IL-2 has multiple functions in T cell-mediated adaptive immunity. The stringent control of its expression is important for T cell activation, proliferation and the subsequent T cell clone contraction. Our lab has recently shown that the transcriptional repressor Blimp-1 is part of a negative feedback loop which controls IL-2 gene expression in mice. Understanding the molecular mechanisms of this signaling loop in T cells might help us to better understand the regulation as well as the role of IL-2 in T cell immunity. The human ortholog to murine Blimp-1 is termed PRDI-BF1 (each encoded by the respective Prdm1 gene). Both genes contain five zinc finger regions, whereby the first two zinc fingers are dispensable for DNA binding. In case of the human protein they are instead required to recruit the G9?Ñ methyltransferase to the gene promotor. We found that the human wild-type PRDI-BF1 protein suppressed IL-2 production in murine T cells, while deletion of the first two zinc fingers abolished this ability. Thus, a similar Blimp-1-mediated methylation mechanism might exist in IL-2 gene silencing. IL-2/IL-2R signaling is indispensable for Blimp-1 induction. PI-3Kinase and Stat5 are downstream of the IL-2 receptor complex and are known to contribute to IL-2 inhibition in T cells from C57BL/6 mice. However, activating only these two pathways are still not sufficient to induce Blimp-1 or suppress IL-2 expression in in IL-2R beta-/- mice. The Blimp-1-dependent IL-2 self regulatory loop is not functional in IL-2R beta-/-mice. In order to conveniently study this dysregulation we crossed these mice with a GFP transgenic strain in which the GFP transgene is under the control of IL-2 promoter sequence. In IL-2R beta-/-IL-2p-GFP mice about five times as many spleenic CD4+ T cells transcribe IL-2pGFP, compared to the littermate IL-2R beta+/-IL-2p-GFP control animals. And most of the GFP cells demonstrate activated phenotype (CD44HighCD62Llow). Blimp-1 is known as a master regulator of B cell terminal differentiation. Since a recent report indicated that IL-2 signaling via STAT5 constrains Th17 Cell differentiation, we speculated that Blimp-1 might play a similar role in effector T cell differentiation. In order to evaluate this possibility, activated CD4+ T cells from C57BL/6 mice were transduced with Blimp-1 and cultured under Th17 polarizing conditions. Blimp-1 overexpression in did not change the profile of IL-17 production.

In order to eradicate HIV-1 infection the virus needs to be specifically eliminated from latently infected memory CD4+ T cells. There does not seem to be a single mechanism that promotes HIV-1 latency. RNA Polymerase II (RNAP II) pausing, chromatin structure, tissue specific transcriptional repressors and transcriptional interference have been implicated in regulating HIV-1 transcription. The transcription factor B Lymphocyte-Induced Maturation Protein 1 (Blimp-1) is expressed in B and T cells and upregulated in patients chronically infected with HIV-1. I hypothesized that Blimp-1 is a T cell intrinsic factor that binds to HIV-1 LTR, inhibits HIV-1 transcription and contributes to HIV-1 latency. Blimp-1 is expressed in primary peripheral blood CD4+ T cells and is further induced by T cell activation. Importantly, Blimp-1 is highly expressed in memory CD4+ T cells compared to naïve CD4+ T cells. Ectopic expression of Blimp-1 in CD4+ T cells represses HIV-1 transcription, whereas decreasing Blimp-1 in memory CD4+ populations activates HIV-1 transcription. Reduction of Blimp-1 in infected primary T cells increases RNAP II processivity and histone H3 acetylation. Blimp-1 binds downstream of the HIV-1 5'-LTR to the interferon-stimulated response element (ISRE) in resting primary CD4+ T cells and strongly represses Tat-dependent HIV-1 transcription. Upon T cell activation, Blimp-1 is released from the HIV-1 ISRE and this correlates with significant increase in HIV-1 transcription. These results demonstrate that Blimp-1 acts to limit HIV-1 transcription in memory CD4+ T cells and promotes the establishment and maintenance of latency. I also examined whether neighboring host promoters could impact HIV-1 transcription. Using a set of inducible cell lines I observed that neighboring promoters have minimal impact on HIV-1 transcription and that enabling release of paused RNAP II by diminishing negative elongation factor (NELF) is sufficient to reactivate transcriptionally repressed HIV-1 provirus. The implications of my results in the different mechanisms regulating HIV-1 latency are discussed.

