Rozprawy doktorskie na temat „PTX”

In many geologic environments, fluids have compositions that are approximated by the H₂O-NaCl system. When minerals grow in the presence of such fluids, some of the solution is trapped in the growing mineral as fluid inclusions. The salinity, temperature of homogenization, and pressure of homogenization are required to predict the trapping conditions of the fluid inclusion. In the laboratory the salinity and the temperature of homogenization of the trapped fluid are easily determined however, the pressure of homogenization cannot be determined directly, and must be calculated from an equation of state.<p> A statistical model that relates the vapor pressure of H₂O-NaCl to the fluid temperature and composition has been developed. The model consists of equations that predict the vapor pressure of H₂O-NaCl from the eutectic temperature (-21.2°C) to 1500°C and for all compositions between the pure end-members. The model calculates the vapor pressure based on the composition (wt% NaCl) and the temperature of homogenization, which can be directly obtained from laboratory studies of fluid inclusions. This information in turn can be used to construct the isochore, or line of constant volume, along which the fluid inclusion was trapped. Finally the isochore can be used to determine the temperature and pressure at which the host mineral of the fluid inclusion was trapped. </p><br>Master of Science

Pectenotoxins (PTXs) are a group of large cyclic polyether compounds associated with diarrhetic shellfish poisoning (DSP) as they are often found in combination with other DSPs such as okadaic acid (OA) and dinophysis toxins (DTXs) in shellfish. Although classified and regulated with the DSPs, there is debate over whether these toxins should be classified with DSP toxins. To date, ten different analogues of PTXs have been identified from shellfish and algae, and of these, the pectenotoxin-2 seco acids (PTX2-SAs) are of particular interest as they have previously been implicated in a shellfish poisoning incident in Australia, but relatively little was known of their toxicology. One such incident occurred in December 1997, when approximately 200 people were reported with severe diarrhoetic shellfish poisoning in Northern New South Wales (NSW). Analysis of the shellfish associated with this incident revealed relatively high PTX2-SA concentrations (approx. 300 micrograms/kg shellfish meat), with only trace amounts of pectenotoxin-2 (PTX2) and OA. Following this incident, PTX2-SAs were considered a health threat and guidelines were implemented in the absence of toxicological data, which has caused a great economic burden to shellfish industries around the globe, in particular to Australia, New Zealand and Ireland. Such regulation created in the absence of scientific data demonstrated the need to determine the toxicology of PTX2-SAs in commercial shellfish. Thus a comprehensive study on the toxicology and possible health implications of the PTX2-SAs in Australian shellfish was conducted. PTX2-SAs were isolated in different batches from shellfish (pipis, oysters and mussels) and from algal bloom samples of Dinophysis caudata. Toxin extraction was conducted with several purification stages and chemical analysis was performed with high-performance liquid chromatography coupled to a tandem mass spectrometer (HPLC-MS/MS). The chemical stability of the PTX2-SAs was investigated to ensure consistency of doses between toxicology experiments. Acute dosing studies with mice were then performed and included toxicopathology investigations with light microscopy and electron microscopy, in addition to toxin distribution studies and investigation of in vivo lipid peroxidation. In vitro studies with HepG2 cells included cytotoxicity assays, cell cycle investigations using flow cytometry and gene expression profiling of cells exposed to PTX2-SAs employing cDNA microarray technology. Acute pathology studies demonstrated that the PTX2-SAs do not cause the characteristic symptoms or lesions associated with DSP toxins. No diarrhoea was observed at any dose level in mice and no deaths occurred up to the maximum dosing level of 1.6mg/kg PTX2-SA. Only one batch of PTX2-SA extract produced toxic lesions characteristic of a DSP toxin (batch 1-pilot study) but after follow up studies, it was determined that this first batch of shellfish most likely contained an additional unidentified shellfish toxin or contaminant that co-extracted with PTX2-SAs during toxin isolation and purification procedures. This finding highlighted the importance of supporting the inclusion of the mice bioassay in procedures for shellfish toxin testing to enable detection of new toxins, and also highlighted the importance of toxin purification for toxicology studies. A significant rise in malondialdehyde excretion was observed within 24 hours of dosing mice, indicating that the PTX2-SAs may cause damage by lipid peroxidation in vivo. In vitro studies showed HepG2 cells to have cell cycle and gene expression changes within 24 hours of a dose of 800ng/mL PTX2-SAs. Cell cycle arrest was observed at the G2/M checkpoint and gene expression changes included alterations in genes involved in cell cycle control, lipid metabolism and transport, lipid genesis and trace metal transport. Many genes involved in DNA repair processes were moderated at the 24 hour point, but as no apoptosis was observed up to 72 hours post dosing it is a promising indication that any DNA damage that may have been caused by the administration of PTX2-SAs was not lethal, and was able to be repaired. In light of the information provided by toxicology investigations in this PhD, with particular reference to evidence of in vivo lipid peroxidation by raised levels of MDA in mouse urine, and changes in cell cycle distribution and gene expression in a cultured human cell line, it is concluded that there is potential for these toxins to induce biological changes in mammalian cells in vivo and in vitro, and hence potential for PTX2-SAs to cause health effects in humans. During the course of this three-year study, developments in techniques for shellfish toxin identification within our laboratories have revealed that the shellfish responsible for the 1997 NSW poisoning incident contained significant concentrations of okadaic acid acyl esters that were not detected at the time of the NSW incident. Although reportedly less toxic than okadaic acid itself, the OA ester concentrations present may have been sufficient to cause the observed symptoms. It is also theorized that these esters could be hydrolyzed in the human gastro-intestinal tract to release okadaic acid. In the light of this new evidence and with no pathology lesions or symptoms of diarrhoea being observed in PTX2-SA dosing studies with mice, we now believe these OA acyl esters to be the causative agent in the 1997 NSW DSP incident and not the PTX2-SAs. Nothing is currently known of the chronic toxicology of PTX2-SAs and thus their potential implications to public health in the long term cannot determined. The toxicology investigations in this thesis were acute studies, and it has not been established if the observed changes could be repaired or returned within normal limits without the manifestation of illness or disease occurring. Utilizing the acute toxicology information in this thesis, a health risk assessment for consumption of PTX2-SA contaminated shellfish was performed. This risk assessment, employing numerous safety factors essential for an incomplete data set, produced guideline values that are lower than the current recommend concentrations. To date, there has been no solid evidence that PTX2-SAs cause illness in humans – all documented incidents involving the PTX2-SAs have also included other DSP contaminants that are known to cause human illness. Pathology has not unequivocally been demonstrated in animal studies and thus, in consideration of the epidemiological evidence, PTX2-SAs cannot be considered as high a risk to public health as was previously thought. For the reasons discussed above, and weighing up risk-benefit considerations of the economic burden the current guideline values are causing to shellfish industries around the globe, it is recommended that levels of PTX2-SAs be monitored in recognition of the precautionary principle, but no longer regulated as tightly with other DSPs until such a time that toxicological or epidemiological evidence can prove that the PTX2-SAs are a DSP and are a more considerable threat to human health than has been indicated by toxicology studies in this thesis. This study has produced a substantial amount of acute toxicology data and has provided a good basis for future chronic toxicology investigations with the PTX2-SAs for regulatory purposes.

