Dissertations / Theses: 'IRDP' – Grafiati (2024)

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Vários estudos apontam alarmantes números referentes à prevalência dos distúrbios do desenvolvimento e dos transtornos mentais na infância e na adolescência na maioria dos países em desenvolvimento, incluindo o autismo. Os estudos mais recentes apresentam uma tendência de encontrar sinais no comportamento do bebê que pudessem evidenciar o curso de um autismo. O objetivo é pensar em intervenções em sinais iniciais de problemas de desenvolvimento visando um melhor desenvolvimento do tratamento, o que ganha força a partir dos expressivos resultados encontrados nessas intervenções. Com isso, cria-se a necessidade de utilização de instrumentos de diagnóstico, avaliação e identificação precoce como ponto inicial para um prognóstico diferenciado. O IRDI apresenta-se como um instrumento que pode ser utilizado com esse objetivo, inclusive na saúde pública, ou seja, atingindo grande escala populacional. Assim, objetiva-se, com esta pesquisa, verificar se há diferença estatisticamente significativa entre crianças com desenvolvimento típico e autistas no que tange aos indicadores e aos eixos estabelecidos pelo IRDI. A amostra do estudo foi composta por 112 crianças de 2,9 anos a 7,6 anos, sendo 36 com autismo e 76 com desenvolvimento típico. Realizamos uma análise estatística dos dados comparando o grupo-controle (crianças com desenvolvimento típico) com o grupo caso (crianças com autismo) para verificar as diferenças entre cada um dos 31 indicadores do IRDI, assim como seus quatro eixos, quais sejam, alternância presença/ausência, suposição do sujeito, estabelecimento de demanda e função paterna. Tendo analisado os dados encontrados dos indicadores do IRDI demonstramos a significância estatística a partir da qual podemos distinguir claramente crianças com autismo das com desenvolvimento típico, posteriormente fizemos a mesma análise a partir dos eixos, na qual também pudemos fazer tal distinção. Concluímos, assim, que a associação estatisticamente significativa entre os eixos do IRDI e a condição autística da criança permite avançar na compreensão da natureza da experiência psíquica da criança com seus pais. Essa é uma contribuição importante no que tange a orientação clínica de crianças com grave sofrimento psíquico que podem estar num percurso autístico, direcionando a uma prática e uma escuta diferenciadas que possibilitem intervenções oportunas antes da instalação de formas mais graves dos quadros vividos
Several studies indicate alarming figures on the prevalence of developmental and mental disorders in childhood and adolescence in most developing countries, including autism. The most recent studies have a tendency to find signs in the baby\'s behavior that could show the course of an autism. The aim of this dissertation is to think of interventions in early signs of developmental problems seeking a better development of the treatment, which is strengthened from the impressive results found in these interventions. This has created the need for the use of diagnostic, evaluation and early identification tools as a starting point for a differential prognosis. The IRDI is presented as a tool that can be used for this purpose, including for public health, i.e., reaching a large population scale. Thus, our objective with this research is to check for statistically significant differences between children with autism and with typical development regarding the indicators and axes established by IRDI. The study sample consisted of 112 children from 2.9 years to 7.6 years, 36 of them with autism and 76 with typical development. We conducted a statistical analysis comparing the control group (typically developing children) with the case group (children with autism) to check the differences between each of the 31 IRDI indicators, as well as its four pillars, namely, presence/absence alternating, subject\'s assumption, establishing of demand and paternal function. Having analysed the data obtained from IRDI indicators, we demonstrate statistical significance from which we can clearly distinguish children with autism from typically developing children, thereafter similar analysis were carried out using the axis, on which we could also make this distinction. We conclude that the statistically significant association between the axes of the IRDI and the child\'s autistic condition allow us to understand the nature of the psychic experience of the child with his parents. This is an important contribution with respect to clinical guidance of children with severe psychological distress that may be on an autistic route, directing a practical and differential listening to enable timely interventions before the installation of more severe forms of experienced scenarios

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The need for alternative cognitive enhancers has risen due to the fact that clinical trial results of the drugs currently approved for treating these disorders have not been satisfactory. IRAP has become a possible drug target for treating cognitive impairment brought about by Alzheimer’s disease, head trauma or cerebral ischemia, among others. This came after the revelation that Angiotensin IV enhances memory and learning. Angiotensin IV, the endogenous ligand of IRAP has been structurally modified with the aim of producing potent IRAP inhibitors. However, the peptidic nature of these inhibitors restricts their use; they are not likely to cross the blood brain barrier. Other strategies for generating IRAP inhibitors have been through structure-based design and receptor based virtual screening. These drug-like molecules have exhibited positive results in animal studies. IRAP inhibitors have been identified via a HTS of 10500 low-molecular weight compounds to give the hit based on a spirooxindole dihydroquinazolinone scaffold, with an IC50 value of 1.5 µM. In this project, some analogues to this hit compound have successfully been synthesized using a known method, whereas others have been synthesized after additional method development. The application of the developed method was found to be limited, because poor yield was obtained when a compound with an electron withdrawing substituent on the aniline was synthesized. As a result of this, modification of this method may be required or new methods may have to be developed to synthesize these types of analogues. Inhibition capability of 5 new spirooxindole dihydroquinazolinones was tested through a biochemical assay. Compound 6e emerged as the most potent inhibitor in the series, with an IC50 value of 0.2 µM. This compound will now serve as a lead compound and should be used as a starting point for future optimization in order to generate more potent IRAP inhibitors.

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Par leur activité permanente à l’état basal et en situation infectieuse, les cellules dendritiques (DC) de l’organisme orchestrent la tolérance du soi et l’élimination du non-soi, en façonnant les réponses immunes. Ce rôle immunologique complexe des DC repose en grande partie sur des mécanismes de biologie cellulaire spécifiques, qui font l’objet d’un effort considérable de caractérisation. Le travail réalisé au cours de cette thèse met en lumière une sous-population endosomale jouant un rôle clé dans les processus cellulaires de modulation de l’immunité par les DC : les endosomes IRAP+ (insulin responsive aminopeptidase). Etudiée dans différents contextes biologiques depuis 1930, IRAP s’est récemment révélée être impliquée dans l’apprêtement endo-phagosomal des antigènes exogènes par les DC, en vue de leur présentation croisée aux lymphocytes T (Saveanu et al., 2009; Weimershaus et al., 2012). Cette découverte a attiré notre attention sur les endosomes IRAP+/RAB14+ peu étudiés dans les DC. Ce travail étudie la place des endosomes IRAP dans la biologie cellulaire des DC ainsi que le rôle de ces endosomes dans les fonctions biologiques des DC. Nous avons étudié l’influence des endosomes IRAP sur les autres compartiments cellulaires et démontré leur implication dans un système endolysosomal de régulation de la réponse inflammatoire aux pathogènes. Nous avons également étudié l’impact de IRAP sur les processus de maturation des phagosomes et montré leur influence sur les processus subséquent d’élimination des pathogènes et de présentation croisée. Les endosomes IRAP+ sont donc mis en jeu dans la modulation de la maturation phagosomale et de l’inflammation, mais également dans l’optimisation de la présentation des antigènes aux lymphocytes T ; trois processus qui reposent sur une régulation fine de la compartimentation intracellulaire. L’ensemble des résultats de cette thèse définit les endosomes IRAP+ comme un des acteurs majeurs de la « régulation compartimentée » des processus cellulaires des DC, au cœur de la machinerie qui régit les équilibres de l’immunité
Dendritic cells (DC) are central in immune system. They are permanently active in the organism at steady state and during infection, where they orchestrate tolerance against self and immunity against non-self, such a complex immunological role relies on specific cell biology mechanisms. These mechanisms are currently extensively studied. This work sheds light on a new endosomal compartment playing a crucial role in immunity modulation: IRAP (insulin responsive aminopeptidase)-containing endosomes. Studied in various contexts since 1930, IRAP was recently revealed to be required for exogenous antigen processing in endophagosomal compartment of DC and subsequent cell surface presentation to T lymphocytes (Saveanu et al., 2009; Weimershaus et al., 2012). This discovery prompted us to study IRAP+ endosomes that are poorly described in DC. This work studies IRAP-containing endosomes in DC compartments and questions their specific contribution in DC biological functions. We therefore investigated IRAP-containing endosomes relationship to other cellular compartments and demonstrated their requirement in an endolysosomal regulation system controlling pathogen related inflammation. We also studied the implication of IRAP-containing endosomes on phagosomes maturation and showed their influence on pathogen killing and cross presentation. IRAP-containing endosomes are required for several cellular functions that all rely on cellular compartmentalization. This work proposes IRAP-containing endosomes as a major actor of a “compartmental regulation” of DC functions, participating to fine tuning of immune balance

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The current study tested the utility of the Implicit Relational Assessment Procedure (IRAP) as an analogue cognitive defusion intervention to alter implicit attitudes toward Abraham Lincoln and Adolf Hitler. One-hundred and twelve participants were randomly assigned to either a control or defusion condition. Participants first completed a series of self-report measures assessing psychological functioning and distress, as well as attitudes toward Lincoln and Hitler. Control condition participants then completed three IRAPs measuring implicit attitudes toward Hitler and Lincoln (H/L IRAP). Defusion conditions participants completed a pre-intervention H/L IRAP, received a rationale for defusion before completing a defusion IRAP, and then completed a post-intervention H/L IRAP. All participants finished the study by completing a second set of self-report measures. Results of the study indicated that when taking into account participant knowledge of defusion there were significant differences in IRAP performance post-intervention between conditions, although there were no significant differences in performance pre- to post-intervention within the defusion condition. Additionally, there were no differences between conditions on self-report measures at either time point, suggesting the IRAP was sensitive to changes in participant attitudes that self-reports were unable to detect. Thus, the results of this study indicate that the IRAP is a viable analogue defusion intervention, and future research should look to expand the defusion effect produced by the IRAP.

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The current study tested the effects of a cognitive defusion intervention on implicit attitudes toward milk and lemon as measured by the Implicit Relational Assessment Procedure (IRAP). One-hundred and eleven participants were randomly assigned to one of four conditions: control math, control defusion, half defusion, or full defusion. Participants filled out a series of self-report measures at the beginning of the study on psychological functioning, as well as attitudes toward milk and lemon. Participants then completed a task specific to their condition, with control math participants completing a simple math task while defusion conditions completed a defusion intervention – word repetition technique (WRT) – for certain words. The control defusion condition completed the WRT for the words “car” and “rabbit,” the half defusion condition completed the WRT for the word “milk,” and the full defusion condition completed the WRT for the words “milk” and “lemon.” After completing the condition specific tasks, all participants completed a milk/lemon IRAP that included the words “milk” and “lemon” and pictures of milk and lemon. All participants finished the study by completing a final set of self-report measures. Results of the study indicated that IRAP performance was not significantly different between conditions following various levels of a defusion intervention. However, results showed that the pattern of IRAP response latencies did significantly vary between conditions, but this effect was driven by a significant difference on a single response latency between two conditions suggesting this finding is an artifact. Thus, the current study cannot conclude that a defusion intervention can significantly affect implicit attitudes towards common objects, and any future research should consider applying a defusion intervention to clinically relevant stimuli to further assess for defusion effects in the IRAP.

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Les iron regulatory proteins controlent l'homeostasie du fer en modulant l'expression de la ferritine et du recepteur de la transferrine. Cette regulation s'effectue par une interaction des irps avec un ou (plusieurs) element(s) de reponse au fer nomme(s) ire (iron responsive element) localise(s) dans les regions non traduites en 5' de l'arnm de la ferritine et en 3' de l'arnm du recepteur de la transferrine. L'interaction irp/ire en 5' bloque la traduction alors que celle en 3' stabilise l'arnm. En plus de son activite trans-regulatrice, l'irp-1 presente une activite aconitase dans le cytosol convertissant le citrate en isocitrate. Ces deux activites s'excluent mutuellement par un changement conformationnel de la proteine due a la presence ou non d'un centre 4fe-4s. Ce dernier est present au site actif de l'irp-1 lorsqu'elle se trouve sous la forme aconitase. Les modulateurs des activites de l'irp-1 sont la concentration de fer intracellulaire et l'activite no synthase. Nous avons en premier lieu, approfondi la nature de la (ou des) espece(s) oxydante(s) capable(s) de convertir l'irp-1 de sa forme aconitase vers sa forme trans-regulatrice. Nous avons montre que ni le peroxynitrite (onoo), ni les especes reactives oxygenees etaient capables de convertir l'irp-1 vers la forme trans-regulatrices bien qu'ils inhibent l'activite aconitase. Seul le no permet la conversion rapide de l'irp-1 en ciblant son centre fe-s. Afin d'expliquer l'effet curieusem*nt discret du onoo, nous avons precise son mecanisme d'action in vitro. Ce dernier altere le centre fe-s de l'irp-1 jusqu'a sa destruction totale. A forte dose, son effet oxydant se prolonge en etablissant des ponts disulfure avec la cysteine 437 et d'autres cysteines proches du site actif formant ainsi une apo-irp-1 oxydee sans activite. Un environnement faiblement reducteur rend cette nouvelle forme d'irp-1 capable de lier les sequences ires. La seconde irp (irp-2) est denuee de centre fe-s et presente une activite trans-regulatrice constitutive qui est inhibee en presence de onoo et restauree par un agent reducteur. Nous avons egalement montre que son activite pouvait etre inhibee independemment du no dans les macrophages stimules avec l'ifn-.

