Titre de l'écran-titre (visionné le 31 juillet 2023) / Au cours des deux dernières décennies, les tissus adipeux ont été de plus en plus reconnus pour leurs propriétés endocrines, c'est-à-dire leur capacité à sécréter un certain nombre d'adipocytokines qui peuvent exercer des effets locaux et/ou systémiques. En plus de ces peptides hormonaux, les tissus adipeux sont depuis longtemps reconnus comme des sites importants de transformation et d'action des hormones stéroïdiennes. La présente thèse se concentre principalement sur deux enzymes stéroïdogéniques exprimées dans les tissus adipeux, à savoir: l'aldocétoréductase 1C1 (AKR1C1) et la 17β-hydroxystéroïde déshydrogénase de type 2 (17β-HSD2). La première enzyme transforme la progestérone en un métabolite inactif : la 20α-progestérone. La seconde transforme la testostérone et l'estradiol en androstènedione et en estrone respectivement. Le projet est basé sur l'étude d'échantillons de tissu adipeux humains obtenus de diverses sources. Quatre objectifs spécifiques sont proposés: 1- Caractériser l'activité et l'expression des aldocétoréductases 1C dans les tissus abdominaux chez la femme; 2- Caractériser l'expression et l'activité de l'aldocétoréductase 1C1 (AKR1C1) en fonction de l'obésité abdominale dans les dépôts adipeux abdominaux chez la femme; 3- Caractériser la relation entre les taux de progestérone circulante et l'adiposité chez l'homme; 4- Caractériser l'activité et l'expression de la 17β-HSD2 dans les tissus adipeux abdominaux chez la femme. Ces travaux nous ont permis de mieux comprendre les liens entre l'homéostasie hormonale et l'obésité chez l'homme et la femme, par l'intermédiaire de travaux qui considèrent l'importance de la transformation locale des hormones par les enzymes stéroïdogéniques selon les principes de l'intracrinologie. À la lumière de nos résultats, il serait pertinent de continuer à considérer l'importance des différents dépôts adipeux et de poursuivre leurs études de manière indépendante et interdépendante afin de caractériser leur développement fonctionnel et organisationnel, leur régulation et impact sur les autres organes. Ces études auront pour finalité une meilleure compréhension globale de l'impact du tissu adipeux sur la santé de l'humain. / Over the past two decades, adipose tissue has been increasingly recognized for its endocrine properties, i.e., its ability to secrete a number of adipocytokines that can exert local and/or systemic effects. In addition to these hormonal peptides, adipose tissue has long been recognized as important sites of steroid hormone processing and action. This thesis focuses mainly on two steroidogenic enzymes expressed in adipose tissue, namely: aldoketoreductase 1C1 (AKR1C1) and 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2). The former enzyme converts progesterone to an inactive metabolite. 20α-progesterone and the second convert testosterone and estradiol to androstenedione and estrone, respectively. The project is based on the study of human adipose tissue samples obtained from various sources. Four specific objectives are proposed: 1- To characterize the activity and expression of 1C aldoketoreductases in female abdominal tissues; 2- To characterize the expression and activity of aldoketoreductase 1C1 (AKR1C1) in relation to abdominal obesity in abdominal fat deposits in women; 3- To characterize the relationship between circulating progesterone levels and adiposity in men; 4- To characterize the activity and expression of 17β-HSD2 in abdominal adipose tissue in women. This work has allowed us to better understand the links between hormonal homeostasis and obesity in men and women, by considering the importance of local processing of hormones by steroidogenic enzymes according to the principles of intracrinology. In light of our results, it would be relevant to keep on considering the importance of the different adipose depots and further study them independently and interdependently in order to characterize their functional and organizational development, their regulation and impact on other organs. These studies will lead to a better global understanding of the impact of adipose tissue on human health.

