Epigenetic misregulation of gene expression is known to be an important feature in cancer. This has mainly been studied at the level of changes in DNA methylation and histone modifications at individual genes. In this thesis I have set out to investigate whether there are long-range changes in chromatin structure linked to altered gene expression in breast cancer. From large published datasets, I used a computational approach to identify large genomic regions which are coordinately misregulated in breast cancer independent of copy number aberrations (genomic effects). I found 26 regions of co-ordinate regulation of neighbouring genes that are consistent between breast tumours and breast cancer cell lines. These regions had different expression phenotypes (activation, repression, no change) compared to normal breast and also with tumour subtype (luminal vs basal and ER status). The regions of epigenetic regulation (RER) identified in breast cancer were mostly cancer type specific. I investigated the mechanism of long-range misregulation at one such region on chromosome 16p11.2 which is aberrantly activated in breast cancer. Interestingly, in estrogen-receptor positive (ER+ve) cells, genes in this region are upregulated relative to estrogen receptor negative (ER-ve) cells. Using fluorescence in situ hybridisation (FISH) I found that in ER+ve breast cancer cell lines and tumour tissue this region is in a more decondensed chromatin architecture than in ER-ve cell lines and tumour tissue. Furthermore this region was very compact in a normal breast epithelial cell line and breast tissue corresponding to what would be expected from the expression data. Estrogen was found to play a key role in maintaining the aberrant decondensation of chromatin at this locus on chr16p11.2, as shown by compaction of the region by starving ER+ve cells of estrogen and decompaction upon subsequent estrogen treatment. Interestingly there was also an estrogen mediated repositioning of the 16p11.2 RER domain away from the nuclear centre in hormone starved conditions and towards the centre upon estrogen stimulation. Together these results show that estrogen is key to regulating the changes in nuclear organisation and chromatin decompaction at this locus, which are associated with aberrant patterns of gene expression in ER+ve breast cancer.

Introduction: NG2/CSPG4 is a unique transmembrane chondroitin sulphate proteoglycan molecule expressed as a core protein and a chondroitin sulphate proteoglycan (CSPG) up to 400kD. NG2/CSPG4 mediates the communication between the extracellular and intracellular compartments through interactions with collagen VI, growth factors and the actin cytoskeleton. NG2/CSPG4 affects cell migration, spreading, apoptosis and proliferation processes. NG2/CSPG4 has been shown to be expressed in developing and adult cartilage where less is known of its function. I tested the hypothesis: NG2/CSPG4 is an important regulator of chondrocytes function and has the potential to be a therapeutic target for treatment of diseases of cartilage such as osteoarthritis and chondrosarcoma. To do this, I had the following aims: 1) investigate whether different types of chondrocytes show variation in the form or distribution of NG2/CSPG4 expression and 2) through a knockdown approach develop a model to study the functional roles of NG2/CSPG4 in human chondrocytes. Materials and Methods: JJ012, a chondrosarcoma cell line, chondrocytes derived from human articular cartilage and C20/A4 an immortalised chondrocyte cell line were used. NG2/CSPG4 expression was investigated by RT-PCR western blotting, flow-cytometry and immunocytochemistry. NG2/CSPG4 interaction with Golgi complex and endoplasmic reticulum (ER) was assessed by double immunofluorescence. Biochemical interactions were assessed by immunoprecipitation and mass spectroscopy. For NG2/CSPG knockdown, a viral transduction method was carried out using 5 different constructs. Different functional roles of NG2/CSPG4 were investigated. The role of NG2/CSPG4 in gene regulation was studied by shRNA knockdown of NG2/CSPG4 in JJ012 cells and RTPCR. Results: NG2/CSPG4 mRNA was detectable in all cells tested. Western blotting showed expression of only a 270kD core protein in JJ012 and C20A4 cells. Using two different anti NG2/CSPG4 antibodies human OA chondrocytes were seen to express multiple molecular weight forms differentially recognised with and without chondroitinase ABC pre-treatment. Expression of NG2/CSPG4 in JJ012 cells was predominantly membrane associated whilst in OA chondrocytes and C20A4 cells, additional, predominant punctuate cytoplasmic distribution was evident. In OA chondrocytes NG2/CSPG4 co-localised with the Golgi complex and ER. Immunoprecipitation and mass spectrometry data