This thesis examines the relationship between language and social reality. The position argued for is one which sees language as having a constitutive role to play in the formation and maintenance of the social world. It elaborates and develops a view expressed by Quentin Skinner, namely, that language and the social world are mutually supportive and exist in a state of dynamic interaction. Because language has this constitutive role in relation to the social world attention to the use of language is important for the language we employ will be a significant factor in determining the nature of that world. The notion of ideology is defined in a critical sense as 'malign decontestation', i. e., the presentation of that which is contestable as if there were only one legitimate perspective. The concepts of absolutism and universalisation are taken as key ideological markers. Given the constitutive role of language, the identification of ideological language becomes important because aspects of the social world which are informed by such a language will reflect the errors inherent in the linguistic structures themselves. One of the central arguments of the thesis is that ideological language often arises when insufficient attention is paid to the ontological differences between activities whose subject matter is the natural world and those whose subject matter is the social world. There is a focus on educational issues because the impetus for this thesis arose out of a growing unease with the nature of the language used in relation to this topic. Although a concern with the language of education is not uncommon, the full significance of the language we use in this area is often unacknowledged because the necessary theoretical background is absent. It is the main purpose of this thesis to provide a philosophical justification for this concern.

This thesis investigates Deleuze-Guattari's notion of stratification through a series of investigations into their material on language. Stratification is their term for the process by which matter-energy comes to assume the relatively stable historical formations of our social world, and in particular the relationship between subjects, objects and words. The complex notion of the order-word/password is proposed as key to this process, with its role in the articulations of the strata (as order-word) and in movements of creation and escape (as password). I explore this apparatus from a variety of angles, in order to present an account of Deleuze-Guattari's pragmatics that demonstrates both its basis in philosophy and its connections with the world. I begin by introducing the notion of 'difference in itself', through Deleuze/Deleuze-Guattari's critique of representation and their account of subjectification, the creation of the subject in space and time (in relation to Bergson and Kant) - and then feed this material through an encounter with Judge Schreber, in the process filling out our account of the subject. The resulting diagram of stratification is further explored through a dialogue with two other key thinkers of language - Wittgenstein, in relation to his social conception of meaning as use, and Derrida, in relation to his critique of Austin and Searle's Speech Act theory - in either case, demonstrating important connections and contrasts with Deleuze-Guattari. I then examine the specifics of stratoanalysis through an examination of the related zones of the formal, the abstract and the incorporeal, bringing this to bear on Deleuze- Guattari's appropriation of the linguist Hjelmslev, and to the criticisms of Ruthrof. The final step is to relate this apparatus both to linguistic and everyday understandings of language, connecting this pragmatics of the order-word with the notion of an 'art of living' through a consideration of standardised language and 'verbal hygiene'.

This dissertation offers a phenomenological approach to the comprehension of Information Technology (IT) and Strategy, and of the relationships between these two phenomena. We argue that in order thoughtfully to understand the manifold connections between IT and Strategy, their contradictions, shortcomings, and possibilities, one has to rely on the essence of each of these phenomena. The rationale of this approach implied the need to make explicit the ontological assumptions on which the investigation relies. An essential uncovering of that which IT and Strategy are can only take place as long as we lay bare a primary position on the nature of that which is. Martin Heidegger's Being and Time and, to a lesser extent, the theory of autopoiesis are the foundations of this investigation. We claim that these theories are paradigmatically consistent and show relevant complementarities, namely in what concerns the issues of action information, and knowledge. The matching of these two theories provides the ontological and epistemological grounds of the investigation. Within this fundamental setting we argue that IT and Strategy will only essentially show up as long as they are accessed in-the-world in which they are. The research applies the phenomenological method of investigation in its original form as developed by Edmund Husserl. However we extend the Husserlian formulation in a last phase by using the arguments of Heidegger on the opening up of possible concealed meanings of phenomena. The method sets the boundaries of the research. IT and strategy are phenomenological analysed not as empirical objects, event, or states of affairs, but as intentional objects of consciousness. These are formally indicated from the outset of the investigation as the ITness of IT and the Strategyness of Strategy. The central conclusions of the investigation are that (1) IT is an ontological phenomenon substantively penetrating the being-in-the-world we, ourselves, are; and, (2) Strategy, essentially choosing to choose, has been unfolding throughout History guided by the concealed meaning of a striving for an authentic identity. These essential notions uncover a complex set of relationships between the phenomena. Those relationships are thus described and characterised. We also show that although phenomenology is not empirical its results have many important implications for the empirical world.

Palliative care is unusual as a specialty within health care in that it has its own philosophy, which is summarised in the WHO definition of palliative care. This philosophy has influenced clinical practice so that specialist palliative care differs significantly from other aspects of health care. The thesis is a critique of that philosophy. It examines the moral problems inherent in implementing the philosophy in clinical practice. It concludes with suggestions for improvements which could be made to the philosophy statement so as to influence clinical care for the better. Thesis 1 is that decisions regarding the use of treatment to control symptoms or prolong life did not need to depend on complex doctrines such as double effect, but instead ought to be based on weighing up the benefits, harms and risks of treatment. Thesis 2 is that the relatives should not be an equal part of the remit of care. It is argued that whilst there is a special relationship, founded on an implicit promise and associated with specific obligations, between patients and health care professionals, this special relationship should not be extended to relatives of the patient. Thesis 3 is that quality of life as a global concept should not be used. Since quality of life depends on many incommensurable factors, and it is not possible to construct a coherent account of quality of life from our everyday notions of what it means, it is not possible to construct a quality of life scale. Thesis 4 is that there are constraints of expertise and propriety on attempts to influence the patient’s psychological, social and spiritual well-being. Thesis 5 is that within health care there ought to be a just distribution of resources to specialist palliative care, and then among terminally ill patients regardless of their illness.