Pectenotoxins (PTXs) are a group of large cyclic polyether compounds associated with diarrhetic shellfish poisoning (DSP) as they are often found in combination with other DSPs such as okadaic acid (OA) and dinophysis toxins (DTXs) in shellfish. Although classified and regulated with the DSPs, there is debate over whether these toxins should be classified with DSP toxins. To date, ten different analogues of PTXs have been identified from shellfish and algae, and of these, the pectenotoxin-2 seco acids (PTX2-SAs) are of particular interest as they have previously been implicated in a shellfish poisoning incident in Australia, but relatively little was known of their toxicology. One such incident occurred in December 1997, when approximately 200 people were reported with severe diarrhoetic shellfish poisoning in Northern New South Wales (NSW). Analysis of the shellfish associated with this incident revealed relatively high PTX2-SA concentrations (approx. 300 micrograms/kg shellfish meat), with only trace amounts of pectenotoxin-2 (PTX2) and OA. Following this incident, PTX2-SAs were considered a health threat and guidelines were implemented in the absence of toxicological data, which has caused a great economic burden to shellfish industries around the globe, in particular to Australia, New Zealand and Ireland. Such regulation created in the absence of scientific data demonstrated the need to determine the toxicology of PTX2-SAs in commercial shellfish. Thus a comprehensive study on the toxicology and possible health implications of the PTX2-SAs in Australian shellfish was conducted. PTX2-SAs were isolated in different batches from shellfish (pipis, oysters and mussels) and from algal bloom samples of Dinophysis caudata. Toxin extraction was conducted with several purification stages and chemical analysis was performed with high-performance liquid chromatography coupled to a tandem mass spectrometer (HPLC-MS/MS). The chemical stability of the PTX2-SAs was investigated to ensure consistency of doses between toxicology experiments. Acute dosing studies with mice were then performed and included toxicopathology investigations with light microscopy and electron microscopy, in addition to toxin distribution studies and investigation of in vivo lipid peroxidation. In vitro studies with HepG2 cells included cytotoxicity assays, cell cycle investigations using flow cytometry and gene expression profiling of cells exposed to PTX2-SAs employing cDNA microarray technology. Acute pathology studies demonstrated that the PTX2-SAs do not cause the characteristic symptoms or lesions associated with DSP toxins. No diarrhoea was observed at any dose level in mice and no deaths occurred up to the maximum dosing level of 1.6mg/kg PTX2-SA. Only one batch of PTX2-SA extract produced toxic lesions characteristic of a DSP toxin (batch 1-pilot study) but after follow up studies, it was determined that this first batch of shellfish most likely contained an additional unidentified shellfish toxin or contaminant that co-extracted with PTX2-SAs during toxin isolation and purification procedures. This finding highlighted the importance of supporting the inclusion of the mice bioassay in procedures for shellfish toxin testing to enable detection of new toxins, and also highlighted the importance of toxin purification for toxicology studies. A significant rise in malondialdehyde excretion was observed within 24 hours of dosing mice, indicating that the PTX2-SAs may cause damage by lipid peroxidation in vivo. In vitro studies showed HepG2 cells to have cell cycle and gene expression changes within 24 hours of a dose of 800ng/mL PTX2-SAs. Cell cycle arrest was observed at the G2/M checkpoint and gene expression changes included alterations in genes involved in cell cycle control, lipid metabolism and transport, lipid genesis and trace metal transport. Many genes involved in DNA repair processes were moderated at the 24 hour point, but as no apoptosis was observed up to 72 hours post dosing it is a promising indication that any DNA damage that may have been caused by the administration of PTX2-SAs was not lethal, and was able to be repaired. In light of the information provided by toxicology investigations in this PhD, with particular reference to evidence of in vivo lipid peroxidation by raised levels of MDA in mouse urine, and changes in cell cycle distribution and gene expression in a cultured human cell line, it is concluded that there is potential for these toxins to induce biological changes in mammalian cells in vivo and in vitro, and hence potential for PTX2-SAs to cause health effects in humans. During the course of this three-year study, developments in techniques for shellfish toxin identification within our laboratories have revealed that the shellfish responsible for the 1997 NSW poisoning incident contained significant concentrations of okadaic acid acyl esters that were not detected at the time of the NSW incident. Although reportedly less toxic than okadaic acid itself, the OA ester concentrations present may have been sufficient to cause the observed symptoms. It is also theorized that these esters could be hydrolyzed in the human gastro-intestinal tract to release okadaic acid. In the light of this new evidence and with no pathology lesions or symptoms of diarrhoea being observed in PTX2-SA dosing studies with mice, we now believe these OA acyl esters to be the causative agent in the 1997 NSW DSP incident and not the PTX2-SAs. Nothing is currently known of the chronic toxicology of PTX2-SAs and thus their potential implications to public health in the long term cannot determined. The toxicology investigations in this thesis were acute studies, and it has not been established if the observed changes could be repaired or returned within normal limits without the manifestation of illness or disease occurring. Utilizing the acute toxicology information in this thesis, a health risk assessment for consumption of PTX2-SA contaminated shellfish was performed. This risk assessment, employing numerous safety factors essential for an incomplete data set, produced guideline values that are lower than the current recommend concentrations. To date, there has been no solid evidence that PTX2-SAs cause illness in humans – all documented incidents involving the PTX2-SAs have also included other DSP contaminants that are known to cause human illness. Pathology has not unequivocally been demonstrated in animal studies and thus, in consideration of the epidemiological evidence, PTX2-SAs cannot be considered as high a risk to public health as was previously thought. For the reasons discussed above, and weighing up risk-benefit considerations of the economic burden the current guideline values are causing to shellfish industries around the globe, it is recommended that levels of PTX2-SAs be monitored in recognition of the precautionary principle, but no longer regulated as tightly with other DSPs until such a time that toxicological or epidemiological evidence can prove that the PTX2-SAs are a DSP and are a more considerable threat to human health than has been indicated by toxicology studies in this thesis. This study has produced a substantial amount of acute toxicology data and has provided a good basis for future chronic toxicology investigations with the PTX2-SAs for regulatory purposes.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Public Health<br>Faculty of Health Sciences<br>Full Text

O recente crescimento da utilização de Unidades de Processamento Gráfico (GPUs) em aplicações científicas, que são voltadas ao desempenho, gerou a necessidade de otimizar os programas que nelas rodam. Uma ferramenta adequada para essa tarefa é o modelo de desempenho que, por sua vez, se beneficia da existência de uma ferramenta de extração de informações de desempenho para GPUs. Este trabalho cobre a criação de um gerador de microbenchmark para instruções PTX que também obtém informações sobre as características do hardware da GPU. Os resultados obtidos com o microbenchmark foram validados através de um modelo simplificado que obteve erros entre 6,11% e 16,32% em cinco kernels de teste. Também foram levantados os fatores de imprecisão nos resultados do microbenchmark. Utilizamos a ferramenta para analisar o perfil de desempenho das instruções e identificar grupos de comportamentos semelhantes. Também testamos a dependência do desempenho do pipeline da GPU em função da sequência de instruções executada e verificamos a otimização do compilador para esse caso. Ao fim deste trabalho concluímos que a utilização de microbenchmarks com instruções PTX é factível e se mostrou eficaz para a construção de modelos e análise detalhada do comportamento das instruções.<br>The recent growth in the use of tailored for performance Graphics Processing Units (GPUs) in scientific applications, generated the need to optimize GPU targeted programs. Performance models are the suitable tools for this task and they benefits from existing GPUs performance information extraction tools. This work covers the creation of a microbenchmark generator using PTX instructions and it also retrieves information about the GPU hardware characteristics. The microbenchmark results were validated using a simplified model with errors rates between 6.11% and 16.32% under five diferent GPU kernels. We also explain the imprecision factors present in the microbenchmark results. This tool was used to analyze the instructions performance profile, identifying groups with similar behavior. We also evaluated the corelation of the GPU pipeline performance and instructions execution sequence. Compiler optimization capabilities for this case were also verified. We concluded that the use of microbenchmarks with PTX instructions is a feasible approach and an efective way to build performance models and to generate detailed analysis of the instructions\' behavior.

Introdução: A Pentraxina-3 (PTX-3), produzida principalmente por macrófagos e células da vasculatura endotelial em resposta aos primeiros sinais pró-inflamatórios, tem sido apontada como um novo marcador de eventos coronarianos. Este estudo objetiva caracterizar os níveis plasmáticos de PTX-3 em pacientes com doença arterial coronariana estável em uma população brasileira, bem como sua relação com outros marcadores de risco cardiovascular e manifestação clínica de doença arterial coronariana (DAC). Métodos: Caracterização dos fatores de risco cardiovascular clássicos, e determinação dos níveis plasmáticos de PTX-3, proteína C reativa ultra-sensível (PCRus), interleucinas 18 (IL-18) e 10 (IL-10) foram realizadas numa coorte de 132 pacientes com doença arterial coronariana documentada, estáveis clinicamente. A determinação dos níveis plasmáticos de PTX-3, PCRus, IL-18 e IL-10 foi realizada pela técnica de ELISA utilizando-se kits comercialmente disponíveis. Os resultados dos valores dos marcadores inflamatórios foram comparados entre participantes que tiveram eventos clínicos ou não durante o seguimento médio de 47 meses. Resultados: Os níveis de PTX-3 e PCR-us coletados na primeira e segunda amostra foram semelhantes 3,45 e 3,84 ng/mL, e 4,89 e 4,72 mg/dL, respectivamente. A correlação de Pearson entre a primeira e segunda amostra foi maior para a dosagem de PCR-us que para o PTX3 (r=0,603 e r=0,356; p<0,001). Os níveis médios de PTX-3 em pacientes sem eventos foram 3,49±1,94ng/mL e nos pacientes que desenvolveram eventos 3,48±2,33ng/mL (p= 0,982). Para PCR, os valores foram de 5,07±8,26mg/mL e 4,60±4,66mg/dL (p= 0,737), respectivamente. Não foi encontrada associação entre níveis de PTX-3 e fatores de risco cardiovascular. Valores de PCRus foram associados com níveis séricos de LDL e a fração de ejeção do ventrículo esquerdo, não havendo relação com outros fatores de risco. Conclusões: Nesta amostra de indivíduos com DAC estável os níveis de PTX- 3 e PCR foram mais elevados do que em outras populações. Não identificamos fatores de risco relacionados com níveis aumentados de PTX-3 ou sua relação com eventos em médio prazo.

