Regulatory T cells (Treg) play a crucial role in controlling immune homeostasis. Several inflammatory diseases including multiple sclerosis and inflammatory bowel disease have been associated with dysfunctional and/or reduced numbers of Treg. While several mechanisms of action have been discovered by which Treg can exert their function, disease-specific Treg requirements remain unknown. The Treg pool consists of highly diverse subpopulations, indicating that there is a potential to optimise Treg-targeted therapies if disease-relevant mechanisms can be established. Microarray data from our lab suggests a marked upregulation of the integrin αv as well as the IL-33 receptor ST2 in Treg retrieved from the inflamed central nervous system (CNS) during experimental autoimmune encephalomyelitis compared to peripheral lymphoid organs. These two molecules were further investigated within this PhD project with the aim to understand their role in Treg function during chronic inflammatory disease. αvβ integrins have been reported to be needed for effector T cell migration to inflamed sites through binding of extracellular matrix components and are involved in TGF-β activation by a variety of cell types. Conditional knockout mice lacking the integrin αv specifically in Foxpγ+ Treg were generated to address the role of αv integrins on regulatory T cells in inflammatory disease. αv-/- Treg showed a deficiency in activating latent TGF-β, but were able to suppress responder T cell proliferation in vitro as well as in vivo. αv-/- Treg were also able to migrate to the inflamed CNS during EAE and resolve disease. However, αv-/- Treg were detected at significantly lower numbers and proportions in the inflamed gut during a curative T cell transfer model of colitis; this led to a quantitative impairment in the ability of αv-/- Treg to cure colitis when compared to wild-type (WT) Treg. Whether this is a deficit in migration, survival, proliferation, or Foxp3 stability, remains to be investigated. IL-33 acts as an alarmin and is best studied as a cytokine released upon tissue damage that induces a potent type 2 immune response by acting on a multitude of immune cells. Expression of the IL-33 receptor ST2 on Treg has recently been associated with positive metabolic parameters in visceral adipose tissue, protection from gut inflammation, and tissue-restorative function in other inflamed tissues such as injured muscle or lung. This project showed that in steady state, ST2+ Treg expressed high levels of several markers which have been associated with potent regulatory function. When stimulated in vitro, ST2+ Treg showed a better survival and expansion rate compared to their ST2- counterparts, even more so in the presence of IL-33. T-bet deficiency in Treg resulted in an increased ST2+ Treg pool, and T-bet-associated cytokine IFN-γ was found to antagonise IL-33-induced expansion of the ST2+ Treg pool in a T-bet-independent manner. When ST2+ and ST2- Treg were tested for their respective suppressive capacity in vivo, ST2+ Treg were able to suppress responder T cell expansion despite being found only at low numbers in secondary lymphoid organs compared to ST2- Treg. However, in a curative model of T cell transfer colitis, ST2+ Treg were less capable of controlling the ongoing immune response than ST2- Treg. A possible explanation for the superiority of ST2- Treg in this setting can be found in the fact that injected ST2- Treg acquired a distribution of ST2 expression reminiscent of WT Treg over the course of disease. On the other hand, an increased starting pool of ST2+ Treg as occurs in T-bet-/- Treg significantly enhanced the capacity of Treg to control colitis compared to WT Treg. In conclusion, both ST2- and ST2+ Treg are likely to have a distinct, non-redundant role in suppressing T cell activation in secondary lymphoid organs and controlling ongoing inflammation in peripheral tissue, respectively.

