Cervical cancer is a multifactorial disease. Infection by oncogenic types of the human papillomavirus (HPV) is the major environmental risk factor and host genetic susceptibility also influences disease development. The aim of this thesis is to identify and analyse risk genes involved in the genetic predisposition to cervical carcinoma. A unique and extensive population-based affected sib-pair (ASP) material and a large case-control sample were used in the investigations. In paper I the human leukocyte antigen (HLA) class II DQB1 and DRB1 loci are confirmed, for the first time in a family-based material, as genetic susceptibility factors for cervical cancer. It is also proposed that the HLA class II DPB1 locus independently contributes to risk of developing disease. In addition, no evidence is found for an involvement of the class I HLA-B and HLA-A loci in the genetic predisposition. Paper II conclude that the Fas receptor –670 single nucleotide polymorphism (SNP) do not have a major impact on the susceptibility to cervical carcinoma in situ in the Swedish population. In paper III we show that interactions between the HPV16 E6 gene subtype and host HLA class II genotype potentially occur during infection and disease progression. Paper IV suggests that three chromosomal regions, 9q32, 12q24 and 16q24, contain risk factors of low to moderate effects on cervical cancer development. In paper V linkage signals are further identified between a 9q32 gene encoding the thymic stromal co-transporter (TSCOT) and the disease in ASPs with mean age over 30.5 years at diagnosis within the sib-pair. These findings are important contributions towards understanding more about the aetiology of this complex cancer. The identification of new susceptibility regions opens up for further characterisation, replication and candidate gene analysis.

One of the promises of High Level Architecture (HLA) is the reusability of simulation components. Although HLA supports reusability to some extent with mechanisms provided by Object Model Template (OMT), when the developer wants to use an existing federate application within another federation with a different Federation Object Model (FOM) problem arises. She usually has to modify the federate code and rebuilt it. There have been some attempts to solve this problem and they, in fact, accomplish this to some extent but usually they fall short of providing flexible but also a complete mapping mechanism. In this work, a model based approach that mainly focuses on Declaration, Object and Federation Management services is explored. The proposed approach makes use of Model Integrated Computing (MIC) and .NET 2.0 technologies by grouping federate transitioning activities into three well-defined phases, namely, modeling, automatic code generation and component generation. As a side product, a .NET 2.0 wrapper to Runtime Infrastructure (RTI) has been developed to help developers create IEEE 1516 compatible .NET 2.0 federates in a programming language independent way.

This thesis addresses the improvement of a physically based modeling simulator Naval Surface Tactical Maneuvering Simulation System (NSTMSS), that combines different simulators in a distributed environment by the help of High Level Architecture (HLA), to be used in naval tactical training systems. The objective is to upgrade a computer simulation program in which physical models are improved in order to achieve a more realistic movement of a ship in a virtual environment. The simulator will also be able to model the ocean waves and ship wakes for a more realistic view. The new naval model includes a 4 degrees of freedom (DOF) maneuvering model, and a wave model. The numerical results from real life are used for modeling purposes to increase the realism level of the simulator. Since the product at the end of the thesis work is needed to be a running computer code that can be integrated into the NSTMSS system, the code implementation and algorithm details are also covered. The comparisons between the wave models and physical models are evaluated for a better real time performance. The result of this thesis shows that the integration of a 4-DOF realistic ship model to the system improved the capability of NSTMSS to give more data to the student officers while making maneuvers. The result also indicates that the use of waves and ship wakes had taken the simulator to a next level in the environment perception.

This research develops a computer simulation method for federating an Arena© port operations model and a VISSIM© roadway network operations model. The development of this method is inspired by the High Level Architecture (HLA) standard for federating simulations, and incorporates several elements of the HLA principles into its design. The federated simulation model is then tested using a time-lag experiment to demonstrate the presence of feedback loops between federated model components wherein changes to input parameters of one model during runtime can be shown to affect the operational performance of the other model. This experiment also demonstrates how several initial transient phase and steady state operating characteristics of the federated system can be determined from the federation output data. The results indicate that the method developed in this study is capable of capturing the dynamic interaction of two models in federated simulation. It is shown that feedback loops can exist between two models in federated simulation. Most notably, the federation output shows that increased traffic volume in the roadway network model influences the accumulation of containers in the port terminal queue of the port model. The federation output also shows that increased container volume leaving the port terminal model affects both port and road truck utilization, as well as the total number of port trucks in the roadway network model. Challenges and future directions for research in federating transportation-related simulations are also presented.

