Decision-making capacity is an increasingly important medico-legal concept. The recent Mental Capacity Act employs a cognitive, process-based test of capacity, but in many psychiatric conditions pathological beliefs and values impair capacity even when the decision-making process is logically coherent. In such cases, capacity assessments implicitly rely on normative epistemic and evaluative standards. This raises a worry for the capacity test’s reliability, objectivity and tolerance of differences in beliefs and values. There is currently little conceptual research on capacity and the normative standards underpinning its assessment. This thesis makes an original contribution to research by employing a number of philosophical approaches to map out a conceptual terrain within which questions about the substantive standards of capacity assessment can be framed. Focusing on the nature of epistemic standards and third-person judgements about decision-making, the thesis examines the normative constraints determining what counts as a recognisable reason for a decision. It employs the theoretical apparatus of Davidson’s project of Radical Interpretation to explore the epistemology of interpretation, interrogating the conditions under which intentional attribution and the provision of reason explanations for behaviour are possible. It is contended that beliefs are intrinsically rational and intersubjective, and that judgements of irrationality are only possible against a background of shared belief between interpreter and observed agent. This view is defended against the objection that rationality is too stringent a constraint on belief. A misconception giving rise to this objection is then diagnosed. Drawing an analogy with Wittgenstein’s rule-following considerations, it is submitted that the constitutive normativity of belief need not be codified in order to exert a genuine constraint on intentional behaviour. Rather, the norms of belief ought to be construed as emerging from shared practice. This indicates that normative judgements are disciplined through expertise and experience, rather than adherence to abstract principles. Finally, the implications of these insights for conceptualising and assessing capacity are considered.

No description available.

No description available.

The present thesis mainly concerns B*-algebras, A*-algebras, and minimal ideals in topological rings.

A low molecular weight po1y-S-a1anine (350 row) was prepared by thermal po1ycondensation of S-a1anine ethyl ester. In thermal analysis, six transitions occurred in the initial polymer in approximate order of increasing temperature: glass transition temperature (Tg), crysta1- crystal transition, cold crystallization, melt crystallization, crystalline disorientation, and melting. Isothermal annealing of this polymer at 200 0 followed by quenching provided structures which exhibited multiple melting peaks in thermal analysis. In this work reasons are proposed for the dual endotherm. By prolonged annealing only, before analysis, part of the recrystallization exotherm can be observed in the differential scanning calorimetry (DSC) scan. DSC thermo grams obtained at varying heating rates on samples showing po1y-S-a1anine endotherms supported the assignment of superheating as the cause of the shift to higher peak temperatures with increasing heating rate. To further support the structural assignment, the infrared absorption showed typical polyamide bands, and the nuclear magnetic resonance spectrum gave two methylene peaks of equal intensity.

La sécurité est un élément crucial dans le développement d'un système d'information. On ne peut pas concevoir un système bancaire sans préoccupation sécuritaire. La sensibilité des données d'un système hospitalier nécessite que la sécurité soit la composante majeure d'un tel logiciel. Le contrôle d'accès est un des nombreux aspects de la sécurité. Il permet de définir les conditions de l'exécution d'actions dans un système par un utilisateur. Entre les différentes phases de conception d'une politique de contrôle d'accès et son application effective sur un système déployé, de nombreuses étapes peuvent introduire des erreurs ou des failles non souhaitables. L'utilisation de méthodes formelles est une réponse à ces préoccupations dans le cadre de la modélisation de politiques de contrôle d'accès. L'algèbre de processus EB3 permet une modélisation formelle de systèmes d'information. Son