Repositório RCAAP

The affinity of a drug candidate for a biological membrane (its lipophilicity) is closely related to the pharmacologically crucial events of absorption, biodistribution, metabolization and excretion. The evolution of knowledge of biological membranes during the past two decades contrasts with the rudimentary parameter most commonly used to assess lipophilicity: Po/w, the octanol–water partition coefficient. Po/w is especially unrealistic when testing molecules that are polar or partially charged. By contrast, lipid vesicle-based methods determine the extent of the actual partition of a drug to a membrane Much more accurately, and have the additional advantage of enabling the choice of the lipid composition considered most suitable to answer a specific biological or pharmaceutical question. In addition, some of these methods are appropriate for high throughput screening, thus shifting determinations of membrane partition to a more preliminary stage of drug development. This stream lines research and development, by saving the time and money that would be spent on unpromising leads.

Clinically significant tumors induce their own vascularization using molecular mechanisms involved in the regulation of physiological angiogenesis. One of these mechanisms is mediated by Delta-like 4 (Dll4)/Notch signaling, which is known to play a fundamental role in the regulation of embryonic angiogenesis and arterial specification. Up-regulated in animal and human tumors, Dll4 represents the focus of the work presented in this thesis, which aimed to characterize its function(s) in the regulation of tumor-driven angiogenesis and validate it as a potential therapeutic target. To achieve the proposed objectives, Dll4 loss- and gain-of-function phenotypes were characterized in grafted and autochthonous mouse tumor models. Additionally, pharmacological inhibition of Dll4/Notch signaling by soluble Dll4 extracellular domain (sDll4) was assessed as a therapeutic strategy, alone or in combination with the inhibition of downstream Ephrin-B2/EphB4 signaling by soluble extracellular EphB4 (sEphB4). Loss of Dll4 function by either targeted Dll4 allele deletion or use of sDll4 was shown to lead to increased, but defective and immature vascular proliferation in subcutaneously grafted malignancies (S180, HT29 and KS-SLK cell lines), as well as in autochthonous insulinomas of transgenic RIP1-Tag2 mice. The increase in endothelial activation was confirmed to reflect higher endothelial sensitivity to vascular endothelial growth factor A (VEGFA), while retarded vessel maturation, indicated by reduced mural cell recruitment, was found associated with EphrinB2 and Tie2 signaling suppression. This induction of unproductive angiogenesis resulted in significantly reduced tumor growth, creating a new perspective for tumor vasculature targeting. Regarding the suppression of vessel maturation and consequent tumor expansion, greater efficacy against RIP1-Tag2 insulinomas was observed when Ephrin-B2/EphB4 signalling inhibition by sEphB4 was combined with either Dll4 allele deletion or sDll4 treatment. Importantly, hepatic vascular alterations arising under chronic Dll4 inhibition were prevented by concomitant sEphB4 treatment. Apparently in contradiction to data obtained from advanced, aggressive and rapidly expanding tumors, my work demonstrated that Dll4 down-regulation in pre-malignant, DMBA/TPA-induced chemical skin papillomas, promotes productive, although less mature angiogenesis, as well as neoplasm growth. In both benign and malignant tumors, Dll4 was found to serve as a fundamental suppressor of excessive endothelial proliferation. The observed difference in skin papillomas might be due to the capacity of tumor neo-vessels to mature and gain functionality in early but not in invasive lesions. In these lesions, higher VEGFA levels and decreased VEGFA gradients result in disorganized endothelial proliferation that does not permit functional vessel formation if Dll4/Notch is even partially suppressed. These findings therefore imply that Dll4 requirement to normalize tumor vasculature increases with the tumor grade, being always critical to hold down VEGFA-induced angiogenesis. Nevertheless, my results reveal that Dll4 functions as a very delicate determinant of tumor success and progression, although vascular response quite expectedly changes with its alteration. By exploring the effects of increased endothelial Dll4 expression to the supra-basal levels in Lewis lung cancer xenografts, chemically-induced skin tumors and transgenic RIP1-Tag2 insulinomas, this work shows that Dll4 over-expression also decreases tumor growth due to significant suppression of angiogenesis and pronounced reduction of overall tumor blood supply. Although increased Dll4 function consistently improved tumor vascular maturation and functionality, the tumor vessel normalization did not predominate over the tumor-suppressive effects of restricted vessel proliferation, in the experimental settings used. Thereby, Dll4 over-expression appeared as an alternative that, beside the anti-angiogenic effects, might reduce malignant cell penetration into the bloodstream and ensure increased delivery and effectiveness of co-applied chemotherapy, due to improved vessel maturation and competence. Collectively, Dll4 plays a prominent role as negative regulator and pro-maturation factor in tumor-driven angiogenesis. Interference with Dll4/Notch may be desirable in cancer patients, while the choice of an agonistic or antagonistic