Magíster en farmacología / El carcinoma escamoso de laringe es una enfermedad altamente invalidante ya que puede afectar la capacidad del habla, respiración y deglución del paciente que lo sufre. Los principales factores causales identificados son cigarro y alcohol. Las vías de respuesta inflamatoria, proliferativa y de reparación de ADN pueden contribuir al riesgo de cáncer de laringe. El objetivo de este estudio es determinar asociaciones entre variantes genéticas COX-2 rs20417, COX-2 rs689466, EGF rs4444903, EGFR rs2227983, P53 rs1042522 y el riesgo de cáncer de laringe en la población chilena. Se realizó un estudio casos y controles, con 100 pacientes con cáncer escamoso de laringe y 139 voluntarios adultos sin cáncer. La genotipificación se realizó mediante PCR-RLFP. Se observa que estos polimorfismos son capaces de incrementar el riesgo de cáncer de laringe asociado a la combinación de consumo de tabaco y alcohol en una razón de 0,34 veces para COX-2 rs20417, 0,5 veces para EGF rs4444903, 0,56 veces para P53 rs1042522, 1,72 veces para EGFR rs2227983 y 4,7 veces para COX-2 rs689466. Esto sugiere que las variantes COX-2 rs20417, COX-2 rs689466, EGF rs4444903, EGFR rs2227983 y P53 rs1042522 actúan como modificadores de riesgo de cáncer de laringe. / Laryngeal squamous cell carcinoma is a kind of cancer that can be highly disabling to the patient, affecting speech, swallowing and respiratory skills, and leading to impaired quality of life. Smoking and alcohol abuse are principal risk factors linked to this disease. Inflammation signaling pathways, mitogens and DNA repair genes are factors that can be involved in carcinogenesis. The aim of this research is to assess the effect of COX-2 rs20417, COX-2 rs689466, EGF rs4444903, EGFR rs2227983, P53 rs1042522 single nucleotide polymorphisms in the risk of laryngeal cancer development in Chilean population. For this case control study, we recruited 100 cancer patients and 139 healthy volunteers. SNP genotype was analyzed from genomic DNA by PCR-RFLP. We observed that these SNPs are capable of increase the smoking plus alcohol risk of laryngeal cancer in a ratio of 0,34 fold for COX-2 rs20417 SNP, 0,5 fold for EGF rs4444903 SNP, 0,56 fold for P53 rs1042522 SNP, 1,72 fold for EGFR rs2227983 SNP and 4,7 fold for COX-2 rs689466 SNP. These findings suggest that COX-2 rs20417, COX-2 rs689466, EGF rs4444903, EGFR rs2227983 and P53 rs1042522 single nucleotide polymorphisms acts as risk modifier factors for laryngeal cancer.

