Trata-se de uma dissertação sobre o pensamento filosófico de Agostinho de Hipona em relação à beleza do discurso e à utilidade da retórica e da eloqüência, temas que aparecem no livro IV do De doctrina christiana (Da instrução cristã) e, por isso, dentro da reflexão sobre o ideal de uma educação tipicamente cristã. Na Antigüidade, embora a eloqüência estivesse intrinsecamente ligada à arte retórica, esta questão, para Agostinho, deve ser tratada em conexão com algumas orientações da filosofia moral e da teologia cristãs, situadas para além da técnica. Em comparação com o antigo ideal oratório romano, sobretudo o ciceroniano, a maior importância conferida por Agostinho à Bíblia cristã, isto é, à sabedoria e à moral dos autores bíblicos, traz novos significados para o termo \'eloqüência\'. Além disso, o aprendizado oratório, que se alicerçava na doutrina e no hábito, é dessa vez resumido e transmitido por Agostinho segundo um método radical de imitação, cujos modelos passam a ser os escritores bíblicos e eclesiásticos, aqueles inspirados por Deus e gratificados com a união da eloqüência à sabedoria. / This dissertation is about the philosophical thinking of Augustine of Hippo in relation to the beauty of speech and the usefulness of rhetoric and eloquence, themes that appear in Book IV of De doctrina christiana (On Christian Teaching) and therefore within the reflection on the ideal of education typically Christian. In Antiquity, although the eloquence was intrinsically linked to the rhetorical art, this issue, for Augustine, it must be treated in connection with some directions of Christian moral philosophy and theology, located beyond the technique. In comparison to the antique ideal of Roman oratory, especially the Ciceronian, the greater importance given by Augustine to the Christian Bible, that is, to the wisdom and morality of the biblical authors, bring new meaning to the term \'eloquence\'. Moreover, the learning of oratory, which was based on the doctrine and habit, this time is summed up by Augustine and transmitted according to a radical method of imitation, whose models have to be the biblical and ecclesiastical writers, those inspired by God and rewarded with union between eloquence and wisdom.

Indiana University-Purdue University Indianapolis (IUPUI) / During gestation, the maternal liver undergoes various adaptive changes to cope with the in-creasing physiological and metabolic demands from both maternal and fetal compartments. Among these changes are robust growth and changes in transcriptome profile. However, how these events happen, and other aspects of this physiological phenomenon remains unexplored. Therefore, we aimed at further understanding how maternal liver responds to pregnancy. We used BrdU labeling combined with a virus-based tracing approach to quantify the percentage of maternal hepatocytes undergoing DNA synthesis and division over the course of gestation in mice. We found that ~50% maternal hepatocytes entered S-phase but, unexpectedly, did not undergo cytokinesis. This strongly suggests that maternal hepatocytes in fact undergo endoreplication instead of hyperplasia, as believed previously. Pericentral Axin2+ hepatocytes were reported to behave as liver stem cells responsible for liver homeostasis and turnover. We generated an in vivo fate-tracing mouse model to monitor the behavior of these cells in the maternal liver. Our results showed that they did not proliferate during pregnancy, homeostasis, and following par-tial hepatectomy. Curiously, we uncovered that, hepatocytes exhibit developmental phenotypes at mRNA level pre-pregnancy and at both mRNA and protein level during pregnancy. In the non-pregnant state, hepatocytes reserved mRNA expression of liver progenitor marker genes Cd133 and Afp, which are localized in the nuclei, without protein translation. During gestation, maternal hepatocytes displayed cytoplasmic translocation of Cd133 and Afp transcripts, con-comitant with corresponding protein expression. Overall, all maternal hepatocytes became CD133+, and a subset of them express AFP. Addi-tionally, in non-pregnant livers, mRNA of Epcam, another liver progenitor marker, was ex-pressed within majority of hepatocytes, whereas its protein was solely translated in the pericen-tral region. In contrast, by end-gestation, EPCAM protein expression switched to the periportal region. These observations indicate that maternal hepatocytes exhibit heterogeneous develop-mental phenotypes, partially resembling fetal hepatocytes. It is intriguing why mature hepato-cytes dedifferentiate into a progenitor state in response to pregnancy. AFP is considered to be produced primarily from fetal liver and thus is used to evaluate fetal development health. A potential clinical relevance of our data is that we identified maternal liver as a new source of AFP. The hippo signaling pathway has been shown to potently control liver growth and hepato-cyte heterogenicity. Surprisingly, we found that pregnancy neither altered the expression nor activities of the components of this pathway and its effector YAP1/TAZ. This finding indicates that pregnancy-induced maternal liver growth is not driven by hippo-YAP1 pathway. However, we demonstrate that the presence of YAP1 is essential for CD133 protein expression in mater-nal hepatocytes. Collectively, we revealed that, as pregnancy advances, maternal hepatocytes likely undergo endoreplication and display developmental phenotypes. Mechanistically, YAP1 dictates the expression of CD133, contributing to the pregnancy-dependent phenotypic changes of maternal hepatocytes.

