My contributions to the research on epistemic value can be divided into two parts: first, I pinpoint some causes of the problems about epistemic value which have not previously been identified; and, second, I offer novel accounts of epistemic value which offer better solutions to the problems about epistemic value. First, there are two trends in the literature on epistemic value that are rarely challenged: (i) epistemologists tend to understand epistemic value in terms of intrinsic value from the epistemic point of view, and (ii) the discussion of epistemic value tends to focus only on the values of properties of belief. I argue that both trends should be rejected if we want to solve several persistent problems about epistemic value: the value problems about knowledge, the teleological account of epistemic normativity, and the triviality objection that some true beliefs (or knowledge) are too trivial to be epistemic goals. My account of epistemic value is in terms of goodness of epistemic kinds, which rejects (i). An epistemic kind is an evaluative kind—a kind that determines its own evaluative standards—whose evaluative standards are truth-directed: e.g. a belief is good qua belief if true. I argue that my account is immune from the triviality objection. Moreover, since the goodness of an epistemic kind is finally valuable, the account gives us simple solutions to the value problems of knowledge. I develop my own solutions through critically appropriating the virtue-theoretic account, according to which epistemic evaluation is a kind of performance evaluation, which rejects (ii). I argue that the value of knowledge consists of the value of epistemic success (true belief) and epistemic competence. Finally, I argue that approaches that focus on the evaluation of belief cannot explain epistemic normativity. Instead, we need an approach that focuses on the evaluation of person, which rejects (ii). I argue that conforming to epistemic norms is part of what makes us good qua person. The goodness of person qua person is an intrinsic value and able to provide pro tanto reasons for a person to be epistemically good qua person, which is the ground of epistemic normativity. Overall, there are two main differences between my account and the mainstream account: first, the purpose of epistemic evaluation is about good cognitive performances rather than good beliefs; and, second, what grounds epistemic normativity is the goodness of a person qua person rather than the goodness (or correctness) of belief qua belief. The upshot of my account is that the focus of epistemology should be on questions such as ‘What is an epistemically good person?’ and ‘What makes a person epistemically good qua person?’ Furthermore, my account shows that epistemic normativity is not distinct from ethical normativity. That is, the question ‘What is an epistemically good person?’ is part of the question ‘What is a good person?’ and a reason why we should be an epistemically good person is consequently a reason why we should be a good person.

This thesis examines Marcel Duchamp’s "The Large Glass" in relation to Homer’s "Odyssey" and by extension to James Joyce’s "Ulysses." It focuses on the idea that Duchamp may have had in mind Penelope and her Suitors when he was creating the Bride and her Bachelors. The aim of the thesis is threefold – to clarify a problematic area in avant-garde art by restoring the important role the "Odyssey" played in the modern culture as evidenced by preceding and contemporary artists; to detect possible Homeric traces on the "Glass" as such, but also by exploring references to Homer in related works by Duchamp; and finally to compare the "Glass" with "Ulysses," which seems to be as convoluted in its relation to the "Odyssey." The thesis is correspondingly divided into three parts. The first places Duchamp in a broader culture that is directly influenced by the Classics and Homer’s "Odyssey." The second sets out to explore possible references to Homer in seminal works of Duchamp, which reveal that he discreetly based his working method and conceptual rationale on the appropriation of tradition. The final part deals with the ways in which specific aspects of the "Glass" may be critically interpreted as Homeric in origin. Throughout the thesis runs a comparison of the "Glass" with "Ulysses," which exemplifies how safe Homeric attributions may be bent by appropriation to serve their authors’ ends. This study is primarily theoretical and thematic, attempting to piece together perhaps a better understanding than before of one of 20th century’s most seminal artistic figures and elusive bodies of work. Thus, the "Glass" may turn out to be read as a morality story about archetypal issues with which human nature grapples eternally – violence, intoxication and lust. As such, the "Glass" may enigmatically emerge as a Homeric paradigm of man’s initiation to inner freedom, which Duchamp called the “beauty of indifference.”

