Matrix Extracellular Phosphoglycoprotein (MEPE) is a member of a family of proteins called small integrin-binding ligand, N-linked glycoproteins (SIBLINGs) which play key roles in biomineralisation. Altered MEPE expression is associated with several phosphate and bone-mineral metabolic disorders such as oncogenic osteomalacia and hypophosphatemic rickets. Despite this, it remains undetermined what impact MEPE has on the growth plate; the cartilage anlagen from which endochondral ossification, the process responsible for linear bone growth, occurs. The work of this thesis has characterised the ATDC5 cell line and the metatarsal organ culture as useful in vitro models of endochondral ossification. These will prove vital in the pursuit of underpinning the molecular mechanisms involved in endochondral bone growth. These models form the basis of the further studies in this thesis examining the role of MEPE within this highly orchestrated process. Before such role can be defined, this thesis details the spatial and temporal localisation patterns of MEPE in 10-day- and 4-week-old murine growth plates. More specifically, MEPE protein and mRNA were preferentially expressed by the hypertrophic chondrocytes as shown by immunohistochemistry and in situ hybridisation respectively. Microdissection of the murine growth plate confirmed this. Localisation of the cleavage product of MEPE, a 2.2kDa acidic serine- and aspirate-rich motif (ASARM) peptide, followed a similar pattern of expression. The localisation of MEPE to sites of mineralisation serves to strengthen its potential role in chondrocyte matrix mineralisation. This thesis identified this role in both mineralising ATDC5 cells and the metatarsal organ culture. The ASARM peptide was found to be the functional component of MEPE and this function was dependent upon its post-translational phosphorylation. Phosphorylated (p)ASARM peptides significantly inhibited chondrocyte matrix mineralisation without altering the proliferation or differentiation of the chondrocyte cells, or their ability to produce an extracellular matrix. mRNA analysis by qPCR indicted a feedback system by which the pASARM peptide functions to allow the release of further ASARM peptides. Moreover, the pASARM peptide inhibited mRNA expression of markers of vascular angiogenesis highlighting a novel mechanism by which they may inhibit chondrocyte matrix mineralisation. This thesis also determines the regulatory cross-talk between the chondrocytes of the murine growth plate, with the most abundant bone cell type, the osteocyte. This cross-talk inhibits chondrocyte matrix mineralisation and is attributed to sclerostin, an osteocyte-specific secretory protein. Furthermore, it is shown that sclerostin acts through the MEPE-ASARM axis to regulate chondrocyte matrix mineralisation and thus endochondral ossification. The work described herein has characterised and validated in vitro models of growth plate chondrocyte matrix mineralisation and has used these to identify the role of MEPE within chondrocyte matrix mineralisation.

Three main issues are explored in this thesis—volatility measurement, volatility spillover and large-dimension covariance matrices. For the first question of volatility measurement, this thesis compares two newly-proposed, high-frequency volatility measurement models, namely realized volatility and realized range-based volatility. It does so in the aim of trying to use empirical results to assess whether one volatility model is better than the other. The realized volatility model and realized range-based volatility model are compared based on three markets, five forecast models, two data frequencies and two volatility proxies, making sixty scenarios in total. Seven different loss functions are also used for the evaluation tests. This necessarily ensures that the empirical results are highly robust. After making some simple adjustments to the original realized range-based volatility, this thesis concludes that it is clear that the scaled realized range-based volatility model outperforms the realized volatility model. For the second research question on volatility spillover, realized range-based volatility and realized volatility models are employed to study the volatility spillover among the S&P 500 index markets, with the aim of finding out empirically whether volatility spillover exists between the markets. Volatility spillover is divided into the two categories of statistically significant volatility spillover and economically significant volatility spillover. Economically significant spillover is defined as spillover that can help forecast the volatility of another market, and is therefore a more powerful measurement than statistically significant spillover. The findings show that, in reality, the existence of volatility spillover depends on the choice of model, choice of volatility proxy and value of parameters used. The third and final research question in this thesis involves the comparison of various large-dimension multivariate models. The main contribution made by this specific study is threefold. First, a number of good performance multivariate volatility models are introduced by adjusting some commonly used models. Second, different models and various choices of parameters for these models are tested based on 26 currency pairs. Third, the evaluation criteria adopted possess much more practical implications than those used in most other papers on this subject area.