Pseudo-spectral optimal solvers are used to optimize numerically a performance index of a dynamical system with differential constraints. Although these solvers are commonly used for space vehicles and space launchers for trajectory optimization, few experimental papers exist on optimal control of small airships. The objective of this thesis is to evaluate the use of a pseudo-spectral optimal control solver for generating dynamically constrained, minimal time trajectories. A dynamical model of a small airship is presented, with its experimental virtual mass, drag and motor experimentally modeled. The problems are solved in PSOPT, a pseudo-spectral optimal control code. Experimental tests with a small scale model are performed to evaluate the generated paths. Although drift occurs, as a consequence of an open loop control, the vehicle is capable of following the path. This results of this thesis may find uses in verifying how close to optimal discreet path planners are, to plan complex trajectories on short distances, or to generate dynamic maneuverer such as take-off or landing. Ultimately, improving path planning of small airships will improve their safety, maneuverability and flight-time, which makes them fit for scientific monitoring, for search and rescue, or as mobile telecommunications platforms.

Increasing demands in areas such as security, surveillance, search and rescue, and communication, has promoted the research and development of unmanned aerial vehicles (UAVs) as such technologies can replace manned flights in dangerous or unfavorable conditions. Lighter-than-air UAVs such as blimps can carry higher payloads and can stay longer in the air compared to typical heavier-than-air UAVs such as aeroplanes or quadrotors. One purpose of this thesis is to develop a sensor suite basis for estimating the position and orientation of a blimp UAV in development with respect to a reference point for safer landing procedures using minimal on-board sensors. While the existing low-cost sensor package, including inertial measurement unit (IMU) and Global Navigation System (GPS) module, could be sufficient to estimate the pose of the blimp to a certain extent, the GPS module is not as precise in the short term, especially for altitude. The proposed system combines GPS and inertial data with information from a grounded infrared (IR) camera. Image frames are processed to identify three IR LEDs located on the UAV and each LED coordinate is estimated using a Perspective-n-Point (PnP) algorithm. Then the results from the PnP algorithm are fused with the GPS, accelerometer and gyroscope measurements using an Extended Kalman Filter (EKF) to get a more accurate estimate of the position and the orientation. Tests were conducted on a simulated blimp using the experimental avionics.