Cette etude a montre que la substitution du palladium par quelques pour-cent atomiques de platine et/ou de rhodium modifie largement les proprietes de stockage du tritium et les phenomenes lies au vieillissement de ces systemes. A l'etat initial, les pressions d'equilibre dependent uniquement du taux de substitution global et pas du tout de la nature des substituants. Au cours du vieillissement, la diminution des pressions de plateaux est plus forte pour les alliages pd-pt, et surtout pour l'alliage ternaire pd#9#0pt#5rh#5. On explique cet effet par une difference du type des defauts crees lors de la formation des bulles d'#3he. Le platine, seul ou associe au rhodium, stabilise les atomes metalliques auto-interstitiels isoles ou assembles en boucles de dislocation, ce qui provoque un gonflement de la maille plus important ; or la stabilite des tritiures est directement proportionnelle au volume des sites d'insertion du tritium. A l'oppose, dans le palladium pur et les alliages pd-rh, les atomes metalliques interstitiels entrent majoritairement dans un reseau de dislocations ou ils sont sans action sur le parametre de maille, donc sur la stabilite des tritiures. Dans tous les cas, les sytemes pd-pt-rh restent parfaitement adptes au stockage du tritium par leur conservation de l'ordre local et des proprietes thermodynamiques.

The diploma thesis deals with conventional transformers and current and voltage sensors. The first half of thesis describes mainly the basic concepts and accuracy classes of these converters used in electrical substations. The emphasis is given primarily on the differences. In the second half of thesis is presented an exact type of converters, which are installed in the substation Medlánky. There is an analysis of measured data from long – term monitoring from this substation and comparing the results from conventional transformers compared to the results from more modern sensors.