This thesis seeks to provide a novel interpretation of Heidegger’s project in the late twenties and of its breakdown and transformation around the turn of the decade. I argue that Heidegger develops a unified project in the late Marburg period that is constructed around the question of the unity of the concept of being in light of its regional multiplicity. Furthermore, I argue that Heidegger’s conception of the framework of this project is highly influenced by his reception of Kant in this same period. Specifically, I identify the elements of the Kantian framework that Heidegger retains and appropriates for his project, as well as those elements that he rejects. In the former case, Heidegger takes up primarily Kant’s framework of a priori transcendental conditions that are to make empirical experience possible, which Heidegger reformulates in terms of the pre-understanding of being that makes possible the apprehension of entities. In the latter case, I isolate two primary criticisms that will serve as desiderata for the execution of Heidegger’s project, namely: that the categories have an excessively subjectivistic status, and that they are based solely on logical functions of judgement. The former constitutes a problem because the location of the categories on the subject side make s difficult their applicability to the objective realm, and lead Heidegger to reject both the quid juris form of posing the question as well as the results of the transcendental deduction in general. The latter, though closely connected, points to a different set of problems, and targets not the applicability claim but the exhaustiveness claim of the metaphysical deduction. In articulating a theory of categories based on logical functions of judgments, Kant’s resulting theory of possible objects of experience is limited merely to objects of explicit judgement, roughly the objects of the natural sciences, at the expense of other kinds of objects. Paradigmatic of these ‘other kinds of objects’, for Heidegger, are ready-to-hand entities, which are neither spatio-temporally individuated, nor fit into the Kantian conditions for what it would be to count as an object of possible experience. I argue that Heidegger develops his late Marburg project as a development of the Kantian-inspired framework of pre-understanding of being in a manner that responds to the two above problems. Specifically, Heidegger seeks to ground the understanding of being in temporal schemata rather than in logical functions of judgement, which is intended to provide both a wider range of possible objects and to provide a unified backdrop against which the subject can apprehend objects. I end with an assessment of Heidegger’s project, arguing that while it is ultimately unsuccessful in its aims, it nonetheless represents a philosophically interesting and innovative post-Kantian project that sheds exegetical light both on Heidegger’s middle period as well as on his later works.

This doctoral submission draws on a range of published material to pursue meandering lines of enquiry into the study of children’s play. At its heart is a claim that playing is quintessentially the process of life going on in an affirmative manner (Lester, 2015a); not merely an outcome or activity but the grounding of life itself, a force productive of creative novelty that precedes its classification. In developing this account, the writings of Gilles Deleuze, including collaborations with Felix Guattari, and contemporary iterations of what might be termed ‘new materialisms’, take centre stage. it is a geo-philosophical quest that seeks to overcome the individualisation of life and its accompanying categorisation of playing as a subordinate state, something that can only be tolerated if it contributes to furthering the progress of a subject. The intention here is to go beyond such value, to re-position playing alongside life itself and by doing so to question the ways in which childhood, adulthood and space are constructed and practised. This it is not merely carried out at a level of abstraction: true to Deleuzian process philosophy this thesis is not concerned with the meaning of play but questions how does it work and how might it be worked differently? In response, it develops an ‘exemplary method’ (Massumi, 2002, p. 17) by drawing on a series of singular examples from playwork practice, everyday life, research projects and more remote sources. These are designed to be generative and bring forth new concepts rather than reducing things to more of the same. Above all it is an ethico-political manoeuvre, a tentative and modest experiment in (re)thinking and thinking anew what constitutes a ‘good life’ and how we might increase capacities to create a more just and equitable world.