<p>Simulation is a good way to gain insight into a system, for example during development, without having to run or build the actual system. This is especially true for real-time systems, which often operate in hazardous environments or control critical entities in the 'real' world, making testing of these systems in their real environment unsafe during development.</p><p>When building simulations, one simulator is not likely to fit every type of simulation project. Therefore, different simulators, which focus on different aspects of simulation, are built. The High Level Architecture (HLA) from the Defense Modeling and Simulation Office (DMSO) is an architecture for distributed simulations providing a means to communicate between different simulations.</p><p>However, the HLA standard has limitations if viewed from a real-time perspective. For example, there is no built-in support for fault tolerance. In this thesis some of the limitations in HLA are identified and an extended architecture that uses a distributed active real-time database as a way to overcome these limitations is presented. One of the major advantages with this new extended HLA architecture is that it is still compliant with HLA, i.e., no modifications have been made to the HLA interfaces.</p>

<p>The aim of this thesis is to exploit the technological capabilities of computer supported collaborative work (CSCW) in the field of collaborative Modelling and Simulation (M&S). The thesis focuses on addressing two main problems: (i) providing flexible means of consistency management in collaborative M&S, and (ii) the ability of providing platform and application independent services for collaborative M&S.</p><p>In this work, some CSCW technologies and how some of the concepts can be incorporated in a distributed collaborative M&S environment, have been studied. An environment for component based simulation development and visualization, which provides support for collaborative M&S, has been designed. Some consistency policies that can be used in conjunction with distributed simulation and the High Level Architecture (HLA) have been investigated. Furthermore, the efficient utilization of HLA and XML in combination, as the foundation of a CSCW infrastructure has been proved. Two consistency policies were implemented utilizing HLA, a strict and an optimistic, in the distributed collaborative environment. Their performance was compared to the performance of a totally relaxed policy, in various collaboration situations.</p>

Deux types de problématiques différentes peuvent motiver l'approche structurale d'une macromolécule. Soit la fonction de cette macromolécule est inconnue et l'on détermine sa structure afin de mieux connaître sa fonction ; cette démarche était l'un des défis du développement de la génomique structurale. Soit la fonction est connue et la structure va permettre de comprendre comment cette molécule remplit son rôle biologique.<br />Durant ma thèse, j'ai eu l'occasion de pouvoir aborder deux projets structuraux très différents, qui correspondent à ces deux approches de biologie structurale. C'est pourquoi mon manuscrit décrit ces deux projets dont la démarche scientifique est différente et complémentaire pour ma formation en biologie structurale. <br />Dans un premier temps, je décrirai les résultats obtenus sur le projet PAB0955, débuté en stage de DEA et poursuivi pendant les deux premières années de ma thèse. Ce projet avait pour objectif de déterminer la fonction de la protéine d'après sa structure. La protéine PAB0955 est de fonction biologique inconnue, elle hydrolyse le GTP et elle n'a pas de proche homologue dont la structure est connue. La démarche scientifique de ce projet a été de déterminer la structure de cette protéine, puis d'analyser sa structure en la comparant de manière systématique à l'ensemble des protéines ATPases et GTPases. Notre étude a été conduite dans l'objectif extraire un maximum d'information fonctionnelle à partir des données structurales.<br />Dans une deuxième partie, je décrirai notre étude sur des protéines du système immunitaire humain débuté en troisième année de thèse. Nous nous sommes intéressés à des molécules impliquées dans la reconnaissance d'antigène : le récepteur du lymphocyte T (TCR) et la molécule du complexe majeur d'histocompatibilité (CMH). L'objectif de ce projet est de comprendre comment un complexe antigène-CMH sélectionne un répertoire de lymphocyte T spécifique. L'objectif étant de déterminer le lien entre les caractéristiques structurales d'un complexe antigène-CMH et la diversité et la fréquence des lymphocytes T activés par ce complexe. En résumé corréler les observations structurales avec les données immunologiques dont nous disposons. En déterminant les bases structurales du caractère antigénique d'un peptide présenté par une molécule CMH nous pourrons, à plus long terme, produire des peptides efficaces dans le cadre d'une vaccination