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To generate a spontaneous EAU model, transgenic mice expressing membrane-bound hen egg lysozyme (HEL) under control of the IRBP promoter were generated. The mice expressed HEL in the photoreceptors, and in the thymus as measured by immunofluorescent confocal microscopy and real-time RT-PCR, respectively. When crossed with the 3A9 TCR-transgenic mice whose CD4+ T cells are HEL-specific, double-transgenic mice developed spontaneous EAU with 100% incidence and an onset age of 22 days post-partum. The ocular inflammation was multifocal and affected the posterior segment of the eye, and led to complete retinal destruction over 5-8 weeks. The lesions comprised multiple retinal granulomas, vasculitis, perivasculitis, mild vitritis and infiltration at the limbus (junction between cornea and sclera). The retina contained numerous CD4+T cells, which made contact with perivascular MHC II+CD11c+ dendritic cells, whilst F4/80 + macrophages were found within the photoreceptor cell layer, implicating them in structural damage. Therefore, the features of spontaneous EAU resembled those of IRBP-induced EAU. One difference, however, was that there were many CD3+CD4-gammadelta-like T cell cells in the inflamed retina, which were also the earliest T cells to enter the eye at EAU onset. CD4SP thymocytes were severely deleted in the double-tg mice, leading to peripheral CD4+ T cell deficiency at EAU onset, which bestowed a CD44hi pseudomemory phenotype on clonotype low CD4+T cells, and may have enabled breakdown of tolerance. The early activation marker CD69 was not upregulated on CD4+ T cells in any of the secondary lymphoid tissues studied, suggesting that HEL presentation may have been exclusive to the eye. The IRBP-HEL mice also constitute a new EAU model system in which self-tolerance and the efficacy of therapeutics can be studied.

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O presente estudo se propôs a explorar o uso de um teste de preconceito implícito (IRAP) e de uma medida de grupo (entrevista sociométrica) para a investigação do preconceito étnico em crianças em contexto escolar. Foram investigados possíveis efeitos de duas intervenções para redução de preconceito que enfatizam características de práticas culturais comuns: descrever contingências de reforçamento envolvendo respostas de tolerância e descrever respostas de punição envolvendo respostas de intolerância. Os participantes foram 65 crianças brasileiras e bolivianas de três turmas do último ano do ensino fundamental, faixa etária entre 10 e 11 anos, e três professoras das turmas correspondentes. A porcentagem de crianças bolivianas nos grupos Controle, Intervenção A e Intervenção B foram, respectivamente, 47,1%, 34,8% e 44%. Foram aplicados o IRAP e a entrevista sociométrica antes e depois das intervenções. Nos resultados, não foram observados efeitos das intervenções, detectáveis com um intervalo de confiança de 95%, nem no IRAP e nem nos dados derivados da entrevista sociométrica. A entrevista sociométrica se mostrou útil para investigar preconceito étnico nas turmas a partir de uma análise das proporções real e esperada de nomeações de aceitação e rejeição de acordo com a nacionalidade, mas não a partir das categorias de status sociométrico. Esse resultado é provavelmente devido à alta porcentagem de estrangeiros nas turmas, equilibrando as nomeações. Uma grande porcentagem dos participantes não conseguiu atingir o critério de porcentagem de acerto (80%) do IRAP nos blocos de prática e outros não conseguiram manter esse critério durante o teste, sugerindo que o critério de 70% empregado em outros estudos do IRAP com crianças é mais adequado. O principal resultado deste estudo demonstrou um índice de preconceito nas salas que já era de conhecimento de algumas das professoras, ainda que não de todas. No entanto, a investigação e quantificação de fenômenos conhecidos é o que permite avaliar os efeitos de intervenções sobre eles, facilitando a realização de novas pesquisas que poderão embasar no futuro práticas e políticas públicas mais eficazes
Prejudice research is an active field in psychology which fosters many studies on interventions aimed at prejudice reduction. Data collected in these studies are usually individual measures, such as questionnaires and implicit prejudice tests. Data is usually collected in laboratories or other non-realistic settings. The present study explored the combination of an individual implicit prejudice measure (IRAP) with a social measure (sociometric interview) to investigate ethnic prejudice in children at school. The effects of two prejudice reduction interventions were investigated, both of which replicate characteristics of common practices: describing reinforcement contingencies of tolerance responses and describing punishment contingencies of intolerance/prejudice responses. Participants were 65 brazilian and bolivian children aged 10 to 11 years old, and their teachers. Control Group, Intervention A Group and Intervention B Group had, respectively, 47,1%, 34,8% and 44% bolivian students. IRAP and the sociometric interview were applied before and after the interventions. No effects of the interventions were observed in either individual or social measures. The sociometric interview proved to be useful to investigate prejudice among the students when expected and actual sociometric nominations ratios were compared, but not when sociometric statuses were compared. This is so probably due to the high percentage of bolivians in the groups, as they balance out the nominations. More than half of the participants were not able to fulfill the practice criterion of accuracy (80%) of the IRAP; others were not able to maintain this criterion across the test blocks. This suggests the 70% accuracy criterion to be best suitable for children. The main result here presented regards the assessment of the amount of prejudice and segregation amongst students, which was already known to some of the teachers. However, quantifying known phenomenons allows the evaluation of the effects interventions have on them, making it possible to further research on the topic and to develop better practices and public policies

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Insulin regulated aminopeptidase (IRAP) was first identified in fat and muscle cells where it is believed to regulate GLUT4 translocation. It has since been found to be behind a variety of functions, many not yet fully understood. Preliminary research from Monash University suggested that IRAP may play a role in cellular senescence. Senescence is a term that describes arrested cell division and is a tumor repressive mechanism. Senescent cells have been shown to secrete, among other things, the growth hormone TGFβ1, which in turn plays an important role in the cell differentiation of fibroblasts to myofibroblasts. The potential link between IRAP and senescence was the basis of this work. Senescent fibroblasts from three different passages (n=3) in the BJ3 cell-line were cultured and treated with different IRAP inhibitors; ANG-4, AL06 and HFI-419 which were all compared to an untreated control group. They were marked with a β-galactosidase stain, a senescent cellmarker, and imaged. The study demonstrated that the IRAP inhibitors led to a certain decrease in % of senescent cells compared to the control groups. However, this reduction was not considered statistically significant. Similarly, inhibition of the enzyme did not indicate any influence over the differentiation of the cells. The lack of effect could be due to chance based on the low number of sample size, or the condition of the cells used in the trial as they were partially immortalized BJ fibroblasts well beyond the passage of their intended use. In order to further demonstrate an association between IRAP and senescence, further trials are required.
Insulin reglerad aminopeptidas (IRAP) introducerades till en början som ett markörprotein. Man har sedan dess funnit att den står bakom en rad olika funktioner, många ännu inte fullt klarlagda. Preliminär forskning från laboratoriet i Monash University tydde på att IRAP kan ha en koppling till senescerande fibroblaster. Senescence är en term som beskriver upphörd celldelning och är en tumörrepressiv mekanism. Senescerande celler har påvisats utsekrera bland annat tillväxthormonet TGFβ1, som i sin tur spelar en viktig roll i celldifferentieringenav fibroblaster till myofibroblaster. Den potentiella kopplingen mellan IRAP och senescence låg som grund till detta arbete. Senescerande fibroblaster från tre olika kulturer (n=3) i BJ3-cellinjen odlades och behandlades med olika IRAP-inhibitorer; ANG-4, AL06 och HFI-419 som alla jämfördes med en kontrollgrupp. Därefter markerades de med en β-galaktosidas-markör, en markör för senescerande celler, och mikroskoperades. Studien påvisade att IRAP-inhibitorerna ledde till en viss procentuell minskning av senescerande celler jämfört med kontrollgrupperna. Dock bedömdes inte denna minskning som statistiskt signifikant i studien. Likväl fann man ingen procentuell minskning av differentierade fibroblaster. Hypotetiskt sett skulle man vilja se att reduktionen av senescerande celler motsvarade en nedreglering av TGFβ1-proteiner. Eftersom närvaron av TGFβ1 tros spela en ledande roll i celldifferentiering till myofibroblastfenotypen, bör den procentuella mängden differentierade cellerna minska med inhibitorbehandlingarna. Den bristande påverkan av enzyminhibitionen kan bero på en rad olika faktorer. Cellerna som användes under försökets gång var väl bortom deras brukliga användningscykel. För att vidare påvisa ett potentiellt samband mellan IRAP och senescence behöver vidare försök utföras.

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A doença articular, especificamente a osteoartrite é uma das enfermidades mais prevalentes e mais debilitantes que acomete os cavalos, tendo um grande impacto econômico na indústria eqüina. Assim sendo, a investigação contínua e avanços na área terapêutica são de fundamental importância. A osteoartrite é uma doença degenerativa que pode ser deflagrada por uma série de fatores e onde, ultimamente, todos os tecidos articulares encontram-se comprometidos. Não obstante, é na degradação da matriz extracelular da cartilagem articular que ocorrem os eventos de maior expressão e repercussão. Na gênese da degradação da matriz extracelular encontra-se um desequilíbrio entre os processos anabólicos e catabólicos responsáveis pela homeostase normal da cartilagem articular e pela adaptação deste tecido às forças que sobre ele incidem. Estes processos são orquestrados por proteínas anabólicas, como, por exemplo o fator de crescimento tipo insulina 1 (IGF-l), e por citocinas inflamatórias que, de forma contrária, são responsáveis pela depleção de colágeno e de proteoglicanas da matriz, representando o grupo de proteínas catabólicas, cujo exemplo clássico é a interleucina-1. A interleucina-1 tem papel central nos processos fisiopatológicos da osteoartrite por desencadear vários eventos catabólicos nos sinoviócitos e condrócitos, incluindo a indução de gens de metaloproteinases e agrecanases e de outros mediadores inflamatórios como a cicloxigenase, a prostaglandina E2 e as espécies reativas do oxigênio. Seus efeitos biológicos se verificam após a ligação com dois tipos de receptores específicos e são modulados pela ocorrência natural de uma proteína antagonista destes receptores. O presente estudo procurou observar os efeitos antiinflamatórios desta proteína antagonista do receptor (IRAP) no líquido sinovial de equino através do emprego da técnica de citometria de fluxo. Nos ensaios observou-se que: 1-a adição de IRAP às células de líquido sinovial estimuladas in vitro por LPS e PMA reduziu a liberação de espécies reativas de oxigênio produzidas por elas; 2 - o plasma, quando utilizado como controle, exibiu efeitos semelhantes aos do IRAP sobre as células de líquido sinovial ativadas in vitro; 3- o efeito antiinflamatório deve-se mais à variação na intensidade de produção de espécies reativas do oxigênio do que à flutuação no percentil de células do líquido sinovial engajadas em sua geração, in vitro. Estes resultados suportam a aplicabilidade terapêutica do IRAP® pelo efeito antiinflamatório verificado sobre as células do liquido sinovial avaliadas por citometria de fluxo. Eles corroboram, ainda, para o uso da citometria de fluxo como instrumento eficaz na avaliação da produção de espécies reativas de oxigênio por células do líquido sinovial ativadas pelos estímulos de LPS e PMA, tanto quantitativamente como qualitativamente.
Joint disease in horses, specifically osteoarthritis, is one of the most prevalent and debilitating illnesses affecting equine industry and for this reason continued research and improvements in therapeutics are needed. Osteoarthritis is a degenerative disease that can be triggered by a number of factors and where ultimately all articular tissues are affected. The hallmark of osteoarthritis is the degeneration of the articular cartilage matrix, where the most relevant and expressive events take place. In the development of osteoarthritis there is disruption in extracellular matrix homeostasis with an overall balance toward cartilage metabolism. Homeostasis of the articular environment relies on balance between anabolic and catabolic events and results in ability of cartilage to respond to molecular or mechanical cues. This apparently antagonic processes are orquestrated by soluble protein mediators, for example the anabolic insulin-like growth factor-I (IGF-I), and, on the other side, by inflammatory cytokines, which in turn, are implicated in degradative processes of articular cartilage, characteristic of osteoarthritis. They deplete cartilage matrix from collagen and proteoglycans and the classical example of such a cytokine is interleukin-1. Interleukin-1 has a central role in the physiopathologic processes of osteoarthritis and has been implicated in the genesis of a number of catabolic events when acting on chondrocytes and synoviocytes. Examples are gene induction for metalloproteinases and agrecanases production, as well as production of other inflammatory mediators like ciclooxygenase, prostaglandin E2 and oxygen-derived reactive species. Its biological effects are observed after interaction with two different but specific types of receptors and are modulated by the occurrence of a natural antagonist, the interleukin-1 receptor antagonist protein (IRAP). In the present study the anti-inflammatory effects of this antagonist protein were evaluated in synovial fluid using cytometric flow techniques. It was observed that: 1- addition of IRAP to synovial fluid cells stimulated in vitro by LPS and PMA reduced the production of oxygen-derived reactive species; 2- plasma, used as a control, exhibited similar effects on activated synovial cells when compared to IRAP in vitro 3- the anti-inflammatory effect is due, in its majority, to the variation in intensity of oxygen-derived reactive species, more than on fluctuations on the percentage of synovial fluid cells actively engaged in its generation in vitro. These results support the therapeutic aplicability of IRAP® for its anti-inflammatory effect observed on synovial fluid cells evaluated with flow cytometric techniques. They also corroborate to the usefulness of cytometric flow techniques in equine synovial fluid cells; they are an invaluable tool to evaluate quantitative and qualitatively the production of oxygen-derived reactive species mediated by their activation with PMA and LPS.

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Devido à ausência de estudo de caracterização da variabilidade genética das populações de Pseudocercospora fijiensis recentemente introduzidas no Brasil, o objetivo desse trabalho foi avaliar a adequabilidade do marcador IRAP para estudar variações genéticas entre indivíduos, bem como determinar a estrutura genética da população brasileira de P. fijiensis com base no fingerprinting gerado por amplificação de polimorfismo entre retrotransposons (IRAP). Um total de 22 locos foi amplificado, sendo 77.3 % polimórficos. A análise de agrupamento revelou dois principais grupos no Brasil. A diversidade gênica (HE) foi de 0.22 e pela análise de variância molecular verificou-se que a maior variabilidade genética está dentro das populações. A Análise Discriminante de Componente Principal (DAPC) revelou que não há nenhuma estruturação relacionada com as origens geográficas e cultiva hospedeiro. O sistema de marcador baseado em retrotransposon IRAP é ferramenta apropriada para estudar a variabilidade genética em P. fijiensis.
Due to the lack of characterization study of genetic variability in populations of Pseudocercospora fijiensis recently introduced in Brazil, the objective of this study was to evaluate the suitability of IRAP marker for studying genetic variations between individuals, and to determine the genetic structure of the population of P. fijiensis based on fingerprinting generated by inter-retrotransposons amplified polymorphism (IRAP). A total of 22 loci were amplified and 77.3% showed a polymorphism. Cluster analysis revealed two major groups in Brazil. The observed genetic diversity (HE) was 0.22, and through molecular analysis of variance, it was determined that the greatest genetic variability occurs within populations. The Discriminant Analysis of Principal Components (DAPC) revealed no structuring related to the geographical origin of culture of the host. The IRAP-based marker system is a suitable tool for the study of genetic variability in P. fijiensis.

