Thesis (PhD (Electrical and Electronic Engineering)--University of Stellenbosch, 2007. / ENGLISH ABSTRACT: A monostatic baseband radar is required with the capability of detecting close range targets that appear at distances comparable to the system’s resolution, without compromising the radar’s maximum range. The application in borehole radar imposes further constraints associated with the physical limitations and variable electromagnetic environment of different borehole diameters and conditions. This dissertation discusses the complete design process of the analog section of a monostatic radar that successfully addresses these issues. The proposed transceiver employs a series duplexing arrangement consisting of an antenna, transmitter, receiver and an isolation switch. An exponentially decaying tail is observed in the current flowing on a borehole radar antenna when excited by pulse waveforms. The characteristics of this tail depend strongly on the borehole environment. A measurement technique is developed that accurately quantifies this exponential decay by digitizing a logarithmic representation of the antenna current while it is operating in various boreholes. Transmitters are then designed to drive these antennas with waveforms that prevent the formation of current tails. This is achieved through the use of pole-zero networks or alternatively by generating certain asymmetric, bipolar waveforms. The transmitters are simultaneously designed to have an output impedance approximating a short circuit after the transient is generated. In the series configuration proposed here, the duplexing of the antenna between transmitter and receiver is then reduced to simply isolating the receiver during transmit-mode. The switch responsible for this isolation disconnects the receiver and presents a short circuit between antenna and transmitter during transmit-mode, while connecting the receiver terminals between the antenna and the short circuited transmitter terminals in receive-mode. The required close-in performance of the transceiver dictates that the transition between these two states of the isolation switch occur in a time similar to the duration of the transmitter waveform. The switching artefacts generated by the switch are consequently similar to the radar data signal. The isolation switch employs an innovative configuration (using both transistors and diodes) which accepts a single control signal and causes the switching artefacts to be generated as a common mode signal, while a differential path is created for the radar data signal which is being switched. This leads to effective suppression of the switching signal in the signal passed to the receiver. Dissipative filtering is advocated as a fundamental design principle for high fidelity receivers and it is shown how it can be applied by using constant impedance equalizers and diplexers as basic building blocks. This principle is used as the basis for the design of this transceiver's receivers, which incorporate both standard gain blocks and operational amplifiers. A complete borehole radar system, based on the transceiver developed here, was built and tested; resulting in the first known practical monostatic borehole radar system. Data obtained in field trials are presented and suggest that the monostatic system compares well with current state of the art bi-static systems. / AFRIKAANSE OPSOMMING: Die behoefte is geïdentifiseer vir 'n monostatiese basisbandradar wat oor die vermoë beskik om nabygeleë teikens op 'n afstand soortgelyk aan die resolusie van die stelsel waar te neem, sonder om die maksimum bereik van die stelsel in te kort. Die toepassing daarvan in 'n boorgatradarstelsel lei tot verdere vereistes vanweë die fisiese beperkings en veranderende elektromagnetiese omgewing van boorgate met verskillende deursnitte en toestande. Hierdie proefskrif is gemoeid met die volledige ontwerpsprosedure van die analoog gedeelte van 'n monostatiese radar wat al hierdie kwessies aanspreek. 'n Serie verbinding van antenne, sender, ontvanger en isolasieskakelaar word ingespan vir hierdie ontwerp. Eksponensieel wegsterwende stertjies word waargeneem in die antennestroom van 'n boorgatradarantenne wanneer dit aangedryf word deur puls golfvorms. 'n Meettegniek word ontwikkel wat hierdie eksponensiële verslapping noukeurig kan monitor deur 'n logaritmiese voorstelling van die antennastroom te versyfer terwyl dit ontplooi word in verskillende boorgate. Senders word dan ontwikkel om hierdie antennes aan te dryf met golfvorms wat juis die vorming van hierdie stertjies voorkom. Dit word bewerkstellig deur die gebruik van pool-zero netwerke of andersins deur die opwek van sekere asimmetriese, bipolêre golfvorms. Die senders se uittree-impedansies moet egter terselfdertyd ontwerp word om 'n kortsluiting te benader sodra die oorgang klaar opgewek is. Met die serie verbinding wat hier gebruik word, raak die vereiste tyddeling van die antenna tussen die sender en ontvanger dan bloot 'n geval van ontvanger-isolasie gedurende uitsaai-modus. Die skakelaar wat verantwoordelik