GPUs (Graphic Processing Units) are of interest for their favorable ratio $\frac{GF/s}{price}$. Compared to the beginning - early 1980's - nowadays GPU architectures are more similar to general purpose architectures but with (much) larger numbers of cores - the GF100 architecture released by NVIDIA in 2009-2010, for example, has a true hardware cache hierarchy, a unified memory address space, double precision performance and has a maximum of 512 cores. Exploiting the computational power of GPUs for non-graphics applications - past or present - has, however, always been hard. Initially, in the early 2000's, the way to program GPUs was by using graphic libraries API's (exclusively), which made writing non-graphics codes non-trivial and tedious at best, and virtually impossible in the worst case. In 2003, the Brook compiler and runtime system was introduced, giving users the ability to generate GPU code from a high level programming language. In 2006 NVIDIA introduced CUDA (Compute Unified Device Architecture). CUDA, a parallel computing platform and programming model specifically developed by NVIDIA for its GPUs, attempts to further facilitate general purpose programming of GPUs. Code edited using CUDA is portable between different NVIDIA GPU architectures and this is one of the reasons because NVIDIA claims that the user's productivity is much higher than previous solutions, however optimizing GPU code for utmost performance remains very hard, especially for NVIDIA GPUs using the GF100 architecture - e.g., Fermi GPUs and some Tesla GPUs - because a) the real instruction set architecture (ISA) is not publicly available, b) the code of the NVIDIA compiler - nvcc - is not open and c) users can not edit code using the real assembly - ELF in NVIDIA parlance. Compilers, while enabling immense increases in programmer productivity, by eliminating the need to code at the (tedious) assembly level, are incapable of achieving, to date, performance similar to that of an expert assembly programmer with good knowledge of the underlying architecture. In fact, it is widely accepted that high-level language programming and compiling even with a state-of-the-art compilers loose, on average, a factor of 3 in performance - and sometimes much more - over what a good assembly programmer could achieve, and that even on a conventional, simple, single-core machine. Compilers for more complex machines, such as NVIDIA GPUs, are likely to do much worse because among other things, they face (even more) complex trade-offs between often undecidable and NP-hard problems. However, because NVIDIA a) makes it virtually impossible to gain access to the actual assembly language used by its GF100 architecture, b) does not publicly explain many of the internal mechanisms implemented in its compiler - nvcc - and c) makes it virtually impossible to learn the details of its very complex GF100 architecture in sufficient detail to be able to exploit them, obtaining an estimate of the performance difference between CUDA programming and machine-level programming for NVIDIA GPUs using the GF100 architecture - let alone achieving some a priori performance guarantees of shortest execution time - has been, prior to this current work, impossible. To optimize GPU code, users have to use CUDA or PTX (Parallel Thread Execution) - a virtual instruction set architecture. The CUDA or PTX files are given in input to nvcc that produces as output fatbin files. The fatbin files are produced considering the target GPU architecture selected by the user - this is done setting a flag used by nvcc. In a fatbin file, zero or more parts of the fatbin file will be executed by the CPU - think of these parts as the C/C++ parts - while the remaining parts of the fatbin file - think of these parts as the ELF parts - will be executed by the specific model of the GPU for which the CUDA or PTX file has been compiled. The fatbin files are usually very different from the corresponding CUDA or PTX files and this lack of control can completely ruin any effort made at CUDA or PTX level to optimize the ELF part/parts of the fatbin file that will be executed by the target GPU for which the fatbin file has been compiled. We therefore reverse engineer the real ISA used by the GF100 architecture and generate a set of editing guidelines to force nvcc to generate fatbin files with at least the minimum number of resources later necessary to modify them to get the wanted ELF algorithmic implementations - this gives control on the ELF code that is executed by any GPU using the GF100 architecture. During the process of reverse engineering we also discover all the correspondences between PTX instructions and ELF instructions - a single PTX instruction can be transformed in one or more ELF instructions - and the correspondences between PTX registers and ELF registers. Our procedure is completely repeatable for any NVIDIA Kepler GPU - we do not need to rewrite our code. Being able to get the wanted ELF algorithmic implementations is not enough to optimize the ELF code of a fatbin file, we need in fact also to discover, understand, and quantify some not disclosed GPU behaviors that could slow down the execution of ELF code. This is necessary to understand how to execute the optimization process and while we can not report here all the results we have got, we can however say that we will explain to the reader a) how to force even distributions of the GPU thread blocks to the streaming multiprocessors, b) how we have discovered and quantified several warp scheduling phenomenons, c) how to avoid phenomenons of warp scheduling load unbalancing, that it is not possible to control, in the streaming multiprocessors, d) how we have determined, for each ELF instruction, the minimum quantity of time that it is necessary to wait before a warp scheduler can schedule again a warp - yes, the quantity of time can be different for different ELF instructions - e) how we have determined the time that it is necessary to wait before to be able to read again the data in a register previously read or written - this too can be different for different ELF instructions and different whether the data has been previously read or written - and f) how we have discovered the presence of an overhead time for the management of the warps that does not grow linearly to a liner increase of the number of residents warps in a streaming multiprocessor. Next we explain a) the procedures of transformation that it is necessary to apply to the ELF code of a fatbin file to optimize the ELF code and so making its execution time as short as possible, b) why we need to classify the fatbin files generated from the original fatbin file during the process of optimization and how we do this using several criteria that as final result allow us to determine the positions, occupied by each one of the fatbin files generated, in a taxonomy that we have created, c) how using the position of a fatbin file in the taxonomy we determine whether the fatbin file is eligible for an empirical analysis - that we explain - a theoretical analysis or both, and d) how - if the fatbin file is eligible for a theoretical analysis - we execute the theoretical analysis that we have devised and give an a priori - without any previous execution of the fatbin file - shortest ELF code execution time guarantee - this if the fatbin file satisfies all the requirements of the theoretical analysis - for the ELF code of the fatbin file that will be executed by the target GPU for which the fatbin file has been compiled.<br>GPUs (Graphic Processing Units) sono di interesse per il loro favorevole rapporto $\frac{GF/s}{price}$. Rispetto all'inizio - primi anni 70 - oggigiorno le architectture GPU sono più simili ad architectture general purpose ma hanno un numero (molto) più grande di cores - la architecttura GF100 rilasciata da NVIDIA durante il 2009-2010, per esempio, ha una vera gerarchia di memoria cache, uno spazio unificato per l'indirizzamento in memoria, è in grado di eseguire calcoli in doppia precisione ed ha un massimo 512 core. Sfruttare la potenza computazionale delle GPU per applicazioni non grafiche - passate o presenti - è, comunque, sempre stato difficile. Inizialmente, nei primi anni 2000, la programmazione su GPU avveniva (esclusivamente) attraverso l'uso librerie grafiche, le quali rendevano la scrittura di codici non grafici non triviale e tediosa al meglio, e virtualmente impossibile al peggio. Nel 2003, furono introdotti il compilatore e il sistema runtime Brook che diedero agli utenti l'abilità di generare codice GPU da un linguaggio di programmazione ad alto livello. Nel 2006 NVIDIA introdusse CUDA (Compute Unified Device Architecture). CUDA, un modello di programmazione e computazione parallela specificamente sviluppato da NVIDIA per le sue GPUs, tenta di facilitare ulteriormente la programmazione general purpose di GPU. Codice scritto in CUDA è portabile tra differenti architectture GPU della NVIDIA e questa è una delle ragioni perché NVIDIA afferma che la produttività degli utenti è molto più alta di precedenti soluzioni, tuttavia ottimizare codice GPU con l'obbiettivo di ottenere le massime prestazioni rimane molto difficile, specialmente per NVIDIA GPUs che usano l'architecttura GF100 - per esempio, Fermi GPUs e delle Tesla GPUs - perché a) il vero instruction set architecture (ISA) è non pubblicamente disponibile, b) il codice del compilatore NVIDIA - nvcc - è non aperto e c) gli utenti non possono scrivere codice usando il vero assembly - ELF nel gergo della NVIDIA. I compilatori, mentre permettono un immenso incremento della produttività di un programmatore, eliminando la necessità di codificare al (tedioso) livello assembly, sono incapaci di ottenere, a questa data, prestazioni simili a quelle di un programmatore che è esperto in assembly ed ha una buona conoscenza dell'architettura sottostante. Infatti, è largamente accettato che programmazione ad alto livello e compilazione perfino con compilatori che sono considerati allo stato dell'arte perdono, in media, un fattore 3 in prestazione - e a volte molto di più - nei confronti di cosa un buon programmatore assembly potrebbe ottenere, e questo perfino su una macchina convenzionale, semplice, a singolo core. Compilatori per macchine più complesse, come le GPU NVIDIA, sono propensi a fare molto peggio perché tra le altre cose, essi devono determinare (persino più) complessi trade-offs durante la ricerca di soluzioni a problemi spesso indecidibili e NP-hard. Peraltro, perché NVIDIA a) rende virtualmente impossibile guadagnare accesso all'attuale linguaggio assembly usato dalla architettura GF100, b) non spiega pubblicamente molti dei meccanismi interni implementati nel suo compilatore - nvcc - e c) rende virtualmente impossible imparare i dettagli della molto complessa architecttura GF100 ad un sufficiente livello di dettaglio che permetta di sfruttarli, ottenere una stima delle differenze prestazionali tra programmazione in CUDA e programmazione a livello macchina per GPU NVIDIA che usano la architecttura GF100 - per non parlare dell'ottenimento a priori di garanzie di tempo di esecuzione più breve - è stato, prima di questo corrente lavoro, impossbile. Per ottimizare codice GPU, gli utenti devono usare CUDA or PTX (Parallel Thread Execution) - un instruction set architecture virtuale. I file CUDA or PTX sono dati in input a nvcc che produce come output fatbin file. I fatbin file sono prodotti considerando l'architecttura GPU selezionata dall'utente - questo è fatto settando un flag usato da nvcc. In un fatbin file, zero o più parti del fatbin file saranno eseguite dalla CPU - pensa a queste parti come le parti C/C++ - mentre le rimanenti parti del fatbin file - pensa a queste parti come le parti ELF - saranno eseguite dallo specifico modello GPU per il quale i file CUDA or PTX sono stati compilati. I fatbin file sono normalmente molto differenti dai corrispodenti file CUDA o PTX e questa assenza di controllo può completamente rovinare qualsiasi sforzo fatto a livello CUDA o PTX per otimizzare la parte o le parti ELF del fatbin file che sarà eseguita / saranno eseguite dalla GPU per la quale il fatbin file è stato compilato. Noi quindi scopriamo quale è il vero ISA usato dalla architettura GF100 e generiamo un insieme di linea guida per scrivere codice in modo tale da forzare nvcc a generare fatbin file con almeno il minimo numero di risorse successivamente necessario per modificare i fatbin file per ottenere le volute implementazioni algoritmiche in ELF - questo da controllo sul codice ELF che è eseguito da qualsiasi GPU che usa l'architettura GF100. Durante il processo di scoperata del vero ISA scopriamo anche le corrispondenze tra istruzioni PTX e istruzioni ELF - una singola istructione PTX può essere transformata in one o più istruzioni ELF - e le corrispondenze tra registri PTX e registri ELF. La nostra procedura è completamente ripetibile per ogni NVIDIA Kepler GPU - non occorre che riscrivamo il nostro codice. Essere in grado di ottenere le volute implementazioni algoritmiche in ELF non è abbastanza per ottimizzare il codice ELF di un fatbin file, ci occorre infatti anche scoprire, comprendere e quantificare dei comportamenti GPU che non sono divulgati e che potrebbero rallentare l'esecuzione di codice ELF. Questo è necessario per comprendere come eseguire il processo di ottimizzazione e mentre noi non possiamo riportare qui tutti i risultati che abbiamo ottenuto, noi possiamo comunque dire che spiegheremo al lettore a) come forzare una distribuzione uniforme dei GPU thread blocks agli streaming multiprocessors, b) come abbiamo scoperto e quantificato diversi fenomeni riguardanti il warp scheduling, c) come evitare fenomeni di warp scheduling load unblanacing, che è non possible controllare, negli streaming multiprocessors, d) come abbiamo determinato, per ogni istruzione ELF, la minima quantità di tempo che è necessario attendere prima che un warp scheduler possa schedulare ancora un warp - si, la quantità di tempo può essere differente per differenti istruzioni ELF - e) come abbiamo determinato il tempo che è necessario attendere prima di essere in grado di leggere ancora un dato in un registro precedentemente letto o scritto - questo pure può essere differente per differnti istruzioni ELF e differente se il dato è stato precedentemente letto o scritto - e f) come abbiamo scoperto la presenza di un tempo di overhead per la gestione dei warp che non cresce linearmente ad un incremento lineare del numero di warp residenti in uno streaming multiprocessor. Successivamente, noi spiegamo a) le procedure di trasformazione che è necessario applicare al codice ELF di un fatbin file per ottimizzare il codice ELF e così rendere il suo tempo di esecuzione il più corto possibile, b) perché occorre classificare i fatbin file generati dal fatbin file originale durante il processo di ottimizzazione e come noi facciamo questo usando diversi criteri che come risultato finale permettono a noi di determinare le posizioni, occupate da ogni fatbin file generato, in una tassonomia che noi abbiamo creato, c) come usando la posizione di un fatbin file nella tassonomia noi determiniamo se il fatbin file è qualificato per una analisi empirica - che noi spieghiamo - una analisi teorica o entrambe and d) come - supponendo il fatbin file sia qualificato per una analisi teorica - noi eseguiamo l'analisi teorica che abbiamo ideato e diamo a priori - senza alcuna precedente esecuzione del fatbin file - la garanzia - questo supponendo il fatbin file soddisfi tutti i requisiti dell'analisi teorica - che l'esecuzione del codice ELF del fatbin file, quando il fatbin file sarà eseguito sulla architettura GPU per cui è stato generato, sarà la più breve possibile.