Proper lung function relies on the precise balance of specialized epithelial cell types that coordinate to maintain homeostasis. The Hippo pathway has emerged as a critical regulator of cell fate both developmentally and in a regenerative setting. The work presented in this dissertation describes essential roles for the transcriptional effectors of Hippo pathway signaling, Yap and Taz, in maintaining lung epithelial homeostasis. The data presented here demonstrate that conditional deletion of Yap and Wwtr1/Taz in the lung epithelium of adult mice results in severe defects with consequent animal lethality. Phenotypes associated with Yap/Taz deletion include alveolar disorganization, a development of mucin hypersecretion throughout the airways, and ciliary disorganization. Through in vivo lineage tracing, analysis of mouse and human tissues, along with in vitro molecular experiments, these studies show that nuclear YAP/TAZ exert transcriptional control over club cell fate, while in multiciliated cells, they function within the cytoplasm to maintain ciliary structures. Within club cells, reduced YAP/TAZ activity promotes intrinsic goblet transdifferentiation of secretory airway epithelial cells. Global gene expression and ChIP-Seq analyses reveal that YAP/TAZ act through the TEAD family of transcription factors to suppress a goblet cell differentiation program in airway epithelial cells, including direct repression of the SPDEF gene, which encodes a transcription factor required for goblet cell identity. Further in vitro studies identify cooperation between YAP/TAZ-TEAD and the NuRD chromatin remodeling complex to inhibit SPDEF expression and that Hippo-regulated YAP/TAZ impinge on cytokine-induced goblet cell differentiation. Within multiciliated cells, we observe that phosphorylated Yap localizes in a planar polarized manner at the base of cilia and controls ciliary and basal body density. Lineage specific Yap/Taz deletion leads to reduced ciliary density and height due to a loss of apically basal bodies. Collectively, this work identifies YAP/TAZ as critical factors in lung epithelial homeostasis and offers new molecular insight into the mechanisms regulating the secretory and multiciliated cell lineages, which are frequently impaired in a broad range of lung diseases. / 2024-02-02T00:00:00Z

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The Hippo tumor suppressor pathway is a highly conserved signaling pathway that regulates cell proliferation, differentiation, and organ size. Activation of the Hippo pathway leads to the phosphorylation and cytoplasmic sequestration of the pro-growth transcriptional co-activators YAP/TAZ; by contrast, impairment of the Hippo pathway enables YAP/TAZ to enter the nucleus where they bind to the TEAD transcription factors and induce the expression of genes involved in cell proliferation. Functional impairment of the Hippo pathway, and subsequent hyperactivation of YAP/TAZ, is common in many human malignancies, including melanoma. Recently, small molecule inhibitors that disrupt YAP/TAZ-TEAD binding, and thus reduce oncogenic transcriptional signaling have been discovered, but their efficacy in preventing cancer cell growth has not yet been well characterized. Moreover, no simple biomarker has been identified that can predict sensitivity to such inhibitors. We hypothesized that cells in which YAP/TAZ are enriched in the nucleus relative to the cytoplasm, indicative of an impaired Hippo pathway, would be more susceptible to TEAD inhibition. This would provide a useful biomarker to identify cancer cell lines most likely to respond to TEAD inhibition. We therefore developed and validated an automated quantification method to score nuclear:cytoplasmic YAP/TAZ localization in melanoma cell lines. This enabled us to identify “Hippo-On” and “Hippo-Off” signatures. We then treated these lines with the TEAD inhibitor MGH-CP1 and performed cell viability assays. Results from these data demonstrated that cell lines that have greater nuclear localization of YAP/TAZ are more susceptible to MGH-CP1 inhibition, suggesting that YAP/TAZ nuclear localization may be a biomarker to identify candidates for TEAD inhibitor treatment.

