Bipartite Assertion: A New Account of Assertion, Defined in Terms of Responsibility and Explicit Presentation

Assertion is a speech act that stands at the intersection of the philosophy of language and social epistemology. It is a phenomenon that bears on such wide-ranging topics as testimony, truth, meaning, knowledge and trust. It is thus no surprise that analytic philosophers have devoted innumerable pages to assertion, trying to give the norms that govern it, its role in the transmission of knowledge, and most importantly, what assertion is, or how assertion is to be defined. In this thesis I attempt to show that all previous answers to the question “What is assertion?” are flawed. There are four major traditions in the literature: constitutive norm theories of assertion, accounts that treat assertion as the expression of speaker attitudes, accounts that treat assertion as a proposal to add some proposition to the common ground, and accounts that treat assertion as the taking of responsibility for some claim. Each tradition is explored here, the leading theories within the tradition developed, and then placed under scrutiny to demonstrate flaws within the positions surveyed. I follow the work of G.E. Moore and William P. Alston, whilst drawing on the work of Robert Brandom in order to give a new bipartite theory of assertion. I argue that assertion consists in the explicit presentation of a proposition, along with a taking of responsibility for that proposition. Taking Alston's explicit presentation condition and repairing it in order to deal with problems it faces, whilst combining it with Brandom's responsibility condition, provides, I believe, the best account of assertion.

ROLE OF MULTIPLE TOLL-LIKE RECEPTOR ACTIVATION IN REGULATING CYTOTOXIC T CELL PRIMING TO LYMPOCYTIC CHORIOMENINGITIS VIRUS INFECTIONS

Foreign pathogens are recognized by toll-like receptors (TLR), present on various immune cells such as professional antigen-presenting cells (pAPCs). On recognition of its ligand, these receptors activate pAPCs, which may in turn influence naïve CD8+ T cell activation and affect their abilities to clear viral infection. However, how TLR ligands (TLR-L) can regulate CD8+ T cell responses have not been fully elucidated. This thesis will focus on examining how the presence of components from foreign pathogens, e.g. viral or bacterial infection, can contribute to shaping host immunity during concurrent viral infections. Since nitric oxide (NO), an innate effector immune molecule, was recently suggested to regulate proteasome activity; we sought to examine if NO can influence MHC-I antigen presentation during viral infections. The data in this section of the thesis provides evidence that combined TLR engagement can alter the presentation of certain CD8+ epitopes due to NO-induced inhibition in proteasome activity. Taken together, the data demonstrate that TLR ligation can influence the adaptive immune response due to induction of specific innate effector molecules such as NO. Next, the influence of combined TLR engagement on CD8+ T cell immunodominance hierarchies during viral infections was examined. In this section, we established that dual TLR2 and TLR3 stimulation alters immunodominance hierarchies of LCMV epitopes as a result of reduced uptake of cell-associated antigens and reduced cross-presentation of NP396 consequently suppressing NP396-specific CD8+ T cell responses. These findings are significant as they highlight a new role for TLR ligands in regulating anti-viral CD8+ T cell responses through impairing cross-presentation of cell-associated antigens depending on the type of TLR present in the environment during infections. Finally, we addressed TLR ligand induced type I interferon production and the signalling pathways that regulate them in two different mouse macrophage populations – those derived from the spleen or bone marrow. In this study, we observed that concomitant TLR2 stimulation blocked the induction of type I IFN induced by TLR4 in bone marrow-derived macrophages, but not spleen-derived macrophages in SOCS3-dependent manner. Taken together, the data presented in this thesis have defined new facets of how anti-viral responses are regulated by TLR activation, especially if multiple receptors are engaged simultaneously.

ThreeDimensional Epigraphic Recording at Stobi (Former Yugoslav Republic of Macedonia): Creating a Virtual Lapidarium

There is an increased need for 3D recording of archaeological sites and digital preservation of their artifacts. Digital photogrammetry with prosumer DSLR cameras is a suitable tool for recording epigraphy in particular, as it allows for the recording of inscribed surfaces with very high accuracy, often better than 2 mm and with only a short time spent in the field. When photogrammetry is fused with other computational photography techniques like panoramic tours and Reflectance Transformation Imaging, a workflow exists to rival traditional LiDAR­based methods. The difficulty however, arises in the presentation of 3D data. It requires an enormous amount of storage and end­user sophistication. The proposed solution is to use game­engine technology and high definition virtual tours to provide not only scholars, but also the general public with an uncomplicated interface to interact with the detailed 3D epigraphic data. The site of Stobi, located near Gradsko, in the Former Yugoslav Republic of Macedonia (FYROM) was used as a case study to demonstrate the effectiveness of RTI, photogrammetry and virtual tour imaging working in combination. A selection of nine sets of inscriptions from the archaeological site were chosen to demonstrate the range of application for the techniques. The chosen marble, sandstone and breccia inscriptions are representative of the varying levels of deterioration and degradation of the epigraphy at Stobi, in which both their rates of decay and resulting legibility is varied. This selection includes those which are treated and untreated stones as well as those in situ and those in storage. The selection consists of both Latin and Greek inscriptions with content ranging from temple dedication inscriptions to statue dedications. This combination of 3D modeling techniques presents a cost and time efficient solution to both increase the legibility of severely damaged stones and to digitally preserve the current state of the inscriptions.