B-cell acute lymphoblastic leukemia (B-ALL) represents a collection of diseases that are categorized into subtypes based on the presence of recurrent cytogenetic abnormalities. These abnormalities often result in the expression of oncogenic drivers that denote a standard- or high-risk for relapse. Currently, survival rates boarder 40% for adult patients and relapses are often observed in patients lacking high-risk markers. Thus, there is an unmet need for biomarkers that can identify all high-risk leukemia, and development of novel therapies based on a better understanding of the molecular drivers of B-ALL. To address this need, I designed a multi-parameter phospho-flow cytometry platform and characterized basal and cytokine-potentiated signaling in adult B-ALL samples. I identified patterns of cytokine-responsiveness across B-ALL patients that correlated with the presence of high-risk oncogenic drivers. Furthermore, I demonstrated that small-molecule inhibitors could abrogate cytokine-induced signaling in high-risk patients suggesting these inhibitors may compliment current chemotherapeutic protocols.

B-cell acute lymphoblastic leukemia (B-ALL) represents a collection of diseases that are categorized into subtypes based on the presence of recurrent cytogenetic abnormalities. These abnormalities often result in the expression of oncogenic drivers that denote a standard- or high-risk for relapse. Currently, survival rates boarder 40% for adult patients and relapses are often observed in patients lacking high-risk markers. Thus, there is an unmet need for biomarkers that can identify all high-risk leukemia, and development of novel therapies based on a better understanding of the molecular drivers of B-ALL. To address this need, I designed a multi-parameter phospho-flow cytometry platform and characterized basal and cytokine-potentiated signaling in adult B-ALL samples. I identified patterns of cytokine-responsiveness across B-ALL patients that correlated with the presence of high-risk oncogenic drivers. Furthermore, I demonstrated that small-molecule inhibitors could abrogate cytokine-induced signaling in high-risk patients suggesting these inhibitors may compliment current chemotherapeutic protocols.

Graduation date: 1940

Graduation date: 1946

Photocopy of typescript. / Thesis (Ph. D.)--University of Hawaii at Manoa, 1979. / Bibliography: leaves 127-138. / Microfiche. / x, 138 leaves ill., maps 29 cm

Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma and liver cirrhosis worldwide. HBV vaccination can prevent new infections, but effective antiviral drugs are not available for a large number of HBV infected patients. To develop novel antiviral drugs, a better understanding of the regulation of HBV gene expression is vital. One important aspect is to understand how HBV hijacks the cellular machinery to export unspliced RNAs from the nucleus of a cell to the site of incorporation into new HBV particles. The HBV post-transcriptional regulatory element (HBV PRE) is a cis acting RNA element found in all HBV transcripts. It has been reported to play an important role in the nuclear export of HBV mRNAs. Moreover, it has the ability to enhance expression of intronless as well as unspliced transcripts. Despite concerted investigations, the functional core element of HBV PRE remains unknown and the exact mechanism of how HBV PRE mediates nuclear export is unclear. This project first produced a complete HBV genome with comprehensive annotation of both coding regions and regulatory signals, which was then used for comparative genomic analysis. The functional elements of the HBV PRE were first subjected to analysis in silico. The HBV PRE is highly conserved among HBVs. Based on this sequence conservation and prediction of conserved RNA secondary structure, potentially functional HBV PRE elements including the previously reported elements (HBV SLα and HBV SLβ) were identified. Experimental deletion analysis of the HBV PRE sequence showed that the effect of each of these elements on the intronless reporter gene�s expression was similar to that of the entire full length HBV PRE. Thus, the results suggested that overall HBV PRE function was not due to additive effects from the individual elements. Surprisingly, a specific sub-section of HBV PRE decreased the level of reporter gene expression. This sub-section has not been identified previously, thus it is a novel HBV PRE inhibitory element. Further analyses using specific reporter assays revealed that the HBV PRE enhanced expression of an unspliced reporter gene whereas the RNA nuclear export elements of retroviruses, CTE (in MPMV) and RRE (in HIV-1) were not able to. Therefore, these results indicate that HBV PRE is involved in inhibition of splicing and it utilizes a different mechanism from CTE and RRE. Interestingly, HBV PRE was observed to be unable to enhance the expression of an intronless luciferase gene. Therefore, HBV PRE is not able to enhance cytoplasmic expression of all intronless transcripts. This project also addressed the idea that the RNA-binding protein, polypyrimidine tract binding protein (PTB) is a positive trans-acting factor for HBV PRE function. Transient expression of exogenous PTB in cultured cells showed no specific effect on constructs containing HBV PRE. Moreover, reduction of endogenous PTB by RNAi did not affect HBV PRE function. Therefore, the results presented in this project do not support the hypothesis that PTB plays a role in HBV PRE function. Given that HBV PRE is highly conserved and present in all HBV transcripts, it makes a good target site for novel molecular therapeutic treatments such as siRNA. To identify potential siRNA target sites within HBV PRE, an RNAi study using a plasmid expressing shRNA against HBV PRE was done. The results from the RNAi study revealed that the expression of a reporter gene could be significantly reduced by siRNA targeted to the HBV PRE. Overall, this project produced a highly annotated HBV genome that can be used as the reference sequence for comparative genomic analysis. Moreover, this work identified novel regulatory elements within HBV PRE that are likely to play an important role in HBV gene expression. Furthermore, the study also identified an excellent siRNA target site within HBV PRE that may inhibit HBV gene expression.