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The current study examined the utility of an idiographic configuration of the Implicit Relational Assessment Procedure (IRAP) as a measure of psychological flexibility. Psychological flexibility is the overarching outcome variable of Acceptance and Commitment Therapy (ACT) and may be defined as the ability to make full contact with the present moment and persist in behavior that serves valued ends (Hayes, 2004). One hundred six participants first completed questionnaires assessing individual valued activities and distressing private events. These data were utilized to populate the IRAP. Depending on the administration order, the subjects either continued with the IRAP or with a series of self-report measures evaluating psychological functioning and ACT processes. Results indicated that IRAP scores modestly correlated with some self-reports of psychological flexibility and were also able to significantly predict symptomology. However, the study revealed inadequate internal consistency of the IRAP, which constitutes a limitation to the validity of the measure. This study represents one step in a long line of research examining a variety of procedural and contextual variables influencing the reliability of the IRAP, offering preliminary support for the utility of an idiographic IRAP as an implicit measure of psychological flexibility. Future additions to IRAP research similar to the current study will continue to enhance the field’s understanding of implicit cognitions and the effectiveness of the IRAP in psychological research.

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Computational methods have become an integral part of drug development and can help bring new and better drugs to the market faster. The process of predicting the biological activity of large compound collections is known as virtual screening, and has been instrumental in the development of several drugs today in the market. Computational methods can also be used to elucidate the energies associated with chemical reactivity and predict how to improve a synthetic protocol. These two applications of computational medicinal chemistry is the focus of this thesis. In the first part of this work, quantum mechanics has been used to probe the energy surface of palladium(II)-catalyzed decarboxylative reactions in order to gain a better understating of these systems (paper I-III). These studies have mapped the reaction pathways and been able to make accurate predictions that were verified experimentally. The other focus of this work has been to develop virtual screening methodology. Our first study in the area (paper IV) investigated if the results from several virtual screening methods could be combined using data fusion techniques in order to get a more consistent result and better performance. The study showed that the results obtained from data fusion were more consistent than the results from any single method. The data fusion methods also for several target had a better performance than any of the included single methods. Next, we developed a dataset suitable for evaluating the performance of virtual screening methods when applied to large compound collection as a replacement or complement for high throughput screening (paper V). This is the first benchmark dataset of its kind. Finally, a method for using computationally derived reaction coordinates as basis for virtual screening was developed. The aim was to find inhibitors that resemble key steps in the mechanism (paper VI). This initial proof of concept study managed to locate several known and one previously not reported reaction mimetics against insulin regulated amino peptidase.

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Le ruissellement pluvial est à l’origine de phénomènes violents tels que des inondations, de l’érosion ou des coulées de boue. Les voies ferrées interceptent les écoulements de surface, ce qui peut engendrer une dégradation précoce de l’infrastructure ou la destruction d’éléments, tels que la plateforme ou les talus. La méthode IRIP, « Indicateur de Ruissellement Intense Pluviale », permet de représenter le ruissellement en trois cartes, la production, le transfert et l’accumulation. La méthode IRIP se veut simple et robuste, pour un usage sur tous types de territoires et sans calage. Comme tout modèle de ruissellement, l’évaluation de la méthode IRIP se heurte au manque de données. Pourtant, l’évaluation est une étape cruciale dans le développement de modèles. Pour un usage opérationnel ou pour poursuivre les développements, il est nécessaire d’estimer la valeur et la fiabilité des informations produites. L’objectif de la thèse est donc de proposer une méthode d’évaluation de la méthode IRIP par comparaison à des données d’impacts sur les voies ferrées. La difficulté réside dans la différence de fond et de forme des données à comparer et dans la nécessité de prendre en compte la vulnérabilité de l’infrastructure. La méthode d’évaluation proposée est basée sur le calcul de tableaux de contingence et d’indicateurs de performance, couplé à des analyses détaillées d’incidents. Après une estimation de la performance de la méthode IRIP, des développements sont testés et évalués grâce à la méthode d’évaluation élaborée. La lisibilité des cartes est finalement améliorée, tout en gardant de bons scores de performance. En appliquant la méthode IRIP à des contextes opérationnels, il est montré en quoi IRIP peut être considéré comme un outil d’aide à l’expertise. Différentes tâches du processus de gestion des risques sont testées, telles que les diagnostics de risques sur les voies ferrées, les retours d’expérience post-évènement ou encore la réalisation de zonage règlementaire. De manière générale, cette thèse contribue à l’amélioration des connaissances sur le phénomène du ruissellement et propose des méthodes pour améliorer la gestion des risques liés au ruissellement
Surface runoff is the source of severe hazards such as floods, erosion or mudflows. Railways can disturb natural surface water flow path, which can generate accelerated deterioration of the infrastructure, or the destruction of railway elements, such as the roadbed or the embankments. The IRIP method ‘Indicator of Intense Pluvial Runoff’ (French acronym) allows mapping surface runoff through three maps, generation, transfer and accumulation. The IRIP method aims to be simple and reliable, in order to be used on all types of lands, without calibration stage. As for others surface runoff models, the IRIP method evaluation faces the lack of data. However, evaluation is a crucial stage for the development of models. In the perspective of an operational use, or simply for the model development, it is essential to estimate the value and the reliability of the model outputs. The thesis objective is to provide an evaluation method using surface runoff impacts on railways. Difficulties lie in the fact that data to be compared differ in terms of form and content. Moreover, the infrastructure vulnerability must be characterized. The proposed evaluation method is based on the computation of contingency tables and of verification indicators, together with detailed analysis of specific impacts. After an estimation of the IRIP method performance, further developments can be tested and evaluated thanks to the proposed evaluation method. Finally, maps comprehensibility is enhanced, while preserving satisfying performance scores. By applying the IRIP method to operational contexts, it has been shown how the IRIP method can be used as a tool in expert appraisals. Different tasks of the risk management process have been studied such as risk analysis on railways, post-event investigation or the realisation of regulatory zonings. More generally, this thesis contributes to improve knowledge about surface runoff and provide methods for improving the risk management

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Introducción: La infección del tracto urinario (ITU) es una infección bacteriana frecuente en niños, del 50% al 75% de los casos de ITU febril desarrollan pielonefritis. La pielonefritis es un factor de riesgo de lesión renal permanente, que se puede asociar en la vida adulta a hipertensión arterial, disminución de la tasa de filtración glomerular, proteinuria y complicaciones durante la gestación. Objetivo: Construimos un Índice de Riesgo de Pielonefritis (IRP) en niños entre 1 mes y 2 años de vida con una primera ITU febril con el objetivo de predecir el riesgo de presentar pielonefritis.Métodos: Estudio prospectivo que incluyó niños entre 1 mes y 2 años de vida con diagnóstico de una primera ITU febril. Se registraron parámetros clínicos y biológicos. El diagnóstico de pielonefritis se estableció mediante alteración en la gamagrafía renal Tc-99m Acido Dimercaptosuccínico en fase aguda. Se construyó un IRP basado en un modelo de acumulación de déficits y regresión logística. Se ajustó una curva ROC para determinar su punto de corte óptimo y se calculó la sensibilidad, especificidad, valores predictivos positivo (VPP), negativo (VPN), cocientes de probabilidad positiva (CPP) y negativa (CPN) del IRP. Resultados: Participaron 34 niños, la media de edad fue de 4,1 meses (DE=3,3), el 67,6% (23) fueron varones y el 61,8% (21) desarrollaron pielonefritis. El IRP estuvo constituido por 7 variables (edad, temperatura, evolución de la fiebre, leucocitos, neutrófilos, proteína C reactiva (PCR) y procalcitonina (PCT). El rango de puntuación del IRP fue de 0 a 12 puntos. El área bajo la curva ROC fue de 0,835 (IC 95%=0.683-0,988). El punto de corte de 5 en el IRP tenía una sensibilidad de 81,0% y especificidad de 76,9. Al aplicar el IRP en la muestra, el punto de corte de 5 puntos tuvo una sensibilidad del 82,6%, especificidad del 81,2%, VPP de 90,4%, VPN de 69,2%, CPP de 4,5 y CPN de 0,21. Conclusión: Los resultados del presente estudio indican que el IRP puede ser un buen marcador de riesgo de pielonefritis en niños entre 1 mes y 2 años de edad con una primera ITU febril. El incremento del tamaño de la muestra permitirá depurar, ajustar el IRP y determinar su validez.
Introduction: Urinary tract infection (UTI) is one of the most frequent bacterial infections in children, 50%-70% of patients with UTI have pyelonephritis. Pyelonephritis may lead to renal scarring with the risk of later hypertension, decrease of glomerular filtration rate, proteinuria and complications during pregnancy.Objetives: We constructed a RisK Scale of Pyelonephritis (RSP) in children 1 month to 2 years old, including clinicals aspects and biomarkers tests.Methods: Prospective study included children 1 month to 2 years old with a first febrile UTI. Clinical information and results from laboratory tests were collected. Pielonephritis diagnostic was based on the alteration of technetium Tc99 dimercaptosuccinic acid (DMSA). The diagnostic value of predictors was analyzed using multivariate logistics modeling and a Risk Scale of Pyelonephritis was derived. The ROC area was determined and the best punctuation to discriminate the pyelonephritis risk was selected. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive probability quotient (PPQ) and negative probability quotient (NPQ) were determined.Results: a total of 34 children were included. The mean age was 4,1 months (SD:3,3), 67,6% (23) were boys and 61,8% (21) had pyelonephritis. The RSP included 7 variables (age, fever, time passed since the onset of fever, white blood cells, granulocytes, C-reactive protein (CRP) and procalcitonin (PCT). The RSP ranged from 0 to 12. The ROC area was 0.835 (IC 95%=0.683-0.988). Five punctuation in the Scale had 81,0% sensitivity and 76,9% specificity. When applying the RSP to the population,we found a sensitivity of 82.6%, specificity of 81.2%, PPV of 90.4%, NPV of 69.2%, PPQ of 4.5 and NPQ of 0.21.Conclusions: a Risk Scale of Pyelonephritis may be useful in assessing the probability of pyelonephritis in children 1 month to 2 years old with a first UTI. Further studies are needed in order to improve the construction of the Scale and to develop its prospective validation.

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Le but de ma thèse est d’étudier les processus de Markov multi-auto-similaires (mssMp’s) à valeurs dans R^d, introduits par Jacobsen et Yor en 2006 dans le but d'étendre la fameuse représentation de Lamperti aux processus à valeurs dans R_+^d. Une description complète de ces processus est donnée, et plusieurs propriétés élémentaires de ces processus sont prouvées dans ce travail. En particulier on donne dans le deuxième chapitre la forme de leur espace d’états, et on montre qu’il n’y a pas une loi d’entrée en 0. On donne également des conditions sous lesquelles ces processus satisfont la propriété de Feller. Une représentation de type Lamperti est encore vraie pour les mssMp’s et on prouve qu’il y a une bijection entre l’ensemble des mssMp’s à valeurs dans R^d, et l’ensemble des processus de Markov additifs à valeurs dans {-1,1}^d×R^d. Ceci nous a permis d’établir dans le troisième chapitre certaines propriétés d’inversion, de dualité et de conditionnement des mssMp’s. En particulier on construit sous certaines hypothèses une fonction excessive h pour un étant donné mssMp. On montre que le h-transformée de Doob est interprété comme le processus initial conditionné à éviter 0 ou à être absorbé continûment en 0. On montre aussi sous certaines conditions de réversibilité que les mssMp’s ont la propriété d’inversion d’espace
This thesis aims at studying all R^d-valued multi-self-similar Markov processes (mssMp’s), introduced by Jacobsen and Yor in 2003 in the aim of extending the famous Lamperti transformation to R_+^d -valued processes. A full description of these processes is given and many properties of these processes are proved in this work. In particular, we give in the second chapter the form of their state space,and we show that there is no finite entrance law at 0. We give conditions for these processes to satisfy the Feller property. A Lamperti-type representation is also valid for mssMp’s and there is a one-to-one relationship between the set of R^d-valued mssMp’s and the set of Markov additive processes with values in {-1,1}^d×R^d. This allowed us to establish, in the third chapter some properties of inversion, duality and conditioning of mssMp’s. In particular, we build under some assumptions an excessive function h for a give nmssMp. Then we show that the Doob h-transformis interpreted as the original process conditioned to avoid 0 or to hit 0 continuously. We show also under some reversibility conditions, that mssMp’s have the space inversion property

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This master’s thesis deals with parameters of the TV Remote Controller. Aim of this work is studying standards of remote controling of TV receiver by the way of infra-red light. For succesful solving of this project is important to learn about the theory of IrDA. In the second part ot this thesis is designed measurement unit for measuring the parameters of the remote control. The measurement unit includes an integrated IR receiver and photodiode for receive IR signals from remote control. The description of measurement unit blocks and principles of measuring parameters are also placed there. The final part is devoted to processing the measurement results of measuring levels and time waveforms of signal in the receiver module, directional characteristics of remote control and receiver. For measuremented unit is created laboratory task including the role specification and protocol.

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research examines associations between perfectionism and acceptance for the self and towards others, alongside their link with psychological health. Reported beliefs are compared with underlying implicit beliefs, as measured by response latencies on the Implicit Relational Assessment Procedure (IRAP; Barnes-Holmes et al., 2006). Ninetynine native English-language speaking university students completed measures of selforiented and other-oriented perfectionism, unconditional self-acceptance, acceptance of others and general health; together with the IRAP computer task. Self-perfectionism scores were observed to be significantly higher than other-perfectionism scores on both explicit and implicit measures. Acceptance of others was significantly higher than selfacceptance on explicit measures; however the two were non-significantly different as recorded by the IRAP. This suggests that participants may have under-reported selfacceptance levels or over-reported their acceptance of others. Possible reasons for this are explored. In addition, all explicit measures demonstrated no significant associations with implicit findings; meaning that participants‟ responses to the assessment tasks appeared to be driven by different processes. Low levels of explicit self-acceptance were the biggest predictor of psychological distress. As such, this research provides further support for the move towards acceptance-based strategies in the treatment of clinical perfectionism.