This thesis is about the creation of a new game framework named Pix and a comparison between it and the game engine Godot. The purpose is to create a game framework that focuses on making the workflow streamlined for the pro- grammer and at the same time giving the programmer a lot of creative power. Pix uses C# as programming language which runs on the .NET Core platform. Pix is built with Entity Component System (ECS) design which means that the design is data-oriented and that it focuses on composition. Thus the ECS design brings with it a clear separation between logic and data. The ECS design also makes it easy to write multithreaded code and to serialize the game world state. The comparison against Godot shows clear differences between how you use them and the philosophy about how the users become familiar with them. The obvious difference between them is that the main time spent working with Godot will be in the graphical user interface. In Pix on the other hand you will only work in a text-editor or an IDE if you do not create your own editor. The coding in Godot is done primarily with the script language GDScript. It is made for creating common game functionality but can’t be used to extend the engine with new advanced functionality. Thus to integrate new more advanced features Godot will need to be recompiled. Being forced to recompile the engine to add new advanced features results in that extending the engine can both be time consuming and challenging. In Pix there is no difference between coding game functionality and extending the framework. This equality in Pix between coding game functionality and extending the framework brings with it that when you can make a game in Pix you can also extend the engine with more functionality. The differences results in that Godot is simpler to learn but also gives the regu- lar user less power. Pix is the opposite of that. I you look at the workflow of us- ing Pix and combine that with the technologies Pix is built upon you can see that Pix differentiates itself from the already existing alternatives. The work- flow Pix provides and the technologies it is built upon shows that Pix can be a good alternative for creating complex games that doesn't need the most ad- vanced graphical features.<br>Rapporten handlar om skapelsen av ett nytt spelramverk namngivet Pix som jämförs mot den existerande spelmotorn Godot. Syftet är att skapa ett spelram- verk som fokuserar på att göra arbetssättet smidigt för programmeraren samtidigt som det ger mycket kreativ makt till programmeraren. Pix använder C# som programmeringsspråk vilket körs på .NET Core plattformen. Det är upp- byggt med en Entity Component System (ECS) design vilket betyder att det är en dataorienterad design med ett fokus på komposition. Det medför en klar separation mellan logik och data. ECS designen medför också att serialisering samt använda sig av flera trådar blir väldigt enkelt. Jämförelsen mot spelmotorn Godot visar tydliga skillnader i hur man använder spelmotorn/spelramverket samt tydliga skillnader i filosofin kring hur en användare blir bekant med spelmotorn/spelramverket. De tydliga skillnader är hur större delen av arbetstiden i Godot spenderas i Godots grafiska gränssnitt medans Pix kan kontrolleras endast från kod om man inte skapar en editor själv. Programmering i Godot görs med skriptspråket GDScript. Det är gjort för att skapa vanlig spel funktionalitet och inte utöka spelmotorn med ny funktionalitet. Det betyder att hela motorn måste kompileras om för att lägga till mer avancerad funktionalitet vilket kan vara tidskrävande. I Pix är är det samma sak att programmera spel funktionalitet och utöka ramverket med ny funktionalitet. Det medför att så fort som man kan programmera ett spel i Pix kan man också utöka ramverket med mer funktionalitet. Det resulterar i att Godot är enklare att lära sig men samtidigt ger mindre makt till den vanlige användaren medans Pix är tvärtom. Kollar man på hur man använder sig av Pix samt de teknologierna Pix är uppbyggt med så kan man se att det skiljer sig från redan existerande alternativ. Det leder till att Pix kan vara ett gott alternativ för komplexa spel som inte kräver den mest avancerade grafiken.

Intravesical Bacillus Calmette–Guérin (BCG) immunotherapy is the main treatment for bladder high-grade non-muscle invasive transitional cell carcinoma (HGNMITCC) following initial resection. Unfortunately, about 30% of patients will not respond to treatment and they carry a high risk of disease progression. The alternative, radical cystectomy, has major risks with high morbidity and mortality. The ability to predict the response to BCG treatment would be a useful tool in the selection of appropriate treatment modalities. This study investigated a variety of detectable immune responses in blood and urine to establish if there were differences between responders and non-responders to BCG treatment. We evaluated whether there were detectable immunological differences in blood or urine that could explain or predict outcome.

This thesis is part of a larger series of studies being conducted by Kristine Tanner, PhD, Associate Professor in the Department of Communication Disorders at Brigham Young University (BYU). The larger project is funded by the National Institute on Deafness and Other Communication Disorders at the National Institutes of Health. This thesis primarily investigated the effects of combination inhaled corticosteroids (ICs) on aerodynamic measures of the voice. In recent years, an increase in the localized laryngeal side effects from IC treatment, including dysphonia, have been reported. This study employed a between-groups experimental design, with two groups of rabbit larynges having been exposed to either ICs or nebulized isotonic saline two times each day for eight weeks at The University of Utah. For this study, the independent variable is group condition (i.e., IC versus saline) and the dependent variables are two aerodynamic measurements made at the onset of phonation using a benchtop experimental setup, namely phonation threshold pressure (PTP; cmH2O) and phonation threshold flow (PTF; L/min). The results of this study indicate a significant difference in PTP and PTF between vocal folds treated with IC as compared to vocal folds treated with nebulized isotonic saline solution. Implications of this study suggest negative changes in the voice due to IC treatment.

Atualmente, o alerta prévio de desastres naturais e ambientais iminentes, a previsão acurada do clima e compreensão detalhada do status dos recursos hídricos globais são assuntos cotidianos extremamente importantes para a comunidade global. Os Serviços Nacionais de Meteorologia e Hidrologia em todo o mundo são responsáveis por fornecer essas informações, que são necessárias para a proteção do meio ambiente, desenvolvimento econômico (transporte, energia, agricultura, etc.) e a segurança da vida e da propriedade. Neste contexto, um dos serviços amplamente utilizado mundialmente é o Sistema Internacional de Coleta de Dados (International Data Collection System) que é composto por redes de satélites geoestacionários e de órbita baixa (não-geoestacionário). O INPE desenvolve e opera o Sistema Brasileiro de Coleta de Dados Ambientais (SBCDA) que é composto basicamente pelos satélites de Coleta de Dados (SCDs) 1 e 2, e Satélite Sino Brasileiro de Recursos Terrestres (CBERS) 4, e pelas cerca de 1100 Plataformas de Coleta de Dados (PCDs) distribuídas no território brasileiro, e pelas Estações Terrenas de Recepção (ETRs) em Cuiabá-MT, e Alcântara-MA, e pelo Centro de Missão (CM) no Centro Regional do Nordeste do INPE (INPE/CRN) em Natal, RN. O SBCDA opera desde 1993 utilizando uma tecnologia analógica que vem se tornando obsoleta, a qual naturalmente deverá ser substituída por sistemas digitais com decodificação e armazenamento de dados a bordo. Neste cenário, a sincronização de frequência e fase da portadora e a estimação de tempo de símbolo é de fundamental importância para a recepção correta do sinal que chega ao receptor. Portanto, foi proposto o desenvolvimento de uma solução para estas funções utilizando processamento digital de sinais através de códigos em MatLab. Para a implementação da sincronização de frequência foi utilizado um PLL Digital de segunda ordem, levando em consideração requisitos como o efeito Doppler. Para o estimador de tempo de símbolo foi utilizado o algoritmo com alimentação direta x (feedforward), o qual utiliza uma estrutura de simples implementação, uma simplificação do proposto em [16]. Também foi adotada uma solução simples de um interpolador linear para determinação do tempo de atraso. O resultado apresentado pelo sincronizador de frequência / fase foi satisfatório para operação em parte da faixa. O estimador de tempo de símbolos também apresentou resultado satisfatório para Eb/N0 na faixa de 0 a 11 dB, com uma perda menor que 0,5 dB em relação ao valor teórico.<br>Nowadays previous warning of impending natural and environmental disasters, accurate climate prediction, and detailed understanding of the status of global water resources are everyday issues that are extremely important to the global community. The National Meteorological and Hydrological Services throughout the world are responsible for providing this information, which is necessary for the protection of the environment, economic development (transportation, energy, agriculture, etc.) and the safety of life and property. In this context, one of the services widely used worldwide is the International Data Collection System which is composed of geostationary and low-orbit (nongeostationary) satellite networks. INPE develops and operates the Brazilian Data Collection System (BDCS), which is basically composed by the Data Collection Satellite (DCS) 1 and 2, the China-Brazilian Earth Resources Satellite (CBERS) 4, 1100+ Data Collection Platforms (DCPs) distributed in the Brazilian territory, two Receiving Ground Stations (RGS) at Cuiabá-MT, and Alcântara-MA, and one MISSION Center (MC) at the INPE Northeast Regional Center (INPE/NRC) at Natal, RN The BDCS has been operating since 1993 using an analog technology that has become obsolete and must be replaced by digital systems with on-board data decoding and storage. In this scenario, carrier frequency and phase synchronization and symbol time estimation have a fundamental importance for the correct reception of the signal arriving at the receiver. Therefore, it was proposed the development of a solution for these functions using digital signal processing using MatLab codes. For the implementation of frequency synchronization, the chosen solution uses xii a second-order Digital PLL, taking into account requirements such as the Doppler Effect. For the symbol time estimator we used the feedforward algorithm, which uses a simple implementation structure, a simplification of the one proposed in [16]. Also a simple solution of a linear interpolator was used to determine the delay time. The result presented by the frequency / phase synchronizer was satisfactory for operation in part of the range. The symbol time estimator also presented satisfactory results for Eb / N0 in the 0 to 11 dB range, with a loss of less than 0.5 dB over the theoretical value.