demonstrated associations between NG2/CSPG4 and both collagen VI and thrombopoietin in OA chondrocytes. A model of NG2/CSPG4 gene knockdown was achieved in JJ012 chondrosarcoma cell line, known as B3. B3 cells spread more and migrate less than JJ012 cells; with a significant difference observed in migration (after 10hours: the closed area was 81.4% for JJ012 and 54.6% for B3). There was no difference in cell adhesion to collagen I, II, VI and fibronectin. EGTA inhibited cell adhesion to fibronectin in dose dependent manner with no significant difference observed between both JJ012 and B3 cells. EDTA reduced adhesion of B3 cells but not JJ012 to fibronectin. A significant difference in cell proliferation was detected with no change in apoptosis. Following NG2/CSPG4 knockdown in JJ012 cells there was no difference in expression of aggrecan, collagen II and SOX-9. In contrast, B3 cells showed a decreased expression of MPP3 and ADAMTS-4, a complete loss of ADAMTS-5 and increased expression of MMP13. Conclusions: I have identified altered expression and multiple forms of NG2/CSPG4 in different types of chondrocytes and shown association of this molecule with type VI collagen and thrombopoietin. Creation of a chondrocyte cell line that has stable knockdown of NG2/CSPG4 allowed further investigation of NG2/CSPG function in chondrocytes. NG2/CSPG4 knockdown reduced the cellular migration and proliferation and increased the chondrocyte spreading. The adhesion mechanism in JJ012 appears to be calcium dependent. Loss of NG2/CSPG4 induced changes in expression of aggrecanases and MMPs. Altered expression or associations of NG2/CSPG4 with extracellular ligands or intracellular signalling cascades may be important in the pathogenesis of OA by regulating proteolytic activity or apoptosis related pathways. NG2/CSPG4 is a potential therapeutic target in degenerative and neoplastic diseases of cartilage.

Introduction Aromatase inhibitors (AIs) have an established role in the treatment of estrogen receptor alpha positive (ER+) post-menopausal breast cancer. However, response rates are only 50-70% in the neoadjuvant setting and lower in advanced disease. There is a need to identify pre- or early on-treatment biomarkers to predict sensitivity which outperform those currently used, in a move towards stratified treatments and improved patient care. Given the heterogeneity known to exist in the breast cancer population, and the limited availability of matched pre- and on-treatment clinical material, this study also sought to develop novel data integration approaches allowing for the inclusion of similar previously published datasets, thus maximising the power of this study. Experimental Design Pre- and on-treatment (at 14 days and 3-months) biopsies were obtained from 34 postmenopausal women with ER+ breast cancer receiving 3 months of neoadjuvant letrozole. Illumina Beadarray gene expression data from these samples were combined with Affymetrix GeneChip data from a similar published study (n=55) and crossplatform integration approaches were evaluated. Dynamic clinical response was assessed for each patient from periodic 3D ultrasound measurements during treatment. Results Despite intrinsic differences between different microarray technologies, suitably similar studies can be directly integrated for robust and meaningful meta-analysis with improved statistical power. After mapping probe sequences to Ensembl genes it was demonstrated that, ComBat and cross platform normalisation (XPN), significantly outperform mean-centering and distance-weighted discrimination (DWD) in terms of minimising inter-platform variance. In particular it was observed that DWD, a popular method used in a number of previous studies, removed systematic bias at the expense of genuine biological variability, potentially reducing legitimate biological differences from integrated datasets. A pipeline for the successful integration of microarray datasets from different platforms was developed. Using this approach a classifier of clinical response to endocrine therapy in the neoadjuvant setting based on the expression of 4 genes was developed which predicted response with 96% and 91% accuracy in training (n=73) and independent validation (n=44) datasets respectively. An early on-treatment biopsy was found to improve predictive power in addition to pre-treatment alone. Conclusions Using a novel data integration approach developed as part of this study, a model comprising 4 novel biomarkers for accurate and robust prediction of clinical response to AIs by two weeks of treatment has been generated and validated. On-going work will investigate the applicability to other anti-estrogens, and the adjuvant setting and will assess the potential for a new therapy response test.