THE EFFECT OF PREECLAMPSIA ON RENAL FUNCTION: CROSS-SECTIONAL STUDIES OF POSTPARTUM PREECLAMPTICS AND WOMEN WHO WERE DESTINED TO DEVELOP PREECLAMPSIA

Preeclampsia (PE) is a pregnancy complication that is new-onset of hypertension and proteinuria after 20 weeks of gestation. However, subclinical renal dysfunction may be apparent earlier in gestation prior to the clinical presentation of PE. Although the maternal syndrome of PE resolves early postpartum, women with a history of PE are at higher risk of renal dysfunction later in life. Mineral metabolism, such as phosphate balance is heavily dependent on renal function, yet, phosphate handling in women with a history of PE is largely unknown. To investigate whether women with a history of PE would exhibit changes in phosphate metabolism compared to healthy parous women, phosphate loading test was used. Women with or without a history of PE, who were 6 months to 5 years postpartum, were recruited for this study. Blood and urine samples were collected before and after the oral dosing of 500mg phosphate solution. Biochemical markers of phosphate metabolism and renal function were evaluated. In order to assess the difference in renal function alteration between first trimester women who were or were not destined to develop PE, plasma cystatin C concentration was analysed. After phosphate loading, women with a history of PE had significantly elevated serum phosphate at both 1- and 2-hour, while controls had higher urine phosphate:urine creatinine excretion ratio at 1-hour than women with a history of PE. Women with a history of PE had no changes in intact parathyroid hormone (iPTH) concentration throughout the study period, whereas controls had elevated iPTH at 1-hour from baseline. In terms of renal function in the first trimester, there was no difference in plasma cystatin C concentration between women who were or were not destined to develop PE. The elevation of serum phosphate in women with a history of PE could be due to the delay in phosphate excretion. Prolong elevation of serum phosphate can have serious consequences later in life. Thus, oral phosphate challenge may serve as a useful method of early screening for altered phosphate metabolism and renal function.

THE EFFECT OF PREECLAMPSIA ON RENAL FUNCTION: CROSS-SECTIONAL STUDIES OF POSTPARTUM PREECLAMPTICS AND WOMEN WHO WERE DESTINED TO DEVELOP PREECLAMPSIA

Preeclampsia (PE) is a pregnancy complication that is new-onset of hypertension and proteinuria after 20 weeks of gestation. However, subclinical renal dysfunction may be apparent earlier in gestation prior to the clinical presentation of PE. Although the maternal syndrome of PE resolves early postpartum, women with a history of PE are at higher risk of renal dysfunction later in life. Mineral metabolism, such as phosphate balance is heavily dependent on renal function, yet, phosphate handling in women with a history of PE is largely unknown. To investigate whether women with a history of PE would exhibit changes in phosphate metabolism compared to healthy parous women, phosphate loading test was used. Women with or without a history of PE, who were 6 months to 5 years postpartum, were recruited for this study. Blood and urine samples were collected before and after the oral dosing of 500mg phosphate solution. Biochemical markers of phosphate metabolism and renal function were evaluated. In order to assess the difference in renal function alteration between first trimester women who were or were not destined to develop PE, plasma cystatin C concentration was analysed. After phosphate loading, women with a history of PE had significantly elevated serum phosphate at both 1- and 2-hour, while controls had higher urine phosphate:urine creatinine excretion ratio at 1-hour than women with a history of PE. Women with a history of PE had no changes in intact parathyroid hormone (iPTH) concentration throughout the study period, whereas controls had elevated iPTH at 1-hour from baseline. In terms of renal function in the first trimester, there was no difference in plasma cystatin C concentration between women who were or were not destined to develop PE. The elevation of serum phosphate in women with a history of PE could be due to the delay in phosphate excretion. Prolong elevation of serum phosphate can have serious consequences later in life. Thus, oral phosphate challenge may serve as a useful method of early screening for altered phosphate metabolism and renal function.