The Unmanned Aerial Vehicle (UAV) has over the last years become an increasingly prevalent technology in several sectors of modern society. Many UAVs are today used in a wide series of applications, from disaster relief to surveillance. A recent initiative by the Swedish Sea Rescue Society (SSRS) aims to implement UAVs in their emergency response. By quickly deploying drones to an area of interest, an assessment can be made, prior to personnel getting there, thus saving time and increasing the likelihood of a successful rescue operation. An aircraft like this, that will travel great distances, have to rely on a navigation system that does not require an operator to continuously see the vehicle. To travel to its goal, or search an area, the operator should be able to define a travel route that the UAV follows, by feeding it a series of waypoints. As an initial step towards that kind of system, this thesis has developed and tested the concept of waypoint navigation on a small and slow airship/blimp, in a simulated indoor environment. Mainly, two commonly used navigation algorithms were tested and compared. One is inspired by a sub-category of machine learning: reinforcement learning (RL), and the other one is based on the rapidly exploring random tree (RRT) algorithm. Four experiments were conducted to compare the two methods in terms of travel distance, average speed, energy efficiency, as well as robustness towards changes in the waypoint configurations. Results show that when the blimp was controlled by the best performing RL-based version, it generally travelled a more optimal (distance-wise) path than the RRT-based method. It also, in most cases, proved to be more robust against changes in the test tracks, and performed more consistently over different waypoint configurations. However, the RRT approach usually resulted in a higher average speed and energy efficiency. Also, the RL algorithm had some trouble navigating tracks where a physical obstacle was present. To sum up, the choice of algorithm depends on which parameters are prioritized by the blimp operator for a certain track. If a high velocity and energy efficiency is desirable, the RRT-based method is recommended. However, if it is important that the blimp travels as short a distance as possible between waypoints, and a higher degree of consistency in its performance is wanted, then the RL-method should be used. Moving forward from this report, toward the future implementation of both methods in rescue operations, it would be reasonable to analyze their performance under more realistic conditions. This can be done using a real indoor airship. Looking at how hardware that do not exceed the payload of the blimp can execute both methods and how the blimp will determine its position and orientation is recommended. It would also be interesting to see how different reward function affect the performance of the blimp. / Den obemannade luftfarkosten (UAV) har under de senaste åren blivit en teknik vars användning blivit allt vanligare i flera sektorer av det moderna samhället. Olika sorters UAV robotar associeras idag med en omfattande serie användningsområden, från katastrofhjälp till övervakning. Ett nyligen påbörjat initiativ från svenska sjöräddningssällskapet (SSRS) syftar till att implementera drönare i deras utryckningar. Genom att snabbt sända drönare till platsen i fråga, kan en bedömning göras innan personal kommer dit, vilket sparar tid och ökar sannolikheten för en framgångsrik räddningsaktion. En farkost som denna, som kommer att resa långa sträckor, måste förlita sig på ett navigationssystem som inte kräver att en operatör kontinuerligt ser farkosten. För att resa till sitt mål, eller söka av ett område, bör operatören kunna definiera en resväg som drönaren följer genom att ge den en serie vägpunkter. Som ett inledande steg mot den typen av system har denna uppsats utvecklat och testat begreppet vägpunktsnavigering på ett litet och långsamt luftskepp/blimp, i en simulerad inomhusmiljö. Huvudsakligen testades och jämfördes två vanligt förekommande navigationsalgoritmer. En inspirerad av en underkategori till maskininlärning: förstärkningsinlärning (RL), och den andra baserad på rapidly exploring random tree (RRT) algoritmen. Fyra experiment utfördes för jämföra båda metoderna med avseende på färdsträcka, medelhastighet, energieffektivitet samt robusthet gentemot ändringar i färdpunktskonfigurationerna. Resultaten visar att när blimpen kontrollerades av den bästa RL-baserade versionen åkte den generellt en mer avståndsmässigt optimal väg än när den RRT-baserade metoden användes. I de flesta fallen visade sig även RL-metoden vara mer robust mot förändringar i testbanorna, och presterade mer konsekvent över olika vägpunktskonfigurationer. RRT-metoden resulterade dock vanligtvis i en högre medelhastighet och energieffektivitet. RL-algoritmen hade också problem med att navigera banor där den behövde ta sig runt ett hinder. Sammanfattningsvis beror valet av algoritm på vilka parametrar som prioriteras av blimpoperatören för en viss bana. Om en hög hastighet och energieffektivitet är önskvärd rekommenderas den RRT-baserade metoden. Men om det är viktigt att blimpen reser så kort avstånd som möjligt mellan färdpunkterna, och har en jämnare prestanda, bör RL-metoden användas. För att ta nästa steg, mot en framtida implementering av båda metoder i räddningsoperationer, vore det rimligt att analysera deras prestanda under mer realistiska förhållanden. Detta skulle kunna göras inomhus med ett riktigt luftskepp. Författarna rekommenderar att undersöka om hårdvara som inte överstiger blimpens maxlast kan utföra båda metodernas beräkningar och hur blimpen bestämmer sin position och orientering. Det skulle också vara intressant att se hur olika belöningsfunktioner påverkar blimpens prestanda.