Thesis advisor: Arthur Madigan / Thesis advisor: Jorge L. Garcia / The relationship between intention, intentional action, and moral assessment is of fundamental importance to ethical theory. In large part, moral responsibility is based on an assessment of agent responsibility, which in turn is based on the connection between an agent's intentions and the actions which they cause. In the last twenty-five years, there has been a debate in contemporary action theory about the relationship between intentions and intentional action. Objecting to what he calls the "Simple View," which he characterizes as the view that all intentional actions are intended under some description, Michael Bratman, among others, argues that not all intentional actions are intended. In this dissertation, we will defend the Simple View by appealing to Aristotle's theory of action as developed in his psychological and ethical works. In the first part of the dissertation, we argue that all intentional actions are intended under some description; however, we argue that distinctions between different types of intention are essential: specifically, the distinction between deliberate and non-deliberate intentions and the distinction between the intention of the end and the intention of the means. Our account centers on Aristotle's concept of prohairesis, which he identifies as the distinctly human principle of action. The term prohairesis in Aristotle's works seems to have at least three senses: 1) primarily, the deliberate intention with which a person acts, an `occurent' choice; 2) the habitual or `dispositional' choice or resolve of `decent' people; and 3) general purposes that men have which may encompass voluntary action as a whole. The first sense of the term is the primary one that properly signifies the concept. Prohairesis fits within the general framework of animal motion which Aristotle sets out in the De Anima and De Motu Animalium. For Aristotle, orexis or desire is the cause of all animal motion, including human motion. Prohairesis is a deliberate desire for the means to an end. It is a principle of action peculiar to mature human beings capable of deliberating, as it is the intention which is the result of deliberation. It marks off a narrow but important stretch of intentional action. Prohairesis is set off against other types of intention, like boulesis, which is an intention of the end, and epithumia (bodily appetite) and thumos (anger), which are non-deliberate intentions relating to non-rational appetites like lust and anger. Aristotle, in contrast to contemporary accounts of intentional action, is unusually specific in his designation of the different kinds of intention. Different orexeis differ not only with regard to specific objects but also with regard to time, planning, and detail. Aristotle traces both the causal and moral responsibility agents have for their actions to the action of these internal principles of desire. Moral assessment is linked to the operative internal principle of an act. This allows for an action to be voluntary and intentional, even if the agent does not fully understand or plan for the consequences of an action. Intention, for Aristotle, if we correctly understand it as orexis and what results from orexis, is not reducible to one mode but is irreducibly plural. Furthermore, each person's capacity for intentional action is shaped by his character, and each character has correspondingly different kinds of intention, both with respect to the objects of intention and in their relation to action. Finally, the scope of intention is not definite, and depending on the agent, can include those things which attend to the means of which he has cognizance, for instance, harmful side-effect consequences or other costs of his action. In the second part of the dissertation, we examine at length the objections to the Simple View, lodged by Bratman, Gilbert Harman, and Joshua Knobe. We give an overview of objections by Bratman, Harman, and Knobe which center on three cases and four objections. The cases are: 1) a hypothetical video game; 2) unexpected success; and 3) unintended consequences. The objections are: 1) with respect to the hypothetical video game, the Simple View ascribes an irrational intention to a gamer playing the game; 2) When agents are doubtful of the success of an action they undertake, the Simple View requires that they intend the act the perform rather than that they merely try to perform the act, which opponents argue that this is irrational and false; 3) The Simple View entails the rejection of the distinction between intention and foresight which itself entails that agents intend all the results of their actions, even when those results are merely foreseen and not intended; 4) The Simple View does not adequately explain ordinary language usage with respect to ascriptions of intention for side-effect consequences, and therefore does not reflect basic, commonly shared notions of intentional action. The first two objections center on cases where it seems irrational for an agent to intend the act he performs. In the case of the video game, the scenario is so set up that the player wins a prize for hitting either target but knows that he cannot hit both or the game will shut down. It seems irrational for him to intend to hit both if he cannot; however, in order to maximize his chance winning, it would be rational to aim at both. In the case of unexpected success, it seems that agents do not intend acts whose chances of success they doubt because intending seems to require the positive belief that one will succeed; rather, it is argued that agents merely try but do not intend the act they perform. Against these cases and objections, we argue that agents are capable of conditional and complex intentions, such that one may conditionally intend to hit whichever target is opportune, while aiming at both. Likewise, we argue that intending to act does not require the positive belief that one will succeed; only that it is possible for one to succeed. Furthermore, the distinction between trying and intending is specious. Finally, we respond to the third and fourth objections centering on the intentionality of side-effect consequences. It is argued by Bratman et al. that the Simple View entails the rejection of the distinction between intention and foresight, and that such a rejection further entails consequentialism. Likewise it is also argued that the Simple View fails to account for ordinary language ascriptions of intentionality for side-effect consequences. We agree that the Simple View entails rejecting the distinction between intention and foresight as it is currently applied, but deny that this entails consequentialism, i.e., the view that the consequences of an action are the primary basis for moral evaluation and not the agent's intentions. Likewise, we agree that the Simple View does not model ordinary language ascriptions of intention; however, this is not necessarily a defect since such ascriptions are inconsistent and imprecise. Furthermore, we argue that the Simple View might be used to more adequately explain such usage. We center our response to these objections on the Doctrine of Double Effect. We argue that the doctrine arises from a mistaken interpretation of St. Thomas Aquinas' treatment of defensive killing. We argue that Aquinas does not hold that the death of an attacker is a foreseen but not intended side-effect, as proponents of Double Effect and opponents of the Simple View hold; rather it is intended as a means to the end of self-defense. Therefore, the two effects are not the desired end and a side-effect but rather the intended end and the intended means. Furthermore, we argue that this does not entail doing evil for the sake of good because Aquinas' Aristotelian account of action specification incorporates circumstances as essential components of intentions which give an act its moral quality. Furthermore, the necessary references to an agent's intentions show how the rejection of the application of the distinction between intention and foresight does not entail consequentialism. Finally, we tackle the underlying assumptions about intention and desire which lead to the rejection of the Simple View. Opponents of the Simple View hold that intention is not a form of desire because then it would not have an essential role in the genesis of action or in rational deliberation. We, however, argue that the major objections to the Simple View are defeasible once one understands intention as a species of desire, i.e. a deliberate desire, whose scope includes consequences beyond acts performed and goals achieved. The paradoxes at the heart of the debate hinge on the ambiguity of the English word `intention' and its usage, as well as the inherent difficulty of examining psychological concepts. `Intention' has several senses unified by the purposiveness of the mental states to which the word is referred. These senses can often, but not always, be distinguished in English usage by the degree and kind of deliberation attendant to them. / Thesis (PhD) — Boston College, 2009. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Philosophy.