Many parasites have evolved to release products that inhibit host defence mechanisms such as enzymes in the mammalian host, in order to promote and sustain their survival within the host. The human filarial nematode Brugia malayi produces larval microfilariae, which circulate in the blood stream. Their most abundant secreted product is a serine protease inhibitor Bm-SPN-2. Serine protease inhibitors (Serpins) are reported to be involved in how the nematodes avoid host immune defences, and in the case of Bm-SPN-2, the protein was found to specifically inhibit the enzymatic activity of human neutrophil elastase and cathepsin G in a dose-dependent manner. More recently, these two enzymes have been linked to the activation of a major innate cytokine IL-33, which is stored as a full-length 270-aa protein in the cell nucleus, and released as an active C-terminal domain upon stimulation. As full-length (FL) human and murine IL-33 are not commercially available, soluble murine and human FL-IL-33 were produced in transfected HEK 293T cells, following mutation of the nuclear binding motif. In this form, IL-33 is no longer retained in the nucleus and can be purified as a soluble protein. It was confirmed that once cleaved, recombinant human IL-33 was able to induce significant IL-6 secretion by mast cells. Bm-SPN-2 was then shown to block human full-length IL-33 cleavage by inhibiting human neutrophil cathepsin G in a dose dependent manner, supporting the hypothesis that Bm-SPN-2 may act in vivo to prevent IL-33 activation and the promotion of the TH2 immune response. However, in the in vivo setting, it was unexpectedly found that IL-33R (ST2) gene deficiency did not enhance the survival of B. pahangi microfilariae. Furthermore, in the absence of IL-33R, murine immune responses to microfilariae were not significantly altered compared to wild-type BALB/c mice, other than in a significant increase in IL-33 expression. Hence while Bm-SPN-2 can act in vitro to forestall one of the key events in TH2 induction, this has not yet been shown to be crucial to the immune response to the parasite in vivo.

Mast cells are tissue-resident immune cells known as effector cells for the innate and adaptive immune systems. Mast cells contribute to host defenses against parasites such as large roundworm parasites, bacterial pathogens, and toxins, and participate in wound healing, but they are mostly known for their role in allergic diseases. It has been well established that during allergic diseases, mast cells are stimulated by IgE cross-linkage to release proinflammatory mediators. However, a newly discovered cytokine, IL-33 has also been implicated in allergic disease. Recently, IL-33 has been implicated as a driver of several Type I sensitivities and previous studies have shown that IL-33 can stimulate mast cells in atopic inflammation. Although the importance of IL-33 has been established, there are still several things unknown about IL-33 signaling regulation or treatment. This dissertation will present two separate studies involving the modulation of IL-33-mediated mast cells function In the first study, the effects of fluvastatin are explored. In a previous study, fluvastatin was shown to inhibit proinflammatory functions of IgE crosslinked mast cells. Contrasting to IgE stimulation, fluvastatin augments IL-6 and TNF production in IL-33 stimulated mast cells, but suppressed MCP-1. This phenomenon was seen in mouse and human mast cells in vitro and replicated in a mast cell-dependent murine model of IL-33-induced inflammation in vivo. In the second study, IL-33 was found to induce miR-146a expression in mouse mast cells and mast cell-derived exosomes in vitro, and in plasma exosomes in vivo. IL-33 induced miR-146a was of interest because miR-146a is a known negative regulator of TLR signaling, which shares the MyD88 signaling pathway with IL-33. We found that miR-146a KO mast cells are hyperresponsive to IL-33 stimulation, data that were replicated by suppressing miR-146a-5p in WT mast cells. In an acute mast cell repopulation model, kitW-sh/W-sh mice containing miR-146a KO BMMC had increased IL-33 induced neutrophilia in comparison to their controls. Collectively, these data reveal new IL-33 signaling pathways and means of altering its inflammatory effects on mast cells. Because IL-33 has important roles in allergy and other Th2-mediated diseases, these results advance clinically relevant areas of immunology.

Act 33 of 1995 is an amendment to Pennsylvania's Juvenile Act (2008). This amendment changed jurisdictional boundaries for juvenile offenders who committed violent crimes with weapons. As a result, youth who committed violent crimes with weapons were automatically transferred to the adult criminal justice system. Using punctuated equilibrium as the theoretical foundation, the purpose of this study was to determine if Act 33, as a punctuating event, resulted in an increase in the number of youth transferred to the adult criminal justice system and sentenced to life without the possibility of parole in an urban county in Pennsylvania. Secondary data (N = 143) were acquired from the Pennsylvania Department of Corrections on juveniles sentenced to life without the possibility of parole in Pennsylvania pre and post Act 33. Chi-square test with 2-way contingency table analysis was used to analyze the data. Results did not indicate a statistically significant association between the numbers of juveniles transferred to the adult criminal justice system and sentenced to life without the possibility of parole and the implementation of Pennsylvania of Act 33. The positive social change implications of this study include recommendations to the Pennsylvania legislators to increase state funds in order to implement service integration for juvenile lifers returning to the community.

