This study provides a new reading of Geoffrey Chaucer’s Prioress’s Tale and considers its purpose within the context of the Canterbury Tales. I argue that the Tale, as an exemplum, demonstrates the dangers of tale-telling, and exposes the moral discrepancies of the Canterbury tale-telling competition and the pilgrims’ use of stories as verbal assaults against one another. I argue that the Tale condemns the unchristian-like “actions” of the Christians within its frame as they respond to the clergeon’s murder; the Tale’s ending presents a cathartic response from this congregation, which indicates their understanding of the clergeon’s martyrdom. It also provokes a similar response from the Canterbury pilgrims, which serves to silence them, and to create a paradox that disrupts possible responses to the Tale. Further, Chaucer’s Retraction at the end of the Tales is intended to silence the poet’s critics through the creation of a similar paradox.

The Hippo signaling pathway has been implicated in both mammalian organ size regulation, as well as tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional co-activator, and downstream effector, Yes-associated protein (YAP), which modulates pro-proliferative transcriptional elements. Recent investigations have demonstrated that this pathway is activated in non-regenerating livers and its inhibition leads to liver overgrowth and tumorigenesis. The majority of the existing evidence regarding the role of the Hippo pathway in hepatocyte proliferation is based on in vitro studies and knock-out animal models. However, the role of the Hippo pathway during the natural process of liver regeneration, remains unknown. Here alterations in the Hippo signaling pathway were investigated, namely its interaction with angiomotin-like 2 (AmotL2) and Set7, during liver regeneration using a 70% rat partial hepatectomy (PH) model. Overall, results indicated no significant difference between AmotL2 levels in control and regenerating tissue at various time points during liver regeneration. No significant alterations in YAP methylation during liver regeneration were found compared to control tissue. In the end, results regarding the role of both AmotL2 and Set7 provided inconclusive evidence about their roles during the regenerative process. Given the role of the Hippo pathway in hepatocyte proliferation, a hypothesis was made that this pathway may play a role in pediatric liver tumors. YAP localization was evaluated using immunohistochemical analysis in tumor sections from patients with hepatoblastoma or hepatocellular carcinoma. Once again, the results were inconclusive at the time of the preparation of this manuscript due to technical difficulties in achieving satisfactory staining of the specimens. Further studies will be directed at elucidating the role of the Hippo pathway during liver regeneration as well as developing better conditions for the immunohistochemical staining of human liver specimens.

The Hippo pathway is a cell signaling pathway involved in organ size regulation and tumorigenesis in mammals. This pathway regulates the activity of Yes-associated protein (YAP), a transcriptional coactivator which binds to the transcription factor TEAD to promote expression of genes controlling growth and proliferation of tissues, as well as inhibition of apoptosis. The Hippo pathway has recently been implicated as a pathogenic mechanism in neurodegenerative disorders. Specifically, mammalian sterile 20 (Ste20)-like kinase 1 (MST1), a protein kinase in the Hippo pathway, has been found to promote neuronal death under conditions of oxidative stress. Moreover, homozygous deletion of MST1 in a mouse model of Amyotrophic Lateral Sclerosis (ALS) significantly delayed onset of neurodegenerative symptoms. We examined the expression levels of key Hippo pathway components in cortex, lumbar spinal cord, and gastrocnemius muscle samples of male and female G39A SOD1 mice using western blots. Our results revealed a significant increase in phosphorylated MST1 (pMST1) in lumbar spinal cord of presymptomatic transgenic animals, and found this increase to be sex and gene copy number dependent. These results suggest that the Hippo pathway is dysregulated in the SOD1 mouse model and that MST1 may play a critical role in pathogenesis and disease progression in ALS.

Thesis (Ph.D.)--Boston University / The purpose of this dissertation is to examine the views of creation that Plato, Augustine, and Brunner advance to deal with problems involved in God's relation to the world. Divine craftsmanship seems to be the model in Plato's view of creation. His view of Pattern, Demiurgos, and Receptacle are advanced in order to deal with such problems in this theory of Ideas as the relation of permanence to change, of perfection to imperfection, and of the one to the many; and the fact that all movement tends toward what is best. Plato submits that the Demiurgos initiates all movement in becoming toward what is best by persuading the Receptacle to take into itself a structure like the Pattern. To create is to persuade a recalcitrant "material" to bring perfect being into existence as far as possible. Plato's hypothesis does seem to account for movement in becoming toward what is best, but it does not render sufficiently comprehensible the relation of perfect being to existence. [TRUNCATED]