O antígeno B (AgB) de Echinococcus granulosus é um dos principais componentes do líquido hidático. O AgB é um proteína oligomérica de 120-160 kDa composta de subunidades de 8 kDa, que em SDS-PAGE dissocia-se em componentes de 8, 16, 24 e 32 kDa. Embora diferentes subunidades do AgB tenham sido isoladas, pouco se sabe sobre a estrutura da proteína e do seu mecanismo de oligomerização. Neste trabalho foi realizada a caracterização estrutural de homo-oligômeros de três subunidades recombinantes do AgB, AgB8/1, AgB8/2 e AgB8/3, expressadas a partir de seqüências previamente clonadas Essas subunidades associam-se em homo-oligômeros com características semelhantes às da proteína purificada de líquido hidático, como massa molecular, conteúdo de estrutura secundária, tendência agregativa e termoestabilidade, fazendo deles ferramentas importantes para o estudo da estrutura do AgB. Diferentes graus de estabilidade e compactação foram verificados entre os oligômeros recombinantes, com o oligômero de AgB8/3 apresentando-se mais estável e compacto. Através da modelagem molecular das subunidades do AgB, foi possível calcular a superfície de potencial eletrostático das moléculas e propor um mecanismo de oligomerização envolvendo interações eletrostáticas e hidrofóbicas. Foram também realizadas tentativas de cristalização de oligômeros de AgB8/3 para ensaios de difração de raios X, e cristais foram obtidos em três condições do screening inicial. Estes cristais difrataram à resoluções máximas de 8 Å, não permitindo a coleta de dados estruturais da proteína. Entretanto, estas condições podem ser refinadas para a obtenção de cristais com melhor qualidade. / Echinococcus granulosus antigen B is one of the major components of the hydatid fluid. AgB is a oligomeric protein of 120-160 kDa composed by 8 kDa subunits, that in SDS-PAGE dissociates in components of 8, 16 , 24 and 32 kDa. Although different AgB subunits have been isolated, little is known about AgB structure and its oligomerization mechanism. In this work we have performed the homo-oligomers structural characterization of three AgB recombinant subunits, AgB8/1, AgB8/2 and AgB8/3, expressed from previously cloned genes. These subunits self-assemble in homo-oligomers with similar characteristics to that of hydatid fluid purified protein, such as molecular mass, secondary structure content, aggregative tendency and thermostability, making them valuable tools for AgB structure study. Different degrees of stability and compactness were verified between the recombinant oligomers, with the AgB8/3 one showing a more stable and compact structure. Using molecular modelling it was possible to calculate the surface electrostatic potencial of AgB subunits and to propose a mechanism of oligomerization involving electrostatic and hydrophobic interactions. Also crystallization attempts had been carried through with AgB8/3 oligomer to X-ray diffraction, and crystals have been obtained in three conditions of initial screening. These crystals difracted to maximum resolutions of 8 Å, and it was not possible to collect protein structural data. However, these crystallization conditions can be refined in order to obtain crystals of better quality.

Introdução: O Vírus da Hepatite B (HBV) é um vírus de DNA com tropismo por hepatócitos, que apresenta um genoma circular parcialmente dupla fita. Baseado na divergência de sequência do genoma completo, dez linhagens evolutivas, denominadas “genótipos” de HBV, foram descritas (A-J), sendo F e H considerados como “indígenas” da América. Os genótipos de HBV apresentam uma forte estruturação geográfica, o que pode refletir padrões das migrações humanas. Na América do Sul, áreas de alto endemismo incluem a região amazônica, e as maiores taxas de infecção têm sido observadas em populações Nativas Americanas. Embora a forte estruturação geográfica seja indicativa de uma origem antiga, a maioria das análises visando datar a origem dos genótipos “americanos” F e H resulta em datações extremamente recentes que não condizem com eventos históricos relacionados ao HBV. Objetivo: Os objetivos desse trabalho compreendem avaliar o impacto de diferentes taxas evolutivas e da seleção purificadora sobre as estimativas de datação molecular a fim de inferir quais taxas são mais condizentes com a origem do HBV na América; caracterizar o HBV circulante em uma amostra histórica de Nativos Americanos, e discutir os processos históricos que possam ser relevantes para entender os padrões observados. Material e Métodos: Nós realizamos análise Bayesiana utilizando sequências disponíveis dos genótipos F e H e diferentes taxas evolutivas previamente reportadas, e comparamos a ocorrência de mutações sinônimas e não-sinônimas em ramos da filogenia classificados como “antigos” ou “recentes” a fim de inferir a atuação da seleção purificadora ao longo do tempo. Para caracterização do HBV presente nas populações Nativas Americanas, detecção e amplificação do DNA viral foi obtida através de PCR seguido de sequenciamento e análise filogenética. Análise Bayesiana de Skyline Plot foi realizada para comparar a dinâmica populacional do subgenótipo A1 presente na