Dissertations / Theses on the topic 'AEFI'

I commenced the Master of Philosophy in Applied Epidemiology (MAE) in February 2015. My field placements were shared between the Communicable Diseases Control Directorate, Public Health Division at the Western Australia Department of Health (CDCD) and the Telethon Kids Institute (TKI), both located in Perth. Two of the three projects that I completed at the CDCD involved a statewide protracted mumps outbreak that went on for the duration of my MAE and reached almost 900 cases. The epidemiology of this outbreak including a discussion about vaccination is presented in Chapter 1. This satisfies the outbreak investigation requirement of the MAE. Chapter 2 comprises a late draft manuscript that explores the vaccine effectiveness (VE) of the measles-mumps-rubella vaccine among paediatric cases during the mumps outbreak. I designed and carried out a matched case-control study using paediatric outbreak cases and controls from a population database. I measured VE using a conditional logistic regression model and compared it with the screening method. Both methods yielded a very low VE this population. This is likely due to a multitude of factors that are discussed in the chapter. My work at TKI involved a data analysis using linked-administrative data on a total population birth cohort involving all children born in Western Australia between 1996-2012. I explored the burden of hospital separations that resulted from otitis media (OM), the most common infectious disease in children, and a common related procedure, myringotomy with ventilation tube insertion (MVTI). I calculated the age-specific hospitalisation rates for OM and MVTI over the study years. The second part of this analysis involved investigating the maternal and infant risk factors and population attributable fractions for OM-related hospitalisation in early life. This work was important because of its implications for practice. All of this is presented in Chapter 3. Chapter 4 is an evaluation of SmartVax, a novel, real-time Adverse Events Following Immunisation (AEFI) surveillance system using SMS text messages to communicate directly with vaccinees after their vaccination. This was the third project that I completed at the CDCD. The chapter begins with a peer-reviewed publication, Continuous active surveillance of adverse events following immunisation using SMS technology, that describes the system and analyses data outputs for children <5 years from 2011-2015. I have included the publication first to provide a brief system overview including summarised surveillance data, to give context to the evaluation since SmartVax is a relatively new and developing system. The publication is followed by the formal evaluation. Finally, I include a summary of the teaching exercises that I was involved in during my MAE. The first was a “lesson from the field” where I prepared an exercise for my fellow scholars. The exercise was useful for me and the feedback from my colleagues was positive. The second was a collaborative teaching exercise about confounding that we taught to the first year MAE scholars on their last day of courseblock. These combined activities at both placements have enriched my understanding of epidemiology while working in health and research environments.

Several items need consideration when products are evaluated for use as transition agents. These are (1) efficacy of ryegrass removal [rate of ryegrass decline and appearance of turf during transition], (2) tolerance and performance of incoming bermudagrass and (3) application safety for next season’s repeat overseed operations. This test was designed to evaluate application safety for the next overseeding which occurs in the early fall. Therefore, AEF was applied in the summer to bermudagrass turf prior to overseed operations. Most responses of the perennial ryegrass (overseed) turf to previous treatments of AEF 130360 occurred immediately after overseeding, from mid-October to early November. AEF 130360 applied 2 weeks before overseeding caused a significant decrease in seedling vigor, percent plot ryegrass cover, and percent bermudagrass plot straw present. Both AEF treatments applied closest to overseeding (2 weeks prior) had the least amount of initial ryegrass, the greatest amount of green bermudagrass, and later in the season, the most amount of straw (dormant) bermudagrass. Differences in turfgrass quality were not significant due to treatments at any time throughout the test, and most treatments ranked higher than the control in overall quality. Under the conditions of this test, application of AEF 130360 at either 0.64 or 1.28 ounces/product/M made one month before actual oversseding did not cause detrimental effects to ryegrass emergence, ryegrass cover, turfgrass color or overall quality.

The mythic story of Niobe, who loses her children due to hubris and is eventually transformed into a crying rock on Mount Sipylos, is well known and rearticulated throughout classical Greek literature. In this master’s thesis I aim to examine fragment 154a of Aeschylus’ lost tragedy Niobe in order to show the significance of the tragic re-enactment of silence and grief. Furthermore, I argue that the fragment of Aeschylus manifests political and aesthetic aspects that enable an immersed and widened understanding of the genre. Loraux (1997/2002) and Montiglio (2000) indicate that there might be a female correlate to the epic tradition of safeguarding honour after death. As I point out in this thesis, there is a potential gap in the study of how ancient Greek literature reenacts such alternative themes and experiences of memory and oblivion. A decisive consequence of the analysis is the new understanding of a tragic hero(ine) inverting the ancient epic tradition of remembrance, glory, and immortality typically accompanying male heroes. By means of classical perspectives on grief, as well as more recent studies of acoustic aesthetics in ancient Greek culture (Nooter 2017), the thesis demonstrates how Niobe can be viewed as a prime symbol of the tragic female, whose resistance to forget resonates throughout the tragic corpus.

El marco general de esta tesis ha sido el Proyecto EDUTODOS: Progresos y limitaciones de la Educación para Todos: la política de la agenda educativa, la tendencia de las desigualdades educativas y la calidad de la democracia en América Latina, del Grupo Interdisciplinar sobre Políticas Educativas de la Universidad Autónoma de Barcelona y la Universidad de Barcelona. Específicamente, se estudió la relación entre el primero de los Objetivos de la Educación Para Todos, la Atención y Educación para la Primera Infancia (AEPI) y la reducción de las desigualdades sociales en México. Actualmente, la Educación Inicial No Escolarizada (EINE) es la principal estrategia de AEPI aplicada en ese país. El objetivo general del trabajo fue elaborar un perfil de indicadores de buenas prácticas en AEPI en contextos de desigualdad social en el Estado de Puebla, México. A partir de la revisión de la bibliografía más relevante en la temática, se describió el estado actual de la AEPI en el mundo y su relación con la disminución de las desigualdades sociales. Se elaboró una propuesta de indicadores de AEPI en contextos de desigualdad social que se denominó Modelo de Indicadores de Buenas Prácticas en Atención y Educación Para la Primera Infancia (MIBP-AEPI). Finalmente, a partir de la propuesta de indicadores, y como resultado del trabajo de campo, se detectaron factores comunes en experiencias de buenas prácticas de AEPI en Puebla y se elaboró un perfil de indicadores de buenas prácticas en AEPI en contextos de desigualdad social. Se concluye que las buenas prácticas estudiadas se insertan en contextos caracterizados por las desigualdades en los ámbitos demográficos, económicos y socioculturales, y que algunas de estas desigualdades son compensadas por las buenas prácticas del programa de EINE.
The general framework of this thesis was the EDUTODOS Project. Progress and limitations of the Education for All: policy of educational agenda, the trend of educational inequalities, and the quality of democracy in Latin America, of the Interdisciplinary Group on Educational Policy (Autonomous University of Barcelona and University of Barcelona). Specifically, it was studied the relationship among the first of the Objectives of Education For All, the Early Childhood Care and Education (ECCE), and the reduction of social inequalities in Mexico. Currently, the Non-schooled Initial Education (NSIE) is the main ECCE strategy applied in that country. The aim of this research was to develop a profile of indicators of good practice in ECCE in contexts of social inequality in the State of Puebla, Mexico. After reviewing the most relevant literature on the subject, it was described the status of ECCE in the world and its relationship with the reduction of social inequalities. It was developed a proposal of indicators of ECCE in contexts of social inequality that was called Model of Indicators of Good Practice in Early Childhood Care and Education. Finally, based on the proposed indicators, and as a result of the fieldwork, common factors were found in experiences of good practice in ECCE in Puebla and it was developed a profile of indicators of good practice in ECCE in contexts of social inequality. It was concluded that good practices are embedded in contexts characterized by inequalities in demographic, economic and socio-cultural areas, and that some of these inequalities are compensated by the good practices of the NSIE program.

L™objectiu de la present tesi era contribuir al coneixement de les conseqüències i l™impacte de la qualitat i seguretat operacional en la rendibilitat de les companyies aèries, així com destacar la importància i necessitat de la comptabilitat de gestió i els seus indicadors clau de gestió (KPIs, o Key Performance Indicators) a la industria aèria. Per tal de cobrir aquest objectiu, es va desenvolupar un compendi de sis articles acadèmics per respondre a les preguntes de recerca plantejades i resoldre els gaps existents a la literatura. Les principals conclusions i resultats van revelar una influencia positiva i significativa de la qualitat de servei en la rendibilitat mesurada com rendibilitat econòmica (ROI, o return on investment) de les companyies aèries nord-americanes; i un efecte no significatiu per a la qualitat sobre els ingressos de passatge de les aerolínies. Per un altre banda, l™efecte de la seguretat operacional era el contrari. Per tant, es va confirmar un efecte no significatiu per a la seguretat operacional en la rendibilitat de les aerolínies, mentre que l™efecte de la seguretat operacional sobre els ingressos de passatge de les aerolínies va ser significatiu.
El objetivo de la presente tesis era contribuir al conocimiento de las consecuencias e impacto de la calidad y seguridad operacional en la rentabilidad de las compañías aéreas, así como destacar la importancia y necesidad de la contabilidad de gestión y sus indicadores clave de gestión (KPIs, o Key Performance Indicators) en la industria aérea. Con el fin de lograr este objetivo, se desarrolló un compendio de seis artículos académicos para responder a las preguntas de investigación planteadas y resolver los gaps existentes en la literatura. Las principales conclusiones y resultados revelaron una influencia positiva y significativa de la calidad de servicio en la rentabilidad medida como rentabilidad económica (ROI, o return on investment) de las compañías aéreas estadounidenses; y un efecto no significativo de la calidad sobre los ingresos de pasaje de las aerolíneas. Al mismo tiempo, se comprobó que el efecto de la seguridad operacional era en sentido contrario. Por lo tanto, se confirmó un efecto no significativo para la seguridad operacional en la rentabilidad de las aerolíneas, mientras que el efecto de la seguridad operacional sobre los ingresos de pasaje de las aerolíneas fue significativo.
This Doctoral Thesis aimed to contribute to an understanding of the consequences and impact of quality and safety on profitability of airline companies, as well as to emphasize the importance and need for management accounting and its Key Performance Indicators (KPIs) in the airline industry. In order to cover this goal, a compendium of six academic papers were developed to answers to the research questions introduced and deal with existing gaps in the literature. The main findings and results revealed a positive and significant influence of service quality on the profitability measured as Economic return (ROI, or return on investment) of US airline companies; and a non-significant effect for quality on airline passenger revenues. While the effect of safety was vice versa. Thus, a non-significant effect for safety on profitability of airlines was confirmed, whereas the effect of safety on airline passenger revenues was significant.

Notre thèse s'appuie sur des travaux en sciences de l'éducation et en sociologie (Huberman, 1995 ; Fullan, 1998 ; Fullan et Hargreaves, 2012) qui défendent l'idée selon laquelle le travail en réseau des enseignants serait le levier de leur développement professionnel. Notre étude analyse les modalités du travail en réseau des enseignants du secondaire dans le réseau des établissements de l'Agence pour l'Enseignement Français à l'Étranger (AEFE) au Liban. En effet, nous défendons l'idée que les spécificités et la complexité inhérentes à ce réseau, et engendrées par la diversité des statuts et des styles de direction de ses établissements, questionnent avec beaucoup d'acuité la problématique de l’articulation entre la formation continue des enseignants, leur développement professionnel et le travail en réseau. Notre objectif principal est de mieux comprendre le fonctionnement de chacun des établissements du réseau de l'AEFE au Liban, les modalités de la mise en place de la formation continue au sein de ce réseau et la perception de son efficacité par les enseignants qui en bénéficient, afin de vérifier si ces dispositifs de formation, tels qu'ils existent actuellement, amènent effectivement les enseignants à travailler en réseau et contribuent à leur développement professionnel. Compte tenu de la complexité des paramètres à prendre en considération, la méthodologie appliquée s'appuie sur une double approche qualitative et quantitative. La combinaison de ces méthodes nous a permis de dresser une cartographie de l'ensemble des interactions au sein du réseau ainsi que des dynamiques de travail en réseau réellement observables sur le terrain. Les résultats de notre étude montrent que, malgré les directives des textes officiels, la formation continue dans le réseau de l'AEFE au Liban favorise peu le développement professionnel de ses enseignants. La coopération en réseau entre les enseignants ou les établissements est partielle. Ces phénomènes empêchent les enseignants de changer leur posture à l'égard de leur métier et d'embrasser un nouveau modèle de développement professionnel. De plus, les dispositifs de formation continue proposés par l'AEFE au Liban ne remplissent pas complètement leurs missions et ne fonctionnent pas en synergie comme ils le devraient. Cela entrave la mise en place d'une véritable « culture de réseau ». Le paradigme de « la culture de cités », emprunté au champ de la philosophie politique, permet de mieux comprendre plusieurs enjeux et causalités complexes. Les modèles de cités qui fonctionnent en systèmes selon des principes définis et variés constituent une véritable « grammaire » des liens politiques et sociaux. Ils fournissent le cadre nécessaire aux interactions entre ses acteurs et assoient leur conception du bien commun. Nous montrons comment ces modèles de gouvernance de cités, qui peuvent varier ou s'entrecroiser en fonction de facteurs conjoncturels, sont pertinents pour étudier les styles de direction des établissements, la manière dont ils s'inscrivent dans le réseau de l'AEFE et y inscrivent ou pas le travail en réseau de leurs enseignants. Nous proposons un nouveau paradigme qui permettrait au réseau des établissements de l'AEFE au Liban de passer d'une « culture de cité » à « une culture de réseau ». Il s'agirait d'élaborer un modèle de formation qui remette en dialectique le travail en réseau intra- et inter-établissements avec une dynamique de travail en synergie de l'ensemble des dispositifs de formation continue. Les parcours de l'élève et de l'enseignant seraient placés au cœur de la réflexion et des modalités de mise en œuvre du travail en réseau des enseignants comme vecteur de développement professionnel pourraient être redéfinies
Study of networking among teachers within the schools of The Agency for French Education Abroad in LebanonRésumé : This dissertation draws on a number of research studies in education and sociology (Huberman, 1995 ; Fullan and Hargreaves, 2012). It is based on the fact that teachers’ networking can be a lever for their professional development. Our research study examines the modalities of secondary school teachers’ interactive dynamics in the AEFE (Agency for French Education Abroad) school network in Lebanon. This specific network which comprises 43 schools across the country is known for being one of the biggest AEFE networks in the world. Its particular geopolitical and multicultural structure helps reflect the excellence and the visibility of French education abroad. Indeed, the inherent specificity and complexity of this network, characterised by its various leadership styles, questions the articulation between teacher training, professional development and networking. Our aim is to better understand how each school operates. Our goal is also to understand teacher training modalities within the school network and the teachers’ perceptions of their efficacy. More precisely, we need to know whether the current three teacher training programmes foster teachers’ networking and enhance their professional development. We have selected a stratified sample of 10 schools. Our representative sample consists of secondary school teachers, school principals, assistant head teachers and academic advisors. Our work is based on the findings of an exploratory survey on head teachers conducted in three AEFE schools in 2010-2011. We have designed many questionnaires : 423 were completed by teachers and coordinators, 380 others were completed by 380 students. We have conducted 51 interviews with schools principals, assistant head teachers, academic advisors as well as AEFE representatives. Given the complexity of the parameters to be taken into consideration, our methodology is both qualitative and quantitative. Statistical analysis tools were designed, sociogrammes and thematic analysis methods were applied as well. The frequency of occurrences in the interviewees’ utterances were analysed. The combination of analysis methods helped us draw a map representing teachers’ interactive dynamics of the school network.Our research findings show that, despite the directives and official texts, the AEFE teacher training programmes offer little support that fosters teachers’ professional development. There is little cooperation between teachers. These phenomena prevent teachers from embracing a professional development model. Furthermore, the three teacher training programmes do not really fulfill their mission since they are not synergistically connected, which hampers the emergence of networking culture. The paradigm of « imaginary cities » belonging to political philosophy helps better understand complex causalities and challenges. We show evidence that governance models can vary or overlap depending on several cyclical factors. These governance models correspond to the various leadership styles in the AEFE network and affect teachers’ networking practices. We suggest a new paradigm which enables the AEFE school network to shift from a culture of « city governance » to a « networking culture ». Our paradigm consists of a teacher training programme which establishes a dialectic unity between intra- and inter-establishment networking and synergy between the teacher training programmes. The student’s academic path as well as the teacher’s professional path will be at the heart of this paradigm. This will launch the essential foundations of a networking culture which fosters teachers’ professional development. Moreover, this new model can be implemented worldwide in other school networks which might be confronting similar issues

