No description available.

To date, the most substantial accounts of our engagement with literature have focused on prose-fiction, in particular the novel, drawing on issues of plot, character and narrative in explaining our understanding of literary works. These accounts do not consider how the poetic features of a literary work may affect our reading experience and how this contributes to the meaning of the work. In this thesis I show the philosophical importance of the experience of reading poetry for the role it can play in inquiry, in particular, how such an experience can facilitate philosophical thinking and active inquiry. Adopting a reader-response view of our engagement with poetry, I argue that the experience of reading lyric poetry can make a valuable contribution to philosophical inquiry by enriching our conceptual understanding. The reading experience helps us to forge explicit awareness of our concepts and the networks of associations and beliefs that determine our use of them. Understanding poetry necessarily requires attending to the unity of form and content, and the particular perspectives on offer in the poem. This complex whole sustains perspectives and emotions where character and narrative are lacking. I argue that the perspectival nature of our reading experience is important for philosophical inquiry into aspects of human life. Encountering the perspectives of the poem helps to activate our own perspectives through our emotional and intellectual responses, bringing into focus what we value. I apply this argument to the moral domain, arguing that poetry can facilitate moral inquiry in particular by exposing moral significance in our concepts, helping us to feel what is at stake, and by testing our moral understanding. The way in which the poetic examples discussed engage us emotionally, imaginatively and cognitively (through the reading experience) help us address moral questions from distinctive and valuable perspectives, which provide us with moral insights of value in philosophical inquiry.

This work present the salient features of existential psychoanalysis across a chronological selection of Sartre's works. It looks at the background in psychology and phenomenology which informed Sartre's concept and presents key aspects of the theory itself, in comparison with Freudian psychoanalysis. A study of Sartre's three existential biographies, on Baudelaire, Genet and Flaubert, shows how the theory and its progressive-regressive method are applied to concrete cases, while also tracing the evolution of Sartre's approach up to his late writings on the topic. The final assessment concerns the possibility of using Sartre's theory as a basis for existential psychotherapy. Sartre's account is shown to provide a consistent framework for analysing individuals in existential terms and through which to understand subjectivity.

Recombinant antibodies have increased in prominence as therapeutics and diagnostic tools since their introduction to the market in the mid-1980s. They are used to treat diverse conditions from Crohn's disease to cancer. Since the Anthrax letter attacks of 2001, a great deal of work has been carried out to develop therapeutics to this disease, and antibodies that neutralize the toxic action of Bacillus anthracis are prominent among them. This dissertation describes the elucidation of the structure of the 14B7 family of neutralizing antibodies directed at protective antigen (PA) of B. anthracis and the complex of PA domain 4 (PAD4) with an ultra-high affinity neutralizing antibody (M18), and then utilizes this information to aid in the engineering of the antibody to various ends. Chapter 2 presents the structure of the M18-PAD4 complex and of the 14B7 family of antibodies, which aids in the understanding of the affinity maturation process for this antibody family. Chapter 3 describes the affinity maturation of M18 to a PA variant by applying the knowledge gained from the complex structure. This previously intractable challenge was met by employing saturation mutagenesis in highly focused libraries to M18 directed by the complex structure to the area of variation on PA. These results indicate that this could be a generalizable method for the engineering of M18 to natural and deliberate variation of PA. Chapter 4 reports work toward the development of a reversible, photoresponsive antibody using small molecule and polymer-protein conjugates. The results indicate that a probable site on M18 was located for placement of the polymer appendage, although further work is necessary to empirically refine the properties of the photoresponsive polymer. Chapter 5 presents an unrelated project, which was to confirm the existence of a proposed RNA thermosensor in the 5' untranslated region of LcrF from the pathogenic bacterium Yersinia pestis, the causative agent of plague. Overall, these studies reveal the power of structure-based engineering in this antibody-antigen system. In addition, the structural elucidation of the M18-PAD4 complex and the 14B7 family of antibodies furthers our basic understanding of protein-protein interactions and the process of affinity maturation of antibodies. / text

published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / abstract / toc / Medicine / Doctoral / Doctor of Philosophy

No description available.

Infundibular (arcuate) neurokinin B (NKB) neurons play a critical role in neuroendocrine control of reproduction. Specifically, a local network of arcuate neurons that co-express kisspeptin, neurokinin B, and dynorphin (so-called, KNDy neurons), has emerged as a potential pacemaker driving the pulsatile secretion of gonadotropin-releasing hormone (GnRH) that is required for normal reproduction. These neurons are the target of estrogen and may be an important link in estrogen negative feedback on GnRH functioning. KNDy neurons respond to estrogen withdrawal with dramatic changes in gene expression and somatic hypertrophy, an effect that is reversible by estradiol replacement. Studies addressing the effects of estrogen withdrawal and replacement on morphological and electrophysiological features of KNDy neurons have been hindered by the inability to target this subpopulation of neurons in the live tissue. This dissertation examines estrogen-induced changes in arcuate NKB circuitry and excitability and discusses its implications in reproductive axis. First, the novel Tac2-EGFP transgenic mouse model was characterized. The reproductive function, EGFP-ir distribution in the brain, and co-localization of EGFP with proNKB in the arcuate nucleus were examined and compared to littermate controls. Indices of reproductive function (puberty onset, estrous cyclicity, and LH pulsatility) were comparable between Tac2 and wildtype mice, suggesting that the transgenic animals have preserved estrogen negative feedback. The long-term estrogen withdrawal via ovariectomy and estradiol replacement model was used to examine electrophysiological and morphological changes in arcuate NKB neurons. We found that low-dose chronic estradiol replacement results in decreased excitability of arcuate NKB neurons, a finding that is consistent with the proposed role of this neuronal population in estrogen negative feedback on reproductive axis. Changes in excitability were seen despite the overall similarity in intrinsic properties of estradiol-treated and untreated ovariectomized mice. We also demonstrated for the first time that single arcuate NKB neurons form a local network by way of recurrent collaterals. Axonal targets of single NKB neurons included the internal zone of the median eminence, ependymal layer of the 3rd ventricle, and sites lateral and dorsal to the borders of the arcuate nucleus. Long-term treatment with estradiol resulted in decreased somatic volume and decreased dendritic spine density. Together, these data demonstrate that low-dose chronic estradiol replacement in ovariectomized mice resulted in morphological plasticity of arcuate NKB neurons that was accompanied by changes in excitability of this neuronal population, supporting the role of these neurons in estrogen negative feedback on GnRH secretion.

No description available.