approach will probably depend on tumor type and further toxicity and efficacy assessments, particularly when applied in combination with other anti-angiogenic and cytostatic drugs.Tumores clinicamente significativos induzem a sua própria vascularização. Para isso, frequentemente utilizam os mecanismos moleculares envolvidos na regulação da angiogénese fisiológica. Uma destas vias é via de sinalização Delta-like 4 (Dll4)/Notch, que se sabe desempenhar um papel fundamental na regulação da angiogénese embrionária e na especificação arterial. Encontrando-se a sua expressão aumentada em tumores humanos e animais, Dll4 constituiu o principal foco deste projecto de Doutoramento, que teve como objectivo caracterizar a sua função na regulação da angiogénese tumoral e validar este ligando de receptores Notch como um potencial alvo terapêutico. Para atingir os objectivos propostos, fenótipos de perda- e de ganho-de-função de Dll4 foram caracterizados em modelos tumorais enxertados e autóctones em murganhos. Além disso, a inibição farmacológica da via Dll4/Notch com uma proteína solúvel contendo o domínio extracelular de Dll4 (sDll4) foi avaliada como uma estratégia mono-terapêutica, e, subsequentemente, em combinação com a inibição da via de sinalização Ephrin-B2/EphB4, que se sabe actuar a jusante da via Dll4/Notch, realizada com administração de uma proteína solúvel contendo o domínio extracelular de EphB4 (sEphB4). A perda da função de Dll4 por deleção monoalélica de Dll4 ou por administração de sDll4 resultou em proliferação vascular aumentada, mas defeituosa e imatura, em tumores enxertados subcutaneamente (linhas celulares S180, HT29 e KS-SLK), assim como em insulinomas autóctones de murganhos transgénicos RIP1-Tag2. O aumento da activação endotelial foi confirmado como resultante do aumento da sensibilidade endotelial ao factor de crescimento endotelial vascular A (VEGFA), enquanto a maturação vascular retardada, indicada pelo recrutamento diminuído das células murais, foi associada com a supressão da sinalização de EphrinB2 e da função de Tie2. Esta indução da angiogénese não produtiva resultou em redução significativa do crescimento tumoral, representando a base racional de uma nova, e potencialmente benéfica, estratégia para interferir com a neo-vascularização em tumores. Em relação à supressão da maturação vascular e à consequente expansão tumoral, observou-se uma maior eficácia na regulação do crescimento de insulinomas em murganhos RIP1-Tag2, quando a administração de sEphB4 foi combinada com a deleção monoalélica em Dll4 ou com o tratamento com sDll4. Adicionalmente, as alterações vasculares hepáticas decorrentes da inibição crónica de Dll4 foram impedidas pelo tratamento concomitante com sEphB4. Aparentemente em contradição com os dados obtidos a partir de tumores avançados, agressivos e em rápida expansão, a deleção de um alelo Dll4 em papilomas cutâneos pré-malignos, quimicamente induzidos com DMBA/TPA, resultou na promoção de produtiva, embora menos madura, bem como no maior crescimento destas neoplasias. Quer em tumores benignos como malignos, encontra-se documentada a função de Dll4 como importante supressor de proliferação endotelial excessiva. A diferença encontrada nestes estudos deve estar relacionada com a capacidade dos vasos tumorais ganharem funcionalidade no caso de lesões iniciais, mas não em lesões invasivas, onde os níveis mais elevados de VEGFA e diminuição dos gradientes de VEGFA resultam em proliferação endotelial tão desorganizada que praticamente não permitia a formação dos vasos funcionais se a sinalização Dll4/Notch estivesse suprimida, mesmo que parcialmente. Assim, os resultados aqui apresentados sugerem que a importância de Dll4 para normalizar a vascularização tumoral aumenta com o grau de malignidade, sendo sempre crítica para moderar a angiogénese induzida por VEGFA. No entanto, a função de Dll4 é um determinante critíco da progressão tumoral, embora a resposta vascular mude de um modo bastante previsível com as alterações na expressão de Dll4. Através da análise dos efeitos devidos ao aumento da expressão endotelial de Dll4 em enxertos de cancro pulmonar de Lewis, em tumores cutâneos quimicamente induzida e em insulinomas dos murganhos transgénicos RIP1-Tag2, é mostrado neste trabalho que Dll4 retarda também o crescimento tumoral devido à supressão significativa de angiogénese e redução acentuada da perfusão sanguínea do tecido neoplásico. Embora a presença aumentada de Dll4 tenha consistentemente melhorado a maturação e funcionalidade vascular nos modelos experimentais utilizados, a normalização dos vasos não predominou sobre os efeitos anti-tumorais decorrentes da restrição da proliferação vascular. Assim, a sobre-expressão de Dll4 surge como uma alternativa que, além dos efeitos anti-angiogénicos, pode reduzir a penetração de células malignas na corrente sanguínea e garantir uma maior eficácia da quimioterapia co-aplicada devido à promoção da maturação e competência vascular dos tumores. Em conclusão, Dll4 desempenha um papel de grande relevo na angiogénese induzida por tumores, quer como um regulador negativo de activação endotelial quer como factor de maturação vascular. Interferência com Dll4/Notch pode ser desejável em doentes oncológicos, embora a escolha de uma estratégia agonista ou antagonista dependerá provavelmente do tipo tumoral e do resultado da avaliação de segurança e eficácia que terá que ser feita, em particular quando aplicada em terapêutica de combinação com outros medicamentos anti-angiogénicos e citostáticos.