Le paludisme est l'une des maladies infectieuses les plus dévastatrices qui a affecté environ 214 millions de personnes dans le monde. Elle est causée par l'infection par le parasite plasmodium, dont P. falciparum et P. vivax sont les plus représentés. Le développement asexué du parasite dans le sang provoque la physiopathologie de la maladie dont l'évolution passe du paludisme simple au paludisme grave, notamment le neuropaludisme. Nos travaux ont d'abord porté sur l'analyse du transcriptome, par la technologie des microarrays, des cellules sanguines d'une cohorte constituée au Sénégal. L'analyse des résultats a permis d'identifier un ensemble de gènes dont l'expression permettait de distinguer le profil transcriptomique du neuropaludisme de ceux du paludisme simple et des autres formes de paludisme grave. Ces gènes sont enrichis en voies biologiques impliquées dans l'activation des récepteurs des lymphocytes B et T mais aussi des TLR et des récepteurs Fcgamma. On y trouve aussi plusieurs gènes candidats qui ont déjà été testés pour leur résistance au paludisme, dont RNASE3 et IL18R. Nous avons aussi réalisé, avec une partie de cette même cohorte sénégalaise, une étude d’association cas-contrôles qui n’a pas permis de détecter d’association entre le polymorphisme NCR3-412 et le paludisme sévère. Enfin l’approche basée sur une métaanalyse a permis de confirmer son implication dans le paludisme simple, ainsi que celle du polymorphisme LTA+252 dans le paludisme sévère, contrairement au LTA+80, au TNF-238 et au TNF-308. L’ensemble des travaux contribuent à une meilleure compréhension des facteurs génétiques et génomiques impliqués dans la résistance de l’hôte au paludisme. / Malaria is one of the most devastating infectious diseases that has affected an estimated 214 million people worldwide and caused nearly 600,000 deaths in 2015. It is caused by infection with the plasmodium parasite, P. falciparum and P. vivax are the most represented. The asexual development of the parasite in the blood causes the pathophysiology of the disease which can evolve from mild malaria to severe malaria, including cerebral malaria. Our work first focused on the analysis of the microarray transcriptome of blood cells of a cohort composed in Senegal. The analysis of the results allow to identify a set of genes whose expression permit to distinguish the transcriptomic profile of cerebral malaria from those of mild malaria and other forms of severe malaria. These genes are enriched in biological pathways involved in the activation of B and T lymphocyte receptors also TLRs and Fcgamma receptors. These genes also include several candidate proteins that have already been tested for resistance to malaria, including RNASE3 and IL1RN.

Em projetos de alvenaria estrutural é indispensável à verificação de elementos submetidos à flexão simples, como vigas, vergas, reservatórios e muros de arrimos. Neste trabalho foram analisados oito grupos de vigas, compostos por três exemplares cada um, diferenciando seu comprimento, altura, tipo da unidade (blocos de concreto e blocos cerâmicos) e taxa de armadura. Os traços de graute e argamassa foram mantidos. As vigas e as armaduras longitudinais foram instrumentadas para obtenção dos deslocamentos e deformações. A finalidade do trabalho foi realizar uma comparação dos resultados obtidos através de ensaios experimentais com os dimensionamentos propostos pelas normas ABNT NBR 15812-1:2010 e NBR 15961-1:2011. Foi possível observar que o dimensionamento proposto pelas normas é conservador, pois limita o comportamento à flexão das vigas em cargas baixas quando comparados com experimentais. Já com a retirada dos coeficientes de segurança pode ocorrer, em alguns casos, que a carga teórica prevista seja maior que a dos resultados experimentais. A formulação adaptada da NBR 6118:2007 para obter valores de deslocamentos apresentou uma boa correlação para as vigas de uma fiada. Já para as vigas de duas fiadas observou-se uma pior correlação entre valores teóricos e experimentais, sendo os deslocamentos teóricos menores que os valores medidos experimentalmente. / In structural masonry projects is essential to verify elements subjected to simple bending, such as beams, lintels, water tanks and retaining walls. In this study, an experimental parametric analysis was conducted. Eight groups of beams composed by three specimens were tested and the parameters varied were: length, height, unit type (concrete blocks and ceramic blocks) and reinforcement ratio. The proportion of grout and the mortar were fixed. The beams and longitudinal bars were instrumented to obtain the displacements and strains. The purpose of this study was to compare the results obtained through experimental analysis with the proposed methods presented on ABNT NBR 15812-1:2010 and NBR 15961-1:2011. In the comparison was observed that the proposed design method is conservative, due to the limit load obtained by the code prescriptions was lower than the experimental results. In some cases, the theoretical load results were greater than experimental results when the safety factors were removed. The adapted formulation of the NBR 6118:2007, to obtain displacement values, showed a good correlation to the beams of one row. Regarding to beams with two rows, the correlation between experimental and theoretical values was not suitable, the theoretical displacements presented smaller than the values measured in the tests.