amostra de Nativos Americanos e em outras cepas isoladas no Brasil. Resultados e conclusão: Nossos resultados mostram que as estimativas de datação molecular são fortemente influenciadas pelas taxas evolutivas utilizadas na análise. Além disso, foi observado excesso de mutações não-sinônimas nos ramos recentes da filogenia, o que é compatível com a ocorrência de seleção purificadora, e pode gerar um viés sobre as estimativas, produzindo datações recentes demais. Na amostra de Nativos Americanos, nós constatamos o predomínio do subgenótipo A1, relacionado com populações africanas. Análise de Skyline Plot mostrou que a expansão populacional nas cepas isoladas de Nativos Americanos é mais recente que aquela inferida para outras cepas brasileiras, sugerindo que os processos históricos que contribuíram para a formação do subgenótipo A1 dos Nativos Americanos são relacionados com ondas migratórias mais recentes em direção à região amazônica. / Introduction: Hepatitis B virus (HBV) is a hepatotropic DNA virus that presents a partially double-stranded circular genome. Based on sequence divergence of the complete genome, ten HBV evolutionary lineages, called “genotypes” have been described (A-J), with F and H being considered as indigenous from the Americas. HBV genotypes present a remarkable geographic structure which may reflect historic patterns of human migrations. In South America, areas of high endemism include the Amazon basin, and high prevalence rates have been observed in Native American populations. Although the strong geographical structure indicates an ancient origin, most analysis trying to date the origin of the “American” genotypes F and H result in extremely recent dates that disagree with historical events related with HBV. Objective: The aims of this study comprise evaluate the impact of different evolutionary rates and of the purifying selection on molecular dating estimates in order to infer which rates are in better agreement with the origin of HBV in the Americas; to characterize the HBV circulating in a historical sample of Native Americans, and discussing the historical processes that might be relevant to understand the observed patterns. Materials and Methods: We performed a Bayesian analysis using the available sequences of F and H genotypes and different evolutionary rates previously reported, and compared the occurrence of synonymous and non-synonymous mutations in branches of phylogeny classified as “old” or “young” in order to infer the effects of purifying selection over time. For the characterization of HBV from Native American populations, detection and amplification of viral DNA were obtained through PCR followed by sequencing and phylogenetic analysis. Bayesian Skyline Plot analysis was performed to compare the population dynamics of the A1 subgenotype present in the sample of Native American and in other strains isolated from Brazil. Results and Conclusion: Our results show that molecular dating estimates are strongly influenced by the evolutionary rate assumed in the analysis. In addition, we observed an excess of non-synonymous mutations in recent branches of phylogeny, which is compatible with the occurrence of purifying selection and may create a bias on the estimates, producing too recent datings. In the sample of Native Americans, we observed a predominance of the A1 subgenotype, related with African populations. Skyline Plot analysis showed that population expansion in strains isolated from Native Americans is more recent than that inferred from other Brazilian strains, suggesting that the historical processes that contributed to the presence of A1 subgenotype A1 Native Americans are related with more recent migratory waves towards the Amazon region.

Parasitos pertencentes ao gênero Echinococcus são platelmintos que necessitam de dois hospedeiros para completar o seu ciclo de vida. Durante a fase larval expressam abundantemente uma proteína chamada Antígeno B (AgB), que é uma lipoproteína oligomérica com massa molecular de aproximadamente 150 kDa formada por subunidades de 8 kDa. As subunidades do AgB são codificadas por pelo menos cinco genes (AgB1-5), com similaridade superior a 70%. A função da proteína nativa tem sido relacionada com a modulação da resposta imune do hospedeiro intermediário, ocasionando um viés para a resposta Th2 e com a detoxificação de metabólitos lipídicos no interior do cisto. Neste trabalho, foi avaliada a ocorrência de rearranjos entre os loci gênicos AgB1-5 durante a fase larval de E. granulosus sensu stricto e E. ortleppi através de Southern blot e de variação do número de cópias dentro de um mesmo cisto de E. granulosus sensu stricto por qPCR. Também foram determinadas a diversidade de seqüências destes cinco genes durante a fase adulta de E. granulosus sensu stricto através de clonagem e o seqüenciamento de produtos de PCR obtidos a partir de um único verme, bem como foram desenvolvidos anticorpos policlonais contra a proteína recombinante dos cinco genes descritos e contra um peptídeo sintético representante do gene AgB2. As diferenças na organização dos genes do AgB entre cistos foram analisadas em três isolados de