Abstract. The aim of this work is to prepare tretinoin/dimethyl-beta-cyclodextrin complexes and fully characterize them through various analytical techniques. According to the phase solubility studies performed, the equilibrium for maximum complexation is reached in about 8 days presenting an AL-type diagram (soluble complexes) corresponding mainly to 1:1 stoichiometry (Ks=13,600 M−1), although the possibility of the presence of 1:2 complexes was mathematically proven. Differential scanning calorimetry, X-ray diffraction and all the other analytical techniques have proven the presence of true complex formation in all the preparation methods tested. H-NMR and FTIR spectra allowed the selection of the best complexation method. The comparison between Raman spectra revealed that the more relevant feature is the band at 1,573 cm−1, which corresponds to the entire delocalization of the superconjugated system, and after inclusion is observed as a positive frequency shift. Based on these results and the data obtained by molecular modelling calculations, it is proposed that the structure of the drug included into the cyclodextrin corresponds to the side chain including the functional group COOH. The complex was also analysed by atomic force microscopy to determine its size distribution which was heterogeneous and polymodal. However, it could be observed that they all have the same phase constitution.

Since 1910 artistic Avant-garde start to reach higher and higher levels of abstraction and progressively leave art as imitation behind. In France Cubism and Fauvism emerge and can somehow coexist with more conservative artistic institutions, while Germany and Italy see the rise of Expressionism and Futurism, two movements that, irrespective of their differences, both aspire to a fusion of art and life, one of the main dogmatic conflicts of the modern art movement. In open opposition to all academic authority these two movements develop formal experiences highlighting the importance of myth and collective instinct in social life. Meanwhile avant-garde architecture strives to create an "overall piece of art" and approaches the sphere of visual art. Thereby idealistic or utopian architecture artists emerge who, lacking the opportunity to construct, design fantastic and imaginative architectural and urban models. These models stretch the borders of architectural thinking and illustrate tendencies of the history of modern architecture. Besides describing these two instances of utopian design, namely Expressionism and Futurism, this investigation presents Surrealism as a moment that relates architecture to the world of desire and the surreal irrational, affirming the liberating power of the dreamt art and architecture as a tribute to materialized architecture. The architectural utopias proposed in these three moments are not more than pencils, colours and ink gliding over paper. The analysis and understanding of these "paper architectures" is the subject of the present investigation

O Surrealismo pela sua amplitude, enquanto movimento artístico que se fundamenta na intervenção e libertação do homem, contribui para uma nova concepção da arte e da vida, nos modos como assume a consequente dimensão ética e poética. Esta tese surge da necessidade de aprofundar o significado histórico do Surrealismo Português e Internacional, onde se insere a obra poética e plástica de Eurico Gonçalves, cuja pertinente e complementar actividade de professor e crítico de arte não pode deixar de ser considerada no âmbito da educação artística. Neste contexto, o nosso estudo parte de um levantamento de dados que envolvem os antecedentes históricos e o desenvolvimento deste movimento até à actualidade, com especial incidência no percurso de Eurico Gonçalves, autor de uma obra que se define entre dois vectores convergentes, a inocência original e a poética do maravilhoso , numa inter-relação com o automatismo psíquico , a exploração do acaso e o vazio libertador zen. O encontro do pintor com o surrealismo situa-se num percurso feito de sucessivos encontros interiorizados com personalidades que admira. Revelou-se a partir de 1949, através da nova figuração onírica e do automatismo psíquico , que nunca deixou de praticar, e que está na origem da sua posterior pintura gestual. Desde o começo dos anos 60, o seu imediatismo, numa relação com a infância, a inocência original e o zen, na sua pureza máxima, sem correcção nem retoque, é consequente do automatismo psíquico . Dada-zen foi a designação criada por Eurico para relacionar o vitalismo dada e a atitude filosófica zen. Ambos propõem uma arte despreconceituada e espontânea, aberta à intervenção do acaso e à revelação dos dados imediatos do inconsciente. Pretende-se, através da obra de Eurico Gonçalves, nas suas dimensões ética e poética, contribuir para a análise e reconhecimento da evolução do surrealismo figurativo para o surrealismo abstracto, que alguns críticos, escritores, poetas e artistas ainda têm dificuldade em aceitar, apesar de André Breton ter sido um dos primeiros a compreender a vocação abstracta da pintura surrealista.