Secondary amyloidosis was induced in mice with daily consecutive injections of casein or in an accelerated form with the injection of the "Amyloid-Enhancing Factor" (AEF). Innate susceptibility to the disease operated at the level of the production of AEF. AEF activity was purified to one protein component with an apparent molecular weight of 55,100Da. Increased disappearance of the amyloid A (AA) fibril precursor apo-SAA2 did not correlate exactly with amyloid deposition. Multiple splenic macrophage phenotypes and functions were modulated during the two induction protocols. Splenic macrophages from normal or casein-injected mice could not degrade in vitro HDL$ sb3$-SAA2. The catabolism was induced by the exogenous addition of soluble AEF and/or Serum Amyloid P. Finally, AA and amyloid PO proteins were simultaneously deposited in the spleen with respect to time and tissue localization during the two induction protocols. In conclusion, the appearance of AEF in organs during the development of secondary amyloidosis was accompanied by the modulation of the splenic macrophage phenotype and function.

This thesis concerns the history of humanitarian nutrition and its political implications. Drawing on aid agency archives and other historical sources, it examines how food has been delivered in emergencies, from the First World War to the present day. The approach is ethnographic: this is a study of the micro-level practices of relief, examining the objects distributed, the plans made, the techniques used. It is also historical: examining how such practices have changed over time. This thesis makes five interlocking arguments. First, I make a political point: that humanitarian action is always political, and that it is impossible to adhere to ‘classical’ humanitarian principles such as neutrality, impartiality and independence. Second, I make a sociological argument: that the activities of humanitarian nutrition have been shaped by a number of themes, which include militarism, medicine, modernity, and markets. Third, I make a historical argument: that the main features of humanitarian nutrition were solidified between the 1930s and the 1970s, and were largely in place by the time of the Biafran war. Fourth, I make a sociological argument: that these mid-century changes involved a profound redefinition of hunger and food (with hunger conceived as a biochemical deficiency, and food as a collection of nutrients). Finally, I make a normative argument, suggesting that this redefinition has not necessarily benefited the starving: the provision of food in emergencies, I argue, is often concerned with control and efficiency rather than the suffering individuals themselves.

The homologous recombination (HR) pathway of DNA repair is essential for the faithful repair of double-stranded DNA breaks (DSBs) in all organisms and as such helps maintain genomic stability. Furthermore, HR is instrumental in the cellular response to exogenous DNA damaging agents such as those used in the clinic for chemo- and radiotherapy. HR in humans is a complex, incompletely understood process involving numerous stages and diverse biochemical activities. Advancing our knowledge of the HR pathway in humans aids the understanding of how chemo- and radiotherapies act and may be used to develop novel therapeutic strategies. Recent studies have identified inhibition of HR as one of the mechanisms via which a number of recently developed chemotherapeutics have their effect. Accordingly, the clinical potential of HR inhibitors is under investigation. My work has centred around the identification of both novel HR proteins and novel, small molecule HR inhibitors. To further these aims, I have successfully employed high-throughput RNAi and small molecule screening strategies. RNAi screens are commonly used to identify genes involved in a given cellular process via genetic loss of function, whilst small molecule, cell based screens are a powerful tool in the drug discovery process.

Around 70% of human genes have been found to contain multiple cleavage and polyadenylation (pA) sites. The alternative usage of these different pA sites is referred to as alternative cleavage and polyadenylation (APA). A wide range of studies have described switches in APA profiles when comparing different cell types and different cell states, notably general shifts to shorter APA isoforms upon the onset of cancer. These shifts have been described at both the individual gene and transcriptome levels. However, the extent to which these changes in APA profiles are contributing to changes in gene expression, and thereby altering the observed phenotype, is still under debate. This thesis develops a novel subcellular fractionation approach to isolate those genes where the alternative use of different pA sites results in APA isoforms that differ in either the cytoplasmic stability or nuclear export rates. These differences would materialise as a differential representation of the resulting APA isoforms in the cytoplasmic and nuclear RNA fractions. This approach was applied to 12 human cell lines using a combination of publicly available generic poly-A+ RNA-sequencing data and 3'end sequencing performed here. Eleven out of twelve of these cell lines showed a significant bias towards an overrepresentation of the shorter, proximal APA isoform in the cytoplasm, which fits with the general model that 3'untranslated regions (3'UTRs) are mainly repressive and promote cytoplasmic instability. Comparisons of the isolated genes for each cell line show that differential regulation of APA isoforms tends to be largely cell type specific. Application of this subcellular fractionation approach to a cell-line based model for colorectal cancer progression highlights a small cohort of genes where APA is likely to have an impact on gene expression, potentially contributing to colorectal cancer progression. This analysis provides an ideal starting point to study these APA events at the individual gene level to elucidate fully whether APA is having a significant impact on gene expression. Furthermore, post-transcriptional regulatory pathways governing these differential regulation events were investigated, including the contribution of micro-RNAs (miRNAs) to the differential regulation of APA isoforms. Unexpectedly, depletion of the endoribonuclease III, DICER1, reveals that it does not only shape the steady-state cytoplasmic APA profile through its well-known function in miRNA biogenesis, but also influences pA site choice in the nucleus.

The postnatal/adult subventricular zone (SVZ) harbours neural stem cells (NSC), which produce neurons that migrate to the olfactory bulbs. SVZ NSC share several biological features with glia, especially reactive astrocytes. However, it is not clear how SVZ NSC simultaneously maintain self-renewal stem cell properties and the potential for generating daughter cells that differentiate into neurons. Multiple cyclin-dependent kinase inhibitors (CDKIs), including p16, p19 and p21 have been identified as indispensable for maintaining stem cell potential, in both cyclin dependent and independent manners. However, how these CDKIs are coordinated remains poorly defined. One possible regulator of CDKIs is the canonical Polycomb Repressive Complex 2 (PRC2) that consists of Eed, Suz12, and Ezh2. Ezh2 functions to methylate lysine 27 of histone 3 (H3K27me3) and consequently suppresses target gene expression. Whereas PRC2 serves to balance self-renewal versus differentiation and neuron versus glial fate choices in early and late embryogenesis, respectively, our understanding of its role in the neonatal and adult SVZ is incomplete. In this thesis, I discovered that the PRC2 core subunit Eed, but not Ezh2, was expressed in SVZ NSC. Eed directly repressed p16 and p19, but indirectly fine-tuned p21 expression in SVZ NSC. Conditional deletion or knockdown of Eed in vivo led to loss of constitutive SVZ stemness and blocked NSC activation. This was partly due to selective activation of the PRC2 targets, Cdkn2a and Gata6; in contrast Ezh2 loss of function only activated Cdkn2a but not Gata6. In the SVZ, Gata6 overexpression was sufficient to limit the neurogenic ability of NSC and also inhibited p21 post-transcriptional expression. I also showed that although reactive astrocytes in the cerebral cortex can acquire stem cell properties in response to brain injury, Eed was not involved in this process. Taken together, I identified novel and divergent regulation of SVZ CDKIs by separate subcomponents of PRC2, and showed that these are essential for SVZ NSC maintenance. Whilst this regulatory pathway was specific in the neurogenic niche it had little influence on parenchymal astrocytes. In a relatively small side project, I screened and identified several long non- coding RNAs (lncRNA) that were highly expressed in the adult rodent SVZ. The lncRNA Paupar, which is transcribed upstream from the Pax6 antisense strand, was enriched in the postnatal SVZ and regulated Pax6 and Ezh2 expression. In vivo, Paupar knockdown showed it is necessary for stem cell maintenance and thus regulates postnatal neurogenesis. To conclude, I discovered two interacting epigenetic regulators that control postnatal SVZ NSC and neurogenesis.

The Apolipoprotein E (APOE) ε4 allele is the best-established genetic risk factor for sporadic Alzheimer's disease (AD) while the ε2 allele confers a reduced risk compared with the most common ε3 allele. Neuroimaging studies using magnetic resonance imaging (MRI) have shown that APOE genotype affects brain structure and function. The aims of the research presented in this DPhil thesis were twofold: 1) to investigate the effect of APOE genotype on brain function in healthy adults using magnetoencephalography (MEG), which is a direct measure of neuronal activity and 2) to explore interactions between the AD risk factors APOE ε4 allele, age and female gender and their effects on brain structure and function using resting-state functional MRI and diffusion tensor imaging. MEG revealed similar neuronal activity at rest for APOE ε2 and ε4 carriers, i.e. those with opposite AD risk, indicating a more general effect on the functional architecture of the brain that is not directly linked to AD risk. However, differences between APOE ε2 and ε4 carriers became apparent when reactivity to stimuli was explored using the excellent temporal resolution of MEG. APOE ε4 carriers showed faster sensory pro- cessing and APOE genotype effects were found for functional networks associated with attention. In the second part of this project, female APOE ε4 carriers showed overall significantly reduced functional connectivity between the hippocampus and precuneus and a significant age-related decrease in connectivity of these regions. Increased vulnerability of this connection might be one reason for increased AD risk and interventions targeting hippocampal connectivity might be especially effective in at-risk populations. The research presented in this DPhil thesis showed a complex pattern of APOE genotype effects on brain structure and function. While global APOE genotype effects on functional and structural connectivity do not follow patterns of AD risk, more specific measures of connectivity and task-related brain function could be of use in the development of preclinical markers for AD development.

Scholars are divided on reading the teachings on riches in 1 Tim. Evidence that has been largely overlooked in NT scholarship, Ephesiaca by Xenophon of Ephesus, suggests that the topic be revisited. Ephesiaca is a story about a rich Ephesian couple. This text brings to life what is known from ancient sources about the social setting and cultural rules of the rich in Ephesus and adds derails to enhance our knowledge of life and society. Recent scholarship has dated Ephesiaca to the mid-first century CE. If the Acts narrative is reliable, this locates the story in broadly the same timeframe as the ministry of Paul in Ephesus. Interestingly. the story contains some of the same general themes and rare terms found in the teachings on riches in I Tim. My argument does not focus on locating specific dates for I Tim or Ephesiaca. but rather, my aim is to analyze these two texts alongside each other and extant ancient sources. My dissertation begins by introducing Ephesiaca and the socio-rhetorical methodology used to explore it alongside other evidence and I Tim. The methodology has five parts: social and cultural texture, inner texture, intertexture. ideological texture, and sacred texture. The first texture is helpful for locating a Sitz im Leben of the rich in Ephesus, the social and cultural context that preceded the texts of I Tim and Ephesiaca. The four remai ni ng textu res are employed to scrutinize five passages: I Tim 2:9- \ 0; 3:1- 13; 6: 1-13; 6:2b- IO; and 6: 17- 19. The findings of this study reveal a fresh perspective on these texts. The teachings on riches in 1 Tim appear to call followers of Jesus to handle riches in a counter-cultural manner that is consistent with the trajectory of other NT teachings when read in light of ancient sources and Ephesiaca by Xenophon of Ephesus.