extension EB3SEC a été conçue pour la spécification de politiques de contrôle d'accès. Le langage ASTD, combinaison des statecharts de Harel et des opérateurs de EB3, permet de modéliser graphiquement et formellement un système d'information. Cependant, ces deux méthodes manquent d'outils de vérification et de validation qui permettent de prouver ou de vérifier des propriétés de sécurité indispensables à la validation de politiques de contrôle d'accès. De plus, il est important de pouvoir prouver que l'implémentation d'une politique correspond bien à sa spécification abstraite. Cette thèse définit des règles de traduction de EB3 vers ASTD, d'ASTD vers event-B et vers B. Elle décrit également une architecture formelle exprimée en B d'un filtre de contrôle d'accès pour les systèmes d'information. Cette modélisation en B permet de prouver des propriétés à l'aide du prouveur B ou de vérifier des propriétés avec ProB, un vérificateur de modèles. Enfin, une stratégie de raffinement B pour obtenir une implémentation de ce filtre de contrôle d'accès est présentée. Les raffinements B étant prouvés, l'implémentation correspond donc au modèle initial de la politique de contrôle d'accès / Security is a key aspect in information systems (IS) development. One cannot build a bank IS without security in mind. In medical IS, security is one of the most important features of the software. Access control is one of many security aspects of an IS. It defines permitted or forbidden execution of system's actions by a user. Between the conception of an access control policy and its effective deployment on an IS, several steps can introduce unacceptable errors. Using formal methods may be an answer to reduce errors during the modeling of access control policies. Using the process algebra EB3, one can formally model IS. Its extension, EB3SEC, was created in order to model access control policies. The ASTD notation combines Harel's Statecharts and EB3 operators into a graphical and formal notation that can be used in order to model IS. However, both methods lack tools allowing a designer to prove or verify security properties in order to validate an access control policy. Furthermore, the implementation of an access control policy must correspond to its abstract specification. This thesis defines translation rules from EB3 to ASTD, from ASTD to event-B and from ASTD to B. It also introduces a formal architecture expressed using the B notation in order to enforce a policy over an IS. This modeling of access control policies in B can be used in order to prove properties, thanks to the B prover, but also to verify properties using ProB, a model checker for B. Finally, a refinement strategy for the access control policy into an implementation is proposed. B refinements are proved, this ensures that the implementation corresponds to the initial model of the access control policy

Determina la relación entre el nivel de conocimiento y la actitud hacia la Hepatitis B que presentan los estudiantes de pre grado de la Facultad de Odontología de la Universidad Nacional Mayor de San Marcos, en el año 2015. La hipótesis planteaba una relación directa entre el nivel de conocimiento y la actitud. El tipo de estudio es descriptivo transversal. La muestra está constituida por 135 estudiantes. Aplica una encuesta tipo cuestionario con 15 preguntas de alternativas múltiple para la variable conocimiento y un cuestionario tipo Lickert con 18 items para la variable actitud. Determina que el nivel de conocimiento es mayoritariamente regular (93.3%), los items relacionados a conocimientos sobre medidas preventivas para evitar una infección con Hepatitis B son los que menos respuestas correctas tuvieron (38,1%). La pregunta con menos respuestas correctas se refiere al esquema de vacunación contra la Hepatitis B (14 alumnos), el origen viral del Hepatitis B es el ítem que obtuvo mayor número de respuestas correctas (133 alumnos). La mayoría muestra un nivel de actitud indiferente hacia la Hepatitis B (93.3%). El 25% de los alumnos piensa que no deberían atender pacientes con Hepatitis B, un 66% de los alumnos piensan que a pesar de tomar todas las medidas de bioseguridad sienten temor de atender pacientes con Hepatitis B. Según los datos obtenidos se concluye que no existe relación entre el nivel de conocimiento y la actitud hacia la Hepatitis B en los estudiantes de la Facultad de Odontología de la Universidad Nacional Mayor de San Marcos.