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The following dissertation has the purpose of studying the relation between motheringand mother s function in neonatal ICU. I intentionally propose to set a distance betweenthe two concepts, being mothering the incumbency of the necessary caretaking forsurvival and mother s function, the practice of a symbolic function that relates thesubject to its psychic constitution in its relation with the language field. In the presentstudy, the inquiry consists in verifying whether the difficulty in practicing mothering,which occurs within the neonatal intensive care unit, may interfere with the conditionsthat support mother function or not, as a rule, practiced by the mother. The inquiry wasconducted at a private hospital in São Paulo city, with mothers of both male and femalebabies, born preterm and admitted at the neonatal ICU and, subsequently, afterdischarge. The clinical extracts of the mother s saying during the interviews andpresented in this paper are analyzed in the light of the Freud and Lacan psychoanalysistheory. And, regarding the investigation of the conditions for the performance ofmother s function, I sought inspiration on the four theoretical axis formulated in theClinical Indicators of Risk for the Child Development (IRDI). By listening to themothers during and after the hospital admission reveals the presence of psychic impactcaused by the preterm birth of a child and the admission in the neonatal ICU, as well asthe difficulty in mothering the baby. Albeit, despite the psychic rapture, in the analysisof the symbolic function based on the four fundamental operations, deduced by meaccording to the IRDI -, it was possible to notice conditions for the mother s function tobe performed
A presente dissertação tem como objetivo estudar a relação entre a maternagem e afunção materna em UTI Neonatal. Proponho propositalmente um distanciamento entreos dois conceitos, onde à maternagem cabe a incumbência dos cuidados necessários àsobrevivência e à função materna o exercício de uma função simbólica - que remete osujeito à dimensão de sua constituição psíquica por sua relação com o campo dalinguagem. Neste trabalho, a investigação consiste em verificar se a dificuldade noexercício da maternagem, que ocorre no âmbito de uma unidade de terapia intensivaneonatal, pode interferir nas condições de sustentação da função materna, via de regraexercida pela mãe. A pesquisa foi realizada em um hospital da rede privada de saúde dacidade de São Paulo, com mães de bebês de ambos os sexos, nascidos prematuros einternados na UTI Neonatal e, posteriormente, no pós-alta. Os recortes clínicos das falasdas mães em entrevista e apresentados neste trabalho são analisados à luz da teoriapsicanalítica de Freud e de Lacan. E, para a investigação das condições para o exercícioda função materna, inspirei-me nos quatro eixos teóricos formulados na pesquisaIndicadores Clínicos de Risco para o Desenvolvimento Infantil (IRDI). A escuta dasmães durante e após a hospitalização revela a presença de sofrimento pelo impactopsíquico causado pelo nascimento prematuro de um filho e a internação em UTINeonatal, bem como pela dificuldade em maternar o bebê. No entanto, apesar doarrebatamento psíquico, na análise da função simbólica a partir das quatro operaçõesfundamentais, deduzidas por mim a partir dos IRDI -, foi possível notar as condiçõespara que a função materna possa vir a se desempenhar

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A relação família-escola é historicamente acompanhada de conflitos, evidenciados no período em que a criança pequena depende significativamente tanto dos cuidados dos pais quanto dos professores, tornando-se preocupação crescente na Educação Infantil. A pesquisa realizada no campo da creche verificou situações de rivalidade e de culpabilização, efeitos da relação ambivalente que pais e educadores estabelecem entre si na divisão das responsabilidades e das funções destinadas ao bebê, fundamentalmente em seu ingresso na instituição. Diante deste cenário, o estudo fundamentou um dispositivo para mediar a aproximação entre pais e professores, servindo também como recurso disparador de reflexões acerca de sua influência no desenvolvimento e na constituição psíquica da criança. Para tal, propôs-se metodologicamente uma formação por meio dos IRDI (Indicadores de Risco do Desenvolvimento Infantil), articulada aos princípios da Educação Terapêutica, ambos pautados na teoria psicanalítica. Por parte dos pais, verificou-se que a formação promoveu debates entre eles acerca de suas funções educativas, das significações atribuídas à criança e de seus efeitos na relação com os filhos. Verificou-se, ainda, que tal formação auxiliou alguns pais a demandarem ajuda, ao detectarem algum sofrimento de ordem psíquica, ou na investigação de alguma afecção de cunho orgânico na criança. Por parte da creche, verificou-se que as professoras apropriaram-se da formação realizada a partir de seu próprio saber e ofício, encontrando meios de auxiliar os bebês que as preocupavam, considerando a singularidade e as necessidades de cada um, ainda que situados no campo coletivo. O estudo permitiu que se extraíssem princípios norteadores para a construção de uma parceria possível entre pais e professores, compondo uma rede de cuidados e promovendo uma educação subjetivante para a criança pequena. A tese apresenta os fundamentos de um tratamento das relações entre pais e professores na Educação Infantil, visando prevenir rupturas nesta relação inicial e colaborando com a promoção da saúde mental no tempo da primeira infância
The family-school relationship is historically surrounded by conflicts, evidenced in the period in which the small child depends significantly on both the care of the parents and the teachers, becoming a growing concern in Early Childhood Education. The research carried out in the field of Day Care Institutions found situations of rivalry and blame, effects of the ambivalent relationship that parents and educators establish among each other in the division of responsibilities and functions related to the baby, fundamentally when entering the institution. Given this scenario, the study formulated a model to mediate the approximation of parents and teachers, which also acts as a trigger for reflections concerning their influence on the development and the psychic constitution of the child. For this, a training was methodologically proposed through the CDRI (Child Development Risk Indicators), articulated to the principles of Therapeutic Education, both based on the psychoanalytic theory. On the parents side, it was found that the formation promoted debates among them regarding their educational functions, the meanings attributed to the child and their effects on the relationship with the children. It was also found that this training also helped some parents to request help, when detecting some suffering of psychic order, or in the investigation of some organic affection in the child. On the Day Care Institutions, it was found that the teachers have appropriated of their training, based on their own knowledge and skills, finding means to assist the babies who concerned them, considering the singularity and the needs of each one individually, although they were inserted in a collective field. The study allowed the establishment of guiding principles for the construction of a possible partnership between parents and teachers, building a network of care and promoting a subjectivist education for the young child. The thesis presents the foundations of a treatment in the relationships between parents and teachers in Early Childhood Education, in order to prevent that there are no ruptures in this relationship and, consequently, this could help in the promotion of mental health in the time of early childhood

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Lung cancer is the second most common cancer in both men and women around the world, and 85% of it is non-small cell lung cancer (NSCLC). It is estimated that in 2020, there will be 228,820 cases of lung cancer and 135,720 deaths from lung (American Cancer Society, 2020). The prognosis of lung cancer is poor (Traditionally, the most commonly used in vitro method for screening therapeutic drugs is monolayer cell cultures, which are reproducible, convenient and of low cost. However, monolayer cell culture models are unable to reproduce many properties of in vivo solid tumors such as the morphological features and the microenvironment including cellular heterogeneity, cell-cell interactions, and gradients of oxygen, pH, and nutrients. Consequently, excessive ineffective drug candidates would proceed to animal studies, which would prolong the time for drug development and increase the overall cost of drug discovery.In consideration of the foregoing, in vitro models of cancer based on three-dimensional multicellular spheroids (MCS) have been developed in our group to characterize drug candidates and drug delivery systems. Compared to monolayer cells, the multicellular spheroids can better simulate drug penetration and drug resistance in solid tumors. Therefore, the multicellular spheroids represent a more clinically relevant in vitro model to evaluate the efficacy of anticancer drugs.This project aims to characterize MCS of lung cancer cells as an improved platform to evaluate drug candidates against lung cancer. Cell viability assays on cisplatin, carboplatin, gemcitabine, and doxorubicin have been conducted to compare the anticancer activities between conventional monolayer cells and the corresponding MCS of human lung cancer cell lines, A549 and A549-iRFP (fluorescently labeled A549 cells). Higher concentrations of the tested anticancer drugs is consistently needed to inhibit 50% the cell viability in MCS than the corresponding monolayer cells of A549 and A549-iRFP.Cycled dosing schedules based on guidelines for NSCLC from National Comprehensive Cancer Network have been designed and used to treat A549-iRFP MCS. The A549-iRFP MCS have been exposed to anticancer drugs either continuously, or in pulsed concentrations according to the drugs’ pharmaco*kinetics (PK). The continuous drug exposure has been found to inhibit more cell growth in MCS than the corresponding PK-mimetic drug exposure. Such phenomenon would bring significant positive bias to the activity of many anticancer drug candidates during their early discovery and development.Taken together, MCS of A549 and A549 iRFP cells better represent the efficacy of anticancer drugs in clinic than the monolayer. MCS can also be used to evaluate anticancer drug candidates by pulsed drug exposure based on their pharmaco*kinetics, and by commonly used cycled dosing regiments to better predict their efficacy in clinical settings.

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Dissertação de Mestrado Integrado em Medicina Veterinária
Vários estudos têm mostrado o impacto das lesões articulares ao nível do desempenho desportivo dos equinos, bem como as suas repercussões a nível económico, associadas aos custos relacionados com tratamentos, mas também com o abandono precoce das competições. De entre as afecções articulares, a osteoartrite é a doença articular mais frequente em equinos de desporto.O objectivo principal desta dissertação é dar a conhecer a terapia regenerativa do soro autólogo condicionado, relatando três casos clínicos submetidos a este tratamento. O exame radiográfico, apesar de ser o método complementar imagiológico mais utilizado para a detecção de lesões a nível articular, mostrou ser uma ferramenta limitada, não revelando alterações significativas. Por outro lado, a realização das ressonâncias magnéticas em dois dos casos clínicos mostrou-se importante, possibilitando a observação de lesões não observadas nas radiografias. Os tratamentos realizados com o soro autólogo condicionado foram executados com sucesso, tendo sido obtidas melhorias significativas, que até então não tinham sido atingidas com os tratamentos anteriores.Apesar da reduzida casuísta, o presente trabalho possibilitou o relato e análise dos casos clínicos acompanhados durante o estágio curricular. É ainda necessário, no futuro, a realização de mais estudos ao nível dos tratamentos com o recurso ao soro autólogo condicionado, para promover a divulgação da terapêutica e obtenção de mais informação associadas ao mesmo.
ABSTRACT - The use of autologous conditioned serum for articular lesions treatment in horses: a preliminary study - Several studies have demonstrated the impact of joint damage on the performance of sports horses and the economic repercussions associated with treatment costs, generally leading to the early withdrawal of the animals from competitions. Osteoarthritis is the most common joint disease in sport horses.The main objective of this dissertation in to present a regenerative therapy ACS/IRAP, reporting three clinical cases in wich this treatment was used. Despite being the most commonly used method for detecting joint lesions, radiographic examination seems to be a limited diagnostic tool as it is sometimes unable to detect significant joint changes. However, the use of magnetic resonance in two of the three clinical cases was important, since it enabled the observation of lesions that were not evidence on radiographs. The treatments performed with autologous conditioned serum were successfully implemented, and significant improvements were achieved, which was not the case with the previously applied traditional treatments. Despite the low number of clinical cases, this preliminary study may be useful in reporting and analyzing the field use of autologous conditioned serum. In the future, it is necessary to promote further studies regarding this treatment, to broaden its use of this and hopefully to obtain more information and knowledge about it.

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The IRDS standard is an international standard produced by the International Organisation for Standardisation (ISO). In this work the process for producing standards in formal standards organisations, for example the ISO, and in more informal bodies, for example the Object Management Group (OMG), is examined. This thesis examines previous models and classifications of standards. The previous models and classifications are then combined to produce a new classification. The IRDS standard is then placed in a class in the new model as a reference anticipatory standard. Anticipatory standards are standards which are developed ahead of the technology in order to attempt to guide the market. The diffusion of the IRDS is traced over a period of eleven years. The economic conditions which affect the diffusion of standards are examined, particularly the economic conditions which prevail in compatibility markets such as the IT and ICT markets. Additionally the consequences of the introduction of gateway or converter devices into a market where a standard has not yet been established is examined. The IRDS standard did not have an installed base and this hindered its diffusion. The thesis concludes that the IRDS standard was overtaken by new developments such as object oriented technologies and middleware. This was partly because of the slow development process of developing standards in traditional organisations which operate on a consensus basis and partly because the IRDS standard did not have an installed base. Also the rise and proliferation of middleware products resulted in exchange mechanisms becoming dominant rather than repository solutions. The research method used in this work is a longitudinal study of the development and diffusion of the ISO/EEC IRDS standard. The research is regarded as a single case study and follows the interpretative epistemological point of view.