The purpose of this dissertation is to establish the connection between the expressive characteristics of the conception drawings of the artistic project, which are generally called sketches (schizzi), and the way they allowed that kind of drawings evolved to an autonomous graphic object. We will see how its incomplete and fragmented character, which results, through the running back to imagination, from the rapid formulation of graphic hypothesis, formaily simplified, to a certain project problem, it will end, since its origin the Renaissance, to reveal an inventive process and, therefore, to contribute to the identification of an authorship for that same project, that is the reason why the conception drawings begin to assume exterior visibility. In a way of having a more profound vísion of the sketch (schizzo) concept, we ran over to the definition that is created by the treaties of Francisco de Holanda and Giorgio Vasari, taking advantage, this way, to separate the sketch (schizzo} from other kind of drawings often confounded with its practise, such are the sketch (bozzeto) and the croquis. Still based on these definitions, we decided to separate which we called "real" and "false" sketches (schizzí), that is to say introspective sketches (schizzi}, which are connected to the creative moments of the project, and sketches (schizzl) which seem to be developed purposely to be seen. Based on this assertion, we admit that, nowadays, the anonymous character of the digital registration in the architecture and design project, in a perspective of the project identification, still exalts the sketch (schizzo}, through the acknowledgement of its own characteristics, in a way next to the one which is connected to its own origin

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The work's goal is reflect about the emergent creative manifests in urban environments. These manifests are born from the great need to get through the role cities have been negatively playing ever since: its deadly effect on creativity. In order to do so, we will present some artists, productions and ways of living and thinking, which may possibly explain the emergent appropriation of the urban space as the ultimate (subversive) art gallery for the city people

The use of images was wide argued since the beginning of Christianity until the Ecumenical Council of Trent, between 1545 and 1563. The image is a formal configuration of an idea, this is, the thought of one culture. The knowledge that characterizes this culture is the same that determines the artistic expression in witch image results. It is the limes limited by time and space of a culture that characterizes the artistic time and space. However, by the long time and space of Universal History we can realize that image is in common with an idea of communication through one language expressed by signs and symbols. In Occidental Art, since the Classic Antiquity, the image looks to establish, through examples of vice and virtue of its tradition, a normalization of social behaviors in accordance with the moral principles stipulated by these cultures. The Christian Art, witch is born of a greco-roman tradition, pursues, necessarily, the same intentions. Since the VI century, the devotion of God and basically,the diffusion of one elaborated process of Salvation through a celestial hierarchy and a Beyond geography that include Purgatory and Hell, became essential an organization of a didatic plan that guarantee Salvation. Since there that image, like spiritual literature, that includes confection manuals, the exempla, the liturgical texts, the laudas, has been the way that Church found to guide its flock to Salvation. The exemplary lives of Mary; Jesus and the Saints served of example of devotion to God and preservation of Faith, which bad to be taken by its followers. The narratives of Sacred History gained visibility through image, and through them, its worshipers could memorize facts, lives and passions, as well as gather the invisible things that they represent as the way to build and to inflame its spirit. In this dissertation we approach the subjects of the Virgin Life, the Lives of Saints and the Apocalyptic Vision, represented Portuguese Renaissence painting, where are also represented the didactic models that these subjects inspire

''Due to the appearance of the new media during the 19th century, and particularly by the end of the 20th century, along with the emerging mass culture, a new character, the one of the spectator/consumer, took shape. Liable to being seduced by the multiplicity of the crafts and technical effects — kind of "enchantment" rooted in the various aspects of the technique allied to the production and mass consumption. In this context, illusion, immersion and interaction become possibilities, which reach the spectator/consumer, who, in a progressive way, influences the appearance, during the 20th century of large numbers of immersive devices. Cinema is the paradigm of this immersion. Virtual reality its greatest exponent. Artists promptly learned how to take advantage of this interventive spectator, as well as of the handling of the same devices and mechanisms presently available, leading them to the world of fine arts, namely to immersion.''