Orientador: Fábio Porto-Foresti / Resumo: A ictiofauna neotropical é uma das mais ricas do mundo, sendo estimada a ocorrência de 9100 espécies de peixes. Dentre estes, o gênero Astyanax (Characiformes, Characidae) se destaca como um dos mais abundantes em espécies, sendo marcante a presença de cromossomos B neste grupo. Cromossomos B, ou supranumerários, são cromossomos adicionais aos cromossomos padrões do organismo e considerados dispensáveis. A origem destes cromossomos ainda é incerta, sendo os modelos mais aceitos a origem intraespecífica, em que os cromossomos B se originam dos próprios cromossomos da espécie e a origem interespecífica, em que os supranumerários se originariam dos cromossomos de outra espécie próxima através da hibridação. Uma das características que definem os cromossomos B é a sua transmissão que foge dos padrões mendelianos, levando a acumulação ou extinção destes elementos. Em peixes, cromossomos B estão presentes em 113 espécies, sendo a variante presente em Astyanax paranae um dos modelos de estudo para o grupo. Esta variante foi diagnosticada como um isocromossomo de origem intraespecífica, e sequencias presentes neste cromossomo também estão presentes nos cromossomos B de outras espécies do grupo, sugerindo uma origem comum. Entretanto, dados em relação à transmissão deste supranumerário ainda não são conhecidos. Diante disto, o objetivo do presente trabalho foi descrever o padrão de transmissão do cromossomo B presente em A. paranae através de cruzamentos dirigidos. A transmissão de cr... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The neotropical ichthyofauna is one of the richest in the world, estimated in 9100 fish species. In this group, the genus Astyanax (Characiformes, Characidae) is considered one of the most abundant in species, being remarkable the presence of supernumerary or B chromosomes in the group. B chromosomes are additional chromosomes to the standard chromosomes and are considered dispensable. These elements are present in plants, animals and fungi and are generally formed by repetitive DNA sequences and fragments of ribosomal and histone genes. The origin of these chromosomes is still uncertain, and the most accepted model intraspecificrelated, where the B chromosomes arise from the same chromosomes of the species and the intraspecific origin, although the supernumerary ones would originate from the chromosomes of another related species by hybridization. One of the important characteristics of B chromosomes is related with their transmission, which does not follow Mendelian patterns, leading to the accumulation or extinction of these elements. In fish, B chromosomes are present in 113 species, and the variant present in Astyanax paranae is one of the studing models for the group. This variant was diagnosed as an isochromosome of intraspecific origin, and sequences present on this chromosome are also present on the B chromosomes of other related species, suggesting a common origin. However, data regarding the transmission of this supernumerary are still unknown. Therefore, the objec... (Complete abstract click electronic access below) / Mestre

Die Transkriptionsfaktoren der NFAT-Proteinfamilie (Nuclear Factor of Activated T cells, NFATc1-4) sind an entscheidender Stelle in die Regulation des Zellzyklus, des programmierten Zelltodes und der Kanzerogenese involviert. NFATc1 nimmt innerhalb dieser Familie eine Sonderrolle ein, da dessen Aktivität auch durch eine stark induzierbare Expression gesteigert werden kann. Dies ist insbesondere für die Differenzierung und Funktion von T- und B-Lymphozyten von Bedeutung. Weiterhin ist NFATc1 für die Muskel- oder Herzentwicklung notwendig. Eine Reihe von Arbeiten belegen darüber hinaus eine Beteiligung dieses Transkriptionsfaktors an der Entstehung von Leukämien und Lymphomen. Während klassische Hodgkin-Lymphome allerdings durch eine abgeschaltete NFATc1-Expression gekennzeichnet sind, wird für T-ALL (Akute Lymphatische Leukämie der T-Zelle) eine Überexpression