In this thesis we propose some new approaches to the study of complex networks, and apply them to multiple domains, focusing in particular on protein-protein interaction networks. We begin by examining the roles of individual proteins; specifically, the influential idea of 'date' and 'party' hubs. It was proposed that party hubs are local coordinators whereas date hubs are global connectors. We show that the observations underlying this proposal appear to have been largely illusory, and that topological properties of hubs do not in general correlate with interactor co-expression, thus undermining the primary basis for the categorisation. However, we find significant correlations between interaction centrality and the functional similarity of the interacting proteins, indicating that it might be useful to conceive of roles for protein-protein interactions, as opposed to individual proteins. The observation that examining just one or a few network properties can be misleading motivates us to attempt to develop a more holistic methodology for network investigation. A wide variety of diagnostics of network structure exist, but studies typically employ only small, largely arbitrarily selected subsets of these. Here we simultaneously investigate many networks using many diagnostics in a data-driven fashion, and demonstrate how this approach serves to organise both networks and diagnostics, as well as to relate network structure to functionally relevant characteristics in a variety of settings. These include finding fast estimators for the solution of hard graph problems, discovering evolutionarily significant aspects of metabolic networks, detecting structural constraints on particular network types, and constructing summary statistics for efficient model-fitting to networks. We use the last mentioned to suggest that duplication-divergence is a feasible mechanism for protein-protein interaction evolution, and that interactions may rewire faster in yeast than in larger genomes like human and fruit fly. Our results help to illuminate protein-protein interaction networks in multiple ways, as well as providing some insight into structure-function relationships in other types of networks. We believe the methodology outlined here can serve as a general-purpose, data-driven approach to aid in the understanding of networked systems.

Doctor of Philosophy / Department of Entomology / Larry L. Buschman / Kun Yan Zhu / European corn borer, Ostrinia nubilalis, is one of the most destructive insect pests of corn in the Midwest corn belt of the United States. The crystal protein toxin (Cry1Ab) expressed by the bacterium, Bacillus thuriginesis (Bt), specifically targets O. nubilalis gut and functions as “stomach poison”. Transgenic corn expressing Cry1Ab can effectively control O. nubilalis larval infestation. However, O. nubilalis has the potential to develop resistance to Bt toxins which prompts concerns that transgenic corn will lose its control efficacy. Previous studies found that O. nubilalis gut serine proteases and membrane proteins were involved in Bt toxicity and resistance. Therefore, this study was to identify and characterize gut transcripts potentially involved in Bt toxicity and resistance, and to compare their transcriptional responses to the ingestion of Cry1Ab protoxin and transgenic corn leaves expressing Cry1Ab toxin. We identified and characterized 34 cDNAs encoding putative trypsins, chymotrypsins, and trypsin- and chymotrypsin-like protease homologs from O. nubilalis gut-specific expressed sequence tags (ESTs). Blast and phylogenetic analysis of their deduced amino acid sequences indicated that 15 were putative trypsins belonging to Try-G2 and Try-G3 groups (none of them was grouped in Try-G1), another 15 were putative chymotrypsins in one large group (CTP-G1), and the remaining four were serine protease homologs in Try-G4 and CTP-G2 groups, respectively. The existence of diverse trypsins, chymotrypsins and serine protease homologs in O. nubilalis could be an adaptation to different food sources and also a defense mechanism against plant-specific protease inhibitors and Cry toxins from transgenic corn. The expressions of four putative trypsins (OnTry4, OnTry5, OnTry6 and OnTry14) were up-regulated in O. nubilalis larvae after the ingestion of Cry1Ab protoxin. The differential expressions of these protease transcripts may implicate a link to Cry1Ab intoxication. To better understand the basic physiology of insect gut and Bt toxin interactions, we developed a high-resolution 8×15K cDNA microarray chips based on the larval gut specific ESTs. Each microarray contains 12,797 probes representing 2,895 unique larval gut transcripts. The expressions of 174 transcripts were differentially regulated at least 2-fold (P-value ≤0.05) after the larvae fed Cry1Ab protoxin for 6 hours. Among them, 13 transcripts, putatively encoding eight serine protease, three aminopeptidase, one alkaline phosphatase, and one cadherin-like protein, were identified and further validated their expression ratios by quantitative PCR (qPCR). Three trypsin transcripts were up-regulated by more than 5-fold in larvae fed Cry1Ab protoxin. Sequence analysis suggests that they may have role in protoxin activation and toxin degradation. The transcriptional responses of laboratory-selected Cry1Ab resistant (R) and susceptible (S) strains of O. nubilalis to the ingestion of transgenic corn (MON811) leaves expressing Cry1Ab toxin were also examined. Even though R-strain larvae showed 200-fold resistance to Cry1Ab protoxin as compared with S strain, the larvae from both strains eventually died after fed transgenic corn leaves. However, the survival time of R-strain larvae was significantly different from that of S-strain larvae. The median lethal time (LT50) for the early third-instar larvae of R- and S-strains were 5.4 and 3.6 days, respectively. Furthermore, we identified 398 and 264 transcripts from the larvae of the S and R strains, respectively, with a significantly increased or decreased expression (expression ratio cut off ≥2.0 fold with p-value ≤0.05) as compared with those in the larvae fed on non-transgenic corn leaves. The number of transcripts and their expression ratios of S-strain larvae are larger than these of R-strain larvae. These significantly differentially expressed transcripts may play important roles in influencing Cry1Ab toxicity from toxin degradation, toxin binding, to intracellular defense. Seventeen transcripts including serine protease and aminopeptdiase in S strain and nine in R strain were further analyzed by qPCR to validate their expression ratios. This study not only revealed information about the difference in the transcriptional responses of these genes to Cry1Ab between Bt-resistant and susceptible strains of O. nubilalis, but also provided new insights into potential interactions of the protoxin, toxin from transgenic corn with important proteins in the gut of O. nubilalis larvae.