HLA-DR1 transgenic (DR1 Tg) mice provide a model for evaluating the breadth and specificity of CD4 T cell responses that may develop in humans following influenza infection or vaccination. Recent studies identified a tremendously broad HLA-DR1-restricted CD4 T cell responses in DR1 Tg mice infected intranasally with influenza A/New Caledonia/20/99 (NC). In this study, our goals were to characterize B cell responses after NC infection in DR1 Tg mice and establish the correlation between B cell responses and CD4 T cell responses in this system. Influenza-specific B cell responses following virus administration were analyzed in DR1 Tg mice and in the genetically matched H-2b strain C57BL/10J (B10). Following intranasal (i.n.) NC infection, B cell responses in B10 mice featured strong IgG2b and IgG2c production and were typical of previously described B cell responses to a variety of mouse-adapted influenza strains. In contrast, B cell responses in DR1 Tg mice followed delayed kinetics and were strongly skewed to IgG1 production, suggesting the Th2 polarization of CD4 T cell responses. The different antibody isotype profile in DR1 Tg mice compared to B10 mice was evident in antibody secreting cells (ASCs) frequencies and in circulating Abs levels. Surprisingly, although DR1 Tg mice had lower influenza-specific Abs levels, they exhibited higher neutralizing Abs titers early in the response. B cell responses following intranasal infection of influenza A/Puerto Rico/8/1934 (PR8) or intramuscular vaccination of inactivated NC in DR1 Tg mice were different from the observed IgG1 bias after i.n. NC infection. After i.n. PR8 infection, B cell responses were similar in DR1 Tg mice and B10 mice, characterized by predominant IgM/IgG3 production. Additionally, following intramuscular administration of inactivated NC, B cell responses were skewed towards IgG2c production in both DR1 Tg mice and B10 mice, suggesting the Th1 polarization of CD4 T cell responses. A mechanistic understanding of IgG1/Th2 biased B cell responses and better neutralizing Abs production in DR1 Tg mice following i.n. NC infection may have implications for the optimal control of influenza infection.

Regulatory T cells represent a specialized subpopulation of T lymphocytes that may modulate spontaneous HIV-1 disease progression by suppressing immune activation or inhibiting antiviral T cell immune responses. While effects of classical \(CD25^{hi}FoxP3^+CD4^+\) regulatory T cells during HIV-1 infection have been analyzed in a series of recent investigations, very little is known about the role of non-classical regulatory T cells that do not express intracellular FoxP3. Here I evaluated two groups of non-classical Treg cells. One is phenotypically identified by the surface expression of HLA-G, an HLA class Ib molecule. The other Treg cell population is characterized by the surface expression of latency-associated peptide (LAP), a membrane-bound form of \(TGF-\beta\). Both HLA-G and LAP-expressing T cells are present in small proportions in peripheral blood of healthy individuals. I performed a systematic study on the phenotypic and functional profile of HLAG- and LAP- expressing regulatory T (Treg) cells in patients with different stages of HIV-1 infection. I found that HLA-G-expressing Treg cells were highly susceptible to HIV-1 infection, and were significantly reduced in individuals with progressive HIV-1 disease courses. Moreover, the proportion of \(HLA-G^+\) CD4 and CD8 T cells was positively correlated with CD4 T cell count and inversely correlated with markers of HIV-1 associated immune activation. Mechanistically, this correlation corresponded to a substantially increased ability of \(HLA-G^+\) Treg cells to inhibit bystander immune activation, while only minimally affecting functional properties of HIV-1-specific T cells. In contrast, no significant change in \(LAP^+\) Treg cell frequencies was found in progressive HIV-1 infection, and these frequencies were not correlated with immune activation. This observation was consistent with functional analysis, which indicated that \(LAP^+\) Treg cells did not suppress bystander activation. These investigations indicate an important role of \(HLA-G^+\) Treg cells for balancing bystander immune activation and anti-viral immune activity in HIV-1 infection, and suggest that the loss of these cells during advanced HIV-1 infection may contribute to immune dysregulation and HIV-1 disease progression. In the meantime, \(LAP^+\) Treg cells do not appear to play an important role in determining HIV-1 disease outcome.