This essay is built upon the search for the understanding of today's status of the processes of artistic creation, and how they have been considered through time, first through an philosophical approach, then through psychological aesthetics and finally, more recently, through psychology. Being art an human creation, and perhaps the most expressive experience (form of livings), we shall conceive an approach so that through psychological aesthetics, through psychology, and most of all through cognitive psychology, will support and concur to build an Psychology of Artistic Creation. If all construction of reality is built upon the interaction between physical world, the psychological or subjective world and the world of human creation, it seems to be clear that the creative process is, by excellency, a paradigm of the human experimental or experiential phenomena. In this line of thinking, and because we consider that each individual keeps on building his project of creation through his own narratives, that assumes itself as way of construction, of understanding upon the individual himself and his interaction with the world, we have chosen this methodology, through an exploratory essay of the creation processes in two visual artists. More than drawing conclusions, we are trying to raise some questions, point ways of reflection for future investigation on the behalf of the understanding of artistic creation and creative processes

L´identité est l'attribut essentiel de notre nature comme être humain. Le contexte sociopolitique de chaque époque a été déterminant dans Ia construction de l'identité dês citoyens, dans Ia mesure où les institutions culturelles, politiques et religieuses, à travers leurs mécanismes d'intervention dans Ia dynamique sociale, ont toujours exerce un pouvoir dans l´observance et l'acquisition dês droits et devoirs dês êtres humains. Avec l'apparition de l'internet, dans lês années quatre-vingts, on a vu se développer lê champ d'action et d'intervention sociale de chaque individu à une échelle presque planétaire. L´internet a permis, entre d'autres desseins, l'auto-construcíion de l'identité dês utilisateurs qui, à partir de Ia conscience d'eux-mêmes, plongent dans une conscience plus universelle, en absorbant alors lês références fondamentales pour leur reconfiguration. Notre étude porte sur l'observation du comportement d'un groupe d'hommes d'âge avance, auto-dénommé "d'âge mûr", qui utilisent l'lnternet comme champ d'action dans lê domaine de l'homosexualité. Nous partons du príncipe que l'internet, moyen si universel et en même temps si particulier, s'est constitué comme véhicule promoteur d'expérimentations dans les domaines les plus varies, facilitant à leurs utilisateurs, Ia prise en compte de plusieurs facettes de l'identité, d'eux-mêmes et dês autres, en s'y investissant et en n'en absorbant le plus commode et essentiel. L´internet est donc le moyen virtuel dans lequel chaque personne peut agir de plusieurs manières, selon sa volonté et moyenhant lês circonstances de chaque instant. Judith Butler, l'un dês principaux défenseurs de Ia "Queer Theory", dans Trouble dans lê genre, (2005), défend que lês identités ne sont pás liées à un déterminisme et, en conséquence, ne sont pás fixe. De cette forme, elles ne résultent pás d'un ordre naturel ou social car il n'y a pas de relation entre sexe, genre et identité. Lês êtres humains, en général, sont lê fruit de cê qu'ils disent, de cê qu'ils font avec eux-mêmes et avec les autres. Nous concluons, ainsi, que l'identité dês personnes en general, telle que celle dês hommes sur lesquels se penche notre étude, est le reflet de leurs actions

We previously showed that lymphocytes and erythrocytes of HIV-1–infected patients, prior to antiretroviral therapy, presented significant changes in intracellular calcium concentration ([Ca2+]int) and membrane fluidity. The present study evaluates the same parameters after response to highly active antiretroviral therapy (HAART). Blood samples were collected from patients prior to and after antiretroviral therapy, and from control subjects. Membrane fluidity and [Ca2+]int were assessed by fluorescence spectroscopy measurements, using three different probes: TMA-DPH and DPH for membrane fluidity, and fura-2 for Ca2+. When compared with the control group, both untreated and treated patients presented increased lymphocyte [Ca2+]int and decreased lymphocyte membrane fluidity, without significant differences between the two groups of patients. On the contrary, the therapy reversed the membrane fluidity variations observed in erythrocytes. The decreased erythrocyte [Ca2+]int of untreated patients was not reversed by HAART. AIDS patients present changes in lymphocyte (mostly noninfected) and erythrocyte properties, partially reversed by HAART, consistent with a process of facilitated propagation of the infection to new cells, stimulation of virion production, and maintenance of a reservoir of erythrocyte-bound infectious virus. These observations can be related with the action of the HIV Nef protein in the cell’s proteins and lipid composition, as well as with the recently observed cell infection by HIV-1 via endocytosis.

