L’analyse des défauts d’épissage est particulièrement complexe. Outre la diversité des transcrits présents à l’état physiologique, les variations nucléotidiques peuvent induire des modifications hétéroclites de l’épissage. Ces variations, appelées variants splicéogéniques, et leur impact au niveau de l’épissage, sont à même de modifier plus ou moins sévèrement le phénotype de l’individu.Au cours de ce travail de thèse, nous nous sommes intéressés à trois grands aspects de l’étude des défauts de l’épissage : (i) la prédiction de ces défauts d’épissage, (ii) l’analyse des données de RNA-seq et (iii) le rôle de l’épissage dans l’interprétation de la pathogénicité d’un variant pour la prédisposition aux cancers du sein et de l’ovaire (syndrome HBOC).Nous avons optimisé les recommandations en vigueur pour identifier les variants splicéogéniques au sein des séquences consensus des sites d’épissage. Ce travail a conduit à la publication d’un nouvel outil SPiCE (Splicing Prediction in Consensus Elements), développé sur 395 variants. SPiCE a le potentiel d’être une aide à la décision pour guider les généticiens vers ces variants splicéogéniques, grâce à une exactitude de 94.4 %. Puis, nous avons comparé les outils de prédiction des points de branchement. Pour cela, une collection sans précédente de 120 variants avec leurs études ARN a été établi dans la région des points de branchements. Nous avons ainsi révélé que ces outils de prédictions sont aptes à prioriser les variants pour des études ARN dans ces régions jusque-là peu étudiées. Pour étendre les prédictions des variants splicéogéniques au-delà d’un motif spécifique, nous avons construit l’outil SPiP (Splicing Prediction Pipeline). SPiP utilise un ensemble d’outils pour prédire un défaut d’épissage quel que soit la position du variant. Ainsi, SPiP peut ainsi s’adresser à la diversité des défauts d’épissage avec une exactitude de 80.21 %, sur une collection de 2 784 variants.Les données issues du RNA-seq sont complexes à analyser, car il existe peu d’outils pour annoter finement les épissages alternatifs. Aussi nous avons publié l’outil SpliceLauncher. Cet outil permet de déterminer une grande diversité de jonctions d’épissage, indépendamment des systèmes RNA-seq utilisés. Cet outil renvoie aussi les résultats sous formes graphiques pour faciliter leur interprétation.Puis nous avons évalué le rôle de l’épissage alternative dans l’interprétation à usage clinique d’un variant. Le gène PALB2, impliqué dans le syndrome HBOC, a été utilisé comme modèle d’étude. Nous avons ainsi démontré que l’épissage alternatif de PALB2 est apte à remettre en cause la pathogénicité de certains variants. La collecte de données fonctionnelles et cliniques sont donc nécessaires pour conclure sur leur pathogénicité.Nos travaux illustrent ainsi l’importance de la caractérisation et de l’interprétation des modifications de l’épissage pour répondre aux défis présents et futurs du diagnostic moléculaire en génétique. / Analysis of splicing defects is particularly complex. In addition to the diversity of physiological transcripts, nucleotidic variations can induce heterogeneous alteration of splicing. These variations, called spliceogenic variants, and their impact on splicing, can involve severe consequences on the individual phenotype.In this thesis work, we focused on three main aspects of the study of splicing defects: (i) the prediction of these splicing defects, (ii) the analysis of RNA-seq data and (iii) the role of splicing in interpreting the pathogenicity of a variant for the hereditary breast and ovarian cancers (HBOC syndrome).We optimized the current recommendations to identify spliceogenic variants within the consensus sequences of splicing sites. This work led to the publication of a new tool, SPiCE (Splicing Prediction in Consensus Elements), developed on 395 variants. SPiCE has the potential to be a decision support tool to guide geneticists towards these spliceogenic variants, with an accuracy of 94.4%. Then, we compared the tools dedicated to branch points prediction. For this purpose, an unprecedented collection of 120 variants with their RNA studies has been established in the branch point region. Thus, we revealed these prediction tools are able to prioritize variants for RNA studies in these hitherto poorly studied regions. To extend the predictions of spliceogenic variants beyond a specific motif, we built SPiP (Splicing Prediction Pipeline) tool. SPiP uses a set of tools to predict a splicing defect regardless of the variant position. Thus, SPiP can address the diversity of splicing defects with an accuracy of 80.21%, on a collection of 2,784 variants.The data from the RNA-seq are complex to analyze, as there are few tools to finely annotate alternative splices. Also we published SpliceLauncher tool. This tool allows to determine a wide variety of splicing junctions, independently of RNA-seq systems used. This tool also returns the results in graphical form to make interpretation user-friendly.Then we evaluated the role of alternative splicing in the clinical interpretation of a variant. The PALB2 gene, involved in HBOC syndrome, was used as a study model. Thus, we demonstrated that the alternative splicing of PALB2 is able of challenging the pathogenicity of certain variants. Collection of functional and clinical data is therefore necessary to conclude on their pathogenicity.Our work thus illustrates the importance of characterizing and interpreting splicing modifications to meet the current and future challenges of molecular diagnosis in human genetics.