Thesis (MSc)--University of Stellenbosch, 2003.<br>ENGLISH ABSTRACT: The 14.2 kb plasmid pTC-FI4 was isolated from the moderately thermophilic (45°- 50°C), highly acidophilic (pH 1.5 to 2.5), chemolithotrophic bacterium Acidithiobacil/us caldus and has a replicon that is closely related to the promiscuous, broad host-range, IncQ-family of plasmids. The region containing the mobilization genes was sequenced and encoded five Mob proteins and an origin of transfer, which are related to the DNA processing (Tral) region of IncPI plasmids, rather than to the three Mob protein systems of the IncQ-l-group plasmids (e.g. plasmids RSFIOIO or R1162). Plasmid pTC-F14 is the third example of an IncQ family plasmid that has five mob genes, with the others being pTF-FC2 and pRAS3.1. The minimal region that was essential for mobilization included the mobA, mobB and the mobC genes as well as the oriT. The mobD and mobE genes were non-essential, but together enhanced the mobilization frequency by approximately 300-fold. The repB gene increased the mobilization frequency but was not essential for mobilization. Mobilization of pTC-F14 between Escherichia coli strains by a chromosomally integrated RP4 plasmid was more than 3500-fold less efficient than the mobilization ofpTF-FC2. When both plasmids were co-resident in the same E. coli host, pTC-FI4 was mobilized at almost the same frequency as pTF-FC2. This enhanced pTC-FI4 mobilization frequency was due to the presence of a combination of the pTF-FC2 mobD and mobE gene products, the functions of which are still unknown. pTF-FC2 could mobilize the oriT of pTC-FI4 whereas pTC-F14 could only mobilize the pTFFC2 oriT if provided with some of the mobilization genes from the pTC-FC2 mobilization region. Unexpectedly either the mobEDC genes or the mobAB genes would allow the mobilization of the pTF-FC2 oriT by pTC-F14 even though there was no common gene between the two subsets. No evidence for any negative effect on the transfer of one plasmid by the related, potentially competitive plasmid was obtained.<br>AFRIKAANSE OPSOMMING: Die 14.2 kb plasmied, pTC-F14, is uit die matig termofiliese (45°C tot 50°C), hoogs asidofiliese (pH 1.5 tot 2.5), chemolitooutotrofiese bakterium Acidithiobaci/lus caldus geisoleer en beskik oor 'n replikon wat verwant is aan die vanaf die IncQ-familie van plasmiede. Hierdie plasmiede is alom bekend vir hulle promiskuïteit tydens konjugasie asook hul vermoë om in 'n groot aantal verskillende gasheer organismes te kan repliseer. DNA volgorde analise van die mobiliserings area het 'n oordrags oorsprong asook vyf oop leesrame onthul wat nader verwant is aan die DNA prosseserings gene van die Tral area op die IncP 1 plasmiede, as die van die mobiliserings stelsel van die IncQ-l-groep plasmiede. Plasmied pTC-Fl4 is die derde voorbeeld, saam met pTF-FC2 en pRAS3.1, van 'n IncQ-tipe plasmied met 'n vyfgeen mobiliserings sisteem. Die kleinste area op die plasmied nodig vir mobilisering van pTC-Fl4 is bepaal, en het die mobA, mobB en mobC gene sowel as die oordrags oorsprong ingesluit. Saam, was die mobD en mobE gene verantwoordelik vir 'n 300- voud toename in die mobilisasie frekwensie van pTC-Fl4 alhowel die gene nie absoluut nodig was vir mobilisering van die plasmied nie. Die repB geen het ook bygedra tot die frekwensie waarteen die volledige plasmied gemobiliseer was, maar hierdie geen was ook nie nodig vir mobilisering van die pTC-F14 plasmied nie. Die frekwensie waarteen pTC-Fl4 tussen Escherichia coli rasse beweeg het tydens konjugasie, terwyl gebruik gemaak is van 'n chromosomaal geintegreerde RP4 plasmied, was ongeveer 3500-voud laer as die van pTF-FC2. Indien beide pTC-Fl4 en pTF-FC2 in dieselfde E. coli gasheer aangetref word, word beide plasmiede teen ongeveer dieselfde frekwensie gemobiliseer. Die verhoogde frekensie vir pTC-Fl4 was as gevolg van die teenwoordigheid van beide die mobD en mobE gene van die pTF-FC2 plasmied, waarvan die funksies nog onbekend is. Plasmied pTF-FC2 kon die oordrags oorsprong van pTC-Fl4 mobiliseer waarteenoor plasmied pTC-FI4 die oordrags oorsprong vanafpTF-FC2 slegs kon mobiliseer indien een van twee dele van die pTF-FC2 mobiliserings gene voorsien word (al was daar geen oorvleuling tussen die twee nie). Alhoewel die plasmiede moontlik kon kompeteer op die vlak van plasmied oordrag is geen negatiewe kompetesie waargeneem tussen dié twee verwante plasmiede nie.

La toxine de pertussis (PTX) est une A-B protéine considérée comme l’un des principaux facteurs de virulence de Bordetella pertussis, l’agent bactérien responsable de la coqueluche. Aujourd’hui, cette maladie représente encore un réel danger pour les nouveaux-nés et les<p>nourrissons non ou partiellement immunisés. Actuellement, la coqueluche provoque encore la<p>mort d’environ 350.000 individus par an. La toxicité de la PTX est liée à l’activité<p>enzymatique de sa sous-unité A capable d’inhiber les voies de signalisation associées aux<p>protéines Gi. La partie B, quant à elle, permet l’entrée de cette sous-unité A dans le<p>cytoplasme des cellules cibles en se liant spécifiquement à son ou ses récepteurs<p>membranaires toujours inconnus de nos jours.<p><p>Des études réalisées chez la souris et chez l’homme ont montré que les vaccins anticoquelucheux combinés à différents antigènes vaccinaux étaient capables de moduler<p>leurs réponses humorales spécifiques. Par ailleurs, la PTX est couramment qualifiée d’agent<p>immunostimulant. En effet, des modèles murins de vaccination permirent d’identifier des<p>propriétés adjuvantes de la PTX coadministrée avec des antigènes non relevants.<p><p>Le travail développé dans ce manuscrit étudie les effets de la PTX sur 2 types cellulaires<p>primordiaux sollicités lors d’une vaccination :la cellule dendritique (DC) et le lymphocyte T<p>CD4+ naïf.<p><p>Les DC sont les seules cellules présentatrices d’antigènes aptes à initier une réponse immune<p>primaire. Dans un premier temps, nous avons montré que la PTX était capable d’activer des<p>DC générées in vitro à partir de monocytes. En effet, elles acquièrent un phénotype mature<p>caractérisé par une augmentation de l’expression membranaire des molécules costimulatrices<p>et du CMH de classe II, démontrant un effet direct et spécifique de la PTX sur les DC<p>myéloïdes. Parallèlement, ces DC produisent du TNF-a, de l’IL-12p40 et de l’IL-12p70 et<p>activent NF-kappaB, un facteur de transcription essentiel au processus de maturation. Nous<p>avons obtenu des résultats similaires avec une toxine génétiquement modifiée qui est<p>enzymatiquement inactive. A partir de sang total incubé avec la PTX, nous avons par ailleurs<p>observé que les DC circulantes du nouveau-né étaient déficientes dans leur maturation et leur<p>sécrétion d’IL-12p70 comparées aux DC de l’adulte.<p><p>D’autre part, il a été décrit précédemment que la PTX exerçait des effets mitogènes sur les<p>lymphocytes T humains et murins. Cependant, le rôle qu’elle joue sur la population des<p>lymphocytes T CD4 naïfs reste peu connu. A l’issue de notre second travail, nous pouvons<p>dès lors affirmer que la PTX est également capable d’activer des lymphocytes T<p>CD4+CD45RA+ naïfs isolés à partir des cellules mononuclées du sang périphérique, et ce<p>indépendamment de son activité enzymatique. En effet, ces lymphocytes T CD4+ naïfs stimulés par la PTX prolifèrent, synthétisent des quantités non négligeables d'ARN messagers<p>codant pour l’IL-2 et le TNF-a, augmentent l’expression membranaire des molécules CD40L,<p>CD69 et CD25 et expriment la protéine Foxp3. Cette activation s’accompagne de la translocation nucléaire de NF-kappaB et NFAT. Parallèlement à l’adulte, la PTX active les lymphocytes T CD4 néonataux. Néanmoins, ceux-ci prolifèrent moins bien et expriment plus faiblement le CD40L à leur surface.<p><p>Enfin, la PTX induit la sécrétion de taux importants d’IFN-g par des T CD4+CD45RA+ naïfs<p>adultes mis en présence de DC autologues.<p><p>Nous terminerons en proposant l’hypothèse suivante :La PTX pourrait exercer ses propriétés<p>adjuvantes par l’intermédiaire de différents mécanismes comprenant notamment la maturation<p>des DC d’origine myéloïde et l’activation des lymphocytes T CD4+CD45RA+ naïfs. Ces 2 populations cellulaires sont en effet les principaux protagonistes impliqués dans la réponse<p>immune primaire.<br>Doctorat en sciences pharmaceutiques<br>info:eu-repo/semantics/nonPublished