La voie Hippo, découverte chez la Drosophile et conservée chez les mammifères, a été identifiée comme un élément essentiel dans le contrôle de la taille des organes. Cette cascade de kinases régule la phosphorylation de l’effecteur terminal YAP (ou de son paralogue TAZ), un coactivateur transcriptionnel reconnu comme oncogène. Sa fonction est médiée par sa translocation nucléaire et son interaction avec les facteurs de transcription TEAD, pour former le complexe YAP-TEAD qui active l’expression des gènes cibles responsable de la prolifération cellulaire et de la croissance des organes. La surexpression des protéines YAP/TAZ/TEAD dans de nombreux cancers perturbe l’équilibre de la voie Hippo et favorise la formation du complexe protéique causant une hyperprolifération et la propagation des cellules cancéreuses. Inhiber cette interaction protéine-protéine est une cible thérapeutique prometteuse pour concevoir de nouveaux anticancéreux. Dans cette optique, le laboratoire a considéré deux stratégies. La première consiste à cibler la protéine YAP en synthétisant des dipyrrines, représentant des fragments de la Vertéporfine dans le but de définir le motif minimal requis pour conserver l’activité biologique. Une seconde approche implique la synthèse de ligands de TEAD capable de se positionner au sein de l’interface 3. Basée sur des études de modélisation moléculaire, une famille avec un noyau central triazolique a été optimisée pour établir des relations structure-activité. Les molécules synthétisées sont actuellement en cours d’évaluation, grâce à la mise au point des tests biologiques et physicochimiques, et les premiers résultats ont permis d’identifier un composé prometteur. / The Hippo pathway, firstly described in Drosophila and highly conserved in mammals, has been demonstrated to play a crucial role in the organ size control. This kinase cascade regulates the phosphorylation of the downstream effector YAP (or its paralogue TAZ), a transcriptional coactivator with oncogenic activity. Its function is mediated by its nuclear translocation and interaction with the transcriptional factor TEAD, to form YAP-TEAD complex which activates the genes expression in charge of cell proliferation triggering organ growth. Overexpression of YAP/TAZ/TEAD protein in several cancers disrupts the Hippo pathway balance and urges on YAP-TEAD complex formation causing excessive proliferation and cancer development. Inhibiting this protein-protein interaction is thus a promising therapeutic target for the design of new anti-cancer drugs. In this goal, the laboratory has considered two strategies. The first one consists in targeting the YAP protein by synthesizing dipyrrins, representing Verteporfin fragments to define the minimal requirement yielding the expected biological activity. A second approach involves synthesizing TEAD ligands able to fit in specific interface 3. Based on molecular modeling, a triazole scaffold family was optimized to establish structure-activity relationship. Thanks to the biological and binding tests development, synthesized molecules evaluation is still in progress and the present first results have already allowed identifying a promising compound.

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M.A. (Latin) / Please refer to full text to view abstract

Indiana University-Purdue University Indianapolis (IUPUI) / The growth of mammary epithelial cells is regulated by interactions with neighboring cells and by exposure to soluble factors including hormones and growth factors. These cues are integrated within the cell, perpetuating changes onto the organization of the actin cytoskeleton, resulting in altered transcriptional programs. Rho family GTPases regulates actin dynamics that facilitate transcriptional reprogramming. In particular, RhoA induces the formation of actin stress fibers to promote the transcriptional co-activator YAP1 to translocate from the cytosol into the nucleus. There, it co-activates TEAD family transcription factors to drive the expression of pro-growth and survival genes. Rho family members are activated by guanine exchange factors (GEF) and inhibited by GTPase activating proteins (GAP). Here, we determined the relative effects of expression of 67 RhoGEFs and RhoGAPs on the activation of TEAD. This revealed that regulator of G-protein signaling (RGS) domain containing ArhGEF1, ArhGEF11 and ArhGEF12 all promoted YAP1 dependent activation of TEAD. These RhoGEFs mediate signaling from heptahelical receptors that are stimulated by lipid mitogens to activate the heterotrimeric G-proteins Gα12 and Gα13. Consistently, loss of expression of ArhGEF12 and to a lesser degree ArhGEF11 prevented actin stress fiber accumulation and activation of YAP1 mediated signaling by serum. Conversely, several complementary experiments revealed that ArhGEF1 dominantly limits Gα13 selective activation of YAP1 and the mitogen activated protein kinase (MAPK) cascades. Furthermore excessive Gα13 activity results in both high levels of filamentous actin and arrest cells in the G1/0 phase of the cell cycle. This is likely due to the systemic inhibition of cell cycle promoting signaling and a loss of protein translation. Further, YAP1 was found to be essential for the survival of ArhGEF1 silenced cells. Together, these studies define a circuit whereby the rgRhoGEFs regulate Gα 12/13-RhoA signaling flux to regulate cellular growth that is promoted by serum factors.

No description available.

No description available.