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Este estudo originou-se do interesse em investigar a sensibilidade do IRDI-Questionário, adaptação do instrumento IRDI, para detecção de sinais iniciais de TEA (Transtorno de espectro de autismo). O autismo ou TEA caracteriza-se por severos déficits na interação social recíproca, na comunicação e na atividade imaginativa, assim como por padrões repetitivos e limitados de interesses e de comportamentos. Nesse sentido, deve-se ressaltar a indefinição de sua etiologia, pois, se trata de um distúrbio complexo e heterogêneo com graus variados de severidade, resultado provável de uma combinação de fatores ambientais e genéticos. Soma-se à ausência de um marcador biológico a acentuada heterogeneidade das manifestações clínicas do transtorno, daí o conceito de espectro que lhe foi atribuído. Tais condições terão como consequências dificuldades no próprio processo diagnóstico. Isso significa que o diagnóstico do autismo e as condições associadas ainda estão baseados em observações de confluência de anormalidades comportamentais nos campos social, de comunicação, do jogo e da imaginação. É importante pensar que a heterogeneidade do quadro implica que os sintomas podem não se expressar do mesmo modo em todas as crianças, apesar de apresentarem certa regularidade que permite a construção de um diagnóstico. Além disso, algumas crianças vão apresentar sinais de risco desde os primeiros meses de vida e, outras, apresentarão sintomas mais tardios. Nesse contexto, os instrumentos de avaliação são importantes ferramentas de auxílio na avaliação clínica da criança com TEA, sendo que vários pesquisadores ressaltam a importância de se realizarem triagens de crianças de até três anos de idade a fim de propiciar o diagnóstico e a intervenção ainda nos primeiros meses de vida. Com o intuito de instrumentalizar a detecção de sinais iniciais de TEA, diversos pesquisadores têm formulado protocolos com foco em diferentes formas de expressão de tais sinais e os instrumentos especializados para fins de rastreamento/ triagem têm se mostrado eficientes na detecção de sinais iniciais de TEA, além disso, são de fácil e rápida aplicação. Esta pesquisa, portanto, se propôs a investigar a sensibilidade de um instrumento para sinais iniciais de TEA, sendo que, para a investigação, participaram 72 pais de crianças/crianças divididos em 2 (dois) grupos: grupo pesquisa-TEA (32 pais) e grupo controle-típico (40 pais). Para ambos os grupos, foram utilizados o IRDI-Questionário e a CARS-BR, os quais tiverem seus resultados comparados. Utilizou-se o teste de inteligência não verbal SON-R 2½-7 no grupo pesquisa-TEA para controlar a variável DI (deficiência intelectual). Os dados foram submetidos a tratamento estatístico e as análises estatísticas demonstraram que as médias descritas pelo IRDI-Questionário foram diferentes, sendo que os IRDI do grupo TEA (85,09) são, em média, menores que os IRDI do grupo típico (129,32). Os grupos juntos mostraram alta correlação negativa entre os valores do IRDI-Questionário e da CARS-BR. Para o estudo de sensibilidade foi realizada uma análise através da curva ROC, que definiu um ponto de corte do escore gerado pelo instrumento IRDI-Questionário. A sensibilidade do IRDI-Questionário para sinais iniciais de TEA foi de 96,9%, resultado este que também indicou que o instrumento pode ser interessante para um instrumento para o rastreamento da condição estudada. Além do estudo de sensibilidade, apresentou-se, ainda, um breve estudo sobre o conceito de Intersubjetividade e suas rupturas, assim como algumas pesquisas atuais a ele referentes, relacionando-o aos indicadores IRDI e ao TEA. O conceito de intersubjetividade tem sido investigado por vários campos de conhecimento. A Psicologia do desenvolvimento é um desses campos, sendo que diversos autores nos apresentam diferentes interpretações sobre o conceito. Neste trabalho, destacou-se a importância de apresentar o conceito, pois, este guarda uma estreita relação com o autismo
This study originated from the interest in investigating the sensitivity of the IRDI - Questionnaire, adaptation of the IRDI instrument to detect early signs of ASD (autism spectrum disorder). Autism or ASD is characterized by severe deficits in reciprocal social interaction, communication and imaginative activity, as well as repetitive and restricted patterns of interest and behavior. His early appearance, profile and chronicity of symptoms are strong arguments for a biological causality, however, not defined a biological indicator present in all cases. In this sense, it should be noted the vagueness of its etiology, because it is a complex and heterogeneous disorder with varying degrees of severity, likely the result of a combination of environmental and genetic factors. Added to the absence of a biomarker a marked heterogeneity of clinical manifestations of the disorder, hence the concept of spectrum allocated to it. Such conditions will have as consequences difficulties in itself diagnostic process. This means that the diagnosis of autism and associated conditions are still based on observations of confluence of behavioral abnormalities in the social, communication, play and imagination. It is important to think that the heterogeneity of the picture implies that the symptoms can not express themselves in the same way in all children, despite having certain regularity that allows the construction of a diagnosis. In addition, some children will show signs of risk in the first months of life, and others, will present the later symptoms. In this context, the assessment tools are important aid tools in the clinical evaluation of children with ASD, and several researchers emphasize the importance of conducting trials of children under three years of age in order to provide diagnosis and intervention still in first months of life. In order to manipulate the detection of initial signs of TEA, many researchers have made agreements with focus on different ways of expressing such signals and specialized tools for tracking / sorting have been shown to be effective in detecting early signs of TEA, moreover, they are quick and easy application. This research therefore aims to investigate the sensitivity of an instrument for early signs of ASD, and for research, participated 72 parents of children / children divided into two (2) groups: research - TEA group ( 32 parents ) and control group - typical (40 parents). For both groups, we used the IRDI - Questionnaire and the CARS-BR, which have their results compared. We used the non-verbal intelligence test SON- R 2½ -7 in the search -TEA group to control the variable DI (intellectual disability). The data were subjected to statistical analysis and statistical analyzes showed that the average described by IRDI - Questionnaire were different, and the IRDI TEA group (85.09) are on average smaller than the typical group IRDI (129, 32). Groups together showed high negative correlation between the values of the IRDI - Questionnaire and the CARS- BR. For the sensitivity study was carried out through an analysis of the ROC curve, it defined a cutoff score generated by IRDI - Questionnaire tool. The sensitivity of the IRDI - Questionnaire for early signs of ASD was 96.9 %, a result which also indicated that the instrument may be interesting to a tool for tracking the condition studied. In addition to the sensitivity analysis presented is also a brief study on the concept of Intersubjectivity and their breaks, as well as some current research relating thereto, relating it to IRDI indicators and TEA. The concept of intersubjectivity has been investigated by several fields of knowledge. Developmental Psychology is one of those fields, and several authors present us with different interpretations of the concept. In this work, we stressed the importance of presenting the concept, because this is closely related to autism

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Made available in DSpace on 2019-03-30T00:13:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-10-18
This work aims to research and discuss the emotional development of children privation and deprivation of the mother-child relationship in the light of psychoanalytic theory of Donald W. Winnicott. From the understanding of the abandonment as neglect by parents and family with the child, which implies a lack of care and psychological support, that is, in an environment that failure, we relate the moment of the abandonment suffered by children who are forwarded to host institutions with Winnicott's concept of privation and deprivation. Therefore, we study the emotional development of four children, from the stages of dependence, that the author called the individual's personal maturation, and of the study¿s methodology, which will be based on the observation method with children, mediated by the instrument of Clinical Indicators of Risk for Child Development (IRDI). As one of the main results found, we saw that, despite failures in the development because of all the experience lived by the abandonment, the educator-child relationship is of fundamental importance to continue the child¿s maturation process, among other things; the four cases presented testify to this assertion.Keywords: psychoanalysis, Winnicott, emotional development, observation of children, institutional environment.
O presente trabalho tem como objetivo pesquisar e discutir o desenvolvimento emocional de crianças privadas e deprivadas da relação mãe-bebê à luz da teoria psicanalítica de Donald W. Winnicott. Partindo da compreensão do abandono como negligência por parte dos pais e familiares com a criança, que implica em uma falta de cuidado e sustentação psíquica, ou seja, em um ambiente que falha, relacionamos o momento do abandono sofrido pelas crianças que são encaminhadas para instituições de acolhimento com a concepção winnicottiana de privação e deprivação. Para isso, estudamos o desenvolvimento emocional de quatro crianças, a partir dos estágios de dependência, que o autor denominou de amadurecimento pessoal, e da metodologia de estudo, que será baseada no método de observação com crianças, mediado pelo instrumento de Indicadores Clínicos de Risco para o Desenvolvimento Infantil (IRDI). Como um dos principais resultados encontrados, vimos que, apesar de falhas no desenvolvimento em decorrência de toda a experiência vivenciada pelo abandono, a relação educadora-criança é de fundamental importância para dar continuidade ao processo de amadurecimento da criança, dentre outros aspectos; os quatro casos apresentados testemunham tal assertiva.Palavras-chave: psicanálise, Winnicott, desenvolvimento emocional, ambiente institucional, observação de crianças.

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Le but de ce travail est de realiser une classification de familles exponentielles naturelles (f. E. N) sur r#d de fonctions variance cubiques. Dans une premiere partie, nous definissons une action (g,f)t#gf du groupe lineaire g de r#d#+#1 sur les f. E. N de r#d. Nous dirons que deux f. E. N f et f#1 de r#d sont dans la meme g-orbite s'il existe g dans g tel que f1 = t#gf. Ainsi les f. E. N de la classe de morris-mora sont partagees en quatre g-orbites. Nous definissons une generalisation de cette classe a r#d, nous montrons qu'elle comprend (d+3)-g-orbites. Dans la deuxieme partie nous donnons une propriete caracteristique des fonctions variance de f. E. N concentrees sur n#d et des resultats concernant l'action de g sur ces familles. Dans la troisieme et derniere partie nous donnons une description complete des (d+3) g-orbites de la classe de morris-mora dans r#d

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Sammanfattning Titel: Digitaliserad word of mouth, en betydande faktor för WTA Nivå: Examensarbete på Grundnivå (kandidatexamen) i ämnet företagsekonomi Författare: Andreas Ståhl och Markus Westblad Handledare: Jonas Kågström, Benny Berggren Datum: 2019 – Juni Syfte: Syftet med denna studie är att öka förståelsen för hur eWOMs volym och valens påverkar konsumenters WTA i valet av tjänst från säljare. I denna studie har en undersökning av begrepp som WTA och eWOM ställts emot varandra i en experimentell design som sedan genom resultatet delat en förståelse för hur volym och valens påverkar valet av en fastighetsmäklare. Studien har genom tidigare forskning önskats applicerats på andra branscher än tidigare utförda vilket vi anser att denna studie uppfyller genom den replikerade metod som använts. Metod: Denna studie är utförd genom en kvantitativ forskningsstrategi med en replikerande metod med experimentell design. Den data som samlats in som underlag för studiens resultat och analys har samlats in genom en digital enkät med manipulerade mäklarprofiler genom rekommendationssajten ”Reco”. Datan har sedan analyserats genom programvaran ”Jamovi” genom deskriptiva analyser samt genom en korrelationsanalys. Resultat & slu*tsats: Studien har visat resultat som motsäger tidigare forskning med bland annat att volym är mer avgörande i valet av en tjänst i relation till valens. Detta resultat visar även på att fler bör studera sina branscher för att öka sin förståelse för hur kraftigt vissa faktorer är inom digitaliserad marknadsföring. Examensarbetets bidrag: Studien presenterar ett teoretiskt såväl som praktiskt bidrag i det avslu*tande kapitlet som i kort visar på hur volym och valens kan variera i jämförelse med den tidigare forskningen som utförts och vad som bör beaktas och noggrant analyseras för att i framtiden kunna appliceras på företagsnivå inom marknadsföring såväl som rekommendationer. Förslag till fortsatt forskning: Jämförande studie av de två begreppen eWOM och WOM, vilket är det mer traditionella uttryck för att beskriva en word of mouth effekt. Hur särskiljer sig dessa åt i resultat, och är de skillnader i effektivitet mot den som faktiskt blir rekommenderad. Studien ger även förslag på att använda sig av demografiska data som underlag för tolkningen utav statistiken, vilket inte gjorts inom denna studie. Vi anser det även intressant med en mer övergripande manipulering av de olika profilerna, såsom att tillägga fabrik eller varumärke och se hur dessa skiljer sig åt. Nyckelord: WTA, WTP, IRP, eWOM, WOM, Valens och Volym.
Abstract Title: Digitized word of mouth, an important factor for WTA Level: Student thesis, final assignment for Bachelor Degree in Business Administration Author: Andreas Ståhl and Markus Westblad Supervisor: Jonas Kågström, Benny Berggren Date: 2019 – June Aim: The purpose of this study is to increase the understanding of how eWOM's volume and valency affects consumers' WTA in the choice of service from sellers. In this paper, a study of concepts such as WTA and eWOM has been compared in an experimental design which then through the result shared an understanding of how volume and valency affects the choice of a real estate agent. Through the previous research, the study has been desired to be applied to other industries previously performed, which we believe this study fulfills through the replicated method used. Method: This study is conducted through a quantitative research strategy with a replicating method with experimental design. The data collected for the study's results and analysis has been collected through a digital survey with manipulated profiles through the recommendation site "Reco". The data has then been analyzed through the software "Jamovi" through descriptive analyzes and through a correlation matrix. Result & Conclusions: The study has shown results that contradict previous research, among other things, that volume is more crucial in the choice of a service in relation to valency. This result also shows that companies should study their industries to increase their understanding of how strongly certain factors are within digitalized marketing. Contribution of the thesis: The study presents a theoretical as well as practical contribution in the final chapter, which briefly shows how volume and valency can vary widely in relation to the previous research carried out and what should be considered and carefully analyzed in order to be able to apply at company level in marketing in the future. as recommendations. Suggestions for future research: Comparative study of the two terms eWOM and WOM, which is the more traditional expression to describe a word of mouth effect. How do they differentiate in results, and are the differences in efficiency against the one that is actually recommended. The study also proposes to use demographic data as a basis for the interpretation of the statistics, which has not been done in this study. We also consider it interesting with a more general manipulation of the different profiles, such as adding factory or brand and seeing how these differ. Key words: WTA, WTP, IRP, eWOM, WOM, Valency and Volume.

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Studies investigating harm avoidance and incompleteness in obsessive-compulsive disorder (OCD) have been limited to the use of questionnaire measures and behavioural tasks. Despite their utility, these methodologies are unable to capture cognitions that are not readily accessible through introspection or that are difficult to articulate, as they operate on a more visceral level. The current study explored harm avoidance and incompleteness using an implicit measure, the Implicit Relational Assessment Procedure (IRAP). Three behavioural tasks based on the main symptom dimensions (contamination/washing, checking, symmetry/ordering) and a series of self-report measures were used for comparative and validation purposes. The group with high obsessive-compulsive tendencies demonstrated no negative bias towards harm avoidance/incompleteness–related stimuli. No associations were identified between scores on the implicit measure and the explicit measures (questionnaires and behavioural task). The findings are interpreted in the light of extant literature with reference to the limitations of the current study.