For millennia, humans, either involuntarily or purposefully, have transported numerous species outside their natural range. Among these species, the house mouse (Mus musculus) has become one of the most successful and ubiquitous mammals worldwide, in particular its western subspecies M. m. domesticus. Due to its commensal relationship with humans, M. m. domesticus has colonised all 5 continents and a large proportion of islands, being transported as a stowaway. As well as being interesting in its own right, the colonisation history of house mice provides exciting and novel insights into movements and colonisations of humans. This study uses a ‘phylogeographic’ approach to examine the colonisation history of the western house mouse at three different geographical scales: regional (insular), continental and global. Regional (insular) scale. Particular emphasis was given to the colonisation of the Azores archipelago, making use of mitochondrial DNA sequences (D-loop) and nuclear markers (microsatellites and subspecies-specific DNA sequences). A complex colonisation history was revealed, with the cultural and historical link with Portugal being reflected on some but not all islands, with a surprising northern European origin relating to Santa Maria, Terceira and Flores. On the other hand, microsatellites seem to have retained little phylogeographic signal, revealing instead generally high levels of genetic diversity within the Azorean house mouse populations. Evidence of recent migration was also detected mainly among islands of the Central group but not with mainland Portugal or the neighbouring Madeiran archipelago. Continental scale. The colonisation of the Australian continent by the invasive house mouse was thought to have occurred soon after the establishment of the first British penal colony. Through the analysis of D-loop sequences from both Australia and potential source areas, the historical link with Britain was confirmed, helping to validate the use of phylogeographic patterns of house mice as a proxy of human settlement history. Global scale. This approach was exploited further with D-loop sequences of the western house mouse being obtained from plentiful locations throughout Western Europe, North, Central and South America, Africa, Australasia and numerous islands worldwide, resulting in the widest sampling yet attained throughout the range of this subspecies. Despite the expected complexity in the patterns of D-loop variation, there is a striking overlap between the presence of certain D-loop lineages in particular regions of the world and the expectations from human history. Both Viking Age and Age of Discovery explorers and subsequent settlers appear to have had a particular influence in the current distribution and genetic makeup of house mouse populations worldwide. Overall, the main achievements of this study comprise additional validation to the use of house mice as proxies of human movements and colonisations, based on both intense regional and broad global coverage. Accordingly, this study confirmed the suitability of the mitochondrial D-loop as a good molecular marker to assess initial colonisation of house mice in a given geographic area.

Este estudo teve como objetivo estudar a relação entre os padrões de vinculação (parental e amorosa) e o temperamento afetivo (depressivo, ciclotímico, hipertímico, irritável e ansioso) conceptualizado em temperamentos estáveis (depressivo e hipertímico) e instáveis (ciclotímico, irritável e ansioso) reunindo dados que nos permitiram perceber se padrões de vinculação seguros se correlacionam positivamente com temperamentos estáveis. A amostra foi constituída por 760 estudantes do curso de licenciatura em enfermagem provenientes de quatro escolas do sistema de ensino superior politécnico português. Os dados foram recolhidos por questionário de autopreenchimento, formado por várias medidas: variáveis sóciodemográficas, a Escala de Temperamento de Memphis, Pisa, Paris e San Diego (TEMPS-A), validação para a população portuguesa (Akiskal & Akiskal, 2005a; Figueira et al., 2008), o Questionário de Vinculação ao Pai e à Mãe – QVPM, Versão IV (Matos & Costa, 2001a), o Questionário de Vinculação Amorosa – QVA, Versão III (Matos & Costa, 2001b). Os participantes são maioritariamente do género feminino (83,3%) com uma média de idades de 21,3 anos, vivem maioritariamente num agregado familiar com pai e mãe, 81,7% têm irmãos e 60,3% mantêm uma relação de namoro. A partir dos dados dos fatores de vinculação parental (pai e mãe) e de vinculação amorosa foram construídos padrões de vinculação (seguro, preocupado, desinvestido e amedrontado). De entre os cinco temperamentos afetivos (depressivo, hipertímico, ciclotímico, irritável e ansioso), o temperamento afetivo dominante para a totalidade da população estudada foi o temperamento depressivo. Apenas o temperamento irritável mostrou não estar associado ao género. Não se encontraram associações entre os temperamentos afetivos e os progenitores com quem os inquiridos coabitam ou com a existência de irmãos, revelando apenas o temperamento ciclotímico uma associação com a existência de uma relação de namoro. Os resultados evidenciam associações significativas entre os temperamentos instáveis (ciclotímico, irritável e ansioso) e o padrão de vinculação desinvestido da vinculação parental (pai e mãe). Na vinculação na relação com a mãe, o temperamento depressivo (estável) e os temperamentos instáveis (ciclotímico, irritável e ansioso) revelaram-se dominantes entre o padrão desinvestido e o hipertímico (estável) entre os preocupados. Na vinculação na relação com o pai, o temperamento depressivo (estável) e os temperamentos instáveis (ciclotímico, irritável e ansioso) revelaram-se dominantes entre o padrão desinvestido e o hipertímico (estável) entre os seguros. No que se refere à vinculação amorosa os resultados evidenciaram associações significativas quer entre temperamentos estáveis ou instáveis e o padrão preocupado sugerindo uma associação pouco clara entre temperamentos (do ponto de vista da sua estabilidade) e os indivíduos com este padrão de vinculação.This study aimed to study the relationship between attachment patterns (parental and loving attachment) and affective temperament (depressive, cyclothymic, hyperthymic irritable and anxious) conceptualized as stable (depressive and hyperthymic) and unstable (cyclothymic, irritable and anxious) collecting data that allowed us to see if secure attachment patterns are positively correlated with stable temperaments. The sample consisted of 760 nursing students from four schools from the Portuguese polytechnic system of higher education. Data was collected by a self-report questionnaire, formed by several measures: socio-demographic data, the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A), validated into the Portuguese population (Akiskal & Akiskal, 2005a, Figueira et al., 2008), the Father/Mother Attachment Questionnaire - QVPM, Version IV (Matos & Costa, 2001a) and the Love Attachment Questionnaire - QVA, Version III (Matos & Costa, 2001b). The participants were mostly female (83.3%) with an average age of 21,3 years, mostly living with both parents, 81.7% had siblings and 60.3% had a dating relationship. The attachment patterns (secure, preoccupied, dismissing and fearful) were built from parental and love attachment data. From the five temperaments (depressive, hypertimic, cyclothymic, irritable and anxious, the dominant temperament for the entire study population is the depressive temperament. Only the irritable temperament showed not to be associated with gender. No associations were found between affective temperaments and parents with whom the respondents or cohabiting, brothers revealing the existence of only a cyclothymic temperament associated with the existence of a dating relationship. The results show significant associations between unstable temperaments and dismissing pattern of parental attachment (father and mother). In the relationship with the mother, depressive temperament (stable) and unstable temperaments (cyclothymic, irritable and anxious) proved to be dominant between the dismissing and hyperthymic (stable) among the preoccupied. In the relationship with the father, the depressive temperament (stable) and unstable temperaments (cyclothymic, irritable and anxious) proved to be dominant between the dismissing and hyperthymic (stable) between secure. Regarding to love attachment the results showed significant associations between both stable or unstable temperament and the preoccupied pattern suggesting an unclear association between temperament (from the point of view of its stability) and individuals with preoccupied pattern.