The next generation of reusable launch vehicles (RLVs) require significant improvements in guidance methods in order to reduce cost, increase safety and flexibility, whilst allowing for possible autonomous operation. Research has focused on the ascent and hypersonic re-entry flight phases. This thesis presents a new method for trajectory design, optimisation and guidance of RLVs during the terminal area flight phases. The terminal area flight phase is the transitional phase from hypersonic re-entry to the approach and landing phase. The trajectory design, optimisation and guidance methods within this thesis are an evolution of previous work conducted on the ascent and re-entry flight phases of RLVs. The methods are modified to incorporate the terminal area flight phase through the adaption of the problem definition and the inclusion of the speed brake setting as a steering parameter. The methods discussed and developed in this thesis are different to previous methods for the terminal area flight phase as they encompass optimisation, trajectory design and guidance based on the definition of the steering parameters. The NLPQL nonlinear optimiser contained within the International Mathematics Standards Library (IMSL) is utilised for trajectory design and optimisation. Real-time vehicle guidance is achieved using the restoration steps of an accelerated Gradient Projection Algorithm (GPA). The methods used are evaluated in a three degrees of freedom (3DOF) simulation environment. To properly evaluate the programs and gain a better understanding of the terminal area flight phase, two different vehicles are utilised within this study. These vehicles are the German sub-orbital Hopper concept vehicle, a previously proposed replacement for the Ariane series of launch vehicles and the recently cancelled joint National Aeronautics and Space Administration (NASA) and Lockheed Martin sub-orbital test bed vehicle, X-33. The two vehicles each have a terminal area flight phase, but their mission profiles and vehicle characteristics are significantly different. The Hopper vehicle is a winged re-entry vehicle, whereas the X-33 vehicle is a lifting body. The trajectory design method takes into account the initial and final conditions, in-flight restrictions such as dynamic pressure and vehicle loads as well as safety margins. The designed trajectories are evaluated to analyse the terminal area flight phase and to assist in the development of the guidance program. The guidance method is evaluated utilising an program consisting of two parts, a real world simulator with high order models and a representation of the on-board guidance computer, the predictor, which uses low order models for computational efficiency. The guidance method is evaluated against a variety of off-nominal conditions to account for dispersions within the high order real world models and common errors experienced by re-entry vehicles. These off-nominal conditions include atmospheric disturbances, winds, aerodynamic, mass, navigation, steering and initial condition errors. The results of this study include a detailed analysis of the terminal area flight phase highlighting the major influences for vehicle and trajectory design. The study also confirms the applicability of the non-linear programming method utilising the vehicle steering parameters as a viable option for trajectory design and guidance. A comparison to other available results highlights the strengths and weaknesses of the proposed method. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1282342 / Thesis (Ph.D.)--School of Mechanical Engineering, 2007.

Stroke is a common multi factorial cerebrovascular disorder with a large impact on global health. It is a disorder primarily associated with old age but environmental factors, lifestyle choices and medical history are all important for the risk of developing the disorder. It is also known that heritability is important for predisposition to the disorder. The aim of this work has been to identify genetic variations that increase the risk of being affected by stroke in the population of northern Sweden, a population well apt for genetic studies due to well kept church and medical records together with limited genetic diversity. In the first paper we used linkage analysis in families with early onset of stroke. By this approach we identified a region on chromosome 5q to be linked to an increased risk of developing stroke, a region previously identified as a susceptibility locus for stroke in the Icelandic population. In the second study we used genealogy to identify common ancestry and thereby identify common susceptibility to stroke. The seven families we connected showed significant linkage to the chromosome 9q31-33 region and four of the families shared a common haplotype over 2.1 megabases. In the third manuscript we investigated sequence variation of two candidate genes, TNFSF15 and TLR4. Sequencing of the TLR4 gene revealed previously identified variations in affected individuals from two of the families. Further SNP analysis showed five separate haplotypes among the investigated families and four haplotypes for TNFSF15. However none of these co-segregated with stroke among the investigated families. In the final paper we used a case-control stroke cohort to ascertain association for genetic variation in five genes and genetic regions previously suggested to be linked with stroke. Initial analyses showed association for the 9p21 chromosomal region and a variant in Factor 5 that showed protection against stroke, but after adjustments for common risk factors for stroke, the findings were no longer significant. In conclusion, by studying selected families we have been able to show linkage to two chromosomal regions, 5q and 9q31-33, that indicate genetic predisposition for developing stroke. Further we have shown that family based studies are still an important tool in deciphering the underlying mechanisms for complex disease.