In the past, the use of a fracture mechanics approach to describe crack growth in elastomers has been shown to work well for specimens of simple test geometry, simply loaded. This has been the case because elastic strain energy density (e.s.e.d.) functions could reliably be used to calculate both the magnitude of elastic stored energy available to drive a crack and the magnitude of the rate of release of such energy as the crack grows. The aim of this thesis was to investigate the applicability of such a methodology to situations of more complex loading. To this end two novel test-piece geometries were developed. The first consisted of a pure shear geometry with the sample having been pre-strained in the longitudinal direction to varying extents, hence introducing a type of bi-axial deformation. The second consisted of a pure shear geometry test-piece inclined at 30° to the horizontal and loaded in the vertical direction, hence inducing simultaneously pure shear and simple shear loading. Both types of test-piece were used to study the validity of the particular e.s.e.d. functions, the energetics and mechanics of crack growth and crack growth geometries on a macro and micro scale. The constants in particular e.s.e.d. functions were determined by uniaxially deforming in pure shear each of the carbon black reinforced materials used in this study. The resulting functions became progressively less good at predicting the elastic strain energy in the novel geometry test-pieces as the deformation modes became more complex. Anisotropy induced by deforming specimens in one direction was not easily removed even by an imposed large deformation in another direction. Nevertheless, the functions were successfully used to predict crack growth directions in the 30° inclined test-piece. However in the pre-strain pure shear test-pieces the functions significantly underestimated the elastic strain energy. Hence the real energies had to be determined from the forces and extensions measured during cyclic crack growth tests. In these tests crack growth rates for a given tearing energy (elastic energy release rate) increased as the magnitude of the pre-strain increased. This significant weakening was associated with the development of a strain induced molecular and carbon black anisotropy.

This thesis studies non-simple Jacobians and non-simple abelian varieties. The moti- vation of the study is a construction which gives a distinguished genus 4 curve in the linear system of a (1, 3)-polarised surface. The main theorem characterises such curves as hyperelliptic genus 4 curves whose Jacobian contains a (1, 3)-polarised surface. This leads to investigating the locus of non-simple principally polarised abelian g- folds. The main theorem of this part shows that the irreducible components of this locus are Is~, defined as the locus of principally polarised g-folds having an abelian subvariety with induced polarisation of type d. = (d1, ... , dk), where k ≤ g/2 Moreover, there are theorems which characterise the Jacobians of curves that are etale double covers or double covers branched in two points. There is also a detailed computation showing that, for p > 1 an odd number, the hyperelliptic locus meets IS4(l,p) transversely in the Siegel upper half space

This thesis investigates stabilisation of the SIMPLE-family discretisations for incompressible flow and their discrete adjoint counterparts. The SIMPLE method is presented from typical \prediction-correction" point of view, but also using a pressure Schur complement approach, which leads to a wider class of schemes. A novel semicoupled implicit solver with velocity coupling is proposed to improve stability. Skewness correction methods are applied to enhance solver accuracy on non-orthogonal grids. An algebraic multi grid linear solver from the HYPRE library is linked to flow and discrete adjoint solvers to further stabilise the computation and improve the convergence rate. With the improved implementation, both of flow and discrete adjoint solvers can be applied to a wide range of 2D and 3D test cases. Results show that the semi-coupled implicit solver is more robust compared to the standard SIMPLE solver. A shape optimisation of a S-bend air flow duct from a VW Golf vehicle is studied using a CAD-based parametrisation for two Reynolds numbers. The optimised shapes and their flows are analysed to con rm the physical nature of the improvement. A first application of the new stabilised discrete adjoint method to a reverse osmosis (RO) membrane channel flow is presented. A CFD model of the RO membrane process with a membrane boundary condition is added. Two objective functions, pressure drop and permeate flux, are evaluated for various spacer geometries such as open channel, cavity, submerged and zigzag spacer arrangements. The flow and the surface sensitivity of these two objective functions is computed and analysed for these geometries. An optimisation with a node-base parametrisation approach is carried out for the zigzag con guration channel flow in order to reduce the pressure drop. Results indicate that the pressure loss can be reduced by 24% with a slight reduction in permeate flux by 0.43%.