Yes / The aldo-keto reductase 1C3 isoform (AKR1C3) plays a vital role in the biosynthesis of androgens, making this enzyme an attractive target for castration-resistant prostate cancer therapy. Although AKR1C3 is a promising drug target, no AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid, a non-steroidal anti-inflammatory drug, is known to potently inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. To diminish off-target effects, we have applied a scaffold hopping strategy replacing the benzoic acid moiety of flufenamic acid with an acidic hydroxyazolecarbonylic scaffold. In particular, differently N-substituted hydroxylated triazoles were designed to simultaneously interact with both subpockets 1 and 2 in the active site of AKR1C3, larger for AKR1C3 than other AKR1Cs isoforms. Through computational design and iterative rounds of synthesis and biological evaluation, novel compounds are reported, sharing high selectivity (up to 230-fold) for AKR1C3 over 1C2 isoform and minimal COX1 and COX2 off-target inhibition. A docking study of compound 8, the most interesting compound of the series, suggested that its methoxybenzyl substitution has the ability to fit inside subpocket 2, being involved in π-π staking interaction with Trp227 (partial overlapping) and in a T-shape π-π staking with Trp86. This compound was also shown to diminish testosterone production in the AKR1C3-expressing 22RV1 prostate cancer cell line while synergistic effect was observed when 8 was administered in combination with abiraterone or enzalutamide. / University of Turin (Ricerca Locale grant 2014 and 2015) and Prostate Cancer UK grant S12-027

Yes / The aldo-keto reductase 1C3 (AKR1C3) enzyme is considered an attractive target in Castration Resistant Prostate Cancer (CRPC) because of its role in the biosynthesis of androgens. Flufenamic acid, a non-selective AKR1C3 inhibitor, has previously been subjected to bioisosteric modulation to give rise to a series of compounds with the hydroxytriazole core. In this work, the hit compound of the previous series has been modulated further, and new, more potent, and selective derivatives have been obtained. The poor solubility of the most active compound (cpd 5) has been improved by substituting the triazole core with an isoxazole heteronucleous, with similar enzymatic activity being retained. Potent AKR1C3 inhibition is translated into antiproliferative effects against the 22RV1 CRPC cellular model, and the in-silico design, synthesis and biological activity of new compounds is described herein. Compounds have also been assayed in combination with two approved antitumor drugs, abiraterone and enzalutamide. / This research was financially supported by the University of Turin (Ricerca Locale grants BOSD_RILO_20_01, LOLM_RILO_21_01, PIPA_RILO_20_01 and PIPA_RILO_21_01), Fondazione Cassa di Risparmio di Torino (Grant BOSD_CRT_17_2) and TUBITAK (The Scientific and Technological Research Council of Turkey-2219 program).

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Deeply influenced by emotional, ethical, and ecological principles, John Steinbeck developed a holistic ideology to describe and analyze the relationships among individuals, society, and the more-than-human world. Although he explored environmental issues with ecological insight and philosophical contemplation that placed him well beyond his literary and scientific contemporaries, Steinbeck’s contributions to modern ecological inquiry and environmental thought have received only intermittent attention from literary scholars. Throughout his writing, Steinbeck develops a view of intellectual holism that encourages (perhaps even enables) us to dovetail science and ethics as we attempt to construct a new environmental paradigm. Viewing the world through his holistic lens, Steinbeck was able to see the global ecosystem, local environments, human communities, and even minute tide pools as objects of scientific and artistic inquiry. Specifically, it is my contention that the American environmental movement owes a greater debt to John Steinbeck than it realizes. In short, John Steinbeck made significant contributions to the growing awareness of human-nature interconnectedness and the parallels between social ills and ecological ailments. Yet, for whatever reasons Steinbeck is not granted a position of honor alongside the other giants of American environmental thought. Now witnessing the full blossoming of 21st century environmentalism, it is useful to cast a reflexive eye upon our ideological forebears with the intent to better understand the genealogy of the American environmental movement. Doing so will not only provide a richer and fuller family tree, but will also promote additional flourishing of new approaches to solving ongoing environmental troubles. / Master of Arts