La ràpida i forta penetració de les tecnologies de la comunicació mòbil als mercats mundials presenta al marketing mòbil amb una forta influència en l'activitat empresarial i en la conducta del consumidor, tant a nivell nacional com a global. Mentre que la recerca acadèmica s'ha centrat a estudiar indústries específiques en el context del marketing mòbil, aquest estudi es centra en un grup professional molt concret: els metges en consulta privada. A la primera part d'aquesta recerca es desenvolupen els conceptes claus relacionats amb el marketing mòbil a l'àrea mèdica. L'estudi dut a terme en ginecòlegs a Alemanya proporciona un nombre rellevant d'aspectes tant en el grup de metges que no utilitzen el mitjà mòbil en la seva pràctica mèdica com per als pocs que ja ho utilitzen. En el grup dels no usuaris, els resultats indiquen diverses barreres determinants que dificulten l'adopció del mitjà mòbil com són la falta de temps del metge, consideracions econòmiques i legals, i la falta d'informació. L'estudi també identifica el grau d'utilitat percebut pels metges per a diverses funcions dels mòbils i aporta suggeriments respecte als factors que poden contribuir a l'adopció d'aquest mitjà. S'utilitzen els mètodes de Regressió logística ordinal i regressió logística directa amb la finalitat d'establir en quina mesura els factors demogràfics i l’experiència prèvia en l'ús de mitjà mòbil influeixen sobre les decisions i percepcions dels metges. L'estudi també presenta els resultats d'un grup de metges que ja està utilitzant canals mòbils en la seva pràctica mèdica. S'identifiquen tendències, les activitats planificades i no planificades a través dels mòbils i s'informa dels resultats de l'ús dels dispositius i tecnologia mòbil en la seva pràctica mèdica. Les implicacions, limitacions i futures línies de recerca conclouen aquesta dissertació. / La rápida y fuerte penetración de las tecnologías de la comunicación móvil en los mercados mundiales presenta al marketing móvil con una fuerte influencia en la actividad empresarial y en la conducta del consumidor, tanto a nivel nacional como global. Mientras que la investigación académica se ha centrado en estudiar industrias específicas en el contexto del marketing móvil, este estudio se centra en un grupo profesional muy concreto: los médicos en consulta privada. En la primera parte de esta investigación se desarrollan los conceptos claves relacionados con el marketing móvil en el área médica. El estudio llevado a cabo en ginecólogos en Alemania proporciona un número relevante de aspectos tanto en el grupo de médicos que no utilizan el medio móvil en su práctica médica como para los pocos que ya lo utilizan. En el grupo de los no usuarios, los resultados indican varias barreras determinantes que dificultan la adopción del medio móvil como son la falta de tiempo del médico, consideraciones económicas y legales, y la falta de información. El estudio también identifica el grado de utilidad percibido por los médicos para diversas funciones de los móviles y aporta sugerencias respecto a los factores que pueden contribuir a la adopción de este medio. Se utilizan los métodos de Regresión logística ordinal y regresión logística directa con el fin de establecer en qué medida los factores demográficos y experiencia previa en el uso de medio móvil influyen sobre las decisiones y percepciones de los médicos. El estudio también presenta los resultados de un grupo de médicos que ya está utilizando canales móviles en su práctica médica. Se identifican tendencias, actividades planificadas y no planificadas a través de los móviles y se informa de los resultados del uso de los dispositivos y tecnología móvil en su práctica médica. Las implicaciones, limitaciones y futuras líneas de investigación concluyen esta disertación. / Mobile communication technologies have penetrated markets throughout the world, and thus mobile marketing is likely to have a strong influence on future business activities and consumer behavior, as well as on national and global markets. While academic research has started to focus on particular industries in the mobile marketing context, this study shifts the focus to the particular professional group of physicians in private practice. After first developing key concepts related to mobile marketing in the physician domain, the research carried out with gynecologists in Germany then provides a number of relevant insights stemming from both physicians not employing the mobile medium in their medical practice and the few who already do so. For the group of Non-Users, the findings indicate that several key adoption barriers seem to prevent the inclusion of the mobile channel, including the physicians’ lack of time, economic and legal considerations, and lack of information. The study also identifies the degree of usefulness for a range of mobile activities as perceived by the physicians themselves, and provides insights into which factors would be conducive for physicians to start using the mobile medium for said purposes. Both ordinal logistics regression and direct logistics regression are employed to gain a better understanding of how demographic factors and status of private mobile use impact physician responses. This yields significant findings across the board, with interesting implications given the demographic shift currently taking place in the German healthcare arena. The research also provides evidence from a group of physicians who already take advantage of the mobile channel in their medical practice. We identify current, planned and not-planned mobile activities, and present the reported experiences along several lines resulting from the use of mobile devices and technology in their medical practice. Implications, limitations and future research avenues conclude this dissertation.