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El presente trabajo de investigación tiene como objetivo principal analizar la problemática detectada en el Instituto Nacional de Radio y Televisión del Perú – IRTP respecto de la interposición de demandas judiciales en materia de desnaturalización de contratos, con el fin de proponer la implementación de mecanismos que permitan disminuir la incidencia de ese tipo de demandas en el futuro. La importancia de esta investigación radica en la posibilidad de demostrar que el uso de las órdenes de servicio para contratar personas que brinden servicios a favor de la entidad, así como las acciones realizadas por las diversas áreas usuarias de dichos servicios generan que los juzgados laborales acojan las pretensiones de los demandantes y por ende se declare la existencia de un contrato de trabajo, lo que se traduce en el pago de cuantiosas sumas de dinero por concepto de pago de sentencias judiciales. Para realizar el presente trabajo, se consultó literatura con el objeto de presentar los elementos teóricos del contrato de trabajo, así como la desnaturalización de contratos. Asimismo, se procedió a revisar procesos judiciales sobre la materia analizada notificados en los años 2018 y 2019. Con los resultados obtenidos se propone establecer lineamientos para mejorar el uso de las órdenes de servicio, así como un proceso donde se pueda verificar el cumplimiento de los mismos.
The main objective of this research work is to analyze the problem detected in the National Institute of Radio and Television of Peru - IRTP regarding the filing of legal claims regarding the denaturing of contracts, in order to propose the implementation of mechanisms that allow reduce the incidence of such lawsuits in the future. The importance of this research lies in the possibility of demonstrating that the use of service orders to hire people who provide services in favor of the entity, as well as the actions carried out by the various user areas of said services, generate that the labor courts accept the claims of the plaintiffs and therefore the existence of an employment contract is declared, which translates into the payment of large sums of money for the payment of court judgments. To carry out this work, literature was consulted in order to present the theoretical elements of the employment contract, as well as the denaturing of contracts. Likewise, we proceeded to review judicial processes on the analyzed matter notified in 2018 and 2019. With the results obtained, it is proposed to establish guidelines to improve the use of service orders, as well as a process where they can be verified.
Tesis

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Le Virus Respiratoire Syncytial (VRS) est responsable de 70 % des cas de bronchiolite chez les enfants de moins de cinq ans. La survenue de bronchiolites sévères chez le nourrisson est un facteur de risque de développement d’asthme en grandissant. Aucun vaccin contre le VRS n’est disponible chez l’Homme. Le système immunitaire inné est la première ligne de défense de l’organisme contre les infections. De plus, en interaction avec la flore bactérienne commensale des poumons, l’immunité innée participe à la maturation de la réponse immunitaire adaptative qui confère à l’individu une protection sur le long terme vis-à-vis des pathogènes. Afin d’expliquer la susceptibilité néonatale au VRS, nous avons caractérisé un nouveau mécanisme de contrôle de la réponse innée antivirale lors de l’infection de souriceaux. Nous avons également testé une nouvelle approche de modulation de la réponse immunitaire au VRS par le microbiote pulmonaire. Ainsi, mieux comprendre les mécanismes immunologiques et virologiques responsables de bronchiolites sévères en période néonatale permettra de développer des moyens de lutte sûrs et efficaces contre l’infection par le VRS
Respiratory Syncytial Virus (RSV) is responsible for 70 % of bronchiolitis in children under five years old. Severe bronchiolitis in infants is a risk factor for asthma development. No vaccine against RSV is available in humans. The innate immune system is the first line of defense against infections. Moreover, in interaction with lung microbiota, innate immunity shapes adaptive immune response responsible for long-term protection against pathogens. To explain the susceptibility of young children to RSV, we characterized a novel regulatory mechanism of the innate antiviral response during neonatal RSV infection in the murine model. We also tested a new approach for modulating immune responses to RSV by the pulmonary microbiota. Thus, a better understanding of immunological and virological mechanisms responsible for severe bronchiolitis during the neonatal period will allow the development of safe and effective therapeutic strategies against RSV infection

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Research into rape-supportive cognition has been hampered by methodological problems such as social desirability. The study of so-called implicit cognition has been dominated by explanations that the effects produced on implicit/indirect measures are mediated by associations held in memory. The Implicit Relational Assessment Procedure (IRAP; Barnes-Holmes et al., 2006) offers an alternative perspective. Derived from Relational Frame Theory (RFT, Hayes, Barnes-Holmes & Roche, 2001), here it is applied for the first time to study the malleability of implicit rape-supportive cognition, following a cognitive-restructuring task in university males. The relationship between implicit (IRAP) and explicit measures (the Acceptance of Modern Myths about Sexual Aggression scale (AMMSA) Gerger, Kley, Bohner & Siebler, 2007), and behaviour was explored (measured by a forced-choice task and ratings of the researcher). IRAP scores did not change following the intervention. Behaviour on the forced-choice measure was predicted by IRAP scores but not by scores on the AMMSA. Additional analyses into the predictive ability of the AMMSA and IRAP measure on behavioural measures (charity-box overall giving score and Researcher Rating Scale) were conducted. Findings from hierarchical multiple regression analyses indicated that the AMMSA predicted none of the variance whereas the IRAP predicted 12.4% and 11.5% of the variance respectively.

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Memoria para optar al Título Profesional de Bioquímico
La colonización del Pacífico se gestó en dos grandes procesos de migración: el primero alrededor de 50.000 a 30.000 años antes del presente, y el segundo hace 5.000 a 1.000 años antes del presente. Este último gran movimiento fue complejo y se ha estudiado integrando evidencias arqueológicas, lingüísticas y genéticas con el propósito de dilucidar incógnitas como las diferentes rutas migratorias propuestas sobre el poblamiento de Oceanía. Entre los modelos de estudios genéticos se han analizado muestras humanas, pero éstas presentan diversas complejidades que limitan el alcance de los estudios con este modelo. Por este motivo, surgen los estudios de especies asociadas a los colonizadores polinésicos, de los cuales se han analizado especies animales y vegetales. Entre estos últimos se encuentra la morera de papel (Broussonetia papyrifera), una planta nativa de Asia e introducida a la región de Oceanía Remota. Debido a su uso como fuente de fibra vegetal para textiles y la importancia cultural que representa, resulta interesante abordar su estudio para aportar a la comprensión de las rutas migratorias en Oceanía Remota.La principal herramienta de los estudios genéticos son los marcadores moleculares, que corresponden a regiones de ADN que presentan cierto grado de variabilidad detectable. En B. papyrifera se han analizado regiones de ADN ribosomal y de ADN de cloroplastos, encontrando ausencia de diversidad en muestras de Oceanía Remota. Una alternativa para este tipo de análisis podría ser el uso de marcadores basados en retrotransposones, los cuales han sido descritos como ubicuos en plantas y como fuente de gran diversidad genética. Entre los marcadores basados en retrotransposones se encuentran los Inter-Retrotransposon Amplified Polymorphisms (IRAP) y Retrotransposon-Microsatellite Amplified Polymorphisms (REMAP), los cuales amplifican regiones entre secuencias de Repeticiones Terminales Largas (LTR), o entre LTR y secuencias microsatélites, respectivamente. Estos marcadores han sido ampliamente empleados en estudios de diversidad genética debido a su facilidad de uso.En base a los antecedentes presentados, se plantea la siguiente hipótesis: “El estudio de B. papyrifera por medio de marcadores moleculares basados en retrotransposones IRAP y REMAP permite detectar diversidad genética presente en muestras obtenidas de Oceanía Remota que no han sido diferenciadas mediante otros marcadores moleculares”. Con el objetivo de caracterizar la diversidad genética de muestras de B. papyrifera provenientes de Oceanía Remota usando marcadores IRAP y REMAP, se seleccionaron partidores a partir de la literatura para el análisis de muestras de B. papyrifera del hábitat nativo y de la región introducida. En primer lugar, se corroboró que las secuencias amplificadas mediante estos marcadores corresponden a retroelementos, caracterizando cinco secuencias amplificadas con un marcador IRAP. Estas secuencias corresponden a dos posibles tipos de elementos TRIM (Terminal-repeat Retrotransposon In Miniature), los cuales son derivados cortos de retrotransposones que conservan algunas regiones características de retroelementos, pero carecen de marcos de lectura abiertos funcionales. En una etapa siguiente se estandarizaron los protocolos IRAP y REMAP para obtener patrones de amplificación óptimos. Además, se ajustaron las condiciones de electroforesis y de captura de imagen.Inicialmente, se probaron 45 combinaciones de partidores IRAP y 36 combinaciones de partidores REMAP con un grupo de cuatro muestras de prueba de Oceanía Remota. A partir de los resultados obtenidos, se seleccionaron cuatro combinaciones REMAP para analizar 55 muestras representativas del banco genómico de B. papyrifera de distintas localidades del Pacífico. Estos análisis mostraron una baja diversidad genética, apoyando la noción de una dispersión clonal de la morera de papel en las distintas islas del Pacífico. Esta información complementa los resultados obtenidos con otros marcadores utilizados en esta y otras especies, y favorecen modelos migratorios como el “tren rápido” o el de la “Triple I”.Esta memoria de título constituye el primer estudio de retrotransposones en B. papyrifera y abre la posibilidad a nuevos trabajos que profundicen el análisis de la dispersión y la diversificación clonal de la morera de papel en Oceanía Remota, considerando que los retroelementos han sido descritos como fuente importante de diversidad en otras especies vegetales
The human colonization of the Pacific occurred in two major stages: the first migration took place about 50,000 to 30.000 years before present, and the second stage occurred more recently, about 5.000 to 1.000 years before present. This latter large movement was complex and has been widely studied gathering archeological, linguistic and genetic evidence in order to elucidate questions such as the different routes proposed for the settlement of Oceania. Human samples have been analyzed using genetic tools, but these present several complexities that limit their scope. Therefore studies centered on human-associated species (known as commensal species) arise. Animal and plant species have been studied, and among the latter, paper mulberry (Broussonetia papyrifera), a plant native from Asia and introduced in the Remote Oceania Region has been used a commensal model species. Due to its use as a fiber source to make textiles and the cultural importance of paper mulberry, it is interesting to address the study of this species to contribute to the understanding of migratory routes in Remote Oceania.Molecular markers are the main tools to analyze DNA regions that present genetic diversity. In B. papyrifera, ribosomal and chloroplast DNA regions have been analyzed, finding no genetic diversity in samples from Remote Oceania. An alternative to approach this kind of analysis could be the use of retrotransposon-based markers, which have been reported as ubiquitous and a major source of genetic diversity in plants. Retrotransposon-based markers are Inter-Retrotransposon Amplified Polymorphisms (IRAP) and Retrotransposon-Microsatellite Amplified Polymorphisms (REMAP), among others. IRAP and REMAP amplify regions between Long Terminal Repeats (LTR), or between LTR and microsatellites, respectively. These markers are easy to apply and have been widely used for genetic diversity studies in different plant species.Based on this background, the following hypothesis is proposed: “The study of B. papyrifera by retrotransposon-based markers IRAP and REMAP allow to detect genetic diversity in samples from Remote Oceania not previously differentiated with others molecular markers”. In order to characterize the genetic diversity of B. papyrifera samples from Remote Oceania by IRAP and REMAP, primers were selected from the literature to analyze samples of B. papyrifera from native and introduced areas. First, we checked that the amplified sequences with these primers were obtained from retroelements. Five sequences amplified with an IRAP marker were characterized and shown to correspond to two types of TRIM (Terminal-repeat Retrotransposon In Miniature) elements, which are short retrotransposon derivatives that have some conserved regions characteristic of retroelements, but lack functional open reading frames. Then, protocols for IRAP and REMAP amplification were standardized in order to obtain optimal amplification patterns. In addition, electrophoresis and image capture conditions were defined.From 45 IRAP and 36 REMAP primer combinations, 4 REMAP combinations showed distinct amplification patterns in a reduced group of B. papyrifera samples from Remote Oceania. The results obtained from the analysis of 55 samples of B. papyrifera using four selected REMAP markers showed little diversity, supporting the notion of a clonal dispersal of paper mulberry among Pacific islands. These results complement data obtained with others markers in paper mulberry and other species, and are consistent with the previously proposed models of human colonization of the Pacific as the “fast train” or the “Triple-I” models.The present work is the first retrotransposon study in B. papyrifera and opens the possibility to further work to analyze the clonal dispersal and diversification of paper mulberry in Remote Oceania, considering that retroelements have been described as an important source of molecular diversity in plant species
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Os roedores compõem a mais numerosa ordem dos mamíferos com, aproximadamente, 43 famílias, 354 gêneros e 1.700 espécies vivas. São membros importantes de quase todas as faunas, sendo cosmopolitas e nativos na maioria das áreas terrestres, exceto em algumas ilhas árticas e oceânicas, Nova Zelândia e Antártica. Possuem hábitos terrestres, fossorial, (semi) arborícola, semi-aquático ou palustre. Usualmente herbívoros, mas podem ser insetívoros, piscívoros ou carnívoros. A enorme variação na morfologia, nos hábitos de vida e alimentar são atributos que fizeram da ordem um dos grupos de mamíferos com maior sucesso evolutivo. Em nosso continente a ordem apresenta enorme importância na composição de sua fauna, pois perfaz, aproximadamente, 42% das espécies de mamíferos que aqui habitam. Entre os roedores sul-americanos, mais de 50% das espécies pertencem à família Cricetidae, distribuídos em apenas uma subfamília, Sigmodontinae, com aproximadamente 80 gêneros e 370 espécies. Oryzomyini é uma das sete tribos reconhecidas de Sigmodontinae, compreendendo cerca de 35% das espécies descritas para esta subfamília. Atualmente são descritos 27 gêneros e cerca de 120 espécies para esta tribo, incluindo propostas atuais que envolvem a descrição de novas espécies e, até mesmo, de novos gêneros.Os oryzomyinos habitam florestas, savanas, banhados, campos e ambientes semi-áridos, além de serem, na maioria das vezes, os mais abundantes pequenos mamíferos destes habitats. Seus hábitos alimentar vão de onívoros a insetívoros. A maioria possui hábito escansorial, mas alguns podem desenvolver hábitos arbóreos (Oecomys) ou até semiaquáticos (Nectomys), constituindo um dos mais claramente definidos grupos multigenéricos de muróides. A distribuição geográfica desta tribo é a mais ampla dentro dos Sigmodontinae, desde o extremo sul da América do Sul (Terra do Fogo) até o sudoeste dos Estados Unidos. Os objetivos desta tese, além de analisar as relações filogenéticas da tribo Oryzomyini com diferentes marcadores moleculares (citocromo b e IRBP), foi comprovar a validades das recentes mudanças propostas na classificação da tribo. Esta validação passa pela observação do caráter monofilético de cada um dos novos gêneros, bem como a comprovação da monofilia dos gêneros previamente reconhecidos. Também tivemos como objetivos estudar a filogenia e a filogeografia de um dos táxons da tribo, o gênero Oligoryzomys e traçar a rota de ocupação deste táxon nos ambientes sul-americanos. Além disto, foram examinadas a filogeografia e as estruturas genéticasdas populações de seis espécies da tribo Oryzomyini (Euryoryzomys russatus, Hylaeamys megacephalus, Oligoryzomys flavescens, O. moojeni, O. nigripes e Sooretamys angouya). Com relação à análise filogenética da tribo Oryzomyini, observamos que esta se comporta de forma monofilética tanto nos resultados com o gene citocromo b, como com o gene IRBP. Além disso, os resultados encontrados neste trabalho dão suporte às reformulações na classificação ocorrida na tribo Oryzomyini, com a proposição de 10 novos gêneros, onde a maioria dos gêneros da tribo Oryzomyini, tanto os antigos como os novos, são monofiléticos. A exceção foi o novo gênero Hylaeamys que se mostrou polifilético na análise com o gene citocromo b, em que cinco espécies se reuniram em um único agrupamento e a espécie H. yunganus se posicionou em um outro agrupamento. Todavia, Hylaeamys apresentou-se monofilético nas análises com o gene IRBP isolado e citocromo b e IRBP concatenados. As análises com o gênero Oligoryzomys mostraram que este táxon se apresenta de forma monofilética e com suas espécies distribuídas em dois grupos denominados, de acordo com suas origens geográficas, de grupo “Amazônico-Cerrado” e clado “Andino- Pampiano”. Estas espécies também apresentaram um gradiente geográfico no sentido norte-sul que fortemente suporta a hipótese de que o gênero iniciou sua ocupação no continente sul-americano a partir da Amazônia. Estudos filogeográficos e das estruturas genéticas das populações de seis espécies da tribo Oryzomyini observou-se a falta de diferenciação populacional, através da ausência de associação entre os haplótipos e suas distribuições geográficas, em duas das três espécies do gênero Oligoryzomys (O. flavescens e O. moojeni) analisadas. Estes resultados sugerem que a ausência intraespecíficas de populações pode ser um padrão geral do gênero. Já as outras três espécies analisadas apresentaram estruturação populacional e geográfica, além de estarem em equilíbrio demográfico. Nas análises filogenéticas realizadas, E. russatus e H. megacephalus mostraram seus espécimes agrupados em três clados distintos distribuídos em gradientes geográficos, sendo que o gradiente geográfico de H. megacephalus ocorre no sentido Norte-Sul. A divergência genética intraespecífica foi maior em H. megacephalus, seguida de E. russatus e sendo menor em S. angouya. Estes resultados podem fornecer subsídios para a elaboração de programas de conservação e manejo destas espécies e dos respectivos biomas que habitam, se necessário.
Rodents constitute the most numerous order of mammals with approximately 43 families, 354 genera and 1,700 living species. They are important members of almost all faunas, cosmopolitan and native to most terrestrial areas, except a few arctic and oceanic islands, New Zealand and Antarctica. They have terrestrial, fossorial, (semi) arboreal, semi-aquatic or palustrial habits. They are usually herbivore, but they may be insectivore, piscivore or carnivore. The huge variation in morphology, life and feeding habits are attributes that have made the order one of the mammal groups with the greatest success in evolution. On our continent, the order is very important as to fauna composition, because it makes up about 42% of the mammal species that inhabit here. Among the South American rodents, more than 50% of the species belong to the Cricetidae family, distributed into only a single subfamily, Sigmodontinae, with approximately 80 genera and 370 species. Oryzomyini is one of the seven acknowledged Sigmodontinae tribes, consisting of about 35% of the species described for this subfamily. Currently, 27 genera and about 120 species are described for this tribe, including current proposals that involve the description of new species and even new genera. The oryzomyines inhabit forests, savannahs, swamps, fields and semi-arid environments, besides often being the most abundant small mammals in these habitats. Their feeding habits range from omnivorous to insectivorous. Most of them have a scansorial habit, but some of them may develop arboreous habits (Oecomys) or even semi-aquatic habits (Nectomys), constituting one of the most clearly defined multigenera groups of muroids. The geographical distribution of this tribe is the broadest within the Sigmodontinae, from the far south of South American (Tierra del Fuego) to the southwest of the United States. The objective of this thesis, besides analyzing the phylogenetic relations of the tribe Oryzomyini with different molecular markers (cytochrome b and IRBP), was to prove the validities of the recent changes proposed in the classification of the tribe. This validation includes the observation of the monophyletic character of each of the new genera, as well as proving the monophyly of previously recognized genera. Our objectives were also to study the phylogeny and phylogeography of one of the taxa of the tribe, genus Oligoryzomys, and to trace the occupation route of this taxon in the South American environments. The phylogeography and genetic structures of the populations of six species of the tribeOryzomyini (Euryoryzomys russatus, Hylaeamys megacephalus, Oligoryzomys flavescens, O. moojeni, O. nigripes and Sooretamys angouya) were also examined. As to the phylogenetic analysis of the tribe Oryzomyini, we observed that the latter behaves in a monophyletic form, both in the results with the cytochrome b gene, and with gene IRBP. In addition the results found in this study support the reformulations in the classification that occurred for the tribe Oryzomyini, with the proposition of 10 new genera, where most of the genera of the tribe Oryzomyini both the old and the new, are monophyletic. The exception was the new genus Hylaeamys which proved be polyphyletic in the analysis with the cytochrome b gene, in which five species assembled in a single group and the species H. yunganus took a position in another group. However, Hylaeamys was monophyletic in the analyses with the isolated gene IRBP and cytochrome b and IRBP genes concatenated.The analyses of genus Oligoryzomys showed that this taxon was monophyletic and with its species distributed in two groups named, according to their geographic origins, the “Amazon-Cerrado” group and the “Pampa-Andean” clade. These species also presented a geographical gradient in the North-South direction which strongly supports the hypothesis that the genus began its occupation of the South American continent in the Amazon. Studies of phylogeography and of the genetic structures of the populations of six species of the tribe Oryzomyini showed a lack of population differentiation in two of the three species of genus Oligoryzomys (O. flavescens and O. moojeni) analyzed by the absence of association between the haplotypes and their geographic distributions. These results suggest that the intraspecific absence of populations may be a general pattern of the genus. On the other hand the three other species analyzed presented a population and geographic structuring, besides being in demographic equilibrium. In the phylogenetic analyses performed, E. russatus and H. megacephalus showed their specimens grouped in three distinct clades, distributed in geographic gradients, in which the geographic gradient of H. megacephalus occurs in the North-South direction. The intraspecific genetic divergence was greater in H. megacephalus, followed by E. russatus and smaller in S. angouya. These can aid to the elaboration of conservation and management programs of these species and biomes studied which they inhabit, if necessary.