The diploma thesis deals with creating of electronic schematics in editor using web interface. The editor generates electrical circuit text file according to Spice netlist specification. The program has been created in Java and takes an advantage of object oriented programming language. The editor is a part of a web page and is executable as an applet. The diploma thesis describes a programming language selection, program layout and implementation. Thesis contains programming code examples, window illustration and component drawings. Depth-first search algorithm has been used for nodes number assignment. An OrCAD PSpice reference guide was used for netlist.

This project deals with the computer analysis of circuits with external switching. At the first of all there is a description of the creation of the entry of the program CIRNAM – description of the circuit, modified netlist. The work also discusses the theory used for solutions of analysed circuits. In the other part there is a description of the program CIRNAM in full details. In the next parts of this project there is the illustration of work in the program, which is shown on the examples with short discussion of output options – he rendering of the frequency characteristics in the program CIRNAM or the export of calculated data to MATLAB. There are also described the source code of CIRNAM for the initial orientation of the programmer, which would extend the possibilities of this program.

The automotive industry is experiencing a rapid increase in software complexity due to various functionalities introduced into modern vehicles. Companies use software development standards like AUTOSAR to develop the application layer software independent from the hardware. Development methodologies such as Model-Based Design are used to increase the efficiency of the development process and decrease the time to market. However, to ensure high-quality software standards such as A-SPICE are imposed on the companies. Conforming to A-SPICE requires having certain traceability between work artifacts. Thus, manual and inefficient development, testing, and requirement management processes lead to higher time to market. This thesis will introduce the concept of virtual validation using VEOS virtual platform from dSPACE. The new toolchain will focus on automatizing the testing process, requirement management, and report generation. To highlight the benefits of the virtual validation concept this new approach will be compared to the existing one, which includes a lot of manual development steps. Besides the application of the virtual validation with AUTOSAR and non-AUTOSAR software architectures will be discussed.

No description available.

A compact model for four-terminal (independent top and bottom gates) junction field-effect transistor (JFET) is presented in this dissertation. The model describes the steady-state characteristics with a unified equation for all bias conditions that provides a high degree of accuracy and continuity of conductance, which are important for predictive analog circuit simulations. It also includes capacitance and leakage equations. A special capacitance drop-off phenomenon at the pinch-off region is studies and modeled. The operations of the junction fieldeffect transistor (JFET) with an oxide top-gate and full oxide isolation are analyzed, and a semi-physical compact model is developed. The effects of the different modes associated with the oxide top-gate on the JFET steady-state characteristics of the transistor are discussed, and a single expression applicable for the description of the JFET dc characteristics for all operation modes is derived. The model has been implemented in Verilog-A and simulated in Cadence framework for comparison to experimental data measured at Texas Instruments.

This thesis involves the creation of a system of embedded touchscreen devices called touchSPICE to aid in the learning of basic circuits. Traditionally, circuit theory is taught to students in two different methods, lectures and laboratory exercises. Lectures focus on auditory and visual learning and are largely passive learning. Lab experiments allow students to physically interact with the circuits, and learn visually through viewing output waveforms from simulators or on measurement devices. The goal of the touchSPICE project is to develop a physical system for virtual, real-time SPICE simulation that mimics the laboratory experience. In touchSPICE, touchscreen devices act as circuit nodes that communicate with immediate neighbors using physical wires. Additionally, the nodes communicate wirelessly with a host computer, running a customized version of SPICE. Data is aggregated on the host computer and plotted in real-time. Changes in configuration of the nodes (component types and values), are then reflected on the host computer’s display. The efficacy of touchSPICE as a learning tool was evaluated by using anonymous surveys from 20 subjects including a pretest, followed by an interactive session with touchSPICE, and a follow-up posttest. Results collected showed that with a few changes to improve the responsiveness of the touchscreen, touchSPICE may be an effective method for teaching circuit theory. Additionally, users enjoyed the quick configuration time that touchSPICE provided, and felt that the real-time feedback of touchSPICE helped support understanding of how circuits operate.

No description available.