Dorsal root ganglion (DRG) neurons are responsive to altered neuromuscular activity and play a role in diabetic peripheral neuropathy (DPN). We present evidence that small and large DRG neurons are differentially affected by exercise and diabetes. We examined gene expression in samples of small and large neurons of rat L4/L5 DRG, and the specific responses after exercise and diabetes, to identify potential molecular processes involved in activity-dependent changes. Small and large DRG neurons were collected using laser capture microdissection. Relative mRNA levels were determined using real-time polymerase chain reaction experiments. In study 1, healthy adult rats received treadmill exercise for 1 or 17 weeks, or voluntary wheel exercise for 16 weeks. In study 2, STZ-induced diabetic rats received 15 weeks of sedentary treatment or voluntary wheel exercise. Behavioural testing of thermal latency response was performed on all animals in study 2. In study 1, there were no significant changes in small or large DRG neuron gene expression after acute treadmill exercise. After chronic treadmill exercise, mRNA levels changed relative to healthy sedentary rats in small (↑ 5HT1D; ↓5HT1F) and large (↓ 5HT1A, TrkC, SYN1) DRG neurons. After chronic voluntary wheel exercise, mRNA levels changed relative to healthy sedentary rats in small (↓ 5HT1D, OPRD1, TrkA; ↑ GAP43) and large (↓ 5HT1D, Nav1.6, OPRD1, TrkA, TrkC, SYN1; ↑ 5HT3A, GAP43) DRG neurons. In study 2, there were no significant changes in large DRG neuron gene expression. In small DRG neurons, mRNA levels were changed in the diabetic sedentary group (↓TrkB; ↑5HT1F) as well as the diabetic wheel group (↓ CGRP) relative to healthy sedentary rats. 5HT1A receptor mRNA levels were higher in diabetic sedentary rats relative to diabetic wheel rats. Our results demonstrate that small and large DRG neurons respond, but in different ways, to the duration and intensity of exercise. DRG neurons show a greater response to voluntary compared to forced exercise, and chronic compared to acute exercise. The genetic changes in small DRG neurons of rats with DPN that exercise may be correlated with the positive change in progression of thermal hypoalgesia associated with exercise. / May 2016

Coercion and repressive legislation are widely recognised measures employed by hybrid regimes as a way of stifling the media. This thesis illustrates the long shadow cast by these measures by examining the impact of transgressions on self-censorship among Ugandan journalists, and how these are weighed against their notion of professionalism. Self- censorship is experienced as an unwanted, but vital practice that moves in tandem with the level of political tension, being an extraordinary rather than general measure. The study was conducted in the summer of 2016, founded by a Minor Field Study scholarship from the Swedish International Development Cooperation Agency (SIDA).

Recent developments in automation and novel experimental techniques have led to the accumulation of vast amounts of biological data and the emergence of numerous databases to store the wealth of information. Consequentially, bioinformatics have drawn considerable attention, accompanied by the development of a plethora of tools for the analysis of biological data. DNA microarrays constitute a prominent example of a high-throughput experimental technique that has required substantial contribution of bioinformatics tools. Following its popularity there is an on-going effort to integrate gene expression with other types of data in a common analytical approach. Pathway based microarray analysis seeks to facilitate microarray data in conjunction with biochemical pathway data and look for a coordinated change in the expression of genes constituting a pathway. However, it has been observed that genes in a pathway may show variable expression, with some appearing activated while others repressed. This thesis aims to add some contribution to pathway based microarray analysis and assist the interpretation of such observations, based on the fact that in all organisms a substantial number of genes take part in more than one biochemical pathway. It explores the hypothesis that the expression of such genes represents a net effect of their contribution to all their constituent pathways, applying statistical and data mining approaches. A heuristic search methodology is proposed to manipulate the pathway contribution of genes to follow underlying trends and interpret microarray results centred on pathway behaviour. The methodology is further refined to account for distinct genes encoding enzymes that catalyse the same reaction, and applied to modules, shorter chains of reactions forming sub-networks within pathways. Results based on various datasets are discussed, showing that the methodology is promising and may assist a biologist to decipher the biochemical state of an organism, in experiments where pathways exhibit variable expression.