Approved for public release; distribution is unlimited / This thesis examines the movement of personnel into, through, and out of the enlisted forces of the U.S. military services during the period FY1974-FY1987. The vehicle for this analysis is the Enlisted Transition Matrix, which is used by DOD and the Office of Management and Budget (OMB), to track the transition characteristics of the enlisted forces. The Matrix data were supplied by the Defense Manpower Data Center, Monterey, CA. The data were aggregated to the service-wide and years-of-service (YOS) level. The main conclusion of this thesis is that analysis of data aggregated to this level does not yield useful information. Economic and demographic factors fluctuated significantly during the period of interest; however, the effects of those fluctuations are not evidenced in enlisted force information aggregated to the force or YOS level. / http://archive.org/details/trendsinenlisted00good / Lieutenant Commander, United States Navy

Les réseaux d’alimentation d’antennes multifaisceaux sont un sous-système particulièrement important dans la mesure où ils permettent de réutiliser une même ouverture rayonnante pour l’ensemble des faisceaux à produire. Ces solutions trouvent naturellement application dans le spatial, l’espace disponible pour aménager des antennes étant fortement contraint sur les satellites. Plusieurs solutions de réseaux d’alimentation sont disponibles dans la littérature, incluant des structures quasi-optique ou lentilles et des structures guidées. Nous avons approfondie cette deuxième catégorie en étudiant différentes solutions, incluant les matrices de Blass, de Butler, de Nolen, ainsi que des structures à lois de phase uniformes. En particulier, un mode de dimensionnement des matrices de Nolen, défini comme un cas particulier asymptotique d’un algorithme de dimensionnement de matrices de Blass, a été proposé et validé expérimentalement en bande S. La flexibilité du dimensionnement des matrices de Nolen proposé a été exploitée pour concevoir une matrice à distribution d’amplitude non-uniforme, afin de réduire le niveau des lobes secondaires. Enfin, le caractère dispersif d’une alimentation en série a été utilisé pour rendre le pointage angulaire du faisceau produit par une antenne réseau linéaire indépendant de la fréquence de fonctionnement et pourrait être étendu à des matrices de Blass et Nolen. Des structures à lois de phase uniformes et à distribution d’amplitudes uniforme et gaussienne ont été approfondies, afin de mettre en évidence notamment le niveau de pertes intrinsèques. La structure à distribution d’amplitude gaussienne a été modifiée pour l’adapter à des applications d’antennes réseaux circulaires. L’ensemble des informations regroupées dans ce mémoire permet d’identifier la topologie de réseau d’alimentation la mieux adaptée à une application donnée. Une combinaison de différents concepts peut s’avérer une bonne solution dans certains cas. / Beam forming networks for multiple beam antennas are a very important antenna sub-system as they enable to reuse the same radiating aperture to produce all the beams. These solutions naturally find application in space as stringent accommodation constraints on board of satellites ask for space saving. Several concepts are available in the literature, including quasi-optic solutions and guided wave solutions. We investigated on this second category, including namely Blass, Butler and Nolen matrices as well as beam forming networks producing uniform phase distribution. In particular, we proposed a designed method, defined as an asymptotic singular case of a more general Blass matrix design procedure. Experimental validation was carried out with a specific design in S-band. Flexibility on the design of Nolen matrix has been used to generate non-uniform amplitude distribution to reduce side-lobe level. Also, natural phase dispersion of a serial feeding network has been used to produce frequency independent beam pointing linear arrays with potential application to Blass and Nolen matrices. Beam forming networks with uniform phase distribution associated to uniform and Gaussian amplitude distributions were also investigated, in particular to highlight the level of the intrinsic losses. The structure with Gaussian amplitude distribution was also modified to be adapted to circular array antennas. All this information should help to identify the best suited beam forming network concept for a given application. In some particular cases, a combination of different concepts can even be considered.