Magnetic sensors are widely used in the field of mineral, navigational, automotive, medical, industrial, military, and consumer electronics. Many magnetic sensors have been developed that are generated by specific laws or phenomena: such as search-coil, fluxgate, Hall Effect, anisotropic magnetoresistance (AMR), giant magnetoresistance (GMR), magnetoelectric (ME), magnetodiode, magnetotransictor, fiber-optic, optical pump, superconducting quantum interference device (SQUID), etc. Each of these magnetic field sensors has their merits and application areas. For low power consumption (<10uW), quasi-static frequency (<10Hz) and high sensitivity (<nT) application, magnetoelectric laminate sensors offer the best potential capability and thus are the topic of my dissertation. Here, in this thesis, I have focused on designs and optimizations of magnetoelectric sensor units (i.e., sensors and circuit). To achieve my goals, I have developed some useful rules for ME sensor and detection circuit design. For ME sensor optimization, designs should consider both frequencies far away from resonance and at resonance. For the former one, both internal and external noise contribution must be considered, as one of them will limit practical applications. With regards to the internal noise sources, I have developed two design optimization methods, designated as ”'scale effect” and “ME array”. I showed that they have the ability to increase the magnetic field detection sensitivity, which was verified by experiments. With regard to external noise consideration, I have investigated how the fundamental extrinsic noise sources (temperature fluctuation, vibration, etc) affect ME laminate sensors. A concept of separating signal and noise modes into difference is put forward. Optimization with this concept in mind required us to redesign the internal structure of ME laminate sensors. At the resonant frequency, the ME voltage coefficient α_ME is the most important parameter. To enhance resonant gain in α_ME, I have developed a three phase laminate concept, which is based on increasing the effective mechanical factor Q while reducing the resonant frequency. A ME voltage coefficient of α_ME ~40V/cm.Oe has been achieved at resonance, which is about 2x higher than that of a conventional bending mode. Investigations of detection circuit optimization were also performed. Component selection strategies and a new charge topology were considered. Proper component values were required to optimize the charge detection scheme. It was also found, under some specific conditions to satisfy the circuit stability, that if the lowest required measurement frequency of the charge source was f1, then that it was not necessary to make the high corner frequency <i>f</i>_p of the charge amplifier lower than <i>f</i>₁: as doing so would decrease the system's signal-to-noise ratio (SNR). A high pass, high order filter placed behind the charge amplifier was found to increase the charge sensitivity, as it narrows the intrinsic noise bandwidth and decreases the output noise contribution, while only slightly affecting the signal's output amplitude. Prototype ME unit were also constructed, and their noise level simulated by Pspice. Experimental results showed that prototypes ME unit can reach their detection limit. In addition, a new magneto-electric coupling mechanism was also found, which had a giant ME effect. / Ph. D.

The research presented here is an effort to characterize changes in marine oxygen availability across a portion of the later Cambrian noted for unique evolutionary dynamics and which includes a significant global oceanographic event known as the SPICE event (Steptoean Positive Carbon Isotope Excursion). Previous studies have revealed the SPICE caused large changes to the global cycles of carbon, sulfur, uranium, molybdenum and the overall trace metal content of seawater. Furthermore, the initiation of these changes appears to have been temporally coupled with marine extinctions across several paleocontinents raising the possibility of a common causal linkage between all these features. In particular, expanding marine anoxia has been invoked as the most parsimonious explanation for these co-occurring features. The research presented here tests this hypothesis directly across a range of spatial scales using the iron speciation paleoredox proxy to characterize redox conditions within individual basins and to facilitate comparison of conditions between basins. In addition to these analyses, we apply a new proxy, thallium stable isotopes to this interval to assess potential global changes in deoxygenation across the event. These iron speciation analyses showed shallow environments deoxygenated coincident with the initiation of the SPICE and extinction horizons, and these conditions were dominantly ferruginous. Importantly, this work also shows deeper-water environments were deoxygenated prior to and remained so across the event and these environments were also largely. Last we looked at changes in thallium isotopes during this same interval to see if this deoxygenation would be recorded as a positive shift across the interval if expanded anoxia were to impact the areal extent of manganese-oxide sedimentation and burial. We found it did record these changes, but with a different expression than during other more recent events explored using the isotope system. We attribute these differences to the unique chemical structure of the oceans during the Cambrian, which as documented herein were widely oxygen-deficient in their deeper depths. Given this recognition we suggest that thallium isotope studies in deep time should account for this redox structure of ancient oceans likely common under the less-oxygenated atmospheres of the ancient Earth. / Doctor of Philosophy / The research presented here is a story about oxygen in the oceans during an ancient portion of Earth history within the Cambrian Period (around 500 million years ago), soon after animal life first appears in the geologic record. The emerging biosphere of this time seems to have been particularly prone to extinctions, leading to the idea that environmental conditions, such as oxygen availability at the seafloor created difficult circumstances for animals in these ancient seas. This work seeks to quantify the levels of marine oxygenation at this time, however this remains a fundamental challenge because they cannot be directly measured from the rocks we study. Therefore, we rely on how the presence or absence of oxygen changed the chemistry of these rocks at the time they were sediments deposited on the seafloor. Here we use the behavior of two different elements, iron (Fe) and thallium (Tl), to understand changes in oxygen in the oceans around a large, globally-recorded extinction event called the SPICE event. Studying how much iron is concentrated in certain minerals in the rocks formed during this event allowed us to track how changes in oxygen may relate to these notable extinctions. We found that shallow coastal areas changed from oxygenated to deoxygenated at the same time of the extinctions, suggesting a direct role for this environmental shift in the biological crisis. Furthermore, we compared other locations from around the world using more new iron measurements in conjunction with previously published ones compiled by a collaborative geochemistry database project. This work revealed the deeper oceans were deoxygenated prior to and across the SPICE event and that the decline in oxygen in shallower environments was where most environmental change occurred during this time. Last we looked at changes in thallium isotopes during this same interval to see if this deoxygenation changed its global cycle. We found it did record global changes, but they were expressed differently than during other more recent events that have been studied. We attribute these differences to the unique chemical structure of the oceans during the Cambrian, which were widely oxygen-deficient in their deeper depths.