beschrieben. Die Kernlokalisation dieses Transkriptionsfaktors erfolgt nach Dephosphorylierung des zytoplasmatischen Proteins durch die Phosphatase Calcineurin. Deren Phosphataseaktivität wird durch einen Anstieg des intrazellulären Ca++-Spiegels aktiviert. Inwiefern die Calcineurin-abhängige Kerntranslokalisation den einzigen Aktivierungsmechanismus für NFAT-Faktoren darstellt, ist noch nicht eindeutig geklärt. Nach optimaler Aktivierung von T- bzw. B-Zellen ist die kurze, induzierbare Isoform NFATc1/A das Hauptprodukt des NFATc1-Gens. In dieser Arbeit wurden für die gezielte Deletion des NFATc1-Gens in der Maus zwei verschiedene konditionelle Systeme verwandt. Hierzu wurden Tiere, die ein mit „flox“-Sequenzen versehenes drittes Exon des NFATc1-Gens in der Keimbahn tragen, mit verschiedenen Cre-Rekombinase expremierenden Linien verkreuzt. Der Verlust funktionellen NFATc1-Proteins erfolgt dann früh in der B-Zell-Differenzierung im Knochenmark (Cd79a/mb-1-cre x Nfatc1flx/fl) bzw. in reifen B-Zellen (Cd23-cre x Nfatc1flx/flx). Während in keiner dieser Linien signifikante Defekte in der Differenzierung “konventioneller B2” B-Lymphozyten beobachtet wurden, hatte die frühe Inaktivierung des NFATc1-Gens im Knochenmark den Verlust der B1a-Zell-Population im Peritoneum zur Folge. In vitro zeigten NFATc1-/--B-Zellen aus der Milz nach Aktivierung über den B-Zell-Rezeptor deutliche Defekte in der Zellteilung bei einer gleichzeitigen Zunahme des aktivierungsinduzierten Zelltodes (AICD, activation induced cell death). Die vergleichende Transkriptomanalyse identifizierte wichtige Gene des Ca++/Calcineurin-Signalweges als NFATc1-Zielgene und mitverantwortlich für die Proliferationsdefekte. In NFATc1-defizienten B-Zellen konnte Re-Expression von NFATc1 in geringer Konzentration den aktivierten Zelltod inhibieren, wohingegen hohe Konzentrationen diesen noch weiter förderten. Zusammengenommen lässt sich daher schließen, dass NFATc1 entscheidend an der Kontrolle von Proliferation und Zelltod peripherer B-Lymphozyten beteiligt ist. Eine weitere wichtige Funktion kommt NFATc1 beim Klassenwechsel im Immunglobulin-Lokus zu. In den untersuchten Mäusen war die IgG3-Produktion nach Immunisierung mit NP-Ficoll (einem T-Zell-unabhängigen Antigen des Typs II) deutlich reduziert, wenn das NFATc1-Gen in den B-Lymphozyten funktionslos war. Auch die Bildung von IgG3+-Plasmablasten war gehemmt. Zu ähnlichen Ergebnissen führten Untersuchungen an isolierten B-Lymphozyten in einem in vitro Klassenwechsel-Modell. Demgegenüber zeigten Immunisierungen der Tiere mit NP-KLH (einem T-Zell-abhängigen Antigen) keine signifikanten Abweichungen im Klassenwechsel. Zusammengefasst zeigen diese Daten die große Bedeutung des Transkriptionsfaktors NFATc1 für das Überleben und die Funktion peripherer B-Lymphozyten. / The Nuclear Factors of Activated T cells (NFATs) are critical transcription factors playing major roles in the control of the cell cycle, apoptosis and, probably, also cancerogenesis. Of all the four genuine NFATc family members, NFATc1 has the unique induction property which appears to be essential for T and B cell development, along with its considerable role in cytokine gene expression and function in non-lymphoid tissues and during organ development (such as in the development of muscle and heart cells). A number of studies have proved the potential role of NFATc1 protein in development of lymphomas and leukemias and provided evidence of differential expression of the same gene in different tumours (Suppression in classical Hodgkin lymphomas but overexpression in T-ALLs). Although the most commonly accepted pathway is the dephosphorylation of NFAT by calcineurin upon a rise in intracellular Ca++ leading to nuclear translocation followed by transcription of Il2 gene and related cytokines, it is quite possible that signaling mechanisms other than (or in addition to) calcineurin activation lead to NFATc1 induction as well. One of the major isoforms of NFATc1, NFATc1/αA, is the short inducible factor, produced