If you have an idea about applying a proven technology to improve the processes in a new area of society, what does it take to implement it in a way that it has wide impact and endures? This is a relevant question particularly now, at the dawn of the age of 'big data', as information and communication technologies are adopted in many areas to harness the ability to collect, retrieve and analyse large amounts of information, and be made available at the level of individual users. Extraordinarily powerful devices developed in recent years offer much promise, but as many examples, such as Betamax, WAP-technology, HD DVD and netbooks, show that even potent technologies may fail to gain predominance and survive. The concept of institutional entrepreneurship is a useful framework to analyse these complex issues as it embodies a comprehensive analytical perspective, combining attention to the institutional environment as well as to the efforts by interested and re-sourced actors. I use this concept to I investigate the efforts to introduce mobile technology into health care in England and Finland. I employ a distinct research strategy that avoids a retrospective bias, through the collection and analysis of qualitative data before known outcomes, from a wide range of technology, care, regulatory and intermediary organisations. I uncover some of the difficulties to technology adoption and develop arguments about the types of efforts and the impact of context at the early moment stage that contribute to the further development of the concept of institutional entrepreneurship.

Genome-wide association studies have greatly improved our understanding of the contribution of common variants to the genetic architecture of complex traits. However, two major limitations have been highlighted. First, common variant associations typically do not identify the causal variant and/or the gene that it is exerting its effect on to influence a trait. Second, common variant associations usually consist of variants with small effects. As a consequence, it is more challenging to harness their translational impact. Association studies of rare variants and complex traits may be able to help address these limitations. Empirical population genetic data shows that deleterious variants are rare. More specifically, there is a very strong depletion of common protein truncating variants (PTVs, commonly referred to as loss-of-function variants) in the genome, a group of variants that have been shown to have large effect on gene function, are enriched for severe disease-causing mutations, but in other instances may actually be protective against disease. This thesis is divided into three parts dedicated to the study of protein truncating variants, their medical relevance, and their functional consequences. First, I present statistical, bioinformatic, and computational methods developed for the study of protein truncating variants and their association to complex traits, and their functional consequences. Second, I present application of the methods to a number of case-control and quantitative trait studies discovering new variants and genes associated to breast and ovarian cancer, type 1 diabetes, lipids, and metabolic traits measured with NMR spectroscopy. Third, I present work on improving annotation of protein truncating variants by studying their functional consequences. Taken together, these results highlight the utility of interrogating protein truncating variants in medical and functional genomic studies.

Many scholars of the First World War have examined the European armies in new ways that have shown not only how those armies actually fought along the Western Front, but how they changed their ideas and methods over time, and why they fought the way they did. This dissertation does the same for the American Expeditionary Forces (AEF). It examines how four AEF divisions (the 1st, 2nd, 26th, and 77th) planned and conducted their battles, what they learned about modern combat in those battles, and how they adapted their doctrine, tactics, and other operational methods during the war. Although this dissertation describes AEF training and operations, its focus is on ideas and methods, and the changes in both during the war. It shows that when the United States joined the war in 1917, the U.S. Army was doctrinally unprepared for the industrial combat of the Western Front. It demonstrates that General John J. Pershing and other AEF leaders accepted this inadequate prewar doctrine, with only minor modification, as the official doctrine of the AEF. Many early American attacks suffered from these unrealistic ideas, which retained too much faith in the infantry rifleman on a battlefield dominated by artillery, machine guns, and barbed wire. However, this dissertation also shows that AEF divisions adjusted their doctrine, tactics, and other operational methods, as they fought. Experienced divisions prepared more comprehensive attack plans, employed more flexible infantry formations, and maximized firepower to seize limited objectives. Although some of these adaptations were accepted by senior officers at AEF General Headquarters (GHQ), the American First Army, and the various corps, the lessons seem to have been learned first, and best, by officers and men within the combat divisions. Often the extent of these changes reduced the operational relevance of senior officers at GHQ, including Pershing, many of whom failed to make the same doctrinal adjustments. In short, this study exposes the battle of ideas waged within the AEF, between those who adhered to the traditional, human-centered ideas of the prewar army and those who increasingly appreciated the modern, industrial ideas then prevalent in the European armies.

In recent years the field of real numbers expanded by a multiplicative subgroup has been studied extensively. In this thesis, the known results will be extended to expansions of the real field. I will consider the structure R consisting of the field of real numbers and an irrational power function. Using Schanuel conditions, I will give a first-order axiomatization of expansions of R by a dense multiplicative subgroup which is a subset of the real algebraic numbers. It will be shown that every definable set in such a structure is a boolean combination of existentially definable sets and that these structures have o-minimal open core. A proof will be given that the Schanuel conditions used in proving these statements hold for co-countably many real numbers. The results mentioned above will also be established for expansions of R by dense multiplicative subgroups which are closed under all power functions definable in R. In this case the results hold under the assumption that the Conjecture on intersection with tori is true. Finally, the structure consisting of R and the discrete multiplicative subgroup 2^{Z} will be analyzed. It will be shown that this structure is not model complete. Further I develop a connection between the theory of Diophantine approximation and this structure.

The research described in this dissertation follows on from the study made by Jewell (1980)into the effects of tensile reinforcement on the mechanical behaviour of sand. For this study Jewell used the direct shear test with reinforcement placed about the central plane as shown in fig. 1.1. The direct shear test was chosen for the following reasons. (1) The reinforcement variables could be better controlled and examined in a unit cell test than in modular field studies of soil reinforcement systems. (2) The pattern of deformation is similar to that experienced by soil in which a rupture band develops, with the principal axes of stress, strain and strain increment free to rotate as is the case in model and field structures. (3) The overall shear strength of the sample is measured directly at the boundaries of the apparatus. The direct shear tests were monitored by boundary measurements and internal measurements using a radiographic technique. The findings are outlined below with reference made to relevant observations by other researchers. 1) The optimum orientation for a relatively flexible steel grid was found to be approximately along the direction of principal tensile strains in the unreinforced sand, see fig.1.2. This indicated that the reinforcement functioned by limiting tensile strains in the sand. McGown et al. (1978) obtained a similar result for plane strain cell tests on sand containing a single layer of flexible reinforcement. However in both studies the reinforcement was observed to waken the sand. Jewell recognized weakening to occur when the steel grid was placed along the direction of principal compressive strains in the unreinforced sand. This was attributed to a reduction in vertical effective stress. McGown et al. observed weakening of the sand when the reinforcement orientation approached the rupture band which developed in the sand alone. This was recognized to be the direction of zero-extension in the unreinforced sand. The weakening was linked to a lower bond between soil and reinforcement than soil alone. 2) Internal strains determined by Jewell showed the tensile reinforcement modified strains in the sand over a well defined zone, see fig.1.3. This resulted in a significant rotation of principal axes of strain increment, with the bond of major strains which developed across the centre of the box in the unreinforced sand being prohibited from forming. This agreed with boundary measurements, indicating the reinforcement functioned by limiting tensile strains in the sand. Consequently a less favourable mode of failure took place. The limit of rotation of principal axes of strain increment was understood to be the alignment of a direction of zero-extension in the sand with the reinforcement. These findings agree with the ideas expressed by Basset and Last (1978) on the mode of action of tensile reinforcement, which in particular was related to the effect of tensile reinforcement on the strain field in a reinforced earth wall as shown in fig.1.4. 3) For efficient use of tensile reinforcement it was demonstrated that the bond with sand should be as high as possible. This could be achieved by roughening the surface. Alternatively, the bond was improved by introducing openings or apertures in the reinforcement, changing the shape to a grid. It appeared that the bond for a suitably proportioned grid could be as high as for a fully roughened surface. 4) The longitudinal stiffness of tensile reinforcement was observed to affect the magnitude and rate of increase in strength in the direct shear tests. The rupture strain of tensile reinforcement relative to maximum tensile strains of the soil, under the same operational stress conditions, have also been observed to influence the reinforcing effect in terms of its limiting behaviour, i.e. whether brittle or ductile (McGown, et al. 1978). With regards to the performance of reinforced earth walls, Al-Hussanini and Perry (1976) observed that steel reinforced strips produced a stiffer and stronger structure than a more extensible fabric reinforcement, even though surface roughness was less. The importance of reinforcement tensile stiffness is recognized in limit equilibrium designs for tensile reinforced soil structures by limiting the available reinforcement force to the tensile strains that can develop in the soil (e.g. Jewell 1985). For highly structured non-woven and composite geotextiles, McGown et al. (1982) demonstrated that the stress-strain behaviour can be significantly affected by soil confinement. Testing wider strips in isolation was not found to replicate the effects of soil confinement. Another factor which needs to be considered when assessing the tensile property of a polymer reinforcement is creep. McGown et al. (1984) illustrated an appropriate method of interpreting creep data using isochronous curves, which enable long term laboratory test data to be extrapolated to the design life of the soil structure. 5) The strain and hence stress fields in the reinforced direct shear tests have been shown to be complex and non-uniform. However Jewell successfully modelled the variation of reinforcing effect for tensile reinforcement at different orientations by using a simple limit equilibrium analysis, see fig.1.5. The effect of the tensile reinforcement force was represented as: - an increase in the normal effective stress acting on the central plane of the box due to the normal component of the force and - a reduction in the applied shear stress due to the parallel component of the force to the central plane. Subsequently this analysis has been applied to limit equilibrium design methods for reinforcing soil retaining walls and embankments, Jewell et al. 1984, and Jewell 1982 respectively. 6) A reduction in the reinforcing effect for individual reinforcement due to the presence of other reinforcement was observed in the shear box. This loss of efficiency of individual reinforcement was termed interference. Interference between tensile reinforcement has also been studied by Guilloux et al. (1979) for the pull-out resistance from soil. However interference between reinforcement has yet to be introduced into a limit equilibrium design method.

My thesis focuses on the Italian poet Giovanni Giudici (1924-2011) and specifically on his activity as a translator from Anglo-American poetry, during the decade 1950-1960. I have investigated Giudici’s translations from a twofold perspective. On the one hand, I acquired a detailed overview of the translations, attempting to establish a definitive and accurate chronology of them all – in most cases, the official dates of the individual texts published not coinciding with the later inclusion of the same texts in three separate collections. On the other hand, I analysed the stylistic and literary rendering of the foreign texts, evaluating their specific artistic value and, where relevant, emphasising in what way they are interrelated with Giudici’s original verse. In doing so, I used archival materials, examining drafts and comparing these with the final versions. In my first chapter, I discussed the emerging notion of error and showed how this soon becomes the bridging element between the poet’s alleged amateurish knowledge of the original languages and his hyperconscious conception of the literary practice. The most innovative aspect of this ambiguous poetics is the poet’s tendency to equate poetic language with what he calls ‘strange language’, that is translation itself. While dealing with each foreign text individually and showing how it contributes to the poet’s language and themes (such as, primarily, those of error, of strange language and of mask), I also argued that the translations of the 50s could fall under the category of ‘metaphysical poetry’. Not unlike other poets of his day, Giudici familiarised himself with ‘metaphysical poetry’ through T. S. Eliot, as I showed in my second chapter. I here devoted special attention to Giudici’s work on Eliot and presented some early translations of Eliot by him which have hitherto escaped critics’ attention. In the last two chapters, I analyse other foreign poets he translated, ranging from Donne to Emily Dickinson, from Milton to Pound. Finally, by mapping Giudici’s interests in Anglo-American poetry, my thesis highlights the centrality that translation progressively acquires alongside the production of the original verse and within the use of the poet’s mother tongue.

Introduction The introduction describes the importance of arylamine compounds to society and provides a brief overview of the methods available for their synthesis. The application of metathesis catalysis to the de novo synthesis of heteroaromatic compounds is also described. Results and discussion The first section describes efforts towards the de novo synthesis of arylamines using a cross metathesis/oxidation protocol to form a 1,5-unsaturated dicarbonyl followed by an amine mediated cyclisation. The scope with respect to the 1,5-unsaturated dicarbonyl and amine is covered as well as the utility of some of the products. The section concludes with a modification of the Bohlmann Rahtz pyridine synthesis to furnish arylamines. The next section describes the applications of our methodology to the synthesis of naphthylamines, specifically using the palladium catalysed α-arylation reaction. A discussion of the α-arylation reaction is included as well as our efforts to explore the scope of the reaction. The third section follows our efforts to apply this methodologyy to the synthesis of five benzo[c]phenanthridine alkaloids including the first reported synthesis of maclekarpine B and C. The final section concludes with a discussion of our efforts towards the de novo synthesis of furans bearing a benzylic stereocentre.

Thiel embalmed cadavers were first used by the Centre for Anatomy and Human Identification, University of Dundee, in 2009, marking their introduction to the UK having been developed by Professor Walter Thiel in the University of Graz, Austria, over a thirty year period to 1992. The cadavers produced by the Thiel embalming method have many advantages over those produced by the more traditional formalin-phenol based method including a high degree of flexibility on par with in vivo conditions. However there is a distinct paucity of information regarding the way in which Thiel embalming affects the cadaveric tissues and the inherent implications for anatomical teaching and research. In addition, the Thiel solution uses formalin and boric acid, two chemicals which may be affected by changes in legislation governing their use within the EU. On that basis, the need to understand the effects of Thiel embalming on tissues, as well as the need to investigate the potential removal of formalin and boric acid from the Thiel solution, was acknowledged. This study presents an analysis of the effects of Thiel embalming using skeletal muscle and tendon samples, taken from an animal model, as these tissues are believed to be important to the flexibility of Thiel cadavers, using a number of methods. The way in which the effects are related to the flexibility caused is also considered in the context of existing relevant literature. In addition, the potential to remove and replace formalin and boric acid from the standard Thiel solution is also addressed. In assessing the effects of Thiel embalming solution on skeletal muscle and tendon, the aim of the thesis is to test the hypotheses that (i) changes in muscle and/or tendon structure, particularly in relation to collagen content, are responsible for the exaggerated flexibility seen in cadavers preserved using this method, (ii) it is the high salt content of Thiel embalming solution which is responsible for the change in tissue structure, and (iii) is it possible to replace the formalin and boric acid content of the Thiel solution and continue to successfully preserve specimens for anatomical teaching and research. The results of this study indicate that Thiel embalmed tissues, skeletal muscle in particular, undergo considerable histological modifications to their internal structure when compared to formalin and fresh samples whilst gross structure appears to remain intact through the maintenance of connective tissue integrity. This is supported by results which show a change in the biomechanical characteristics and protein content profile of target tissues. It is suggested that these changes are the basis for the increased flexibility observed in Thiel embalmed specimens. The results of a pilot study also indicate that it is possible to replace formalin and boric acid from the Thiel solution whilst maintaining successful preservation of specimens. A number of preservation techniques are considered throughout the study including Thiel, formalin and modified Thiel, and are compared to fresh samples as a control. A number of methods, including histological, biomechanical and protein analysis, are used to investigate differences between samples from each treatment group.