Os objetivos principais da presente pesquisa são apresentar o romance futurista Il Codice di Perelà, de Aldo Palazzeschi, fazer o cotejo entre os originais da primeira (1911) e da última (1958) edições desta obra, para garantir um ponto de vista privilegiado sobre o romance e sua evolução ao longo do tempo, e propor, em anexo, a versão brasileira do romance publicado em 1911: O Código de Perelá. Palazzeschi é um autor que sempre apresenta novidades, não raro subvertendo a matéria da tendência poética e literária ou do movimento do qual se aproxima, o que conduz a novas formas. Com isso, tornam-se evidentes a independência e as características peculiares do autor, se comparado aos seus contemporâneos. A narrativa do Il Codice di Perelà é realizada predominantemente por meio de breves diálogos conduzidos por várias vozes, com ritmos rápidos e dissonantes, conferindo à obra um caráter teatral. Por outro lado, o protagonista, precisamente por ser bastante diferente do gênero humano, apenas com sua presença imprime ao texto um tom fabular, além de fazer com que a história adquira características épicas. Ademais, a supremacia da síntese, do dinamismo, da compenetração e da velocidade, expressos com palavras essenciais e em liberdade, o uso de onomatopeias, de concisão, de justaposição de estilos, todos esses elementos heterogêneos que ainda assim resultam em um texto harmonioso ao conferir originalidade à estrutura do romance, também o ligam aos valores mais caros ao Futurismo, sobretudo no que diz respeito ao Manifesto técnico da literatura futurista. Por fim, o estudo mostra, também, como este romance coloca em prática, ao longo de sua narrativa, os preceitos do Manifesto palazzeschiano Il controdolore. / The main objectives of this research are to present Aldo Palazzeschis futuristic novel Il Codice di Perelà, make the comparison between the first (1911) and last (1958) original editions of this work to ensure a privileged point of view over the romance and its evolution over time and proposes, attached, the Brazilian version of the novel: O Código de Perelá. Palazzeschi is an author that he always presents news, often subverting the subject of poect and literary trend or of movement to which he approaches, leading to new forms. Hence the independence and the peculiar characteristics of the author become apparent if compared to his contemporaries. The Il Codice di Perelà narrative is accomplished mainly through short dialogues from various voices, with fast and dissonant rhythms, granting the work a theatrical tone. In the other hand, the protagonist, precisely because of his difference among mankind, just his presence adds to the book a fable tone, besides making the story to acquire epic characteristics. Furthermore, the synthesis supremacy, the dynamism, the interpenetration and speed, expressed with essential words and freely, the use of onomatopoeia, the brevity, the juxtaposition of styles, all these heterogeneous elements - which still result in a matching text - imprint originality to the novel structure, also bind it with the most important Futurism values, especially with regard to the technical Manifesto of Futurist literature. Finally, the study also shows how this novel puts into practice throughout its narrative, the precepts of the Manifesto palazzeschiano, Il Controdolore.

L’esprit dialectique qui caractérise la posture intellectuelle d’Aldo Rossi en tant qu’enseignant et architecte, cristallise durant les années 1960, en Italie, une nouvelle approche de l’enseignement de la théorie du projet en architecture. Cherchant à être rationnel tout en intégrant la question de « l’élément subjectif » de l’architecte, au travers de son expérience, la posture intellectuelle de Rossi s’est positionnée en réponse à un contexte politique et universitaire en crise. Dans la continuité des recherches menées sur l’épistémologie et la pédagogie de l’architecture ainsi que sur son ouverture réflexive à d’autres champs disciplinaires, Rossi tente de construire un essai théorique à la Fabrique du projet (la Città analoga). Il y questionne la pensée analogique face aux études typologiques en cherchant à esquisser une méthode didactique fonctionnant par étapes. Face à la difficulté de rationaliser « l’élément subjectif », Rossi, prolonge son essai sur la Fabrique du projet, au travers de ses propres œuvres. / The dialectical spirit which characterizes Aldo Rossi's intellectual disposition as a teacher and architect practitioner, crystallized during the 1960s, in Italy, a new approach to the teaching of the theory of the project in architecture. Trying to be rational while integrating the question of " the subjective element " of the architect, through his experience, the intellectual posture of Rossi was positioned in response to a political and university crisis. In the continuity of the researches led by the epistemology and the pedagogy of architecture and on his reflexive openness to other disciplinary fields, Rossi tries to build a theoretical essay to the Fabric of the project (Città analoga). He questions the analogical thought in front of the typological studies and tries to sketch a didactic method step by step. Facing the difficulty of rationalising " the subjective element ", Rossi, extends his essay on the Factory of the project, through his own works.