Tyrimo tikslas buvo įvertinti sensitizaciją ŽLA antigenais, inksto transplantatų recipientams, kurie greta standartinės imunosupresijos vartojo monokloninius antikūnus prieš IL-2 receptorių ir monokloninių antikūnų nevartojusiems recipientams. Tyrime dalyvauja VULSK pacientai, kuriems 2000-2005 metais imtinai buvo atliktos inkstų transplantacijos (Tx), bei kurie prieš ir po Tx buvo tirti dėl teigiamai su limfocitų panele reaguojančių antikūnų skaičiaus, išreikšto procentais (PRA). Iš viso tyrime dalyvauja 189 recipientai. Dalis jų (n=83) greta standartinės imunosupresijos vartojo monokloninius antikūnus prieš IL-2 receptorių (basiliksimabą ar daklizumabą), kiti (n=106) gavo tik standartinę imunosupresiją. Pagrindiniai sensitizaciją ŽLA antigenais lemiantys veiksniai abiejose grupėse pasiskirstė nevienodai. Didesnė monokloninius antikūnus vartojusių dalis gavo kraujo perpylimus (72% vs. 57,3%), šioje grupėje taip pat daugiau buvo pakartotinų Tx (9,6% vs. 7,5%), tik gimdžiusių moterų skaičius didesnis buvo monokloninių antikūnų nevartojusioje grupėje (47,7% vs. 30,8%). Tirtos ligonių grupės palygintos taikant &#967;² kriterijų, skirtumas laikytas statistiškai reikšmingas, kai p<0,05. Išanalizavus recipientų sensitizaciją prieš Tx paaiškėjo, kad dauguma (58%; 110/189) buvo nesensitizuoti (PRA 0-10%), likę 42% (79/189) - sensitizuoti, iš kurių 14% (11/189) – labai sensitizuoti (PRA 50-100%). Po Tx monokloninius antikūnus vartojusių recipientų grupėje (n=83) 2% padaugėjo... [toliau žr. visą tekstą] / The aim of this study was to evaluate the sensitization with HLA antigens in kidney transplant recipients, who received induction therapy with monoclonal antibodies against IL-2R and in the group of patients, who were only under the triple drug therapy. This study comprises recipients, who received kidney transplant in the year 2000-2005, and who were tested for panel reactive antibody test before and after transplantation (Tx). The total number of 189 kidney transplant recipients takes part in this study. 83 received monoclonal antibodies against IL-2R (basiliximab or daclizumab), others (n=106) – did not. These groups were unequal in comparison to the main factors causing sensitization with HLA antigens. The group of patients, who received induction therapy with monoclonal antibodies had more blood transfuzions (72% vs. 57,3%), and previous transplantations (9,6% vs. 7,5%), in comparison with the other group. Only the number of pregnancies was higher in the group of patients who were only under the triple drug therapy (47,7% vs. 30,8%). Statistical analyses were caried out using chi-square test, differences were considered significant at p<0,05. 58% (110/189) of kidney transplant recipients were unsensitized (PRA 0-10%) before Tx, the rest 42% (79/189) were sensitized, from which 14% (11/189) were highly sensitized (PRA 50-100%). After Tx the number of medium sensitized (PRA 11-50%) kidney transplant recipients, who received induction therapy by monoclonal antibodies... [to full text]