Molecular framework materials - materials constructed like atomic scaffolding where anionic polyatomic linkers join cationic metal nodes - have great currency in contemporary functional material design. In this thesis the structures and properties of transition metal cyanides are investigated, focusing on the impact of mechanical and configurational degeneracy. These related phenomena give rise to materials with unusual and extreme negative mechanical responses on the one hand, and exotic structural states on the other. The mechanical response of primary interest here is negative linear compressibility (NLC), a rare but desirable property where a material actually expands in one direction against increasing hydrostatic pressure. The performance of NLC materials|for use in areas such as sensitive pressure sensing, actuators, and development of artificial muscle|critically depends on the intrinsic NLC response. Until recently very few NLC materials were known and, of those, the expansion was small in comparison to the normal contraction of common engineering materials. Here I show that several dicyanometallate frameworks, those based on the almostlinear [M(CN)2]- (M = Ag, Au) linker, exhibit a prolonged NLC response up to ten times larger than established NLC candidates. Using two structure design modifications - soft-mode frustration to prevent structure collapse and supramolecular motifs that enhance compressibility - both the range over which NLC is observed and the magnitude of response have been increased. In the former, the extended perovskite-like system KM[M'(CN)2]3 is used as a model system, whilst 'spring'-like supramolecular interactions in zinc(II) dicyanoaurate(I), Zn[Au(CN)2]2, gives rise to an exceptional response - the first report of 'giant' NLC. Variable-pressure studies on the canonical isotropic negative thermal expansion (NTE) material zinc (II) cyanide reveals both its intrinsic phase transition behaviour, giving insight into the mechanism of NTE, and NLC as a result of the improper ferroelastic phase transition at 1.52GPa. This investigation resolves several discrepancies and contradictions in the field and suggests the mechanical responses of isostructural frameworks may be understood in terms of underlying dynamic instabilities, in much the same way as for many conventional ceramic materials. In the second part of this thesis, configurational degeneracy is explored focusing on structural disorder. Beginning with a summary of well-characterised examples of disorder in molecular frameworks, I go on explore the collective states arising from degeneracy in the 'simple' chain cyanides AgCN, AuCN and (Ag1/2Au1/2)CN. By considering chains as geometric objects with simple pairwise interactions, we find the emergence of complex structural states that are directly related to the XY magnetic structures on a triangular lattice. Structurally degenerate states appear inherent in a range of framework materials; many possibilities exist in this field for targeting, enhancing and coupling counterintuitive mechanics and complex states with other functionalities.

La presente tesis doctoral se centra en la preparación de zeolitas de poro pequeño (3.5-4 Å), en concreto, aquellas cuya estructura presenta además cavidades grandes. Este tipo de materiales ha despertado un enorme interés en los últimos años debido al potencial que presentan como catalizadores en procesos de relevancia industrial y medioambiental, tales como el proceso de transformación de metanol a olefinas (MTO) o la reducción catalítica selectiva (RCS) de NOx. Por ello, existe un interés creciente en la preparación de nuevas estructuras de poro pequeño y en la mejora de las propiedades físico-químicas o de los métodos de preparación de las zeolitas ya existentes. Esto se debe, a que en ocasiones, la aplicación industrial de estas zeolitas se ve limitada, tanto por las condiciones de síntesis, como por el coste del agente director de estructura orgánico (ADEO) empleado en la preparación. En este sentido, el desarrollo de nuevas estrategias de síntesis podría dar lugar a la obtención de algunas estructuras de poro pequeño con propiedades físico-químicas mejoradas (relación Si/Al, acidez, tamaño de cristal, entre otras), así como a una reducción en los costes de preparación eliminando el uso de ADEOs o sustituyéndolos por moléculas de menor coste. Todo ello favorecería la posible aplicación industrial de dichas zeolitas de poro pequeño. La primera parte de la tesis se centra en la optimización del proceso de síntesis de dos estructuras zeolíticas de poro pequeño, CHA y AEI, con elevado contenido en sílice y buenos rendimientos de síntesis. Para ello, se desarrolla una nueva metodología de síntesis que combina el uso de agentes directores de estructura orgánicos con el uso de una zeolita cristalina como única fuente de Si y Al. Mediante dicho procedimiento se obtienen ambas zeolitas con unas propiedades físico-químicas (tamaño de cristal y acidez) óptimas para su empleo como catalizadores del proceso MTO. En la segunda parte de la tesis se preparan diferentes zeolitas de poro pequeño (CHA, AEI, AFX y ERI) que contienen cobre o hierro como centros activos aislados. Para la introducción de especies metálicas en su interior, se emplean tanto métodos convencionales de intercambio iónico como métodos de síntesis directa, que eliminan la necesidad de tratamientos post-síntesis, además de permitir obtener una dispersión más homogénea en los cristales de la zeolita. La actividad catalítica y estabilidad hidrotermal de estas zeolitas, se evalúa para la RCS de NOx.
The present doctoral thesis focuses on the preparation of small-pore zeolites (3.5-4 Å), preferentially those also containing large cavities. This type of materials has attracted great technological interest during the last years due to their recent commercial application as catalysts in relevant industrial and environmental processes, such as the transformation of methanol into light olefins (MTO), or the selective catalytic reduction (RSC) of NOx. Therefore, there is an increasing interest in the preparation of new small pore structures and/or the improvement of the physico-chemical properties or the synthesis protocols of the zeolites currently in use. In fact, the industrial application of a particular zeolite could be limited by the high costs associated to its preparation, and in particular, to the high costs associated to the organic structure directing agent (OSDA) employed. In this sense, the discovery and development of new synthetic strategies could not only favor the crystallization of novel small-pore zeolites with improved physico-chemical properties (i.e. Si/Al ratio, crystal size, among others), but also optimizing the production costs, avoiding the use of expensive OSDAs or, at least, substituting those by less-expensive organic molecules. These features could encourage the potential commercialization of such novel small pore zeolites as competitive catalysts for relevant industrial processes. In the first part of this thesis, the synthesis protocols of two different high-silica small pore zeolites, CHA and AEI, have been intensively evaluated in order to develop a new procedure to direct the crystallization of these two zeolites with excellent solid yields. It has been found that the combination of a particular OSDA with a crystalline zeolite as the sole Si and Al sources, as FAU, allows the obtention of both zeolites with optimal physico-chemical properties (crystal size and acidity) for its application as efficient catalysts for the MTO process. In the second part of this thesis, different small-pore zeolites (CHA, AEI, AFX y ERI) containing copper or iron as isolated active catalytic sites, have been prepared. To introduce these metallic species within the zeolite crystals, either conventional ion-exchange methods or direct 'one-pot' synthetic methods have been employed. Interestingly, the use of 'one-pot' synthesis methods not only eliminates the need for post-synthetic ion-exchange treatments, but also allows obtaining better metal dispersions along the zeolite crystals. The catalytic activity and hydrothermal stability of such zeolites has been evaluated for the SCR of NOx.
Aquesta tesi doctoral es centra en la preparació de zeolites de por menut (3.5-4 Å), i en particular, aquelles amb una estructura que presenta, a més, grans cavitats. Aquest tipus de materials han despertat un gran interès als últims anys, degut al potencial que presenten com a catalitzadors eficients en processos rellevants per la indústria i el medi ambient, com son el processos de transformació de metanol a olefines (MTO) o la reducció catalítica selectiva (RCS) de NOx. Per aquest motiu, existeix un interès creixent tant en la preparació de noves estructures de por menut, com en la millora de les propietats fisico-químiques o dels mètodes de preparació de les zeolites ja existents. Aquest motiu es deu a que en ocasions, l'aplicació industrial d'aquestes zeolites, es pot veure limitada per els costs associats a la seua preparació, en particular de l'agent director d'estructura orgànic (ADEO) emprat. En aquest sentit, el desenvolupament de noves estratègies de síntesi podria donar lloc a l'obtenció d'algunes estructures de por menut amb propietats físico-químiques millorades (relació Si/Al, acidesa, tamany de cristall, entre altres), així com a una reducció dels costos de preparació, eliminant l'ús de ADEOs o substituint-los per molècules de menor cost. Tot això, podria afavorir la possible aplicació industrial d'aquestes noves zeolites de por menut. La primera part de la tesi es centra en l'optimització del procés de síntesi de dos estructures zeolítiques de por menut, CHA i AEI, amb un elevat contingut de sílice i amb bons rendiments de síntesi. Per això, s'ha desenvolupat una nova metodologia de síntesi que combina l'ús d'agents directors d'estructura orgànics (ADEO) amb una zeolita cristal¿lina com a única font de Si i Al. Mitjançant aquest procediment, s'han pogut obtenir els dos materials amb unes propietats físico-químiques (tamany de cristall i acidesa) òptimes per al seu ús com a catalitzadors en el procés MTO. En la segona part de la tesi s'han preparat diverses zeolites de por menut (CHA, AEI, AFX I ERI), amb àtoms de coure o ferro com a centres catalítics aïllats. Per a la introducció de les espècies metàl¿liques al seu interior, s'han utilitzat tant mètodes convencionals d'intercanvi iònic com mètodes de síntesi directa. En particular, els mètodes directes eliminen la necessitat de introduir diferents tractament post-síntesi, a més de permetre una dispersió més homogènia del metall als cristalls de la zeolita. L'activitat catalítica i l'estabilitat hidrotermal d'aquestes zeolites s'ha avaluat per a la RCS de NOx.
Martín García, N. (2017). PREPARACIÓN DE ZEOLITAS DE PORO PEQUEÑO CON CONTROL DE SUS PROPIEDADES FÍSICO-QUÍMICAS PARA SU APLICACIÓN EN CATÁLISIS [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/94628
TESIS

This project aims to study fossil amphibian and reptile (herpetofaunal) remains from Quaternary sites in the British Isles. This neglected group of vertebrates hold great potential for Quaternary Science. Collectively, they cover a wide range of ecological tolerances, although individual species often have very specific tolerances. The biology and ecology of individual species are discussed (Chapter 2) to facilitate their use in Quaternary palaeoenvironmental reconstructions, and an account of previous work on fossil herpetofaunas is given (Chapter 3). Very little work on fossil herpetofaunas has been carried out in the British Isles, mainly due to a lack of the required osteological expertise. The preparation and study of a modern osteological collection (Chapter 4), for comparative purposes, has therefore constituted a large and essential part of the project. The resulting manual for the identification of fossil herpetofaunal remains, appropriately illustrated with SEMs and hand-drawn figures, is presented (Chapter 5). The difficulties encountered in identifying some taxa are discussed in detail, and points of caution are stressed where necessary.

Mise au point d'un capteur solaire à air performant pour avoir des températures élevées du fluide caloporteur. Le sol constitue le réservoir de chaleur formant un accumulateur dans lequel sont enterrés des tuyaux qui constituent l'échangeur de chaleur.

Human action recognition in challenging video data is becoming an increasingly important research area. Given the growing number of cameras and robots pointing their lenses at humans, the need for automatic recognition of human actions arises, promising Google-style video search and automatic video summarisation/description. Furthermore, for any autonomous robotic system to interact with humans, it must rst be able to understand and quickly react to human actions. Although the best action classication methods aggregate features from the entire video clip in which the action unfolds, this global representation may include irrelevant scene context and movements which are shared amongst multiple action classes. For example, a waving action may be performed whilst walking, however if the walking movement appears in distinct action classes, then it should not be included in training a waving movement classier. For this reason, we propose an action classication framework in which more discriminative action subvolumes are learned in a weakly supervised setting, owing to the diculty of manually labelling massive video datasets. The learned models are used to simultaneously classify video clips and to localise actions to a given space-time subvolume. Each subvolume is cast as a bag-of-features (BoF) instance in a multiple-instance-learning framework, which in turn is used to learn its class membership. We demonstrate quantitatively that even with single xed-sized subvolumes, the classication performance of our proposed algorithm is superior to our BoF baseline on the majority of performance measures, and shows promise for space-time action localisation on the most challenging video datasets. Exploiting spatio-temporal structure in the video should also improve results, just as deformable part models have proven highly successful in object recognition. However, whereas objects have clear boundaries which means we can easily dene a ground truth for initialisation, 3D space-time actions are inherently ambiguous and expensive to annotate in large datasets. Thus, it is desirable to adapt pictorial star models to action datasets without location annotation, and to features invariant to changes in pose such as bag-of-feature and Fisher vectors, rather than low-level HoG. Thus, we propose local deformable spatial bag-of-features (LDSBoF) in which local discriminative regions are split into axed grid of parts that are allowed to deform in both space and time at test-time. In our experimental evaluation we demonstrate that by using local, deformable space-time action parts, we are able to achieve very competitive classification performance, whilst being able to localise actions even in the most challenging video datasets. A recent trend in action recognition is towards larger and more challenging datasets, an increasing number of action classes and larger visual vocabularies. For the global classication of human action video clips, the bag-of-visual-words pipeline is currently the best performing. However, the strategies chosen to sample features and construct a visual vocabulary are critical to performance, in fact often dominating performance. Thus, we provide a critical evaluation of various approaches to building a vocabulary and show that good practises do have a signicant impact. By subsampling and partitioning features strategically, we are able to achieve state-of-the-art results on 5 major action recognition datasets using relatively small visual vocabularies. Another promising approach to recognise human actions first encodes the action sequence via a generative dynamical model. However, using classical distances for their classication does not necessarily deliver good results. Therefore we propose a general framework for learning distance functions between dynamical models, given a training set of labelled videos. The optimal distance function is selected among a family of `pullback' ones, induced by a parametrised mapping of the space of models. We focus here on hidden Markov models and their model space, and show how pullback distance learning greatly improves action recognition performances with respect to base distances. Finally, the action classication systems that use a single global representation for each video clip are tailored for oine batch classication benchmarks. For human-robot interaction however, current systems fall short, either because they can only detect one human action per video frame, or because they assume the video is available ahead of time. In this work we propose an online human action detection system that can incrementally detect multiple concurrent space-time actions. In this way, it becomes possible to learn new action classes on-the-fly, allowing multiple people to actively teach and interact with a robot.