Publicación a texto completo no autorizada por el autor / Desarrolla y caracteriza films poliméricos cargados de aciclovir (ACI) para el tratamiento tópico del herpes simple. Complejos interpolielectrolito - fármaco (CIPEF) basados en chitosan (Ch), ácido hialurónico (AH) y aciclovir (ACI) fueron desarrollados mediante el método de coacervación en medio acuoso empleando una cantidad de ACI y AH suficientes para neutralizar el 50 y 10% de los equivalentes de grupos amino ionizables del chitosan, respectivamente; obteniéndose un complejo de Ch - ACI50 - AH10. Adicionalmente, los films fueron obtenidos utilizando el método de casting, mediante la adición de glicerina al 2% p/v y caracterizados posteriormente. El diámetro hidrodinámico (Dh) y el potencial zeta (PZ) de las dispersiones fueron medidos mediante espectroscopía de correlación de fotones (DLS). Complejos con y sin fármaco exhibieron tamaños de 834,3 ± 59 nm y 662,3 ± 29 nm respectivamente. El potencial zeta de los CIPEF presentaron valores de 59,6 ± 0,79 mV. El desplazamiento iónico, mediante la adición de NaCl 0,9%, mostró un ligero cambio en el pH debido a la liberación del grupo amino por sustitución con sodio indicando interacción iónica. Por el contrario, el agregado de glucosa al 5 % no produjo cambios. La calorimetría exploratoria diferencial (DSC) reveló ausencia de pico de fusión a 250 °C del ACI evidenciando ausencia de fármaco libre. El análisis termogravimétrico (TGA) mostró que los polielectrolitos (PE), ACI y los complejos son estables a altas temperaturas (~200°C) indicando estabilidad térmica en comparación con la mezcla física. La difracción de rayos X (Dx) y microscopía óptica de los CIPEF revelaron que los complejos no presentan picos en el difractograma, evidenciándose ausencia de fármaco (F) libre. Los films mostraron coeficiente de variación (Cv)<5%, evidenciando un proceso de secado homogéneo y una distribución uniforme del fármaco en el film, respectivamente. In vitro, films presentaron una liberación controlada de ACI. En conclusión, los resultados mostraron que los films obtenidos presentan buenas propiedades y podrían constituirse en alternativas prometedoras para el tratamiento tópico del herpes. / Tesis

Tese de mestr.. Métodos Computacionais em Ciência e Engenharia. Faculdade de Engenharia. Universidade do Porto. 2000

The purpose of this thesis is to develop original symmetric presentations of finite non-abelian simple groups, particularly the sporadic simple groups. We have found original symmetric presentations for the Janko group J1, the Mathieu group M12, the Symplectic groups S(3,4) and S(4,5), a Lie type group Suz(8), and the automorphism group of the Unitary group U(3,5) as homomorphic images of the progenitors 2*60 : (2 x A5), 2*60 : A5, 2*56 : (23 : 7), and 2*28 : (PGL(2,7):2), respectively. We have also discovered the groups 24 : A5, 34 : S5, PSL(2,31), PSL(2,11), PSL(2,19), PSL(2,41), A8, 34 : S5, A52, 2• A52, 2 : A62, PSL(2,49), 28 : A5, PGL(2,19), PSL(2,71), 24 : A5, 24 : A6, PSL(2,7), 3 x PSL(3,4), 2• PSL(3,4), PSL(3,4), 2• (M12 : 2), 37:S7, 35 : S5, S6, 25 : S6, 35 : S6, 25 : S5, 24 : S6, and M12 as homomorphic images of the permutation progenitors 2*60 : (2 x A5), 2*60 : A5, 2*21 : (7: 3), 2*60 : (2 x A5), 2*120 : S5, and 2*144 : (32 : 24). We have given original proof of the 2*n Symmetric Presentation Theorem. In addition, we have also provided original proof for the Extension of the Factoring Lemma (involutory and non-involutory progenitors). We have constructed S5, PSL(2,7), and U(3,5):2 using the technique of double coset enumeration and by way of linear fractional mappings. Furthermore, we have given proofs of isomorphism types for 7 x 22, U(3,5):2, 2•(M12 : 2), and (4 x 2) :• 22.