<p>There is always a need for easy-to-follow processes that enable accurate and non-time consuming solutions. Nowadays we see a lot of different approaches to development processes in software engineering. This project is concerned with how to manage a software development process in a reliable, secure and efficient way. Software is available which provides some help for project managers / administrators to work more productively, with effective communication. Using such systems, it is possible to keep track of all the phases of development, including task distribution, making maximum use of previous hands-on experience and increasing productivity, to deliver a finished product in minimum time. No existing solution, however, fulfills all the desirable criteria. This paper describes the motivation, design and implementation of an improved development management system using Active Server Pages and Microsoft Internet Information Services with a backend Microsoft Access Database developed using a waterfall software development process. The resulting system is described and evaluated. This system will be beneficial for software houses, because they can communicate on the web, allowing efficiency gains by avoiding the need to call meetings for distribution of tasks among employees, with the additional advantage of location-transparent team management through the Internet.</p>

PowerPoint is an excellent tool for creating presentations and people are accustomed to using it. Its only handicap is that it is not installed everywhere and it exists in numerous versions. But there is an application that is installed almost everywhere and that application is the web browser. This work aims to create the PowerPoint presentation viewer for the web browser. With the internet as the environment, it may have a wide range of applications from the content sharing point of view. The solution is a web application that allows to upload the PowerPoint file and then the application displays the content of the file. The application also offers functionality such as navigation between slides and full-screen mode. The rendered slides in the web browser are very similar to the slides in PowerPoint. It does not support advanced features, but it supports displaying text, pictures, video and audio. Further, it supports basic styling options such as colours, margins, position and line height.

The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed –137 T>C and –53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.

The peroxisome is a subcellular organelle that carries out a diverse range of metabolic functions, including the b-oxidation of very long chain fatty acids, the breakdown of peroxide and the a-oxidation of fatty acids. Disruption of peroxisome metabolic functions leads to severe disease in humans. These diseases can be broadly grouped into two categories: those in which a single enzyme is defective, and those known as the peroxisome biogenesis disorders (PBDs), which result from a generalised failure to import peroxisomal matrix proteins (and consequently result in disruption of multiple metabolic pathways). The PBDs result from mutations in PEX genes, which encode protein products called peroxins, required for the normal biogenesis of the peroxisome. PEX1 encodes an AAA ATPase that is essential for peroxisome biogenesis, and mutations in PEX1 are the most common cause of PBDs worldwide. This study focused on the identification of mutations in PEX1 in an Australasian cohort of PBD patients, and the impact of these mutations on PEX1 function. As a result of the studies presented in this thesis, twelve mutations in PEX1 were identified in the Australasian cohort of patients. The identified mutations can be broadly grouped into three categories: missense mutations, mutations directly introducing a premature termination codon (PTC) and mutations that interrupt the reading frame of PEX1. The missense mutations that were identified were R798G, G843D, I989T and R998Q; all of these mutations affect amino acid residues located in the AAA domains of the PEX1 protein. Two mutations that directly introduce PTCs into the PEX1 transcript (R790X and R998X), and four frameshift mutations (A302fs, I370fs, I700fs and S797fs) were identified. There was also one mutation found in an intronic region (IVS22-19A>G) that is presumed to affect splicing of the PEX1 mRNA. Three of these mutations, G843D, I700fs and G973fs, were found at high frequency in this patient cohort. At the commencement of these studies, it was hypothesised that missense mutations would result in attenuation of PEX1 function, but mutations that introduced PTCs, either directly or indirectly, would have a deleterious effect on PEX1 function. Mutations introducing PTCs are thought to cause mRNA to be degraded by the nonsense-mediated decay of mRNA (NMD) pathway, and thus result in a decrease in PEX1 protein levels. The studies on the cellular impact of the identified PEX1 mutations were consistent with these hypotheses. Missense mutations were found to reduce peroxisomal protein import and PEX1 protein levels, but a residual level of function remained. PTC-generating mutations were found to have a major impact on PEX1 function, with PEX1 mRNA and protein levels being drastically reduced, and peroxisomal protein import capability abolished. Patients with two missense mutations showed the least impact on PEX1 function, patients with two PTC-generating mutations had a severe defect in PEX1 function, and patients carrying a combination of a missense mutation and a PTC-generating mutation showed levels of PEX1 function that were intermediate between these extremes. Thus, a correlation between PEX1 genotype and phenotype was defined for the Australasian cohort of patients investigated in these studies. For a number of patients, mutations in the coding sequence of one PEX1 allele could not be identified. Analysis of the 5' UTR of this gene was therefore pursued for potential novel mutations. The initial analyses demonstrated that the 5' end of PEX1 extended further than previously reported. Two co-segregating polymorphisms were also identified, termed –137 T>C and –53C>G. The -137T>C polymorphism resided in an upstream, in-frame ATG (termed ATG1), and the possibility that the additional sequence represented PEX1 coding sequence was examined. While both ATGs were found to be functional by virtue of in vitro and in vivo expression investigations, Western blot analysis of the PEX1 protein in patient and control cell extracts indicated that physiological translation of PEX1 was from the second ATG only. Using a luciferase reporter approach, the additional sequence was found to exhibit promoter activity. When examined alone the -137T>C polymorphism exerted a detrimental effect on PEX1 promoter activity, reducing activity to half that of wild-type levels, and the -53C>G polymorphism increased PEX1 promoter activity by 25%. When co-expressed (mimicking the physiological condition) these polymorphisms compensated for each other to bring PEX1 promoter activity to near wild-type levels. The PEX1 mutations identified in this study have been utilised by collaborators at the National Referral Laboratory for Lysosomal, Peroxisomal and Related Genetic Disorders (based at the Women's and Children's Hospital, Adelaide), in prenatal diagnosis of the PBDs. In addition, the identification of three common mutations in Australasian PBD patients has led to the implementation of screening for these mutations in newly referred patients, often enabling a precise diagnosis of a PBD to be made. Finally, the strong correlation between genotype and phenotype for the patient cohort investigated as part of these studies has generated a basis for the assessment of newly identified mutations in PEX1.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Biomolecular and Biomedical Sciences<br>Full Text

Der Vortrag gibt einen Überblick der Neuerungen im Werkzeug Mechanism der Creo Versionen 1.0 und 2.0. Zudem werden 10 hilfreiche "Tips und Tricks" vorgestellt, welche den Mechanismuseinsatz vereinfachen.