Ce travail de recherche s’inscrit dans le champ théorique de la didactique des langues et du bilinguisme. Il a pour objet l’étude et la réflexion sur l’harmonisation des pratiques d’enseignement dans deux écoles primaires du réseau de l’Agence de l’Enseignement Français à l’Étranger (AEFE) en Amérique latine : l’école de Santiago du Chili et celle de La Paz (Bolivie). À partir d’un certain stade de son développement, cette étude s’étend à d’autres écoles du réseau AEFE implantées sur le continent latino-américain. L’interlangue des jeunes apprenants constitue la matrice à partir de laquelle se fonde ce travail de théorisation. Une grande partie de la thèse est consacrée à l’analyse des interactions linguistiques en classe de français, d’espagnol et en classe bilingue afin d’appréhender les moyens pédagogiques déployés par les enseignants pour traiter de faits de langue et en particulier des interférences linguistiques qui leur sont inhérentes. Cette analyse s’attache donc à la dynamique d’articulation entre la langue nationale et la langue française dans les pratiques quotidiennes de classe. À partir de réflexions théoriques et d’expériences menées sur le terrain, cette recherche s’interroge, d’une part, sur la prise en compte de certains paramètres didactiques nécessaires à la construction d’un curriculum d’enseignement convergent, et, d’autre part, sur la conceptualisation et la mise en œuvre d’un curriculum de formation des enseignants en didactique convergente
This investigative work is part of the theoretical field of language instruction and bilingualism. Its purpose is the study of, and the reflection upon the harmonization of teaching practices in two primary schools belonging to the network of the Agency for French Instruction Abroad (AEFE) in Latin America: one in Santiago, Chili, and the other in La Paz, Bolivia. After a certain point in its development, this study extends to other schools in the AEFE network located in Latin America. The interlanguage of young learners is the matrix for this theorization work. A large part of the dissertation is dedicated to analyzing linguistic interactions in French class, Spanish class and bilingual class in order to grasp the pedagogical means used by instructors to deal with language features and in particular, inherent linguistic interferences. This analysis deals closely with the dynamics of articulation between the national language and the french language in daily classroom practices. This investigation uses theoretical reflections and field experiments to examine the taking into account of certain didactic parameters needed to implement a convergent instruction curriculum, on the one hand, and the conceptualization and implementation of an instructor training curriculum in convergent didactics, on the other hand
Este trabajo de investigación se enmarca en el ámbito teórico de la didáctica lingüística y del bilingüismo. Contempla el estudio y la reflexión sobre la armonización de prácticas de enseñanza y de aprendizaje en dos escuelas primarias asociadas a la red educativa de los centros de la Agencia para la Enseñanza Francesa en el Extranjero (A.E.F.E): la escuela de Santiago de Chile (Centro de la Alianza Saint-Exupéry) y la de La Paz en Bolivia (Centro del Colegio Franco Boliviano Alcide d’Orbigny). A partir de cierto grado de su desarrollo, este estudio abarca otras escuelas de la red de centros A.E.F.E ubicadas en el continente suramericano.La interlengua de los alumnos que en este contexto inician su aprendizaje a una edad temprana constituye la matriz en la que se fundamenta este trabajo de teorización.Gran parte de la tesis se centra en el análisis de las interacciones lingüísticas en las clases de francés, de español y en la clase bilingüe, a fin de potenciar la comprensión de los recursos pedagógicos utilizados por los docentes para plantear fenómenos lingüísticos y, en particular, las interferencias lingüísticas que los caracterizan. Siendo así, este análisis se fija en la dinámica de articulación entre la lengua nacional y la lengua francesa en las prácticas educativas cotidianas.A partir de reflexiones teóricas y de experiencias directas, esta investigación cuestiona, por una parte, el tener presentes ciertas consideraciones didácticas necesarias en el planteamiento convergente de una enseñanza curricular, y, por otra, la conceptualización y la aplicación de un currículo de capacitación docente en didáctica convergente

Orientador: Sara Terezinha Olalla Saad
Tese (doutorado) - Universidade Estadual de Campinas. Instituto de Biologia
Made available in DSpace on 2018-07-27T08:46:05Z (GMT). No. of bitstreams: 1 Lima_PauloRobertoMoura_D.pdf: 4111332 bytes, checksum: 7243dfc06daf8a58f41c137629b12750 (MD5) Previous issue date: 2000
Resumo: A esferocitose é um tipo comum de anemia hemolítica hereditária cujo primeiro defeito molecular foi caracterizado em 1992. A proteína banda 3, codificada pelo gene AE1, foi a primeira isoforma clonada de uma famma de genes de trocadores de ânions "Anion Exchanger-AE gene family" e é a mais abundante das proteínas integrais da membrana eritrocitária. Alterações moleculares neste polipeptídeo estão associadas à formação de esferócitos. Hemácias esferocíticas são osmoticamente frágeis, estando mais sujeitas à lise e ao sequestramento pelo baço, o que encurta seu tempo de vida. A proteína banda 3 também é expressa nos rins, na membrana basolateral de células alfa intercaladas do tubo coletor cortical, onde é responsável pela reabsorção de bicarbonato, compensando a secreção de ácidos pela H+ ATPase vacuolar apical, e participando da regulação fina do equilíbrio ácido-básico. Tanto a banda 3 eritrocitária como a renal são isoformas de um mesmo gene que através de um promotor tecido específico, diferem quanto à transcrição. O mRNA da banda 3 renal não apresenta os três primeiros exons observados na forma eritróide. O presente estudo teve o objetivo de investigar as alterações moleculares e regulação do gene da banda 3 na esferocitose hereditária em 5 pacientes com deficiência de banda 3, e investigar possíveis alterações neste gene em cinco pacientes com acidose renal tubular distal. Este estudo foi baseado no rastreamento de mutações e polimorfismos no gene mencionado, incluindo a região promotora, que também pode estar envolvida na fisiopatologia da doença. Para detecção das alterações moleculares foram utilizadas as técnicas de PCR, análise de polimorfismo de conformação em fita simples, subclonagem e sequenciamento. O estudo do cDNA foi realizado após a transcrição reversa do mRNA extraído de reticulócitos por RT-PCR. Outro objetivo foi investigar as alterações renais de pacientes com esferocitose hereditária e deficiência de banda 3, uma vez que esta proteína também é expressa nos rins. Os estudos renais foram realizados através da avaliação da capacidade de acidificação tubular distal e obtenção de medidas de bicarbonatúria, pH urinário, acidez titulável e excreção de amônia no período basal e após estímulo com furosemida. Também foi avaliado o contratransporte de sódio e lítio em hemácias de pacientes com esferocitose hereditária, uma vez que esta é uma medida indireta do contra-transporte Na+/H+, envolvido na regulação do pH intracelular do eritrócito e na homeostase ácido-básica do organismo, por secretar ácido e reabsorver Na+ em epitélio renal. Nossos resultados caracterizaram duas novas mutações no gene AEI. O estudo da Banda 3 Campinas, uma mutação no sítio doador de clivagem no intron 8, demonstrou a perda de bicarbonato pela urina dos pacientes afetados e um aumento na atividade de contra-transporte de sódio e lítio nas hemácias. A Banda 3 Pinhal, uma substituição de um resíduo de arginina altamente conservado, por histidina no domínio transmembrana, é a segunda mutação afetando o codon 490 da banda 3, e pode ser um "hot spot" para mutações no gene AEI. As hemácias destes pacientes apresentaram menor número de sítios para o inibidor DIDS. Outra mutação caracterizada foi a Banda 3 MODtefiore, previamente descrita. O estudo dos pacientes com acidose renal tubular distal revelou uma nova mutação na região promotora renal em um paciente com acidose renal tubular distal incompleta, que pode estar associada com o defeito na reabsorção de bicarbonato pelos rins. O estudo da acidose também caracterizou um novo polimorfismo no intron 3, a deleção da adenina 1233, com frequência alélica de 0,34 em 120 cromossomos analisados. Um conflito de sequência (quatro guaninas no lugar de três nt. 1272-1274) também foi verificado em todos indivíduos estudados. O polimorfismo Asp38-7Ala (Darmstad) foi encontrado em uma paciente com acidose, mas parece não estar relacionado com a doença. Finalmente concluímos que mutações no gene da banda 3 podem estar associadas com a esferocitose hereditária e com a acidose renal tubular distal incompleta, pois isoformas da proteína são expressas nas hemácias e nas células a-intercaladas. Sugerimos que em casos onde há perda de ânions pelos rins, mecanismos de compensação podem estar ativados, como o aumento da atividade excretora de prótons pela Na+/H+, ou pela H+-ATPase vacuolar apical. A fim de realizar estudos de interações protéicas, foi subclonado o domínio citoplasmático completo da fosfolípide scramblase dos seguintes tecidos humanos: cérebro, testículos e baço. A sequência do cDNA da enzima scramblase usada no ensaio duplo-híbrido resultou no fenômeno de auto-ativação, que é uma razão comum da falha do rastreamento pelo método duplo-híbrido
Abstract: Hereditary spherocytosis is a common type of hemolytic anemia. The first molecular defect in the band 3 gene associated with spherocytosis was characterized in 1992. Band 3, codified by the AEl gene, was the first isoform to be c10ned of a family of genes of anion exchangers (Anion Exchanger-AE gene family) and is the most abundant of the integral proteins of the erythrocyte membrane. The molecular alterations in this polypeptide are associated to spherocyte formation. Spherocytic red cells have osmotic fragility , and are more liable to undergo lise and splenic sequestration, which decreases their life span. Band 3 protein is also expressed in the kidney, in the basolateral membrane of the cortical collecting duct intercalated alpha cells, where it is responsible for the bicarbonate reabsorption, compensating the acid secretion at apical membrane by the H+ ATPase vacuolar, and taking part in the fine regulation of the acid-base equilibrium. Both erythrocyte and renal band 3 are isoforms of the same gene, which differ in transcription due to a tissue-specific promoter. The first three exons are not present in the erythroid form of renal band 3 rnRNA. The aim of this study was to investigate the molecular alterations and gene regulation, of band 3 in hereditary spherocytosis in 5 families with band 3 deficiency. This study was based on the screening of mutations and polymorphisms of the gene formerly mentioned, inc1uding the promoter region, which might be involved in the pathophysiology of the disease. In order to detect the molecular alterations, PCR technique, single strand conformation polymorphism analysis, subc10nning and sequencing were used. The cDNA study was performed afier the reverse transcription of the rnRNA extracted from the reticulocytes using RT-PCR. Another aim was to investigate the renal alterations of patients with hereditary spherocytosis and band 3 deficiency, as this protein is also expressed in the kidneys. Renal studies were performed using urinary acidification tests and measures of. bicarbonate, urinary pH, acid titration and ammonia excretion during the basal period and afier furosemide stimulation. The sodiumllithium countertransport activity in the red blood cells of patients with hereditary spherocytosis was also assessed, as it is an indirect measure of the Na + /Ir countertransport, which is involved in the intracellular pH regulation of the erythrocyte and in the acid-base homeostasis of the organism, secreting acid and reabsorbing Na + in the renal epithelium. Our results caracterized two novel mutations in the AEI gene. The study of Band 3 campinas, a mutation at the splice donor site in the intron 8, revealed a bicarbonate loss by the urine from patients and an increase in the sodiumllithium countertransport activity of their red blood cells. The Band 3 Pinhal is a highly conserved arginine to histidine substitution in the transmembrane domain. This is the second mutation affecting the codon 490 of band 3, and could represent a hot spot for mutations in the AEI gene. The red blood cells of these patients showed a reduced number of sites for DIDS, the band 3 anion exchange inhibitor. Another mutation found was the Band 3 Montefiore, previously described. The study of the patient's tubular acidosis revealed a new mutation neighboring the kidney promoter in a child presenting incomplete distal renal tubular acidosis, which might be associated with the kidney bicarbonate reabsorption defect. The acidosis study also caracterized a novel polymorphysm in intron 3, the adenine 1233 deletion, with an allele frequency of 0.34 in the 120 chromossomes analyzed. A sequence conflict (four guanines in the place of three nt.1272-1274) was also verified in all subjects studied. The polymorphysm Asp38-7Ala (Darmstad) was found in one patient with acidosis, but was not related with the disease. Finally, we conc1uded that mutations in the band 3 gene may be associated with hereditary spherocytosis and with incomplete distal renal tubular acidosis, as the band 3 isoforms are expressed in the red cells and in the renal {X-intercalated cells. We suggest that the proton excretion mechanisms, as the Na+/H+ exchanger or the vacuolar Ir-ATPase, might be activated to compensate the basal bicarbonate loss by the kidney. In order to perform protein interaction studies, we have subc10ned the entire cytoplasmic domain inc1uding part of the transmembrane segment of phospholipid scramblase from the following human cDNA tissues: brain, testis and spleen. The cDNA sequence of phospholipid scramblase used in the two-hybrids system caused auto-activation, a common reason for failure of two-hybrid screens
Doutorado
Bioquimica
Doutor em Biologia Funcional e Molecular