upon full T and B cell activation. Here we used two different conditional knock-out mice as our study model. Inactivation of the murine Nfatc1 gene in bone marrow (of Cd79a/mb-1-cre x Nfatc1flx/flx mice) and spleen (of Cd23-cre x Nfatc1flx/flx mice) resulted in complete ablation of NFATc1 expression in splenic B cells. Although no severe developmental defects were found for the generation of ‘conventional’ B2 cells, NFATc1 inactivation in bone marrow B-cells led to a strong decrease in the peritoneal B1a cell population. In-vitro studies showed a clear-cut decrease in proliferation and an increase in Activation Induced Cell Death (AICD) of NFATc1-/- splenic B cells upon BCR stimulation. While NFATc1 appears to control directly the AICD of peripheral B cells, further studies revealed an effect of NFATc1 on proliferation by a sustained differentiation program controlling Ca++ flux and calcineurin activity which are needed to maintain transcription and proliferation of primary B cells. Re-expression of NFATc1 at a low dose could protect cells against AICD, whereas at a higher dose it initiated AICD. These data suggest an important dual role of NFATc1 in controlling proliferation and apoptosis of peripheral B lymphocytes. NFATc1 ablation also impaired the Ig class switch to IgG3 by T cell-independent (TI) type II antigens and impaired IgG3+ plasmablast formation when studied in-vivo by NP-Ficoll immunization or in-vitro using an in-vitro class-switch model. Contrary to the immunizations with TI-type II antigen, no significant differences were documented in Ig class switch upon immunization with NP-KLH, a T-cell dependent (TD) antigen. Taken together, the data indicate NFATc1/αA as a crucial player in the activation and function of splenic B cells upon BCR stimulation. Missing or incomplete NFATc1/αA induction appears to be one reason for the generation of B cell unresponsiveness, whereas uncontrolled NFATc1/αA expression could lead to unbalanced immune reactions and autoimmune diseases.

BOB.1/OBF.1 ist ein Lymhozyten-spezifischer transkriptioneller Koaktivator. Er bindet an die Oct1 und Oct2 Transkriptionsfaktoren und verstärkt deren transkriptionelles Potential. Die Untersuchung BOB.1/OBF.1- defizienter Mäuse ergab, dass BOB.1/OBF.1 eine entscheidende Funktion hat in verschiedenen BZellentwicklungsstadien. Überraschenderweise zeigte die Analyse BOB.1/OBF.1-defizienter Mäuse eine weitgehend normale Expression von Genen, welche ein Oktamer-Motiv in ihren regulatorischen Regionen enthalten wie z. B. die Immunglobulingene. Im ersten Teil dieser Arbeit wurde die Rolle von BOB.1/OBF.1 für oktamerabhängige Transkription in einer aus BOB.1/OBF.1-defizienten Mäusen etablierten B-Zelllinie untersucht. Es konnte gezeigt werden, dass Promotoren, die von einem funktionellen Oktamer-Motiv abhängen, gänzlich inaktiv sind in BOB.1/OBF.1-defizienten B-Zellen. Mittels eines in diesen Zellen stabil exprimierten, regulierbaren BOB.1/OBF.1-Fusionsproteins konnte gezeigt werden, dass dieser transkriptionelle Defekt eine direkte Folge des Fehlens des Koaktivators BOB.1/OBF.1 ist. Dies gilt für einen synthetischen Oktamer- Promotor-regulierten Reporter ebenso wie für einen Immunglobulin-k-Promoter-regulierten Reporter. Diese Ergebnisse zeigten, dass BOB.1/OBF.1 selbst ein nicht-redundantes Protein in B-Zellen ist und absolut notwendig ist für oktamerabhängige transkriptionelle Aktivität. Zahlreiche in B-Zellen exprimierte Gene enthalten ein Oktamer-Motiv in ihrer regulatorischen Region, jedoch wurden erst wenige beschrieben, deren Expression von BOB.1/OBF.1 reguliert wird. Um die molekulare Basis der Funktion von BOB.1/OBF.1 für die B-Zellentwicklung zu verstehen, wurde im zweiten Teil der vorliegenden Arbeit mit verschiedenen Methoden nach BOB.1/OBF.1-regulierten Zielgenen gesucht. Mit der cDNA-RDA-Methode konnte MLC1A als ein in präB-Zellen durch BOB.1/OBF.1 indirekt reguliertes Gen identifiziert werden. Affymetrix-Genchip-Experimente identifizierten sowohl durch BOB.1/OBF.1 