El campo de estudio centrado en los tipos de interés es muy amplio y ha merecido una gran atención, tanto por parte de los académicos como por parte de los profesionales. Esta afirmación queda avalada por la extensa bibliografía sobre el tema generada en los últimos años. Concretamente, el objetivo de esta tesis doctoral se centra en el planteamiento, desarrollo y contrastación de un modelo dinámico de la estructura temporal de tipos de interés, que incorpora tres variables de estado. El comportamiento temporal de estos factores se representa mediante ecuaciones diferenciales estocásticas. Aplicando el lema de Itò, la condición de inexistencia de posibilidades de arbitraje y una definición funcional de los precios que el mercado asigna al riesgo, se obtiene una ecuación cierta en derivadas parciales de segundo orden, para el precio de la obligación cupón cero, libre de riesgo de insolvencia. La ecuación que se obtiene en el modelo admite solución analítica, por separación de variables, por lo que es posible definir la función de descuento, para cualquier plazo, a partir de los valores de las tres variables de estado.Obtenida la función de descuento, la definición de la estructura de tipos al contado y la de tipos implícitos es inmediata. También se obtienen las expresiones correspondientes a la prima de riesgo y prima "forward" asociadas al modelo. Finalmente, se deducen las expresiones de duración y convexidad asociadas a cada factor estocástico del modelo.Esta tesis doctoral se ha estructurado en cuatro capítulos. El primer capítulo, de carácter introductorio, define el concepto de estructura temporal de tipos de interés. El segundo capítulo se centra en los modelos dinámicos de la curva de tipos. El tercer capítulo se inicia con el planteamiento del modelo propuesto de la dinámica de la estructura temporal, considerándose tres variables de estado: dos "spreads" y un tipo de interés al contado a largo plazo. En el cuarto y último capítulo se efectúa la contrastación empírica del modelo, mediante los datos proporcionados por el Servicio de Estudios del Banco de España. Finalmente, y a modo de resumen, se detallan las conclusiones de este trabajo.La tesis se completa con tres anexos. En el primero se presentan gráficamente las series temporales con las que se trabaja en el capítulo de aplicación empírica. En el anexo dos, se incluye el programa de Mathcad 2000 utilizado en la segunda fase de estimación del modelo. En el último anexo, se efectúa un análisis gráfico del modelo. Se comprueban, empíricamente, una serie de propiedades de la función de descuento obtenida y se analiza el comportamiento de la curva de tipos, cuando cambian los parámetros que la definen.