Ce travail s'articule autour de l'étude de matériaux coulés pour des composants électroniques. Une méthodologie est proposée pour analyser le comportement de fissures initiées dans des matériaux homogènes ou à l'interface entre différents matériaux. Une procédure expérimentale est décrite afin de mesurer le facteur d'intensité de contrainte critique d'un matériau homogène. Cette procédure est ensuite appliquée dans la comparaison du comportement d'une fissure d'un bimatériau et à la détermination du degré de validité des résultats. Une méthode est ensuite proposée pour déterminer la propagation de fissures dans les différents matériaux sous des chargements sous-critiques. Dans le cas d'une fissure à l'interface de bimatériaux, une méthodologie a été développée pour mesurer le taux de restitution d'énergie nécessaire à la propagation de la fissure. Les facteurs d'intensité de contraintes correspondants sont calculés à l'aide de simulations numériques, ainsi que l'angle de mode mixte résultant. L'ensemble des travaux expérimentaux réalisés et des simulations numériques développées permet de proposer une méthodologie d'analyse du comportement d'une fissure située au sein d'un composant multimatériau sollicité sous chargement thermo-mécanique
The work focuses on potting materials for electronic components. A methodology to analyse the behaviour of cracks initiated in homogeneous materials or at the interface between different materials is addressed. An experimental procedure is described in order to measure the critical stress intensity factor of a homogeneous material. This procedure is then used to compare the crack behaviour in a bimaterial structure and to determine the results degree of validity. Hereafter a method is proposed to determine crack growth under subcritical loading conditions. In the case of a crack at the interface of bimaterials, a methodology has been developed to measure the energy release rate necessary to let the crack propagates. With the help of numerical simulations, the corresponding stress intensity factors are computed as well as the resulting mixed mode angle. The whole work realised experimentally and the developed numerical simulations allow to propose a methodology to analyse the behaviour of a crack placed in a multi-materials structure under thermo-mechanical loads
Die vorliegende Arbeit befasst sich mit Vergussmassen fur elecktronische Erzeugnisse. Eine Vorgehensweise wird vorgeschlagen, um das verhalten von initiierten Rissen in homogenen Materialien oder entlang der Grenzschicht zwischen verschiedenen Materialien zu analysieren. Ein experimenteller Verfahrensschritt wird beschrieben, um den kritischen Spannungsintensitatsfaktor von homogenen Materialien zu messen. Dann wird dieser Verfahrensschritt benutzt, um das Rissverhalten in verschiedenen Materialien zu vergleichen und um das Ergebnisskonfidenzintervall festzulegen. Danach wird eine Methode vorgeschlagen, um das Risswachstum des betrachteten Materials unter subkritischer Belastung festzulegen. Im Fall eines Grenzschichtrisses wird eine Vorgehensweise entwickelt, um die Energiefreisetzungsratezu messen, die benotigt wird, um den Riss sich ausbreiten zu lassen. Mit Hilfe von von numerischen Simulationen werden die entsprechenden Spannungsintensitatsfaktoren und die Modusmischungswinkel ermittelt. Die komplette experimentelle, um das Verhalten von einem Riss verbundwerkstoffen und Bauteilen unter thermischen und mechanischen belastungen zu beurteilen

Les canaux ioniques voltage-dépendants sont des protéines membranaires permettant les échanges ioniques entre les cellules et leur environnement. Ces protéines régulent le passage des ions tels que potassium, sodium et calcium, et sont responsables de l'activité électrique notamment dans le coeur, les muscles squelettiques et le cerveau. L'activité de ces canaux ioniques est régulée par le potentiel membranaire mais aussi par des composés extracellulaires, cytosolique ou membranaire comme le phospahatidylinositol (4,5)- bisphospahe (PIP2). Un défaut de régulation de ces canaux entraine des pathologies cardiaques, musculaires ou neuronales appelées canalopathies dont les moyens de traitements actuels sont limités par leur manque de spécificité. La découverte de molécules thérapeutiques spécifiques et efficaces contre ces canalopathies nécessite une meilleure compréhension des mécanismes moléculaires à la base de la régulation de ces canaux ioniques. Par conséquent, mes travaux de recherche doctorale se sont focalisés sur trois principaux projets : 1) l'étude des mécanismes moléculaires à la base de la régulation des canaux potassiques voltage-dépendants par le PIP2 et 2) l'étude des mécanismes de dépendance au potentiel du canal potassique cardiaque KCNQ1. Dans ce deuxième projet, nous avons établi un nouveau modèle moléculaire de la régulation de KCNQ1 par le potentiel membranaire, ce qui nous a permis de générer des peptides modulateurs (activateurs et inhibiteurs) spécifiques de ce canal. Par conséquent, je me suis intéressé à 3) l'étude de la généralisation de ce modèle sur les canaux sodiques dont le canal sodique musculaire Nav1. 4 afin de générer des peptides régulateurs spécifiques de ce canal également. Afin d'améliorer l'efficacité de ces peptides modulateurs, les bases structurales de l'interaction peptide-canal sont en cours d'étude. En somme, ces études sur les mécanismes de régulation des canaux ioniques par le PIP2 et par le potentiel membranaire présentent des enjeux à la fois fondamental et thérapeutique
Voltage-dependent ion channels are plasma membrane proteins allowing ionic exchanges between cells and their environment. These proteins regulate the passage of ions such as potassium, sodium and calcium, and are responsible of the electrical activity in the heart, the squeletal muscles and the brain. The activity of these ion channels is regulated by the membrane potential as well as extracellular, cytosolic or membrane compounds such as the phosphatidylinositol (4,5)-bisphosphate (PIP2). Impaired regulation of these channels triggers cardiac, muscular or neuronal pathologies called channelopathies, whose treatments are limited by their low specificity. Discovery of efficient and more specific pharmacological tools against these channelopathies requires a better understanding of the molecular mechanisms underlying ion channels regulation. Consequently, my thesis researches were focused on three main projects: 1) the study of the molecular mechanisms underlying voltage-gated potassium channels regulation by PIP2 and 2) the study of the mechanisms of the cardiac potassium channel KCNQ1 voltage dependency. In this second project, we established a new molecular model of KCNQ1 regulation by the membrane potential, allowing us to generate KCNQ1-specific modulator peptides (activators and inhibitors). Consequently, I was interested to study (3) if this new model applies to other ion channels such as the muscular sodium channel Nav1. 4, in order to generate specific modulator peptides for these channels. In order to improve the potency of these modulator peptides, the structural bases of peptidechannel interaction are under investigations. In short, these studies on the mechanisms of ion channels regulation by PIP2 and by the membrane potential provide both basic and therapeutic insights

Aujourd’hui, les systèmes numériques sont interconnectés au travers d’architectures complexes. Les participants à ces systèmes réalisent activités telles que communiquer ou partager des données. Humains, matériels et logiciels sont impliqués dans ces activités, de sorte qu’un système peut être décrit comme la représentation de deux mondes, le monde social et le monde numérique et leurs relations. L’évaluation de ces systèmes est limitée aux aspects techniques. Aujourd’hui, la confiance envers les est devenue un facteur important dans les procédures d’évaluation. Dans ce contexte, nous soulevons deux questions : comment formaliser les entités composant un système ainsi que leurs relations pour une activité particulière ? et comment évaluer la confiance envers un système pour cette activité ? Nos contributions sont divisées en deux parties. La première partie propose un métamodèle formel, nommé SocioPath, qui permet de modéliser un système avec les entités du monde social et numérique et leurs relations. La deuxième partie consiste à évaluer la confiance des utilisateurs envers les systèmes qu’ils utilisent pour une activité donnée. Nous proposons une approche, nommé SocioTrust permettant de calculer le niveau de confiance, qui utilise la théorie des probabilités. Puis nous proposons une seconde approche, sous le nom de SubjectiveTrust, pour prendre en compte l’incertitude dans les valeurs de confiance, cette approche se basant sur la logique subjective
Nowadays, digital systems are connected through complex architectures. Participants to these systems perform activities like chatting or sharing data. Persons, physical and digital resources are involved in these activities, such that a system can be considered as a representation of two worlds, the social world and the digital world and their relations. Evaluating these systems is generally limited to technical aspects. Today, trust becomes an important key in the evaluation process. In this context, we raise two questions: how to formalize the entities that compose a system and their relations for a particular activity? and how to evaluate trust in a system for this activity? Our contributions are divided into two parts. The first part proposes a formal metamodel named SocioPath, to model a system with all entities of social and digital worlds and their relations. The second part evaluates the users’ trust in the systems they use for a given activity. We propose an approach named, SocioTrust, to compute the user’s trust in a system using probability theory. Then we propose a second approach named, SubjectiveTrust that takes into account the uncertainty in the trust values. This approach is based on subjective logic

La maladie de Crigler Najjar de type I est une maladie métabolique du foie due à un déficit total en UDP-glucuronosyl transférase A1 (UGT1A1). Chez les patients, Dans cette maladie, une mutation du gène codant l'enzyme UGT1A1 entraîne une hyperbilirubinémie non conjuguée responsable d'un ictère. Le traitement actuel repose sur une photothérapie, voire une transplantation hépatique. Cette maladie représente un paradigme pour la thérapie génique des maladies héréditaires du foie. Une guérison du modèle animal spontané de CNI, le rat Gunn, a été obtenue par thérapie génique daddition avec des vecteurs viraux. Cependant, ces approches présentent notamment le risque potentiel de mutagenèse insertionnelle. Ces inconvénients font apparaître l'intérêt du développement de nouvelles approches de thérapie génique ciblée. Les nucléases à doigts de zinc (ZFNs) et les Transcription Activator-like Effectors Nucleases permettent la modification du génome à façon par correction génique notamment. La première partie de la thèse a consisté à développer un système de vectorisation virale de ZFNs avec des vecteurs lentiviraux et AAV. Dans un second temps, nous avons utilisé les outils développés pour mettre au point une stratégie de réparation génique in vivo de l'UGT1A1 chez le rat Gunn. Cette stratégie a permis une correction subthérapeutique de la bilirubinémie. Ce projet a démontré la faisabilité d'une stratégie de thérapie génique ciblée pour les maladies héréditaires du foie. Cela offre de nouvelles possibilités de thérapie génique avec une meilleure spécificité et une amélioration de la biosécurité
Crigler Najjar type 1 (CNI) disease is a liver metabolic inherited disease due to UDP-glucuronosyl transferase (UGT1A1) enzyme deficiency. The patients have a mutation into the UGT1A1 gene responsible for an unconjugated hyperbilirubinemia that lead to an icterus. They are treated with phototherapy and liver transplantation. CNI is a paradigm for liver inherited diseases. Gene therapy represents a new hope for the treatment of such diseases. Lifelong cure of the Gunn rat model of CNI has been obtained through gene therapy with viral vectors. However, there are still drawbacks, such as risks of insertional mutagenesis. Thus, it is important to develop strategies of targeted gene therapy. Zinc Finger Nucleases (ZFNs) and Transcription Activator-like Effectors Nucleases (TALENs) allow targeted genome editing, through gene repair for example. They induce a specific DNA double strand break that promotes the insertion of an exogenous custom DNA donor through homologous recombination. The first part of this thesis consisted in the development of lentiviral and AAV vectors to deliver a whole ZFNs pair. The second part consisted in using these tools for in vivo gene repair in the Gunn rat. We showed that the endogenous mutation of UGT1A1 gene in the Gunn rat can be repaired in vivo at a level sufficient to obtain a subtherapeutic effect. Such recent strategies may offer safer therapeutic options to treat inherited monogenic diseases