A diapausa é um fenômeno amplamente presente nos artrópodes e é considerada como primordial para o sucesso evolutivo da Classe Insecta, pois possibilita a sobrevivência em condições adversas, como estações frias e secas. Sabe-se que durante a diapausa ocorre o silenciamento de muitos genes e que outros são unicamente expressos nesta fase. Embora existam evidências de que o processo da diapausa tenha se mantido conservado durante a evolução das espécies, ainda há lacunas no conhecimento sobre o nível de conservação dos padrões metabólicos. Um bom modelo para se estudar a diapausa é Tetrapedia diversipes, uma espécie bivoltina de abelha solitária. Os indivíduos que nascem na primeira geração seguem o desenvolvimento desde ovo até adulto em tempo bem menor do que aqueles que nascem na segunda geração; estes retardam o desenvolvimento na fase larval. Além disso, essa espécie é de fácil obtenção no seu ambiente natural, pois apresenta alta taxa de nidificação em ninhos-armadilha. O objetivo deste trabalho foi comparar o perfil de expressão de genes entre as larvas da 1ª geração (que não entram em diapausa), larvas da 2ª geração (que entrariam em diapausa) e das larvas em diapausa. Foram identificados 196 genes diferencialmente expressos, destes 87 foram anotados. Muitos destes genes já foram descritos na literatura como relacionados à diapausa em outras espécies, no entanto, o padrão de expressão não é conservado. Os genes aqui identificados foram divididos em cinco grupos: relacionados à desintoxicação celular, cutícula e citoesqueleto, metabolismo de lipídeos e esteróis, ciclo celular e outros genes relacionados à diapausa / The diapause is broadly distributed among the arthropods and has had an important role for the evolutionary success of the Class Insecta, mainly because this process permits insects to explore adverse conditions, such as cold and dry seasons. It is known that there are many genes being silenced and others being uniquely expressed during diapause. And although there are evidences that the diapause process has remained conserved during the evolution of species, it is still not clear how conserved are the metabolic patterns involved in this behavior. Tetrapedia diversipes is a solitary bee and a good model to study diapause. Individuals from the first generation do not enter in diapause and develop faster than individuals from the second generation, which enter in diapause during the winter. Moreover, this species is easy to capture in natural conditions due to the high rate of nesting in trap nests. The aim of this work was to compare the gene expression profile among non-diapause larvae from first and second generation (about to enter diapause) and larvae already in diapause, trough transcriptome data. One hundred ninety-four genes were identified as differentially expressed and 87 of them were annotated. Many of these genes have already been described as related to diapause in others species, but the expression pattern was not conserved. These genes were divided in five groups: related to cellular detoxification, cuticle and cytoskeleton, lipids and steroids metabolism, cell cycle and other genes related to diapause

Thesis advisor: John Sallis / This dissertation attempts to give an account of philosophical language in Hegel, with particular emphasis on his claim that a philosophical exposition must be living and self-moving. Since Hegel did not provide an extended, thematized account of philosophical language, my primary approach is to take the resources of his thought in general and attempt to construct an account which is consistent with his philosophy as a whole. Thus, a large portion of this dissertation is not directly about philosophical language, but about other determinations such as becoming, indifference, contradiction, life, the understanding, reason, etc., which lay the groundwork for discussing philosophical language in the final chapter. As a preface to all of this, however, I devote Part I of the dissertation to an investigation of Hegel's view of how one should go about comprehending philosophical determinations, i.e., those things which are the subject matter of philosophy (e.g., the determination 'plant' but not 'poison ivy'; the determination 'art' but not 'Flemish Baroque painting'). Chapter 1 deals with his critique of the formalistic approach which attempts to comprehend things by 'applying' categories to them (e.g., applying 'thinking' and 'animal' to comprehend 'human being'). In Chapter 2 I discuss Hegel's alternate view of comprehension, describing this view in terms of the idea of 'expression': later categories in his encyclopedia are comprehended not by applying earlier ones to them, but by grasping the later ones as developmental expressions of the earlier ones. Thus, expression is not only a linguistic but also an ontological category, a point which is investigated in more concrete detail in Chapter 3 through a close reading of the statement "being and nothing are one and the same." As it turns out, this linguistic expression of being plays an essential role in being's ontological expression and development. In Part II, I explore the logical determinations of 'mechanism' and 'life' in the Science of Logic. To set the stage for this, Chapter 4 gives an account of the relation of 'indifference' (present