heraufregulierte Gene, wie Ahd2like, Rbp1, Creg als auch herabregulierte Gene, wie Id3. Eine Klassifizierung der potentiellen Zielgene nach ihrer Funktion legt eine Funktion von BOB.1/OBF.1 nahe für verschieden Aspekte der B-Zellphysiologie wie Zellmetabolismus, Zelladhäsion und Zelldifferenzierung. BOB.1/OBF.1 hat also sehr wahrscheinlich eine sehr weitgefächerte Funktion in verschiedenen regulatorischen Mechanismen von B-Zellentwicklung und -funktion. Das Fehlen von Immunglobulin-Expression in Hodgkin-Reed-Sternberg-Zellen (HRS-Zellen) des klassischen Hodgkin-Lymphoms wurde ursprünglich erklärt durch inaktivierende Mutationen im Promotor oder in kodierenden Sequenzen des Gens. Im dritten Teil dieser Arbeit konnte gezeigt werden, dass in HRS-Zellen weder BOB.1/OBF.1 noch Oct2 exprimierte werden. Durch Transfektion von Reportern, die durch Oktamer- Motive oder durch einen Immunglobulin-Promotor reguliert werden, in HRS-Zelllinien konnte gezeigt werden, dass das Fehlen dieser Proteine sehr wahrscheinlich maßgeblich am Defekt der Immunglobulin-Transkription in HRS-Zellen beteiligt ist. / BOB.1/OBF.1 is a lymphocyte-restricted transcriptional coactivator. It binds to the Oct1 and Oct2 transcription factors and increases their transactivation potential. Targeted gene disruption experiments revealed that BOB.1/OBF.1 is critical at different stages of B cell development. Surprisingly, animals deficient for BOB.1/OBF.1 showed virtually normal expression of genes that contain octamer motifs in their regulatory regions, like immunoglobulin genes. In the first part of this work the role of BOB.1/OBF.1 for octamerdependent transcription in a B cell line established from BOB.1/OBF.1-deficient mice was addressed. We show that promoters exclusively dependent on functional octamer motifs are completely inactive in BOB.1/OBF.1- deficient B cells. To demonstrate directly that the lack of activity is a consequence of lack of the coactivator, we constructed a hormone regulated conditional allele of BOB.1/OBF.1, which was introduced into the BOB.1/OBF.1-deficient B cells. This resulted in the hormone-dependent transcriptional activity of octamerdependent reporters in these cells. The BOB.1/OBF.1 requirement for octamer promoter function was also observed when an authentic immunoglobulin k-promoter was assayed. Thus, these results demonstrate that BOB.1/OBF.1 itself is a non-redundant protein in B cells and absolutely required for octamer-dependent transcriptional activity. A large number of genes expressed in B cells contain octamer motifs in their regulatory regions. However, only few genes have been described so far whose expression is dependent on BOB.1/OBF.1. To understand the molecular basis of BOB.1/OBF.1 function in B cell development we searched for BOB.1/OBF.1 target genes by different screening methods, in the second part of this work. Using the cDNA-RDA method MLC1A could be identified as a gene indirectly regulated by BOB.1/OBF.1 in preB cells. Genechip experiments identified genes induced by BOB.1/OBF.1, like Ahd2like, Rbp1, Creg, and genes repressed by BOB.1/OBF.1, like Id3. Classification of BOB.1/OBF.1 target genes by function suggests that they affect various aspects of B cell physiology such as cellular metabolism, cell adhesion and differentiation. Our observations suggest that by regulating genes in different functional pathways, BOB.1/OBF.1 has a widespread effect on B cell development and function. The absence of immunoglobulin expression in Hodgkin-Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma was initially suggested to be caused by inactivating mutations in the immunoglobulin promoter or coding region. In the third part of this work it was shown, that HRS cells express no BOB.1/OBF.1 and Oct2. By transfection experiments in HRS cell lines, using octamer-motif dependent and immunoglobulin regulated reporters, it was shown that the lack of this proteins is likely to be critically involved in the observed defect of immunoglobulin transcription in HRS cells.