Nous considérons plusieurs problèmes autour des matrices à signes alternants (MSA). Dans un premier chapitre nous donnons une formule de comptage des MSAs selon le nombre k de -1 qu'elles contiennent et leur taille n. Cette formule permet d'obtenir une évaluation asymptotique pour un k donné lorsque n tend vers l'infini et une expression simple pour les valeurs de k inférieures ou égales à 7.Une deuxième partie est consacrée à une famille de MSAs dont les triangles Gogs (ou triangles monotones) associés sont en bijection avec une famille de triangles Magogs (ou des partition planes auto complémentaires symétriques). Nous présentons une méthode de minoration du nombre d'éléments de taille n dans cette famille d'objets.Enfin, nous évaluons la probabilité d'apparition de motifs (sous-diagrammes) dans des diagrammes de cordes tirés selon la distribution limite introduite par la conjecture de Razumov et Stroganov. / Abstract

La matriz FODA es la herramienta de análisis por excelencia para fines de negocios, y se enseña en cursos de pregrado y postgrado. Sin embargo, se entiende que la elección de los factores críticos de éxito (FCEs) que se incluyen en la matriz para el análisis es un proceso muy subjetivo y no estructurado, que da cabida a sesgos y arbitrariedad. Una forma de dar una mejor base y respaldo a los resultados del análisis es mediante la utilización del Proceso Jerárquico Analítico (AHP) con el fin de ponderar la importancia de los FCEs en la matriz FODA y aumentar la fiabilidad de los resultados. Este documento contiene el diseño de una estrategia para enseñar este tema en un curso de planificación de marketing, con la adición de una técnica útil para superar las limitaciones de la herramienta. / The SWOT matrix is the quintessential analysis tool for business purposes, and is taught both in undergraduate and postgraduate courses. However, it is widely understood that the selection of the critical success factors (CSFs) that are included for analysis in the matrix is a very subjective and unstructured process, leaving room for bias and arbitrariness. One way to give a better foundation and support to the analysis results is by utilizing Analytic Hierarchical Process (AHP) in order to weigh the importance of CSFs in the SWOT matrix and increase reliability of the output. This paper contains the design of a strategy to teach this topic in a marketing planning course, with the addition of a useful technique to overcome the limitations of the tool.

Fibrillin-1 is the main component of the 10-12 nm microfibrils, which are found in several elastic and non-elastic tissues. Human fibrillin-1 contains multiple calcium-binding epidermal growth factor-like (cbEGF) domains interspersed with transforming growth factor β-binding protein-like (TB) domains. TB4 domain contains a flexible RGD loop which mediates cell adhesion via αVβ3, α5β1 and αVβ6 integrins. Mutations which introduce amino acid substitutions into TB4 are associated with a wide spectrum of diseases such as Marfan syndrome (MFS), ectopia lentis, Stiff skin syndrome (SSS). Amino acid substitutions such as W1570C, C1564S and C1577G in the TB4 domain have been found to cause SSS. The upstream TB5 domain has been predicted to modulate integrin binding and a deletion in the domain has been found in Weill-Marchesani syndrome (WMS), phenotype of which is similar to SSS (skin fibrosis and short stature), thereby suggesting that the underlying pathogenic mechanism might be similar. This study has used cellular, biochemical and biophysical methods to investigate the effects of SSS substitutions C1564S and W1570C on domain structure and function and compared it to a MFS substitution C1564Y in the TB4 domain and WMS deletion in the TB5 domain. Effects of the SSS mutations on structure of the domains were studied using limited proteolysis, nuclear magnetic resonance spectroscopy and calcium chelation experiments. Subsequently, the ability of human fibroblasts to secrete wild-type and mutant fibrillin-1 was examined to identify the effect of the mutations on the trafficking of the protein. Finally, cell binding assays and SPR was employed to investigate the effect of disease-causing mutations on fibrillin-1/integrin interactions. The results demonstrate that the SSS mutations affect TB4-cbEGF23 interface and calcium-binding to cbEGF23 but do not alter secretion of recombinant fibrillin-1 mutant fragments from the cell. On the other hand, intracellular retention was observed for MFS substitution C1564Y which was shown to be more susceptible to proteolysis than SSS substitution C1564S. WMS deletion also gives rise to partial retention of the recombinant fragment, suggesting a different pathogenic mechanism for these disorders. Cell binding assays and surface plasmon resonance (SPR) experiments show that SSS mutations affect binding to αvβ3 integrin, but not αvβ6 integrin suggesting that selectively impaired integrin interactions may contribute to pathogenesis of SSS.