Aldo Crommelynck (1931-2008) a animé l'atelier Crommelynck à Paris de 1956 à 1986, en compagnie de son frère Piero, puis a travaillé seul entre Paris et New York en partenariat avec Pace Editions, jusqu'en 1998. Sa collaboration avec les peintres modernes, dont Picasso à Mougins, a inauguré une carrière internationale auprès d'une quarantaine d'artistes contemporains. Sa maîtrise de l'eau-forte s'est intégrée au milieu artistique international, entre Paris, Londres et New York, dans un contexte profitable au marché de l'art. Son nom est associé à un mouvement de retour à la taille­douce qui coïncide avec le goût des artistes issus du Pop pour le travail de la main et pour la figuration du quotidien. D'autres, issus du minimalisme et du néo-expressionnisme, verront en lui le dépositaire d'un certain métier de la gravure identifié à Paris. Cette thèse entend déterminer ce que fut le «style Crommelynck», dans toutes ses dimensions. / Aldo Crommelynck (1931-2008) run the Crommelynck studio, in Paris from 1956 to 1986, with his brother Piero, and then worked alone between Paris and New York in partnership with Pace Editions until 1998. His collaboration with modem painters, including Picasso in Mougins, preceded his international career with forty or so contemporary artists. His mastery of etching well integrated into the artistic world of Paris, London and New York, in a context profitable to the art market. His name is associated with the revival of printmaking in the United States that coincided with the taste of the artists coming from Pop Art for handmade creation and for the representation of daily life. Others, who came afterwards, impregnated with Minimalism or Neo-expressionism, saw him as the repository of a certain etching craft identified with Paris. This thesis intends to determine what was the « Crommerlynck style » in all its dimensions.

Este estudo é um ensaio acerca da história da Igreja Católica de Roraima e seu engajamento na luta pelas causas dos povos indígenas. Nele, delineia-se a atuação do bispo emérito, D. Aldo Mongiano, entre os anos de 1975 e 1996. Ele, junto com os padres e missionários da Consolata, se uniu em defesa de uma causa comum: a demarcação e homologação das terras indígenas ocupadas por fazendeiros e garimpeiros. Os fatos aqui narrados e analisados se baseiam em livros e artigos científicos, bem como em documentos disponibilizados pela Diocese de Roraima e por uma entrevista, realizada pelo professor Jaci Guilherme, com D. Aldo. Portanto, indo além de uma pesquisa bibliográfica, ele também se configura como uma pesquisa documental, a partir de cuja análise é possível perceber os conflitos existentes entre a Igreja e o poder local pela causa indígena, bem como a forma como ela tem contribuído para a formação e fortalecimento da cidadania indígena, em um processo de alteridade que emerge paulatinamente. / This study is a test about the history of Roraima Catholic Church and its engagement to the fight of the native causes. In it, it is showed the acting of the emeritus bishop Dom Aldo Mongiano, between the years of 1975 and 1996. Together with the priests missionaries of Consolata, he put his ministry in defense of a cause: the limitation and ratification of Indians territories occupied by farmers and prospectors. The facts narrated and analyzed here, are based on books and scientific articles, as well as documents available at the Roraima Diocese and also an interview done by Professor Jaci Guilherme, with Dom Aldo himself. Therefore, breaking the specific methodology of a bibliographic research, the work is also a documentary inquiry. The analysis of the collected documents, revealed that, there were conflicts between the church and the local power for the Indians cause, as well as the way how the ecclesial institution has contributed to the formation and strengthen of Indian citizenship in a process of boldness which emerges gradually.