E. granulosus sensu stricto e três isolados de E. ortleppi por Southern blot. O padrão de bandas de hibridização revelou que esta família gênica contém pelo menos nove genes em E. granulosus sensu stricto e dez em E. ortleppi. Foram observadas diferenças entre os cistos de E. ortleppi quanto ao padrão de bandas de AgB3, o que indicaria a ocorrência de rearranjos. A análise do número de cópias dos genes AgB1-5 em protoescóleces de um único cisto revelou uma grande heterogeneidade no número de cópias de todos os genes do AgB analisados, muitas vezes superiores a 10 vezes entre os protoescóleces. A grande divergência entre os protoescóleces sugere que o mecanismo responsável pela variação origine elementos de DNA instáveis. A diversidade de seqüências dos genes do AgB1-5 do verme adulto foi menor que a encontrada na fase larval. Interessantemente, o verme adulto analisado neste trabalho apresentava seqüências típicas de duas espécies, AgB2 e Mdh de E. ortleppi e AgB1, AgB3, AgB4 e AgB5 além do haplótipo mitocondrial de Cox1 de E. granulosus sensu stricto. Esta é a primeira vez que um verme adulto, possivelmente hibrido, de Echinococcus é encontrado, e indica que o intercruzamento entre E. granulosus sensu stricto e E. ortleppi pode gerar organismos viáveis. A síntese de anticorpos contra cada uma das cinco subunidades do AgB descritas foi obtida pela inoculação de proteína recombinante (recAgB1-5) em camundongos BALB/c. Embora todas as proteínas recombinantes tenham sido imunogênicas, observou-se reação cruzada entre elas, e apenas os anticorpos contra recAgB3 e recAgB4 foram mais reativos contra a proteína inoculada. Para melhorar a especificidade dos anticorpos, sintetizou-se oligopeptídeos de 12-15 aminoácidos representativos de cada subunidade acoplados a uma proteína carreadora (oliAgB1-5) e imunizaram-se camundongos BALB/c. A análise do soro obtido dos camundongos revelou que dos cinco peptídeos testados, apenas oliAgB2 foi imunogênico e apresentou uma resposta específica. / Parasites belonging to the genus Echinococcus are flatworms that require two hosts to complete their lifecycle. During their larval stage, Echinococcus abundantly expresses a protein called antigen B (AgB), which is a 150 kDa oligomeric lipoprotein composed by 8 kDa subunits. AgB is encoded by at least five genes (AgB1-5) with similarity above 70%. The function of native protein has been related to the modulation of host immune responses leading towards a Th2 cellular response bias. The protein is also involved with detoxification of lipid metabolites inside the cyst. In this study we evaluated the occurrence of rearrangements within AgB1-5 loci on metacestodes of E. granulosus sensu stricto and E. ortleppi using Southern blot and the variation at AgB number of copies within an E. granulosus sensu stricto cyst by qPCR. We also analyzed the sequence diversity of these five genes during the adult stage of E. granulosus sensu lato by cloning and sequencing PCR products obtained from a single adult worm. Finally, we have developed antibodies against AgB1- 5 recombinant proteins (recAgB1-5) and against a synthetic peptide representative of subunit AgB2. The differences in AgB gene organization among isolates were analyzed in three E. granulosus sensu stricto and three E. ortleppi cysts. The banding pattern revealed that this gene family contains at least nine genes in E. granulosus sensu stricto and ten in E. ortleppi. Differences in the AgB3 banding pattern were observed among the E. ortleppi cysts, which would indicate the occurrence of rearrangements. The AgB1-5 number of copies analysis in protoscoleces from a single cyst revealed a large heterogeneity of all AgB genes analyzed, often more than 10 times between protoscoleces. The large divergence among protoscoleces suggests that the mechanism responsible for copy number variation originates unstable DNA elements. The sequence diversity of AgB within an adult worm was lower than that found in the larval stage. Interestingly, the adult worms examined in this study showed typical sequences of two species: AgB1, AgB3, AgB4 and AgB5, as well as the Cox1 mitochondrial haplotype, are similar to E. granulosus sensu stricto sequences and Mdh and AgB2 were identical to those described for E. ortleppi. That is the first time that an adult worm of Echinococcus possibly hybrid is found, and it may indicate that the cross fertilization between E. granulosus sensu stricto and E. ortleppi generates viable organisms. Antibodies against each of the five subunits of AgB described were obtained by inoculating BALB/c mice with recombinant proteins recAgB1-5. Although every recombinant protein was immunogenic, we observed crossreaction between them, and only the response against recAgB3 and recAgB4 showed some specificity. To improve the antibody specificity, we synthesized oligopeptides of 12-15 amino acids representative of each AgB subunit (oliAgB1-5) coupled to a carrier protein and used these antigens to immunize BALB/c mice. Analysis of serum obtained from mice showed that only one of five oligopeptides tested (oliAgB2) was immunogenic, and it leads to a specific response.