Naegleria fowleri (N. fowleri) and Naegleria lovaniensis (N. lovaniensis) are closely related amebae found in the environment. N. fowleri causes Primary Amebic Meningoencephalitis (PAM), a fatal disease of the central nervous system, while N. lovaniensis is nonpathogenic. N. fowleri infection occurs when amebae enter the nasal passages, and migrate to the brain. The molecular mechanisms involved in the pathogenesis of PAM are not well-defined. Therefore, the purpose of this study was to define phenotypic characteristics that may be functionally linked to the pathogenicity associated with N. fowleri. Studies revealed that N. fowleri has a faster growth rate and is more resistant to complement-mediated lysis when compared to N. lovaniensis. Additionally, contact-independent cytotoxicity was observed only for N. fowleri. The ability to invade tissues can be a characteristic that distinguishes pathogens from nonpathogens. Therefore, adhesion to extracellular matrix components (ECM), laminin-1, fibronectin, and collagen I, was assessed. N. fowleri exhibited a higher level of adhesion to ECM components and was shown to invade tri-dimensional ECM scaffolds (matrigel and collagen I) to a greater extent than N. lovaniensis. Scanning electron microscopy revealed that N. fowleri attached on ECM substrata exhibited a spread-out appearance that included the presence of focal adhesion-like structures. Attachment of N. fowleri to ECM components was decreased significantly when amebae were pretreated with trypsin, suggesting a role for a surface protein in this process. Pretreatment of N. fowleri amebae with periodate, a sugar oxidant, led to a decrease in attachment to laminin-1 and fibronectin suggesting that the surface component contained a sugar moiety. Western immunoblotting revealed two integrin-like proteins for both species. However, one with a molecular mass of approximately 70 kDa, was detected at a higher level for N. fowleri. Confocal microscopy indicated that the integrin-like proteins co-localized to the focal adhesion-like structures. An anti-integrin antibody decreased adhesion of N. fowleri to ECM components. Zymographic analysis demonstrated differential expression of proteases occurs when N. fowleri and N. lovaniensis invade ECM components using an in vitro invasion assay. These results indicate a distinction in adhesion to, and invasion of, extracellular matrix proteins between N. fowleri and N. lovaniensis.

No description available.

Model formulas are the standard approach for specifying the variables in statistical models in the S language. Although being eminently useful in an extremely wide class of applications, they have certain limitations including being confined to single responses and not providing convenient support for processing formulas with multiple parts. The latter is relevant for models with two or more sets of variable, e.g., regressors/instruments in instrumental variable regressions, two-part models such as hurdle models, or alternative-specific and individual-specific variables in choice models among many others. The R package Formula addresses these two problems by providing a new class "Formula" (inheriting from "formula") that accepts an additional formula operator | separating multiple parts and by allowing all formula operators (including the new |) on the left-hand side to support multiple responses. / Series: Research Report Series / Department of Statistics and Mathematics