My background in clay has emphasized the development of technical considerations in functional ceramics as well as the search for personal images. The past two years have seen an emphasis on the exploration of technical areas chosen to lead to the development of a familiarity with techniques and a solidification of statement. The process has nurtured in me the realization that the objects I produce do not represent an attempt to attain an axiom of art but are personal statements developed through an empirical use of forms and images.

It was the best of cities, it was the worst of cities, it was a place of giddying boom, it was a place of economic despair, it was a utopia, it was a dystopic no-topia, it was the world centre of fantasies, and the world centre of nightmares, a town where some struck it rich while others lost themselves in their desires for wealth, in short, the place was so far unlike the present place, that some of the noisiest authorities insisted on its being received, for good or for evil, in the superlative degree of comparison only. This thesis is constructed of fragmented stories but not in the classic sense as there is no over-arching narrative, no beginning, middle and end, no synthetic conclusion. Rather this thesis is similar to Los Angeles itself; it is a multi-faceted exploration of competing themes that have birthed a city of fictions, a centre of fantasy, a place that shapes our collective memories, even for those of us who grew up in far-off places. Los Angeles has searched for a down-town core, a collective identity, a dominant narrative and these attempts are explored through different themes – the story of film noir, the development of the Los Angeles Aqueduct, the redevelopment of Bunker Hill, the violence and upheavals of the riots. I have explored how the city has tried to re-brand itself, Through these prisms, and how these attempts have shaped its development and history. It is said that Los Angeles has an architecture of absence, with its superficiality and lack of depth, and as a visual metaphor, this can represent the giddy changes happening in the field of architecture, where hyper-realism trumps facts. This idea of Los Angeles as a mirror should not surprise: it has long been a world centre for myth-making, an epicenter of fiction, cinema, architecture, et cetera, spewing out seductive, grotesquely exaggerated reflections of North America itself.

The studies presented within this dissertation provide the first description of PRDM1 (also known as Blimp-1 or PRDI-BF1) function in natural killer cells. NK cells are major effectors of the innate immune response via antigen-independent cytotoxicity and link to the adaptive immune response through cytokine release. Molecular mechanisms mediating NK activation are relatively well-studied; however, much less is known about the mechanisms that restrain activation. In the first study, the transcriptional repressor PRDM1 is shown to be a critical negative regulator of NK function. Microarray analysis was used to characterize transcriptional changes associated with cytokine-mediated activation. PRDM1 is expressed at low levels in resting NK cells and three distinct PRDM1 isoforms are selectively induced in the CD56dim NK population in response to activation. PRDM1 coordinately suppresses the production of IFNγ, TNFα and TNFβ through direct binding to multiple conserved regulatory regions. Ablation of PRDM1 expression leads to enhanced production of IFNγ and TNFα but does not alter cytotoxicity, whereas over-expression blocks cytokine production. PRDM1 response elements are defined at the IFNG and TNF loci. To further delineate the targets of PRDM1-mediated regulation in NK cells, global approaches were utilized. Experiments utilizing chromatin immunoprecipitation coupled to promoter tiling arrays identified 292 novel direct targets of PRDM1 binding. These studies revealed widespread binding of PRDM1 to the genome, which was not limited to proximal promoter regions. Furthermore, microarray analysis of stimulated NK cells combined with PRDM1 knockdown has enabled the identification of genes responsive to PRDM1 knockdown using primary cells. Collectively, these experiments identify both direct and indirect targets of PRDM1 regulation and help define a PRDM1-centered gene regulatory network in NK cells. Data presented in the final chapter pertains to an independent project aimed at identifying small molecule inhibitors of the methyltransferase G9a, which is recruited by PRDM1 and is required for silencing of target genes. A mass spectrometry-based assay was developed and used to screen a small molecule library. Several hits were identified and combinatorial chemistry yielded several compounds with < 20µM IC50 values. In cell-based assays, however, treatment with the small molecules had limited efficacy, indicating additional chemical modifications are necessary to yield bioactive compounds. The data presented here demonstrate a key role for PRDM1 in the negative regulation of NK activation and position PRDM1 as a common regulator of the adaptive and innate immune response.