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HIV-1 inhibitor sifuvirtide presents increased affinity for cationic dipalmitoylethyl-phosphatidylcholine (EDPPC) in contrast to viral/raft-mimicking (VRM) membranes. When associated to sifuvirtide, EDPPC-containing vesicles fuse with VRM vesicles. After fusion, the peptide co-localizes on VRM vesicles, indicating an effective delivery and concentration of sifuvirtide towards the viral and lipid raft vicinity.

A nefrolitíase é uma doença comum nas sociedades desenvolvidas. Demonstrou-se a associação da litíase renal com algumas doenças metabólicas e cardiovasculares, tais como a hipertensão, a obesidade e a diabetes Mellitus. Demonstrou-se que os indivíduos com cálculos renais apresentam maior probabilidade de sofrer enfartes do miocárdio e acidentes vasculares cerebrais. A ligação da nefrolitíase e o risco cardiovascular não se encontra completamente esclarecida mas aceita-se que, em muitos indivíduos, a nefrolitíase seja uma manifestação clínica precoce de um ambiente adverso mais generalizado, o que aumentaria a prevalência de comorbilidades. Neste trabalho realizámos uma extensa revisão bibliográfica das diferentes hipóteses explicativas para a maior prevalência de doença cardiovascular nos doentes com litíase renal, com maior incidência nas alterações metabólicas que têm sido sugeridas para explicar a maior prevalência de hipertensão, tais como a obesidade e a síndrome metabólica, bem como as possíveis relações entre a hipertensão e alguns factores de risco para a nefrolitíase, como a hipercalciúria e hiperuricosúria. Estudámos uma hipótese inovadora na tentativa de explicar a associação de nefrolitíase com doença cardiovascular: a actividade do sistema nervoso autónomo, cuja influência no desenvolvimento da hipertensão e outras doenças cardiovasculares tem sido referida nos últimos anos. Descreveram-se manifestações de disfunção autonómica em várias comorbidades frequentemente observadas em doentes com cálculos renais. Efectuámos um conjunto de estudos originais para testar a hipótese de uma associação entre disfunção autonómica e nefrolitíase, incluindo um estudo clínico em doentes com nefrolitíase idiopática recorrente. Este teve um desenho caso-controlo e consistiu na realização dum conjunto de cinco provas autonómicas destinadas a avaliar a actividade autonómica eferente. Usaram-se métodos não invasivos baseados na análise da variabilidade da frequência cardíaca e da pressão arterial no domínio do tempo, com recurso a uma adaptação do protocolo de Ewing, e no domínio tempo frequência, com a transformada wavelets e a transformada de Hilbert-Huang. Este estudo documentou anomalias subtis da actividade autonómica em todos os doentes com nefrolitíase. A disfunção autonómica caracterizou-se por hiperactividade do ramo simpático do sistema nervoso autónomo em resposta a vários estímulos e por diminuição do cardioreflexo simpático em resposta ao teste de ortostatismo passivo. A hiperactividade simpática foi responsável por um aumento da pressão arterial na maioria dos pacientes com nefrolitíase. A análise dos resultados no domínio do tempo não demonstrou alterações significativas da actividade parassimpática mas as análises efectuadas no domínio tempo-frequência permitiram identificar alterações subtis no controle vagal da frequência cardíaca. Associámos a disfunção autonómica a algumas comorbilidades existentes no grupo de doentes, principalmente com a existência de antecedentes de hipertensão e obesidade. Além da obesidade, também associámos a diminuição do controle parassimpático da frequência cardíaca com o aumento da excreção urinária de ácido úrico, um dos principais factores de risco para a nefrolitíase recorrente. Não relacionámos a diminuição do cardioreflexo simpático em resposta ao ortostatismo com qualquer factor independente. No nosso estudo, verificámos que os ratos Zucker obesos não desenvolveram espontaneamente cálculos renais pelo que modelo animal de obesidade não foi utilizado nas restantes experiências. Realizámos três estudos em animais com base no modelo experimental de litíase renal induzida em ratos por tratamento com calcitriol e etileno glicol. Num destes, encontrámos um menor controlo simpático da frequência cardíaca e uma grande diminuição do baroreflexo nos ratos