Indiana University-Purdue University Indianapolis (IUPUI) / Hepatic fibrosis is a cellular repair mechanism that is initiated upon prolonged damage to the liver, resulting in an accumulation of excess extracellular matrix. This eventually leads to the formation of scar tissue, which disrupts the hepatic architecture and causes liver dysfunction. Hepatic stellate cells (HSCs) play a major role in hepatic fibrosis. However, the molecular mechanisms remain incompletely understood. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ or WWTR1), key players of the Hippo pathway, have been implicated in the liver fibrosis, but the HSC-specific functions of YAP and TAZ are largely unclear. Here we have identified Sirtuin 6 (SIRT6), an NAD+ dependent deacetylase, as a key epigenetic regulator in the protection against hepatic fibrosis by suppressing the YAP/TAZ activity. SIRT6 has been previously implicated in the regulation of the canonical transforming growth factor β (TGFβ)-SMAD3 pathway. This study has revealed the significant contribution of the non-canonical pathways including the Hippo pathway to the development of hepatic fibrosis. HSC-specific Sirt6 deficient mice developed severe fibrosis when fed a high-fat-cholesterol-cholate diet compared to their wild-type counterparts. YAP became more active in the SIRT6-deficient HSCs. Expression of the YAP/TAZ downstream genes like CTGF, CYR61 and ANKRD1 were elevated in the SIRT6-deficient HSCs. Biochemical and mutagenic analyses have revealed that SIRT6 deacetylates YAP and TAZ at key lysine residues and reprograms the composition of the TEA domain transcription factor complex to suppress the YAP/TAZ function in the hepatic fibrogenesis.

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Thesis (MA)--Stellenbosch University, 2001. / ENGLISH ABSTRACT: Augusine's search for the nature of God's exisistence as well as the origin of evil, reaches a climax in Book 7 of his Confessions. This study assumes the position that Augustine strives to find answers to the above mentioned two questions in the first six books of the Confessions. The answers to both these questions were vitally important to Augustine, since it would then convince him to convert to the Christian faith. Augustine repeatedly thought he grasped the true answer to the existence of God and the origin and the nature of evil but he was disillusioned time and again. His quest for an answer started with his reading of Cicero's Hortentius (Conf. 3.4.7), a book that urged Augustine to search for Truth. Augustine then joined the Manicheans, a sect claiming that their doctrine was based on reason and contained the Truth (Conf. 3.6.10). Augustine believed that the Manicheans could resolve his quest for answers to the existence and nature of both God and evil. The Manichean intellectual and scientific exposition of the cosmos allowed Augustine to imagine God and evil as opposing substances. Eventually, promted by his own intellect, Augustine discovered weaknesses in their theories (Conf. 5.3.3-5.6.10). Augustine's final break with the Manicheans, after nine years as an adherent, came when he heard the sermons of Ambrose of Milan. Not only was Augustine impressed by Ambrose's eloquence but his sermons also embodied an interpretation of Platonism in Christian terms. Augustine's reading of the Neoplatonic books in a Latin translation urged him to turn into himself (Conf. 7.10.16) and search for God there. Once Augustine could pronounce upon the intelligible existence of God, his inquiry into the origin of evil resolved itself (7.12.18). / AFRIKAANSE OPSOMMING: Augustinus se soeke na die bestaanswyse van God en die aard en onstaan van die kwaad bereik 'n klimaks in Boek 7 van die Confessiones. In hierdie studie word daar van die standpunt uitgegaan dat Augustinus onder andere in die eerste ses boeke van die Confessiones poog om antwoorde te kry op bogenoemde twee vraagstukke. Antwoorde op beide hierdie vrae was van kardinale belang, aangesien dit Augustinus sou oortuig om hom tot die Christelike geloof te bekeer. Augustinus het herhaaldelik gepoog om die ware antwoorde op die vraag na bestaanwyse van God sowel as die oorsprong en die aard van die kwaad te vind. Hy was egter telke male ontnugter. Augustinus se soeke het begin toe hy in aanraking gekom het met Cicero se Hortensius (Conf. 3.4.7), 'n boek wat Augustinus aangemoedig het om die Waarheid na te jaag. Gevolglik het Augustinus by die Manicheërs aangesluit, aangesien dié sekte geglo het dat hulle leerstellinge gebaseer is op die rede en sodoende die volle waarheid bevat (Cant. 3.6.10). Augustinus het geglo dat die Manicheërs sy soektog na antwoorde op die vraag van God en die kwaad se bestaanswyse kon oplos. Die Manicheërs se intellektuele en wetenskaplike uiteensetting van die kosmos het Augustinus toegelaat om God en die kwaad as teenstrydige entiteite te beskou. Ongeveer nege jaar na sy aansluiting by die Manicheërs, aangemoedig deur sy eie intellek, het Augustinus die swak punte in die Manichese leerstellinge ontdek (Cant. 5.3.3-5.6.10). Die finale breek met die Manicheërs het gekom toe Augustinus die preke van Ambrosius in Milaan gehoor het. Nie alleen was Augustinus ingenome met Ambrosius se welsprekendheid nie, maar sy preke het ook die interpretasie van Platonisme in Christelike terme beliggaam. Die Neoplatoniese leerstellinge het Augustinus aangemoedig om na homself, in homself te draai (Conf. 7.10.16) en vir God daar te gaan soek. Sodra Augustinus kon verklaar dat God in die vorm van 'n kenbare wese bestaan, het sy soeke na die oorsprong en die aard van die kwaad dit self opgelos (Cant. 7.12.18).