This thesis intends to address one type of approach to evolutionary theory that seeks to criticise the neo-Darwinist account of evolution and individuation, that of symbiosis. This thesis will begin by examining current evolutionary theory through Darwin to neo-Darwinism, with a view to discerning which types of mechanisms neo- Darwinism rules out, and which it allows. This will be achieved by using a methodology which treats groups of related scientific theories or practices as research programmes. This methodological approach will allow comparison between competing research programmes, and it will be possible to determine whether or not a competing research programme is really a challenge to neo-Darwinism, or simply a sub- programme which shares some of the same metaphysical commitments and mechanisms as neo-Darwinism. The second half of the thesis will assess the ‘symbiosis’ challenge to neo-Darwinism on these terms. This section will conclude that symbiosis as it is usually formulated by its proponents is not a separate research programme that rejects neo-Darwinism in any significant way, but rather it is a sub-programme of neo- Darwinism. But I will also argue that there are aspects of this programme, if they were to be made more prominent, would in fact constitute an alternative research programme which could not only be treated as a separate research programme, but a research programme that is incompatible with neo-Darwinism. Bacteria in particular are organisms which function through symbiosis and their functioning problematises neo-Darwinism’s account of individuation on a fundamental level. It will be concluded that neo-Darwinism is either a theory of very limited scope, or one which can be made into a general theory, but this can only be achieved through fundamental changes to neo-Darwinism itself.

There is a reflexive paradox (or set of paradoxes) associated with self-deception, and a variety of theories have been proposed in response, to explain self-deception. The study of reflexive paradoxes has been fruitful in the history of philosophy. Such a paradox may appear to be no more than a minor puzzle, which we will easily be able to mop up after having formulated solutions to more major problems. Sometimes the minor puzzle turns out to be surprisingly resistant to our "mopping up" operations; it may force us to re-think our major theories. For example the "truth-teller" paradox and other paradoxes of self-reference have been viewed initially as minor puzzles, while later on they have provoked major theories, e.g. theories of truth; in mathematics, Godel's theorem.

Relationalism claims that the phenomenal character of perception is constituted by the obtaining of a non-representational psychological relation to mind-independent objects. Although relationalism provides what seems to be the most straightforward and intuitive account of how experience strikes us introspectively, it is very often believed that the argument from hallucination shows that the view is untenable. The aim of this thesis is to defend relationalism against the argument from hallucination. The argument claims that the phenomenal character of hallucination and perception deserves the same account, and that relationalism cannot be true for hallucinations, therefore relationalism must be rejected. This argument relies on the Indiscriminability Principle (IND), the claim that two experiences that are introspectively indiscriminable from each other have the same phenomenal character. Before assessing the plausibility of this principle, I first consider and dismiss versions of the argument which wouldn’t depend on IND. Although widely accepted, no satisfactory support for IND has been presented yet. In this thesis I argue that defending IND requires that we understand the notion of ‘indiscriminability’ employed in IND in an impersonal sense. I then identify what underwrites IND: the intuition that, in virtue of its superficiality, the nature of a phenomenal character must be accessible through introspection, together with the claim that it is not possible to deny IND without denying the superficiality of phenomenal characters too. I argue that the relationalist can deny IND while preserving the superficiality of phenomenal characters. This can be done by adopting a negative view of hallucination and an account of introspection whereby the phenomenal character doesn’t exist independently of one’s introspective awareness of it and where having introspective access to our experience depends on our perceptual access to the world.