La tesi doctoral que aquí es presenta no és fruit d'una idea aïllada sinó que n'és el resultat d'una evolució molt concreta en la recerca tant a nivell teòric com aplicat de l'autor al voltant de l'anàlisi i tractament de sèries econòmiques temporals en el sí del Grup d'Anàlisi Quantitativa Regional del Departament d'Econometria, Estadística i Economia Espanyola de la Universitat de Barcelona.A nivell aplicat, l'experiència assolida en la modelització de sèries econòmiques, sobretot com a eina fonamental per a l'anàlisi de la conjuntura econòmica, demostra que les tècniques i models aplicats per obtenir prediccions a curt i mig termini de variables econòmiques poden influir en els resultats obtinguts de manera que, usant unes altres tècniques o models és possible arribar a resultats diferents. Així, l'elecció d'un o altre tipus de modelització, lluny de ser un tema marginal a la pràctica, pot condicionar la interpretació que hom acaba fent de la situació econòmica actual.A nivell teòric la tesi és conseqüència d'un treball de recerca previ al voltant de l'aplicació de les tècniques estadístiques de l'anàlisi espectral a l'àmbit de l'Econometria. Aquestes tècniques, tot i la seva popularitat en l'anàlisi estadística, conformen un cos teòric poc usat en certs àmbits econometries relacionats amb les sèries temporals fins no fa gaire. Durant els darrers anys, però, és habitual cada cop més recórrer al domini de les freqüències per analitzar certs aspectes de les sèries econòmiques.Sovint hom es troba amb certes contradiccions entre la modelització suggerida per les característiques de la variable en el domini temporal i la suggerida per les característiques en el domini de les freqüències, mentre a nivell teòric ambdós tipus d'anàlisi no són més que les dues cares de la mateixa moneda. En aquest sentit, la motivació de la tesi que aquí es presenta és la d'avançar en la resposta a aquestes aparents contradiccions. Així l'objectiu principal de la tesi és mostrar com algunes d'aquestes aparents contradiccions desapareixen quan es té en compte el que considerem una característica fonamental de les sèries temporals i que hem anomenat a la tesi "memòria".A nivell intuïtiu es pot interpretar aquest concepte com la màxima distància temporal a través de la qual es manté una certa dependència entre els valors de la variable. De fet, la idea de "memòria" és present de manera indirecta a l'anàlisi estadística de sèries temporals d'ençà el desenvolupament del concepte d'estacionarietat en forma de restriccions per a que els moments mostráis siguin bons estimadors dels moments poblacionals. En aquest sentit, posar restriccions a la memòria d'una sèrie temporal consisteix a limitar el nivell d'informació que les observacions passades aporten a la predicció de les observacions futures i la manera més popular de formalitzar aquestes restriccions és a través del concepte d'ergodicitat.Sovint, en el tractament econometric de variables econòmiques a partir d'informació de caire temporal no es té en compte el tipus de memòria que contenen aquestes dades o, si es té en compte s'imposen restriccions que poden ser excessives. Per tant, la tesi neix de la preocupación pels errors que pot provocar no considerar de manera adequada el tipus de memòria i especificar models que no reprodueixen de manera adequada les característiques temporals d'aquestes variables.Així, tot i que aquests problemes d'especificació i selecció de models per sèries temporals són part de l'estadística matemàtica, cal remarcar que l'interès final de la tesi es troba en les conseqüències économétriques del concepte de memòria tot i que per assolir aquest objectiu, calgui tractar en alguns moments al llarg de la tesi aspectes purament estadístics. / Desde el punto de vista del dominio frecuencia, los modelos ARMA y ARIMA presentan características muy extremas en cuanto a la concentración de potencia en determinadas frecuencias. Por tanto, si se utilizan dichos modelos para modelizar datos que presentan un grado de memoria intermedio, se está vulnerando la condición de que la memoria del modelo sea coherente con la memoria de los datos y es importante conocer cuales pueden ser las consecuencias econométricas de este problema. En este sentido, el objetivo de la tesis que aquí se presenta consiste en valorar las posibles consecuencias prácticas que diferentes grados de memoria pueden tener para el análisis econométrico de datos temporales. Para ello se propone, en primer lugar, una clasificación concreta de las series temporales atendiendo a dicha característica. A continuación se analiza tanto la sensibilidad de algunos de los estadísticos y técnicas más habituales en el análisis tanto la sensibilidad de algunos estadísticos y técnicas más habituales en el análisis de series temporales económicas a nivel univariante frente al tipo de memoria. Finalmente, se estudia la relación que existen entre el grado de memoria y el peligro de obtener regresiones estadísticamente significativas a partir de series temporales independientes, es decir, lo que se conoce habitualmente como relaciones espurias.

La justificació de l'Euroregió de l'Arc Mediterrani com a regió econòmica, a partir de les variables habitualment utilitzades en l'economia i la necessitat d'aplicar-hi politiques pensades per la seva realitat. Descripció de les polítiques necessàries per mantenir la competitivitat del sistema i les estrangulacions més importants que ho poden impedir.