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Iron Regulatory Protein 1 (IRP1) est une protéine cytosolique dont le rôle est de réguler la concentration de fer intracellulaire chez les métazoaires par un mécanisme post-transcriptionnel. Elle interagit avec certains ARN messagers au niveau de motifs spécifiques appelés IRE (Iron Responsive Element) situés dans leurs régions non traduites et modifie la synthèse des protéines correspondantes. En présence de fer, IRP1 perd cette capacité de fixation, intègre un agrégat [4Fe-4S] et acquiert une activité aconitase. La régulation s'effectue donc par un processus d'assemblage et de désassemblage du centre fer-soufre.
La réactivité de la protéine recombinante IRP1 humaine, purifiée sous sa forme aconitase [4Fe-4S], a été étudiée vis à vis d'autres effecteurs que le fer capables de modifier l'activité des IRP. Ainsi des excès assez modestes de diverses espèces réactives de l'oxygène ne peuvent former que l'espèce [3Fe-4S] de la protéine. La doxorubicine, un composé cytostatique utilisé comme anti-cancéreux, a une action sur IRP1, mais elle dépend des conditions d'application et implique certainement des mécanismes multiples. In vitro, IRP1 est complètement activée pour la fixation d'ARN par un fort excès de 2-mercaptoéthanol. Parmi les diverses causes possibles de cet effet, les propriétés de solvant de ce produit (comme de l'éthanol) en sont responsables.
La recherche d'éventuels partenaires physiologiques de la protéine IRP1 a été entreprise par une étude double hybride chez la levure Saccharomyces cerevisiae, mais les constructions utilisées n'ont pas permis de déterminer de candidats potentiels. L'utilisation d'autres constructions ainsi que d'autres systèmes double hybride est envisagée pour la poursuite de cette étude.
Une nouvelle méthode de dosage de l'activité de fixation au motif IRE a été envisagée par l'utilisation d'un substrat fluorescent et de l'électrophorèse capillaire. Les résultats préliminaires obtenus n'ont pas encore abouti, mais ils contribuent à donner des orientations pour le développement de cette méthode présentant de nombreux avantages.
Des changements de conformation entre les deux formes actives de IRP1 ont été analysés par deux méthodes structurales en solution. La formation de certains éléments de structure secondaire d'IRP1 dépend de l'état d'activité de la protéine et ils sont sensibles à la fixation des substrats. Les propriétés hydrodynamiques d'IRP1 varient aussi lors de ces différents changements. Faute de structure à haute résolution, ces informations permettent toutefois de se représenter le comportement structural d'IRP1 dans son rôle de régulateur.

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The future role of nuclear power in global sustainable development, and particularly in the development of industrialising countries is contentious; the debate is often highly emotive. The Republic of South Africa's (RSA) progress towards its largest nuclear procurement program is taking place in the midst of changes within the African National Congress (ANC) ruling party, an increase in global demand for uranium and growing energy needs within South Africa. Major nuclear accidents such as Chernobyl or f*ckushima have set nuclear power plant security on top of the public agenda. The internalisation of governance through the creation of responsible eco-citizenship is a primary technique to screen perceived risk, which works through the course of public participation. Participation however, must include those that drive the objectives within the nuclear context. Eskom's Koeberg Nuclear Power Station (KNPS) has a workforce of more than 2000 employees. In 2016, the Department of Energy (DOE) had decided that Africa's leading power utility will be the owner operator and procurer of the planned 9.6 Gigawatts (GW) (e) nuclear fleet that is set out in the IRP2010 report. The perceptual impact of this workforce that keeps the country's economic lifeblood moving is often understated, which was the focus of this study. This study had a distinct focus on what Eskom employee's perceptions are with respect to the IRP2010 nuclear new build program. It was limited to the Western Cape Province and included views from divisions that may be involved in the realisation of the nuclear project. It is unique in its context, as very little has been documented on employee perception within RSA's nuclear industry. It is comparative to a public perception survey, which had a distinct focus on nuclear risk. The public's greatest concerns were noted to be corruption, project mismanagement, excessive cost and lack of trust in stakeholders. The outcome of this study discovered similarities with the public perception survey, however here within nuclear safety and compliance to business best practice were greater significant factors. Most respondents had sufficient knowledge and support for RSA's nuclear plans set out in the IRP reports. Dimensions of how perception was created were voted as being heavily dependent on the leadership within the organisation. With this in mind, Eskom employees have indicated that they are more likely to influence the public if they have their leadership's support, and have gone as far as selecting nuclear power over renewable energy to drive towards the country's commitment towards low greenhouse gas (GHG) emissions. So while there may be shades of perceptual similarities between the public and Eskom employees, fundamentally this study revealed that these two bodies do not have the same perception on nuclear power. The study revealed that if Eskom employee's nuclear perception is disregarded and mismanaged, it may delay the realisation of the nuclear new build program in line with IRP 2010 timelines. This is mainly due to the concern of adherence to good corporate governance by Eskom's leadership.

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On radar level gauges currently shipped by Saab Rosemount, some adjustments of the unit's parameters has to be performed in the field. Presently, this is a cumbersome procedure; the operator has to be very close to the gauge and he either has to carry with him a bulky configuration unit or use a basic control unit on the gauge. A wireless solution, where a portable device and a receiver replace the control unit, would both allow the operator to work from a distance and eliminate the need for the bulky device.

The most conspicuous restraint for such a solution is a very low allowed power dissipation. The reason for this is that some gauges do not have a separate power supply, but are fed directly off the communication bus. A viable solution should also be commercially available and robust enough to operate in an industrial environment.

To meet these requirements both a theoretical and a practical assessment was conducted, where the two techniques for wireless communication, IrDA, and Bluetooth, was given special consideration. As for the portable device, the market for hand-held computers was investigated and ultimately a PDA from Palm was selected for this project. Together with this PDA, a prototype for each of the two wireless techniques was tested to ascertain their performance with respect to power dissipation, communication range, and communication robustness.

This investigation revealed that Bluetooth could be used over a much greater distance than IrDA and it did also provide a more robust solution overall. IrDA is nonetheless also a competent technique, and has its primary advantage in terms of much lower power dissipation compared to Bluetooth.

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CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
Manioc (Manihot esculenta Crantz) performs an important social role as a food source in the tropical world. The germplasm maintained manioc forms the basis for technological exploitation of the species in the development of new cultivars. To be efficiently used require different methods of genetic characterization. Markers based on transposable elements are suitable for genetic analyzes because of their qualities of reproducibility and abundant polymorphism. We used 430 manioc accessions that compose the Embrapa germplasm collected in the Amazon basin. The retrotransposons sequences were located in the Phytozome database, IRAP primers designed with Primer3 program, structuring within the germplasm has been detected by STRUCTURE software v. 2.2 and the genetic diversity was assessed using the Popgen software v1.32. IRAP data to the software STRUCTURE suggested the existence of two gene clusters (k = 2) with 93 and other with 127 varieties of total 430 plants, considering only the fidelity above 80%. The AMOVA for K = 2 showed greater variation within the group (89%) than among groups (11%). The six IRAP primer pairs were informative for assessing genetic diversity, with averages of 96% polymorphism, 0.4 heterozygosity and Shannon index 0.57, however, did not detect structuring within cassava germplasm compared to other assisted structuring markers.
A mandioca (Manihot esculenta Crantz) desempenha importante papel social como fonte de alimentação nas regiões tropicais mundiais. O germoplasma conservado constitui a base para aproveitamento tecnológico da espécie no desenvolvimento de novas cultivares. Para que seja eficientemente utilizado necessita de diferentes métodos de caracterização genética. Os marcadores com base em elementos transponíveis são indicados para análises genéticas devido as suas qualidades de reprodutibilidade e polimorfismo abundante. Foram utilizados 430 acessos de mandioca que compõem o germoplasma da Embrapa, coletados na bacia amazônica. As sequências de retrotransposons foram localizadas no banco de dados do Phytozome, os primers IRAP desenhados com o programa Primer3, a estruturação dentro do germoplasma foi detectada através do software STRUCTURE v 2.2 e a diversidade genética foi avaliada utilizando o software Popgen v1.32. Para os dados de IRAP o software STRUCTURE sugeriu a existência de dois agrupamentos genéticos (K=2) um com 93 e outro com 127 variedades do total de 430 plantas, considerando apenas a fidelidade acima de 80%. A AMOVA para K = 2 revelou mais variação dentro do grupo (89%) que entre os grupos (11%). Os seis pares de primers IRAP foram informativos para avaliar a diversidade genética, com médias de 96% de polimorfismo, 0.4 de heterozigosidade e com índice de Shannon de 0.57, porém, não detectaram estruturação dentro do germoplasma de mandioca comparada com a estruturação assistida por outros marcadores.