La Limitació del Flux Espiratori (EFL) determina l’existencia d’un flux espiratori màxim per cada volum pulmonar i limita la capacitat ventilatoria. L’EFL enlenteix el buidament pulmonar, afavorint l’increment del volum tele-espiratori (End-Expiratory Lung Volume - EELV) o Hiperinflació Dinàmica (HD). L’HD permet un flux espiratori màxim superior, però EFL i HD tenen efectes negatius sobre la capacitat ventilatoria: sobrecàrrega i malfunció muscular inspiratoria, increment del treball respiratori elàstic, contribució a la percepció de dispnea. La clàssica determinació de l’EFL per superpossició de corbes flux-volum espontànies amb la màxima tendeix a sobrevalorar-la. La validació el 1994 de l’aplicació de pressió negativa espiratoria (Negative Expiratory Pressure, NEP) per detectar l’EFL, tècnica senzilla i aplicable durant l’exercici, ens permet revisar i ampliar els coneixements. Objectiu: Estudiar el desenvolupament d’EFL i canvis dels volums pulmonars, així com les interrelacions d’ambdós amb l’exercici en atletes i pacients amb MPOC severa. En el segon escenari, avaluar el paper de la possible disfunció dels músculs respiratoris en el comportament de EFL-HD i les relacions dels tres amb variables clíniques fonamentals: dispnea i qualitat de vida relacionada amb la salut (CVRS). Població, material i mètodes: El treball consta de dos subestudis: A) atletes i B) pacients amb MPOC. A inclogué 10 varons, ciclistes de competició, als que es realitzà espirometria (pre i postexercici), mesura de pressions respiratories màximes i Ventilació Voluntaria Màxima (VVM) i cicloergometria màxima incremental, amb mesures de EFL (NEP -10cm H2O) i EELV (Capacitat Inspiratoria, CI). B inclogué 25 homes amb MPOC estadi 3-4, als que determinàrem funció pulmonar (espirometria, VVM, pletismografia i difusió), capacitat d’esforç (cicloergometria incremental i proba de marxa), cicloergometries submàximes amb NEP (-3) i EELV (CI), funció muscular respiratoria (força: pressions màximes ins- i espiratoria; resistencia: càrrega dintell màxima ins- i espiratoria en proba incremental i temps de tolerància del 80% d’aquestes càrregues), dispnea (escala MRC) i CVRS (Saint George Respiratory Questionnaire, SGRQ). Resultats: A) El consum pic d’oxigen fou 72(67-82)ml.kg-1.min-1 i la Ventilació 147(122-180)l.min-1 (88% VVM). FEV1 i fluxos mesoespiratoris s’havien incrementat significativament després de l’exercici; només el ciclista de més edat (33 a) presentà EFL (26% del volum circulant) i sols en el pic d’exercici; l’EELV del grup descendí durant l’exercici lleuger-moderat un 13(5-33)%FVC (p<0,05), incrementant-se posteriorment (en el pic d’esforç era similar al valor pre-exercici). B) Els pacients (FEV1 promig= 31%v.ref.) presentaven una reducció moderada de força i resistencia dels músculs respiratoris; 19 mostraven EFL en repòs i 24 al 70% de la càrrega màxima (Wmax); els pacients amb EFL en repòs referien menys dispnea en l’exercici màxim (Borg) i en l’escala MRC, i millor puntuació en el domini d’Impacte del SGRQ; l’EELV s’incrementà des de repòs al 70%Wmax (9% FVC ref), al 70%Wmax es correlacionava inversament amb el percentatge de la corba flux volum amb EFL, amb la resistència muscular respiratoria i amb la capacitat d’esforç i positivament amb dispnea i puntuació del SGRQ; els 6 que no incrementaren l’EFL durant l’exercici tenien menor resistencia muscular espiratoria; l’anàlisi multivariant trià FEV1, resistencia muscular espiratoria i l’EFL com predictors independents d’EELV al 70%Wmax. Conclusions: L’EFL és infreqüent i no explica l’HD prop del màxim, que retorna EELV al nivell de repòs, en l’exercici progressiu en homes joves, ciclistes entrenats. Els homes amb MPOC evolucionada presenten freqüentment EFL en repòs, i l’exercici sol incrementar-la, malgrat la gran variabilitat. L’exercici submàxim produeix generalment HD, però no sempre. La relació inversa %EFL - EELV podria indicar que l’ús de la reserva de flux espiratori o de volum són mecanismes alternatius i complementaris per incrementar la Ventilació, depenent l’augment de volum del grau d’obstrucció, %EFL i de la resistencia muscular espiratoria. La freqüent disfunció muscular espiratoria podria afavorir el desenvolupament d’HD i menys EFL, estrategia ventilatoria clínicament més desfavorable, associada amb més dispnea, menor capacitat d’exercici i pitjor CVRS.
The expiratory flow limitation (EFL) determines the existence of a peak flow for each lung volume and ventilatory capacity limits. The EFL slow down the emptying lung, favoring an increase in teleexpiratory volume (End-Expiratory Lung Volume - EELV) and Dynamic Hyperinflation (HD). The HD allows a higher peak flow, but EFL and HD have negative effects on ventilatory capacity: inspiratory muscle overload and disfunction, increased respiratory elastic work and contributing to dyspnea perception. The classical determination of the EFL by superimposition of spontaneous flow-volume curve with the maximum tends to overestimate it. The validation in 1994 of the application of negative expiratory pressure (Negative Expiratory Pressure, NEP) to detect EFL, a simple technique applicable during exercise, allows us to revise and expand knowledge. Objectives: To study the EFL development and changes in lung volumes and the relationships of both during exercise in athletes and severe COPD patients. In the second scenario, to assess the potential role of dysfunction of the respiratory muscles in the behavior of EFL-HD and their relations with main clinical variables: dyspnea and quality of life related to health (QOL). Population, material and methods: The work includes two substudy A) athletes and B) COPD patients. A) Ten men, racing cyclists, were enroled; they performed spirometry (pre and postexercise), measure of maximum respiratory pressures and maximum voluntary ventilation (MVV) and maximum incremental cycloergometry with measures of EFL (NEP-10cm H2O) and EELV (inspiratory capacity, IC). B) included 25 men with COPD stage 3-4; lung function (spirometry, MVV, plethysmography and diffusion), exercise capacity (incremental cycloergometry and 6-minutewalking test), submàximal cycloergometries with NEP (-3) and EELV ( CI) measures, respiratory muscle function (strength: maximum ins-and expiratory pressures; endurance: maximum load threshold ins-and expiratory time and incremental test tolerance of 80% of these charges), dyspnea measure (MRC scale) and QOL assessement (St. George Respiratory Questionnaire, SGRQ) were performed. Results: A) peak oxygen consumption was 72 (67-82) ml.kg-1.min-1 and Ventilation 147 (122-180) L.min-1 (88% VVM). Middle-expiratory flows and FEV1 were significantly increased after exercise, only the older rider (33) presented EFL (26% of tidal volume) and only at peak exercise, the group EELV descended during light-moderate exercise in 13 (5-33)% FVC (p <0.05), increasing later (at peak exercise was similar to pre-exercise value). B) Patients (mean FEV1 = 31% v.ref.) showed a moderate reduction of respiratory muscles strength and endurance; 19 showed EFL at rest and 24 at 70% of the maximum load (Wmax); those patients with EFL showed less resting (MRC scale) and at maximal exercise (Borg) dyspnea, and best score on the SGRQ impact domain; the EELV increased from rest to 70% Wmax (9% FVC ref), at 70% Wmax correlated inversely with the percentage of tidal EFL, with respiratory muscle endurance and exercise capacity and positively with effort dyspnea and SGRQ score; those 6 patients who showed not EFL increase during exercise had lower expiratory muscle endurance; multivariate analysis selectioned FEV1, expiratory muscle endurance and EFL as independent predictors of 70% Wmax EELV. Conclusions: EFL is rare and does not explain the HD near the maximum, which returns to the level of resting EELV in progressive exercise in young men, trained cyclists. Men with advanced COPD often have EFL at rest, exercise often increase it, despite the great variability. Submaximal exercise usually produces HD, but not always. The inverse relationship EFL% - EELV could indicate that the use of the volume and expiratory flow reserves are alternative and complementary mechanisms to increase ventilation, depending the volume increase of the degree of obstruction, expiratory muscle endurance and % EFL. The frequent expiratory muscle dysfunction may favor the development of HD and less EFL, a more clinically unfavorable ventilatory strategy associated with more dyspnea, lower exercise capacity and worse QOL.

Tot i que en les últimes dècades la reducció del soroll emès pels avions ha estat substancial, el seu impacte a la població ubicada a prop dels aeroports és un problema que encara persisteix. Contenir el soroll generat per les operacions d'aeronaus, tot assumint al mateix temps la creixent demanda de vols, és un dels principals desafiaments a que s'enfronten les autoritats aeroportuàries, els proveïdors de serveis per a la navegació aèria i els operadors de les aeronaus. A part de millorar l'aerodinàmica o les emissions sonores de les aeronaus, l'impacte acústic de les seves operacions es pot reduir també gràcies a la definició de nous procediments de vol més òptims. Aquests procediments s'anomenen generalment Procediments d'Atenuació de Soroll (PAS) i poden incloure rutes preferencials de vol (a fi d'evitar les zones poblades) i també perfils de vol verticals optimitzats.

Els procediments actuals per a la reducció de soroll estan molt lluny de ser els òptims. En general, la seva optimització no és possible a causa de les limitacions d'avui en dia en els mètodes de navegació, els equips d'aviònica i la complexitat present en alguns espais aeris. D'altra banda, molts PAS s'han dissenyat de forma manual per un grup d'experts i amb l'ajuda de diverses iteracions. Tot i això, en els propers anys s'esperen nous sistemes d'aviònica i conceptes de gestió del trànsit aeri que permetin millorar el disseny d'aquests procediments, fent que siguin més flexibles. En els pocs casos on s'optimitzen PAS, se sol utilitzar una mètrica acústica en l'elaboració de les diferents funcions objectiu i per tant, no es tenen en compte les molèsties sonores reals. La molèstia és un concepte subjectiu, complexe i que depèn del context en que s'usa i la seva integració en l'optimització de trajectòries segueix essent un aspecte a estudiar.

La present tesi doctoral es basa en el fet que en el futur serà possible definir trajectòries més flexibles i precises. D'aquesta manera es permetrà la definició de procediments de vol òptims des d'un punt de vista de molèsties acústiques. Així doncs, es considera una situació en que aquest tipus de procediments poden ser dissenyats de forma automàtica o semi-automàtica per un sistema expert basat en tècniques d'optimització i de raonament aproximat. Això serviria com una eina de presa de decisions per planificadors de l'espai aeri i dissenyadors de procediments.

En aquest treball es desenvolupa una eina completa pel càlcul de PAS òptims. Això inclou un conjunt de models no lineals que tinguin en compte la dinàmica de les aeronaus, les limitacions de la trajectòria i les funcions objectiu. La molèstia del soroll es modela utilitzant tècniques de lògica difusa en funció del nivell màxim de so percebut, l'hora del dia i el tipus de zona a sobrevolar. Llavors, s'identifica i es formula formalment el problema com a un problema de control òptim multi-criteri. Per resoldre'l es proposa un mètode de transcripció directa per tal de transformar-lo en un problema de programació no lineal. A continuació s'avaluen una sèrie de tècniques d'optimització multi-objectiu i entre elles es destaca el mètode d'escalarització, el més utilitzat en la literatura. No obstant això, s'exploren diverses tècniques alternatives que permeten superar certs inconvenients que l'escalarització presenta. En aquest context, es presenten i proven tècniques d'optimització lexicogràfica, jeràrquica, igualitària (o min-max) i per objectius. D'aquest anàlisi es desprenen certes conclusions que permeten aprofitar les millors característiques de cada tècnica i formar finalment una tècnica composta d'optimització multi-objectiu. Aquesta última estratègia s'aplica amb èxit a un escenari real i complex, on s'optimitzen les sortides cap a l'Est de la pista 02 de l'aeroport de Girona. En aquest exemple, dos tipus diferents d'aeronaus volant a diferents períodes del dia són simulats obtenint, conseqüentment, diferents trajectòries òptimes.
Aunque en las últimas décadas la reducción del ruido emitido por los aviones ha sido sustancial, su impacto en la población ubicada cerca de los aeropuertos es un problema persistente. Contener este ruido, asumiendo al mismo tiempo la creciente demanda de vuelos, es uno de los principales desafíos a que se enfrentan las autoridades aeroportuarias, los proveedores de servicios para la navegación y los operadores. Aparte de mejorar la aerodinámica o las emisiones sonoras de las aeronaves, su impacto acústico se puede reducir también gracias a la definición de nuevos procedimientos de vuelo optimizados. Éstos, se denominan generalmente Procedimientos de Atenuación de Ruido (PAR) y pueden incluir rutas preferenciales de vuelo (a fin de evitar las zonas pobladas) y también perfiles de vuelo optimizados.

Los procedimientos actuales para la reducción de ruido están muy lejos de ser los óptimos. En general, su optimización no es posible debido a las limitaciones de hoy en día en los métodos de navegación, los equipos de aviónica y la complejidad presente en algunos espacios aéreos. Por otra parte, muchos PAR se han diseñado de forma manual por un grupo de expertos y con la ayuda de varias iteraciones. Sin embargo, en los próximos años se esperan nuevos sistemas de aviónica y conceptos de gestión del tráfico aéreo que permitan mejorar el diseño de estos procedimientos, haciendo que sean más flexibles. En los pocos casos donde se optimizan PAR, se suele utilizar una métrica acústica en la elaboración de las diferentes funciones objetivo y por lo tanto, no se tienen en cuenta las molestias sonoras reales. La molestia es un concepto subjetivo, complejo y que depende del contexto en que se usa y su integración en la optimización de trayectorias sigue siendo un aspecto a estudiar.

La presente tesis doctoral se basa en el hecho de que en el futuro será posible definir trayectorias más flexibles y precisas. De esta manera se permitirá la definición de procedimientos de vuelo óptimos desde un punto de vista de molestias acústicas. Se considera una situación en que este tipo de procedimientos pueden ser diseñados de forma automática o semi-automática por un sistema experto basado en técnicas de optimización y de razonamiento aproximado. Esto serviría como una herramienta de toma de decisiones para planificadores del espacio aéreo y diseñadores de procedimientos.

En este trabajo se desarrolla una herramienta completa para el cálculo de PAR óptimos. Esto incluye un conjunto de modelos no lineales que tengan en cuenta la dinámica de las aeronaves, las limitaciones de la trayectoria y las funciones objetivo. La molestia del ruido se modela utilizando técnicas de lógica difusa en función del nivel máximo de sonido percibido, la hora del día y el tipo de zona a sobrevolar. Entonces, se identifica y se formula formalmente el problema como un problema de control óptimo multi-criterio. Para resolverlo se propone un método de transcripción directa para transformarlo en un problema de programación no lineal. A continuación se evalúan una serie de técnicas de optimización multi-objetivo y entre ellas se destaca el método de escalarización, el más utilizado en la literatura. Sin embargo, se exploran diversas técnicas alternativas que permiten superar ciertos inconvenientes que la escalarización presenta. En este contexto, se presentan y prueban técnicas de optimización lexicográfica, jerárquica, igualitaria (o min-max) y por objetivos. De este análisis se desprenden ciertas conclusiones que permiten aprovechar las mejores características de cada técnica y formar finalmente una técnica compuesta de optimización multi-objetivo. Esta última estrategia se aplica con éxito en un escenario real y complejo, donde se optimizan las salidas hacia el Este de la pista 02 del aeropuerto de Girona. En este ejemplo, dos tipos diferentes de aeronaves volando a diferentes periodos del día son simulados obteniendo, consecuentemente, diferentes trayectorias óptimas.
Despite the substantial reduction of the emitted aircraft noise in the last decades, the noise impact on communities located near airports is a problem that still lingers. Containing the sound generated by aircraft operations, while meeting the increasing demand for aircraft transportation, is one of the major challenges that airport authorities, air traffic service providers and aircraft operators may deal with. Aircraft noise can be reduced by improving the aerodynamics of the aircraft, the engine noise emissions but also in designing new optimised flight procedures. These procedures, are generally called Noise Abatement Procedures (NAP) and may include preferential routings (in order to avoid populated areas) and also schedule optimised vertical flight path profiles.