There is always a need for easy-to-follow processes that enable accurate and non-time consuming solutions. Nowadays we see a lot of different approaches to development processes in software engineering. This project is concerned with how to manage a software development process in a reliable, secure and efficient way. Software is available which provides some help for project managers / administrators to work more productively, with effective communication. Using such systems, it is possible to keep track of all the phases of development, including task distribution, making maximum use of previous hands-on experience and increasing productivity, to deliver a finished product in minimum time. No existing solution, however, fulfills all the desirable criteria. This paper describes the motivation, design and implementation of an improved development management system using Active Server Pages and Microsoft Internet Information Services with a backend Microsoft Access Database developed using a waterfall software development process. The resulting system is described and evaluated. This system will be beneficial for software houses, because they can communicate on the web, allowing efficiency gains by avoiding the need to call meetings for distribution of tasks among employees, with the additional advantage of location-transparent team management through the Internet.

To establish comprehensive pharmacology of P2X₇ receptors, membrane current recording, intracellular calcium transient recording and ethidium bromide uptake were carried out to examine several selective (A-740003, A- 438079) and non-selective (suramin) P2X₇ antagonists across mammalian P2X₇ receptors (human, mouse and rat). These P2X₇ receptors demonstrated species-dependent sensitivities to antagonists. In each species, A-740003 revealed variant IC50 values with different assays, indicating the assay- dependent pharmacology of P2X₇ receptors. Conventionally, pharmacology can be used to define a native current but not in the case of the human breast cancer cell line, Hs578T. It is found that P2X₇ was expressed at both mRNA and protein level. The ATP-evoked currents recorded from Hs578T cells were P2X₇-like with distinctive electrophysiological features. But the pharmacology profile of the currents did not fit with P2X₇ receptor. Further experiments are needed to either include or exclude the existence of functional P2X₇ receptors in Hs578T. Transmembrane domain 2 (TM2) is known as the pore-forming region for P2X receptors. TM2 of P2X₇ receptor was investigated with cysteine substitution scanning. The predicted α-helix structure of the TM2 segment was in good agreement with the results from the substituted cysteine accessibility method (SCAM). Thr336, Ser339, Tyr343, Phe344 and Thr348 were found important for both channel dilation and aqueous pore formation. Ser339 was further studied. Various substitutions at Ser339 were explored. The results suggest that the polarity of the side chain at Ser339 is essential for the channel dilation. Furthermore, disulfide bond formation was identified between S339C in the trimeric receptor, implying that the side chains of Ser339 might turn very close to each other during the channel opening and dilation.

This thesis deals with the possibilities of video conferencing in Asterisk PBX and their use in practice. They also described the contingencies and how its configuration. Particular attention is paid to the protocols SIP, IAX and H.323, which are described in one of the chapters. The thesis was created by the Asterisk PBX, which demonstrates cooperation with videoconferencing clients. The thesis describes the configuration files so that the central set. Conclusion the work assesses the use of codecs for different clients.

För att utöka ett fordons användningsområde kan det utrustas med olika typer av arbetsredskap och lasthanteringsutrustning. För att driva dessa finns möjlighet till kraftuttag (PTO - Power Take-Off) från ett antal anslutningar vid motor och drivlina. I dagsläget saknar motorns styrsystem information om dessa laster vilket kan påverka styrningen negativt. I detta arbete presenteras en metod för att estimera det okända lastmomentet på kraftuttaget. Metoden utgår från Newtons andra lag för svänghjulet och det drivande momentet till drivlinan beskrivs av en dynamisk modell. Genom att beräkna hur mycket moment som borde krävas vid aktuellt körfall och jämföra detta med det moment som motorn levererar kan parasitförluster och okända externa laster estimeras. En känslighetsanalys av omgivningens inverkan på modellen och PTO-estimeringen visar att estimeringen i dagsläget inte går att utföra på ett robust och tillförlitligt sätt. De fel som uppstår till följd av bristfällig information om bland annat väglutning och fordonsmassa ger upphov till fel i PTO-estimeringen som är vida större än de lastmoment som ska estimeras. Vidare konstateras att värdet på det levererade motormomentet i motorstyrsystemet (EMS) kan ha ett statiskt fel på upp till cirka 70Nm.<br>To extend the possible use of a truck it can be equipped with auxillary equipment for handling cargo and different working tools. These are powered using a Power Take-Off (PTO) connected to the vehicle´s drivetrain. In the current situation the control system lacks information about these loads, which can have a negative impact on the control. In this thesis a method for estimating the unknown PTO torque is presented. The method is based on Newtons second law of motion describing the motion of the flywheel. The driving torque from the drivetrain is described by a dynamic model. By calculating how much torque that should suffice in the present driving situation and comparing this to the torque delivered by the engine, the parasitic losses and unknown external loads can be estimated. A sensitivity analysis of the ambient influence on the model and the PTO estimation shows that the estimation cannot be performed in a robust and reliable way. The errors that arise from faulty input to the model such as deficient road slope and vehicle mass information result in errors with greater magnitude than the load torque to be estimated. It is also concluded that in the Engine Management System (EMS), the calculation of the torque delivered by the engine can show a static error of up to approximately 70Nm.

SANTRAUKA Bakalauro baigiamajame darbe pateikiama užsienio ir lietuvių autorių suformuotos vartotojų lojalumo sampratos ir esmė, atskleisti ir analizuojami vartotojų lojalumą formuojantys veiksniai, lojalių klientų nauda įmonei, nagrinėjami lojalumo tipai ir lojalumo matavimo metodai. Remiantis išanalizuota literatūra lojalumo formavimo aspektu ir naudojantis lojalumo ekspertų F. Reicheldo bei J. J. Ellingo ir S. Jorgenseno lojalumo matavimo metodais atlikta UAB „PTA Group“ vartotojų lojalumo analizė. Šio bakalauro sudedamosios dalys: 1. vartotojų lojalumo sampratų, formavimo, naudos ir matavimo analizės teoriniu aspektu; 2. UAB „PTA Group“ vartotojų lojalumo Šiaulių mieste tyrimo analizė. Tyrime dalyvavo 100 Šiaulių miesto moterų, kurios žino ir bent kartą buvo apsilankiusios, pirko PTA rūbų parduotuvėje. Atlikus ne tik esamų ir pastovių, bet ir potencialiai lojalių PTA klienčių apklausą, nustatyta, ne tik kokie veiksniai labiausiai įtakoja prisirišimą ir teigiamą požiūrį PTA atžvilgiu bet atskleistos ir nelojalumo, nepirkimo PTA priežastys bei kas paskatintų neutralių ir potencialiai lojalių vartotojų grupes pirkti PTA. Atsižveldama į atitinkamą lojalumo lygį pasiekusius vartotojus, PTA įmonė gali kurti marketingo strategijas, teikti skirtingus pasiūlymus ir skatinimo priemones. Šio tyrimo duomenys gali būti naudingi tobulinant savo įmonės marketingo strategiją, plečiant aptarnaujamą segmentą, atsižvelgiant į klientų nuomones, poreikius ir į daugumą, kuri neša įmonei... [toliau žr. visą tekstą]<br>SUMMARY In this final work of Bachelor studies are submitted the concept and essence in customer loyalty structured by foreign and Lithuanian authors, analyzing the factors, witch form customer loyalty, benefits of the company of loyal customers, examined the types of loyalty and loyalty measurement methods. According to literature reviewed in the formation of loyalty and respect through loyalty expert F. Reicheldo, J. J. Elling, S. Jorgensen loyalty measurement approaches was taken UAB “PTA Group's” customer loyalty analyze. Component parts of final work of Bachelor studies are: 1. customer loyalty concepts, formation, value and measurement analysis of the theoretical aspect; 2. customer loyalty study analysis on UAB “PTA Group” in the city of Siauliai. The study included 100 women in the city of Siauliai, which know and have been visited at least once or bought in PTA clothing shop. After not only current and stable, but potentially loyal customers survey done, was found not only what factors most affect the attachment and a positive attitude to PTA but also was founded the reasons of disloyalty and what neutral and potentially loyal consumers groups lead to buy PTA. Considering to permitted level of loyal consumers, PTA can create marketing strategies to differentiate their offerings and incentives. These studies may be useful in improving PTA company's marketing strategy, expanding the catchment segment according to customer opinions and needs and of the majority of the... [to full text]