of being and not just on doing. An escalation of the importance of "doing" and "action" refers to both our post-technological society, focusing on the productivity of the individual, and a Catholic prescriptive moral. However, the ethics of character offers a path of conversion of knowing "what to do" to knowing "how to live". On theological level, it refocuses and reinterprets essential aspects of Christianity, namely stories, tradition as history, community and imagination. This is a new approach that revitalizes the ethic landscape and pastoral accompaniment style of young adults. As a Catholic priest often consulted by people in this age group (20-35 years), my thesis project seeks inspiration for a new practice of ethical and pastoral accompaniment

C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays

Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, the conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggest that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells

Pyrido[3,4-<i>d</i>]pyrimidin-4(3<i>H</i>)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution

<p>1. We have previously described C8-substituted pyrido[3,4-<i>d</i>]pyrimidin-4(3<i>H</i>)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases.</p> <p>2. Although exemplar compound <b>1</b> exhibited moderate clearance in mouse liver microsomes, it was highly cleared <i>in vivo</i> due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-<i>d</i>]pyrimidin-4(3<i>H</i>)-one scaffold and other C8-substituted derivatives.</p> <p>3. We identified the C2-position as the oxidation site by LC-MS and ¹H-NMR and showed that C2-substituted derivatives are no longer AO substrates.</p> <p>4. In addition to the experimental data, these observations are supported by molecular modelling studies in the human AO protein crystal structure.</p