Present noise abatement procedures are far from being optimal in regards to minimising noise nuisances. In general, their optimisation is not possible due to the limitations of navigation methods, current avionic equipments and the complexity present at some terminal airspaces. Moreover, NAP are often designed manually by a group of experts and several iterations are needed. However, in the forthcoming years, new avionic systems and new Air Traffic Management concepts are expected to significantly improve the design of flight procedures. This will make them more flexible, and therefore will allow them to be more environmental friendly. Furthermore, in the few cases where NAP are optimised, an acoustical metric is usually used when building up the different optimisation functions. Therefore, the actual noise annoyance is not taken into account in the optimisation process. The annoyance is a subjective, complex and context-dependent concept. Even if sophisticated noise annoyance models are already available today, their integration into an trajectory optimisation framework is still something to be further explored.

This dissertation is mainly focused on the fact that those precise and more flexible trajectories will enable the definition of optimal flight procedures regarding the noise annoyance impact, especially in the arrival and departure phases of flights. In addition, one can conceive a situation where these kinds of procedures can be designed automatically or semi-automatically by an expert system, based on optimisation techniques and approximate reasoning. This would serve as a decision making tool for airspace planners and procedure designers.

A complete framework for computing optimal NAP is developed in this work. This includes a set of nonlinear models which take into account aircraft dynamics, trajectory constraints and objective functions. The noise annoyance is modelled by using fuzzy logic techniques in function of the perceived maximum sound level, the hour of the day and the type of over-flown zone. The problem tackled, formally identified and formulated as a multi-criteria optimal control problem, uses a direct transcription method to transform it into a Non Linear Programming problem. Then, an assessment of different multi-objective optimisation techniques is presented. Among these techniques, scalarisation methods are identified as the most widely used methodologies in the present day literature. Yet, in this dissertation several alternative techniques are explored in order to overcome some known drawbacks of this technique. In this context, lexicographic, hierarchical, egalitarian (or min-max) and goal optimisation strategies are presented and tested. From this analysis some conclusions arise allowing us to take advantage of the best features of each optimisation technique aimed at building a final compound multi-objective optimisation strategy. Finally, this strategy is applied successfully to a complex and real scenario, where the East departures of runway 02 at the airport of Girona (Catalonia, Spain) are optimised. Two aircraft types are simulated at different periods of the day obtaining different optimal trajectories.

Tot i que en les últimes dècades la reducció del soroll emès pels avions ha estat substancial, el seu impacte a la població ubicada a prop dels aeroports és un problema que encara persisteix. Contenir el soroll generat per les operacions d'aeronaus, tot assumint al mateix temps la creixent demanda de vols, és un dels principals desafiaments a que s'enfronten les autoritats aeroportuàries, els proveïdors de serveis per a la navegació aèria i els operadors de les aeronaus. A part de millorar l'aerodinàmica o les emissions sonores de les aeronaus, l'impacte acústic de les seves operacions es pot reduir també gràcies a la definició de nous procediments de vol més òptims. Aquests procediments s'anomenen generalment Procediments d'Atenuació de Soroll (PAS) i poden incloure rutes preferencials de vol (a fi d'evitar les zones poblades) i també perfils de vol verticals optimitzats. Els procediments actuals per a la reducció de soroll estan molt lluny de ser els òptims. En general, la seva optimització no és possible a causa de les limitacions d'avui en dia en els mètodes de navegació, els equips d'aviònica i la complexitat present en alguns espais aeris. D'altra banda, molts PAS s'han dissenyat de forma manual per un grup d'experts i amb l'ajuda de diverses iteracions. Tot i això, en els propers anys s'esperen nous sistemes d'aviònica i conceptes de gestió del trànsit aeri que permetin millorar el disseny d'aquests procediments, fent que siguin més flexibles. En els pocs casos on s'optimitzen PAS, se sol utilitzar una mètrica acústica en l'elaboració de les diferents funcions objectiu i per tant, no es tenen en compte les molèsties sonores reals. La molèstia és un concepte subjectiu, complexe i que depèn del context en que s'usa i la seva integració en l'optimització de trajectòries segueix essent un aspecte a estudiar.La present tesi doctoral es basa en el fet que en el futur serà possible definir trajectòries més flexibles i precises. D'aquesta manera es permetrà la definició de procediments de vol òptims des d'un punt de vista de molèsties acústiques. Així doncs, es considera una situació en que aquest tipus de procediments poden ser dissenyats de forma automàtica o semi-automàtica per un sistema expert basat en tècniques d'optimització i de raonament aproximat. Això serviria com una eina de presa de decisions per planificadors de l'espai aeri i dissenyadors de procediments. En aquest treball es desenvolupa una eina completa pel càlcul de PAS òptims. Això inclou un conjunt de models no lineals que tinguin en compte la dinàmica de les aeronaus, les limitacions de la trajectòria i les funcions objectiu. La molèstia del soroll es modela utilitzant tècniques de lògica difusa en funció del nivell màxim de so percebut, l'hora del dia i el tipus de zona a sobrevolar. Llavors, s'identifica i es formula formalment el problema com a un problema de control òptim multi-criteri. Per resoldre'l es proposa un mètode de transcripció directa per tal de transformar-lo en un problema de programació no lineal. A continuació s'avaluen una sèrie de tècniques d'optimització multi-objectiu i entre elles es destaca el mètode d'escalarització, el més utilitzat en la literatura. No obstant això, s'exploren diverses tècniques alternatives que permeten superar certs inconvenients que l'escalarització presenta. En aquest context, es presenten i proven tècniques d'optimització lexicogràfica, jeràrquica, igualitària (o min-max) i per objectius. D'aquest anàlisi es desprenen certes conclusions que permeten aprofitar les millors característiques de cada tècnica i formar finalment una tècnica composta d'optimització multi-objectiu. Aquesta última estratègia s'aplica amb èxit a un escenari real i complex, on s'optimitzen les sortides cap a l'Est de la pista 02 de l'aeroport de Girona. En aquest exemple, dos tipus diferents d'aeronaus volant a diferents períodes del dia són simulats obtenint, conseqüentment, diferents trajectòries òptimes.
Aunque en las últimas décadas la reducción del ruido emitido por los aviones ha sido sustancial, su impacto en la población ubicada cerca de los aeropuertos es un problema persistente. Contener este ruido, asumiendo al mismo tiempo la creciente demanda de vuelos, es uno de los principales desafíos a que se enfrentan las autoridades aeroportuarias, los proveedores de servicios para la navegación y los operadores. Aparte de mejorar la aerodinámica o las emisiones sonoras de las aeronaves, su impacto acústico se puede reducir también gracias a la definición de nuevos procedimientos de vuelo optimizados. Éstos, se denominan generalmente Procedimientos de Atenuación de Ruido (PAR) y pueden incluir rutas preferenciales de vuelo (a fin de evitar las zonas pobladas) y también perfiles de vuelo optimizados.Los procedimientos actuales para la reducción de ruido están muy lejos de ser los óptimos. En general, su optimización no es posible debido a las limitaciones de hoy en día en los métodos de navegación, los equipos de aviónica y la complejidad presente en algunos espacios aéreos. Por otra parte, muchos PAR se han diseñado de forma manual por un grupo de expertos y con la ayuda de varias iteraciones. Sin embargo, en los próximos años se esperan nuevos sistemas de aviónica y conceptos de gestión del tráfico aéreo que permitan mejorar el diseño de estos procedimientos, haciendo que sean más flexibles. En los pocos casos donde se optimizan PAR, se suele utilizar una métrica acústica en la elaboración de las diferentes funciones objetivo y por lo tanto, no se tienen en cuenta las molestias sonoras reales. La molestia es un concepto subjetivo, complejo y que depende del contexto en que se usa y su integración en la optimización de trayectorias sigue siendo un aspecto a estudiar. La presente tesis doctoral se basa en el hecho de que en el futuro será posible definir trayectorias más flexibles y precisas. De esta manera se permitirá la definición de procedimientos de vuelo óptimos desde un punto de vista de molestias acústicas. Se considera una situación en que este tipo de procedimientos pueden ser diseñados de forma automática o semi-automática por un sistema experto basado en técnicas de optimización y de razonamiento aproximado. Esto serviría como una herramienta de toma de decisiones para planificadores del espacio aéreo y diseñadores de procedimientos.En este trabajo se desarrolla una herramienta completa para el cálculo de PAR óptimos. Esto incluye un conjunto de modelos no lineales que tengan en cuenta la dinámica de las aeronaves, las limitaciones de la trayectoria y las funciones objetivo. La molestia del ruido se modela utilizando técnicas de lógica difusa en función del nivel máximo de sonido percibido, la hora del día y el tipo de zona a sobrevolar. Entonces, se identifica y se formula formalmente el problema como un problema de control óptimo multi-criterio. Para resolverlo se propone un método de transcripción directa para transformarlo en un problema de programación no lineal. A continuación se evalúan una serie de técnicas de optimización multi-objetivo y entre ellas se destaca el método de escalarización, el más utilizado en la literatura. Sin embargo, se exploran diversas técnicas alternativas que permiten superar ciertos inconvenientes que la escalarización presenta. En este contexto, se presentan y prueban técnicas de optimización lexicográfica, jerárquica, igualitaria (o min-max) y por objetivos. De este análisis se desprenden ciertas conclusiones que permiten aprovechar las mejores características de cada técnica y formar finalmente una técnica compuesta de optimización multi-objetivo. Esta última estrategia se aplica con éxito en un escenario real y complejo, donde se optimizan las salidas hacia el Este de la pista 02 del aeropuerto de Girona. En este ejemplo, dos tipos diferentes de aeronaves volando a diferentes periodos del día son simulados obteniendo, consecuentemente, diferentes trayectorias óptimas.
Despite the substantial reduction of the emitted aircraft noise in the last decades, the noise impact on communities located near airports is a problem that still lingers. Containing the sound generated by aircraft operations, while meeting the increasing demand for aircraft transportation, is one of the major challenges that airport authorities, air traffic service providers and aircraft operators may deal with. Aircraft noise can be reduced by improving the aerodynamics of the aircraft, the engine noise emissions but also in designing new optimised flight procedures. These procedures, are generally called Noise Abatement Procedures (NAP) and may include preferential routings (in order to avoid populated areas) and also schedule optimised vertical flight path profiles. Present noise abatement procedures are far from being optimal in regards to minimising noise nuisances. In general, their optimisation is not possible due to the limitations of navigation methods, current avionic equipments and the complexity present at some terminal airspaces. Moreover, NAP are often designed manually by a group of experts and several iterations are needed. However, in the forthcoming years, new avionic systems and new Air Traffic Management concepts are expected to significantly improve the design of flight procedures. This will make them more flexible, and therefore will allow them to be more environmental friendly. Furthermore, in the few cases where NAP are optimised, an acoustical metric is usually used when building up the different optimisation functions. Therefore, the actual noise annoyance is not taken into account in the optimisation process. The annoyance is a subjective, complex and context-dependent concept. Even if sophisticated noise annoyance models are already available today, their integration into an trajectory optimisation framework is still something to be further explored. This dissertation is mainly focused on the fact that those precise and more flexible trajectories will enable the definition of optimal flight procedures regarding the noise annoyance impact, especially in the arrival and departure phases of flights. In addition, one can conceive a situation where these kinds of procedures can be designed automatically or semi-automatically by an expert system, based on optimisation techniques and approximate reasoning. This would serve as a decision making tool for airspace planners and procedure designers.A complete framework for computing optimal NAP is developed in this work. This includes a set of nonlinear models which take into account aircraft dynamics, trajectory constraints and objective functions. The noise annoyance is modelled by using fuzzy logic techniques in function of the perceived maximum sound level, the hour of the day and the type of over-flown zone. The problem tackled, formally identified and formulated as a multi-criteria optimal control problem, uses a direct transcription method to transform it into a Non Linear Programming problem. Then, an assessment of different multi-objective optimisation techniques is presented. Among these techniques, scalarisation methods are identified as the most widely used methodologies in the present day literature. Yet, in this dissertation several alternative techniques are explored in order to overcome some known drawbacks of this technique. In this context, lexicographic, hierarchical, egalitarian (or min-max) and goal optimisation strategies are presented and tested. From this analysis some conclusions arise allowing us to take advantage of the best features of each optimisation technique aimed at building a final compound multi-objective optimisation strategy. Finally, this strategy is applied successfully to a complex and real scenario, where the East departures of runway 02 at the airport of Girona (Catalonia, Spain) are optimised. Two aircraft types are simulated at different periods of the day obtaining different optimal trajectories.

Se evalúo las propiedades psicométricas del Test de Aptitudes de Educación Infantil Revisado (AEI-R) en una muestra de niños y niñas de 4 y 5 años del nivel inicial de instituciones educativas de Lima Metropolitana. La selección de los participantes fue a través del muestreo no probabilístico por conveniencia, siendo elegidos un total de 930 estudiantes de niños y niñas. El instrumento utilizado fue el AEI-R, test que mide las principales aptitudes involucradas en el aprendizaje de niños de 3 a 5 años publicado en el 2018 por Tea Ediciones. La aplicación del instrumento fue de forma colectiva. El análisis descriptivo se realizó a través de distribución de frecuencias, medidas de tendencia central y la prueba de bondad de ajuste a la curva normal de Shapiro-Wilk. El análisis de las evidencias de validez de estructura interna, fue a través del Análisis Factorial Confirmatorio (AFC); para el caso de las evidencias de fiabilidad se utilizó el método de consistencia interna y el cálculo del coeficiente Omega. Los resultados reportaron evidencias de fiabilidad adecuada (α = 0.913; ω = 0.914), y que el modelo propuesto por el instrumento no presenta un buen ajuste a la muestra de estudio (CFI = 0.807; TLI = 0.801).