It was the best of cities, it was the worst of cities, it was a place of giddying boom, it was a place of economic despair, it was a utopia, it was a dystopic no-topia, it was the world centre of fantasies, and the world centre of nightmares, a town where some struck it rich while others lost themselves in their desires for wealth, in short, the place was so far unlike the present place, that some of the noisiest authorities insisted on its being received, for good or for evil, in the superlative degree of comparison only. This thesis is constructed of fragmented stories but not in the classic sense as there is no over-arching narrative, no beginning, middle and end, no synthetic conclusion. Rather this thesis is similar to Los Angeles itself; it is a multi-faceted exploration of competing themes that have birthed a city of fictions, a centre of fantasy, a place that shapes our collective memories, even for those of us who grew up in far-off places. Los Angeles has searched for a down-town core, a collective identity, a dominant narrative and these attempts are explored through different themes – the story of film noir, the development of the Los Angeles Aqueduct, the redevelopment of Bunker Hill, the violence and upheavals of the riots. I have explored how the city has tried to re-brand itself, Through these prisms, and how these attempts have shaped its development and history. It is said that Los Angeles has an architecture of absence, with its superficiality and lack of depth, and as a visual metaphor, this can represent the giddy changes happening in the field of architecture, where hyper-realism trumps facts. This idea of Los Angeles as a mirror should not surprise: it has long been a world centre for myth-making, an epicenter of fiction, cinema, architecture, et cetera, spewing out seductive, grotesquely exaggerated reflections of North America itself.

Récemment, le robot dirigeable a attiré l'attention de plus en plus des chercheurs grâce à ses avantages par rapport à d'autres aéronefs, tels que la capacité de VTOL, le vol stationnaire et à basse vitesse, une grande autonomie, et une interaction Homme-Robot sûre, etc. Ainsi c'est une plate-forme idéale pour diverses applications d'intérieur. Dans cette thèse, nous étudions la modélisation et le contrôle du mouvement d'un robot dirigeable d'intérieur et développons un prototype pour les opérations intérieures comme la surveillance. Le travail est composé de parties théoriques et pratiques. Concernant la partie théorique, d’abord, sous des hypothèses raisonnables, le modèle dynamique à 6-DOF est simplifié et divisé en deux parties indépendantes: le mouvement de l’altitude et le mouvement dans le plan horizontal. Ensuite, à fin d'assurer la précision de la modélisation et du contrôle, le modèle nominal est complété par des termes de perturbation qui sont estimés en temps réel et compensés dans les contrôleurs conçus. Des simulations sont effectuées pour vérifier les performances et la robustesse des contrôleurs. Pour la partie pratique du travail, basée sur l'analyse des fonctionnalités du robot afin de réaliser les applications intérieures souhaitées, le matériel du robot dirigeable est conçu et créé. Enfin, de vrais tests sont effectués sur la plate-forme de robot dirigeable pour la validation des lois de contrôle de mouvement conçues, et des résultats satisfaisants sont obtenus. / Recently, the blimp robot has attracted more and more attentions of the researchers for its advantages compared to other aircrafts, such as ability for VTOL, stationary and low speed flight, long endurance in air and safe Human-Robot interaction, etc. Therefore it is an ideal platform for various indoor applications. In this thesis, we study the modeling and motion control of an indoor blimp robot, and develop a real robot for indoor operations such as the long-term surveillance. The work is composed of both theoretical and practical parts. For the theoretical part, first, under reasonable assumptions, the 6-DOF dynamic model is simplified and divided into two independent parts: the altitude motion and the horizontal plane movement. Then, to ensure the accuracy of modeling and control, the nominal model is complemented with disturbance terms which are estimated in real-time and compensated in the designed controllers. Simulations are carried out to verify the performance and robustness of the controllers. For the practical part of the work, based on the functionality analysis of the robot to achieve desired indoor applications, the hardware of the blimp robot is conceived and created. Finally, real tests are made on the blimp robot platform for the validation of the designed motion control laws, and satisfying results are obtained.