between the 'parts' of a whole) and the relation of 'reciprocity' (present between the 'moments' of a whole). These two kinds of relations allow us in Chapter 5 to see more clearly why Hegel views the logical determination of mechanism as involving a movement of thought whose source is external to it, and the logical determination of life as involving self-movement and self-determination. To further clarify what Hegel means by calling philosophical thought 'living,' I discuss what he might mean by the word 'movement' in the Logic, along with his view of the relation between becoming, contradiction, and self-movement. In Part III I argue that, regarding the logical determinations of mechanism and life, the former finds particularly vivid expression in the operations of the understanding and its 'ordinary language' (Chapter 6), while the latter finds such expression in the operations of reason and its 'philosophical language' (Chapter 7). The faculty of the understanding, whose nature it is to have objects standing over against it (Gegenstände) and to operate according to the category of formal identity, is characterized by finitude and abstract thinking. As such, the ordinary language which it produces is characterized by these same qualities. This entails a.) that this language is incapable of expressing the interdependence of identity and difference, b.) that it thus views the copula ('is') as containing merely formal identity, and c.) that it tends to define its words in abstraction from each other. Another result of ordinary language being produced by the understanding is that it is incapable of providing a genuinely philosophical account of anything, insofar as such an account requires a level of self-reflexivity which the faculty of the understanding, in isolation, renders impossible. The faculty of reason, on the other hand, both includes the understanding (with its abstracting powers) and goes beyond it, particularly in its rejection of identity as merely formal (i.e., identity as independent of difference). Crucially, it is this rejection which allows reason to comprehend the dissolutions of the contradictory logical determinations which move thinking forward. Directed not toward 'objects' but toward its own self, the goal of reason is self-knowledge via the concrete experience of thinking through its own thinking, a 'thinking through' which is necessary and self-moving insofar as its internal contradictions propel it down one (and only one) logical path. The language of reason - philosophical language - is an essential part of this process. Philosophical language, qua language, possesses a contingent dimension, e.g., the way the words sound and the letters are shaped. But this contingency, I argue, does not compromise philosophical language's ability to mediate the non-contingent nature of philosophical thought; for, the nature of logic is that it can reach its full expression only through the determinations of spirit, and all such determinations (with the exception of philosophy itself) necessarily contain contingencies. Philosophical language belongs not to the logical sphere (i.e., the sphere which is wholly 'within itself' and thus wholly necessary), but rather to the spiritual one (i.e., the human realm). As a result, this language must possess contingent dimensions, for it is precisely its 'not-being-within-itself' which allows it to be other to the realm of logic, and thus to be its expression. In contrast to ordinary language, philosophical language is able to give expression to the interdependence of identity and difference, and to create the meaning of its words not as isolated 'parts' but rather as 'moments' which depend on the meanings of all the other words which it has generated. Because of this, philosophical language engages in a continual diaeresis (division) and synagoge (collection) of its meanings, splitting the meaning of a term into an opposed meaning which contradicts the previous one and leads to a new word with a new meaning, containing the remnants of the previous ones. This dialectical process is a living one insofar as the oppositions and contradictions which move the exposition forward are immanent to the exposition itself. Operating throughout the entire encyclopedia (Science of Logic, Philosophy of Nature, Philosophy of Spirit), the self-moving linguistic diaeresis and synagoge reaches its conclusion in the final definition, that of the term 'philosophy,' thereby bringing together in one word the living remains of the meanings of all prior determinations. Because philosophy and philosophical language constitutively determine one another, neither can be, or be comprehended, apart from the other. In Hegel's view, although one is doing philosophy from the very first words of the Science of Logic, one can only account for philosophy at the 1,500-page encyclopedia's very end; my claim is that, in the same way, although one is using philosophical language from the very beginning, one can only account for this language at the very end. Philosophical language receives its determinateness from philosophy, and vice versa. As a result, only at the encyclopedia's end can one fully comprehend what one has been doing and saying for the last 1,500 pages. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Philosophy.