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Infrared photodissociation is used to record the vibrational spectrum of FeO2+(He)2–4 which shows three bands at 1035, 980, and 506 cm−1. Quantum chemical multi-reference configuration interaction calculations (MRCISD) of structures and harmonic frequencies show that these bands are due to two different isomers, an inserted dioxo complex with Fe in the +V oxidation state and a side-on superoxo complex with Fe in the +II oxidation state. These two are separated by a substantial barrier, 53 kJ/mol, whereas the third isomer, an end-on complex between Fe+ and an O2 molecule, is easily converted into the side-on complex. For all three isomers, states of different spin multiplicity have been considered. Our best energies are computed at the MRCISD+Q level, including corrections for complete active space and basis set extension, core-valence correlation, relativistic effects, and zero-point vibrational energy. The average coupled pair functional (ACPF) yields very similar energies. Density functional theory (DFT) differs significantly from our best estimates for this system, with the TPSS functional yielding the best results. The other functionals tested are BP86, PBE, B3LYP, TPSSh, and B2PLYP. Complete active space second order perturbation theory, (CASPT2) performs better than DFT, but less good than ACPF.

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Autism Spectrum Disorders (ASD) are considered developmental disorders that appears in infancy. Early identification and diagnosis enable early intervention. The earlier the child can be identified and treated, the better the long-term outcome. Aim: to adapt the IRDI instrument to retrospective parent report for children from 3;0 to 7;0 years old, administer it in 2 groups and evaluate its sensitivity to screening ASD in comparison with CARS-BR (Brazilian version of Childhood Autism Rating Scale). Method: Participated on the study 72 subjects, parents of children aged from 2;11 to 7;7 years, divided into 2 groups: research group (RG) and control group (CG). The proposed IRDI modification into IRDI-questionnaire, transformed the 31 affirmations from the first into retrospective self-administered questions to parents, with responses in Likert scale. The IRDI-questionnaire was administered in the two groups and the CARS-BR was administered in the CG. The data were submitted to statistical analysis - the chi-square test and the comparison of means test, T-student were used to verify the hom*ogeneity of the groups. For validity, the Pearson's correlation coefficient between IRDI-questionnaire and CARS-BR were performed. A ROC curve was plotted in order to identify the best cut-off point. Sensitivity, specificity and positive predictive value were calculated based on the cut-off point established. In order to study the agreement in IRDI-questionnaire, Kappa s correlation coefficient was calculated. Results: IRDI-questionnaire showed to be easy and quick to administer (average 15 minutes) and with low cost. The internal consistency analysis of the questions calculated by Cronbach s alpha coefficient obtained 0,89 as value. The comparison between the groups by the parents answers to the 31 questions, showed statistically significant difference in 16 questions, with p<0,05. IRDIquestionnaire and CRS-BR comparison by Spearman's correlation coefficient obtained r=0,42, positive correlation, statistically significant between the results of both instruments (p=0,011). The ROC curve plotted identified an area of 84,6%, good performance, statistically significant (p<0,001). The cut-off point established for IRDI-questionnaire indicated sensitivity of 88,9%, specificity of 63,9% and positive predictive value of 71%. Final remarks: we verified that most items of IRDI-questionnaire concerns the main ASD risc signs pointed out in literature. The sensitivity evaluation from the new instrument showed good rates (around 90%), assuring that most children with ASD were identified by IRDI-questionnaire
Os Transtornos do Espectro Autista (TEA) são considerados distúrbios nodesenvolvimento que se apresentam na infância cuja identificação e diagnóstico precocepossibilitam o início das intervenções terapêuticas, melhorando o prognóstico. Objetivos: Adaptaro instrumento IRDI (Indicadores Clínicos de Risco para o Desenvolvimento Infantil) paraquestionário retrospectivo para pais de crianças de 3;0 a 7;0 anos, aplicá-lo em 2 grupos desujeitos e avaliar a sua sensibilidade para rastreamento de TEA por meio da comparação com aescala CARS-BR (Childrood Autism Rating Scale). Método: Participaram do estudo 72 sujeitos,familiares de crianças de 2;11 anos a 7;7 anos, divididos em dois grupos: grupo pesquisa (GP) egrupo controle (GC). A proposta de modificação do instrumento IRDI para IRDI-questionáriotransformou os 31 indicadores (afirmações) do primeiro em perguntas de caráter retrospectivo,dirigidas aos pais em formato auto-aplicável, com respostas em escala Likert. O IRDI-questionáriofoi aplicado nos dois grupos estudados e a CARS-BR foi aplicada no GC. Os dados foramsubmetidos à análise estatística - utilizou-se o teste de associação Qui-quadrado e o teste decomparação de médias T-Student para verificar a hom*ogeneidade entre os grupos. Para avalidade foi realizado o coeficiente de correlação de Pearson entre o IRDI-questionário e CARSBR,somente para o grupo autista. Na definição do ponto de corte do escore gerado peloinstrumento IRDI-questionário, foi utilizada a curva ROC (Receiver Operating Characteristic) ecalculados os valores de sensibilidade, especificidade e valor preditivo positivo (VPP). Na análisede concordância para o IRDI-questionário foi utilizado o coeficiente de Kappa e concordância total.Resultados: O IRDI-questionário mostrou-se de fácil aplicação, rapidez no preenchimento (tempomédio de 15 minutos) e baixo custo. A análise da consistência interna das questões doinstrumento pelo alpha de Cronbach apresentou valor de 0,89. A comparação entre os grupos,segundo as respostas dos pais às 31 questões do IRDI-questionário, mostrou diferençaestatisticamente significativa em 16 delas, com valor de p<0,05. Na comparação com a CARS-BR,o coeficiente de correlação de Spearman foi de r=0,42, apresentou correlação positiva,estatisticamente significativa entre os resultados de ambos os instrumentos (p=0,011). A análiseda curva ROC, identificou uma área de 84,6%, boa performance, estatisticamente significativa(p<0,001). O ponto de corte definido para o IRDI-questionário revelou sensibilidade de 88,9%,especificidade de 63,9% e valor preditivo positivo (VPP) de 71,1%. Considerações Finais: Foipossível verificar que os ítens do questionário recobrem os principais sinais de risco para TEAapontados na literatura. A avaliação da sensibilidade do novo instrumento para fins derastreamento de TEA, mostrou bons índices (em torno de 90%) a partir do ponto de corteestabelecido no estudo, garantindo que boa parte das crianças com TEA da amostra estudadafossem identificadas com o IRDI-questionário

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Dissertação (mestrado)—Universidade de Brasília, Faculdade de Direito, 2014.
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A sociedade brasileira passou por importantes modificações nos últimos quarenta anos. O modelo liberal do processo civil revelou-se insuficiente para acompanhar tais modificações, provocando uma crise de acesso à justiça. Os novos instrumentos de tutela processual coletiva que foram introduzido no ordenamento pátrio ainda não estão sedimentados e consolidados, o que dá azo ao aparecimento dos direitos repetitivos, fenômeno que se traduz em milhares de demandas individuais, seriadas e massificadas, que tratam dos mesmos assuntos e, com isso, ameaçam obstruir e inviabilizar os trabalhos do Poder Judiciário. O estudo de ferramentas processuais que impeçam ou minorem tal fenômeno é então necessário. De tal modo, importante se investigar como os ordenamentos jurídicos de outros países lidam com esse problema, estudando os principais mecanismos que eles desenvolveram. Assim, estudam-se as class actions do direito norte-americano, as group litigation orders do direito inglês e também o Musterverfahren do ordenamento alemão, procurando-se descrever seus procedimentos e extrair daí as suas principais características. De igual modo, a maneira pela qual se trata a nefasta questão dos direitos repetitivos dentro do ordenamento processual pátrio é importante. Logo, examinam-se os institutos de tutela coletiva, como ações civis públicas e outros, mais diretamente voltados para o enfrentamento dos direitos repetitivos, como súmulas vinculantes, repercussão geral, recursos especiais repetitivos, improcedência liminar do pedido, o pedido de uniformização de interpretação perante os juizados especiais junto ao STJ e outros instrumentos de coletivização. Traçado o panorama da atual legislação, a análise das inovações que estão sendo introduzidas pelo novo CPC, atualmente em votação pela Câmara dos Deputados – PL nº 8.046/2010 – também deve ser examinada, eis que o novo estatuto processual tem como uma de suas premissas o combate aos direitos repetitivos. Por aí, discute-se os institutos já existentes e como serão mantidos, alterados, afetados e harmonizados pelo novo diploma legal, segundo a cultura de precedentes judiciais que está sendo entronizada. Enfim, também é importante que se faça o exame mais acurado do novo incidente de resolução de demandas repetitivas, inspirado justamente no Musterverfahren do direito tedesco. A comparação com os institutos existentes no direito comparado e nacional dá uma pista sobre como o novo instrumento processual pode ser aprimorado e utilizado de mais efetiva e integrada no enfrentamento da questão dos direitos repetitivos.
Brazilian society went through important changes in the last forty years. The liberal model of civil procedures has presented itself insufficient to follow such changes, which has created a crisis into the access of justice. The new class actions procedural protection tools introduced into the domestic law are not yet settled and consolidated. This unsettled and unconsolidated situation gives rise to the appearance of repetitive rights; a phenomenon that brings forth thousands of individual, serial and massed lawsuits, addressing the same issues and thereby threaten to obstruct and derail the work of the Judiciary. The study of procedural tools to prevent or lessen such phenomenon is then necessary. Hence, it is important to investigate how legal systems of other countries deal with this problem by studying the basic mechanisms they have developed. Thus, in the present dissertation, U.S. Law class actions, English Law group litigation orders and the German Law Musterverfahren are studied; and, an attempt to describe their respective procedures, in order to extract its main features, is endeavored. Similarly, it is studied the manner in which the pernicious issue of repetitive lawsuits is dealt with within the domestic procedural law. As such, this dissertation examines the institutes of class action protection, such as civil suits and other; and, more directly, institutes geared to face repetitive lawsuits, such as binding precedents, general repercussion, repetitive special appeals, preliminary dismissal of requests, requests for uniformity of interpretation before small claims courts by the Supreme Court of Justice, and other instruments of collectivization. Once an overview of the current legislation is done, the analysis of the innovations that are being introduced by the new Code of Civil Procedure (currently in debate by the House of Representatives – Bill No. 8.046/2010) should also be examined, as this new procedural code has as one of its premises the fight against repetitive lawsuits. From this exam, existing institutes should be assessed as how will they be maintained, changed, affected and harmonized by new procedural legislation, according to the judicial binding precedents being enthroned therein. Finally, it is also important to make the most accurate examination of the new incident of resolution to repetitive requests, inspired precisely in the German Law Musterverfahren. The comparison with existing institutes in the domestic and foreign law gives a hint about how the new Civil Procedural Code could be enhanced, effectively used, and integrated in confronting the issue of repetitive lawsuits.

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Les aminopeptidases de la famille M1 sont des protéases qui catalysent l’hydrolyse d’une liaison peptidique en position N-terminale. Ce sont des métalloprotéases avec un ion zinc dans leur site actif conservé dans tous les membres de cette famille de protéine. Ces enzymes sont impliqués dans de nombreux processus physiologiques normaux, mais également dans des désordres métaboliques, tels que la progression tumorale, des maladies auto-immunes, ainsi que dans des infections virales, bactériennes et parasitaires. Pour ces raisons, ces aminopeptidases sont considérées comme des cibles thérapeutiques potentielles pour traiter ou diagnostiquer diverses maladies. En 2006, le laboratoire a découvert le châssis moléculaire de type 3-amino-2-benzosubérone inhibant puissamment et sélectivement et un des membres de cette famille d’aminopeptidases, à savoir l’APN. La conception et la synthèse des dérivés de ce châssis moléculaire comme inhibiteurs potentiels et sélectifs pour cinq autres membres de la famille M1 (APN, ERAP1/2, IRAP et PfA-M1) est au cœur de ce travail. Des études pharmacologiques, pharmacocinétiques jusqu’aux essais précliniques ont été menées et leurs résultats seront présentés dans le cas de l’inhibition de PfA-M1
Aminopeptidases of the M1 family are proteases that catalyze the hydrolysis of a peptide bond in the N-terminal position. These are metalloproteases with a zinc ion in their active site conserved in all members of this protein family. These enzymes are involved in many normal physiological processes, but also in metabolic disorders, such as tumor progression, autoimmune diseases, as well as in viral, bacterial and parasitic infections. For these reasons, these aminopeptidases are considered potential therapeutic targets for treating or diagnosing various diseases. In 2006, the laboratory discovered the powerful and selectively inhibiting 3-amino-2-benzosuberone molecular chassis and one of the members of this family of aminopeptidases, namely the APN. The design and synthesis of derivatives of this molecular chassis as potential and selective inhibitors for five other members of the M1 family (APN, ERAP1 / 2, IRAP and PfA-M1) is at the heart of this work. Pharmacological, pharmaco*kinetic and preclinical studies have been conducted and their results will be presented in the case of PfA-M1 inhibition

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