com nefrolitíase comparativamente com os ratos do grupo de controlo. Noutro estudo, encontrámos um aumento significativo na actividade basal do nervo renal nos ratos com nefrolitíase quando comparados com ratos do grupo de controlo. Neste estudo, a obstrução urinária subaguda, obtida por 20 minutos de bloqueio do ureter, provocou uma diminuição significativa da actividade do nervo renal ipsilateral no grupo de ratos com nefrolitíase. Consideramos que a demonstração do aumento da actividade nervosa basal nos ratos com nefrolitíase seria um argumento favorável à hipótese de envolvimento da disfunção autonómica. Os resultados sugeriram que o aumento da actividade no nervo renal nos ratos com nefrolitíase não seria totalmente explicado pela obstrução provocada pelos cálculos renais. Efectuámos um conjunto de experiências com um modelo de desenervação renal unilateral em ratos com nefrolitíase induzida por calcitriol e etileno glicol. Neste modelo, seccionámos as fibras nervosas que enervam o rim esquerdo e mantivemos íntegra a enervação do rim contralateral que foi utilizado como controlo. Os ratos recuperaram completamente da cirurgia de desenervação antes de iniciar o tratamento com medicamentos litogénicos. Após quatro semanas de tratamento, os animais foram sacrificados e os rins analisados com o objectivo de comparar as lesões histológicas nos rins desnervados e nos rins de controlo. Este estudo não demonstrou o efeito da desenervação renal na litogénese ou nas lesões renais associadas à presença de cálculos renais. Descrevemos neste trabalho os aspectos histológicos dos rins enervados e desenervados. Apesar das limitações inerentes à extrapolação dos resultados de estudos em animais para a nefrolitíase humana, os nossos resultados confirmam uma disfunção autonómica no modelo do rato de nefrolitíase e representam os primeiros estudos da função autonómica em modelos animais de nefrolitíase experimental.

DIAS .POR. AQUI is the title of a contemporary art exhibition project presenting the artists Francisco Vidal, Kiluanje Liberdade, Marco Kabenda and Carlos Bunga. These are artists of African origin (specifically, from portuguese speaking countries) who live, or have lived diasporic situations/experiences. DIAS.POR.AQUI is based on reflections on postcolonial theories, the history of the relations between Portugal and the portuguese speaking african countries, the relations between the occident and the african art and contemporary african art, and the relations between the portuguese contemporary art world and contemporary african art. The special focus that is given in this work to the presence of contemporary african art in Portugal, resulted in an appendix chapter, where some exhibitions, artists, galleries and projects that took or are taking place in Portugal are presented and analysed. The reflection made about this issues, that contextualizes some of the problematics associated with the african art and culture in the occident, in Portugal and in África, gives place to the presentation of an exhibition project. The exhibition's goal is to promote interpretations and better understanding of african diaspora, to challenge the present definitions of contemporary art, to problematize questions só diverse as the postcolonial view of the portuguese and the portuguese speaking african realities, or the way contemporary art relates itself with social and political criticism. The second half of this thesis consists of the presentation of the concept of the exhibition, of the participating artists and of the art works that will be displayed. An installation proposal is also presented, where the relationships between the art works and the concept of the exhibition are analysed

The following dissertation analyses the concept of postmodernism and its mainly perspectives, rather reporting its relation with others segments of art. It tries to understand the meaning, the ranging and the operationally of postmodernism, at the same time that approaches it of the historical, philosophical and artistic framework. In fact, this research observes the importance of the exposition Alternativa Zero (1977), the first great moment of the post-modern art in Portugal, and establishes the linkage between the postmodernism principles and how portuguese artists absolved it