is vir hierdie isolasie ontkoppel die ontvanger en vertoon soos 'n kortsluiting tussen sender en antenne tydens uitsaai-modus, maar verbind weer die terminale van die ontvanger tussen die antenne en kortgeslote senderterminale tydens ontvang-modus. Die vereiste kortafstand vermoë van die stelsel veroorsaak dat die tysduur van die oorgang tussen hierdie twee modusse soortgelyk is aan dié van die sender golfvorm en enige skakelverskynsels wat opgewek word deur die skakelaar is gevolglik soortgelyk aan die radardatasein self. Die isolasieskakelaar gebruik egter 'n innoverende konfigurasie (met transistors sowel as diodes) wat funksioneer met 'n enkele beheersein en die skakelverskynsels as gemene modus seine opwek, terwyl 'n differensiële seinpad geskep word vir die radardatasein wat geskakel word. Die skakelseine word gevolglik effektief onderdruk in die sein wat oorgedra word aan die ontvanger. Die gebruik van verkwistende filters word voorgestel as 'n fundamentele ontwerpsbeginsel vir hoëtrou ontvangers en daar word getoon hoe dit toegepas kan word met konstante impedansie vereffeningsbane en dipleksers. Hierdie beginsel is dan ook gebruik as basis vir die ontwerp van hierdie stelsel se ontvangers, wat gebruik maak van beide standard aanwinsblokke sowel as operasionel versterkers. 'n Volledige boorgatradarstelsel, gebaseer op die stelsel wat hier ontwikkel is, is gebou en getoets. Die gevolg is die eerste bekende, praktiese monostatiese boorgatradarstelsel. Data wat hiermee verwerf is word aangebied en dui daarop dat die monostatiese stelsel baie goed opweeg teen huidige bi-statiese stelsels.

This is a foundational study that applies Receiver Operating Characteristic (ROC) analysis to the evaluation of a chronic disease model that utilizes Remote Monitoring (RM) devices to identify clinical deterioration in a Chronic Obstructive Pulmonary Disease (COPD) population. Background: RM programmes in Disease Management (DM) are proliferating as one strategy to address management of chronic disease. The need to validate and quantify evidence-based value is acute. There is a need to apply new methods to better evaluate automated RM systems. ROC analysis is an engineering approach that has been widely applied to medical programmes but has not been applied to RM systems. Evaluation of classifiers, determination of thresholds and predictive accuracy for RM systems have not been evaluated using ROC analysis. Objectives: (1) apply ROC analysis to evaluation of a RM system; (2) analyse the performance of the model when applied to patient outcomes for a COPD population; (3) identify predictive classifier(s); (4) identify optimal threshold(s) and the predictive capacity of the classifiers. Methods: Parametric and non-parametric methods are utilized to determine accuracy, sensitivity, specificity and predictive capacity of classifiers Saturated Peripheral Oxygen (SpO2), Blood Pressure (BP), Pulse Rate (PR) based on event-based patient outcomes that include hospitalisation (IP), accident & emergency (A&E) and home visits (HH). Population: Patients identified with a primary diagnosis of COPD, monitored for a minimum of 183 days with at least one episode of in-patient (IP) hospitalisation for COPD in the 12 months preceding the monitoring period. Data Source: A subset of retrospective de-identified patient data from an NHS Direct evaluation of a COPD RM programme. Subsets utilized include classifiers, biometric readings, alerts generated by the system and resource utilisation. Contribution: Validates ROC methodology, identifies classifier performance and optimal threshold settings for the classifier, while making design recommendations and putting forth the next steps for research. The question answered by this research is that ROC analysis can provide additional information on the predictive capacity of RM systems. Justification of benefit: The results can be applied when evaluating health services and planning decisions on the costs and benefits. Methods can be applied to system design, protocol development, work flows and commissioning decisions based on value and benefit. Conclusion: Results validate the use of ROC analysis as a robust methodology for DM programmes that use RM devices to evaluate classifiers, thresholds and identification of the predictive capacity as well as identify areas where additional design may improve the predictive capacity of the model.

Traditional methods of imaging the Earth’s subsurface using seismic waves require an identifiable, impulsive source of seismic energy, for example an earthquake or explosive source. Naturally occurring, ambient seismic waves form an ever-present source of energy that is conventionally regarded as unusable since it is not impulsive. As such it is generally removed from seismic data and subsequent analysis. A new method known as seismic interferometry can be used to extract useful information about the Earth’s subsurface from the ambient noise wavefield. Consequently, seismic interferometry is an important new tool for exploring areas which are otherwise seismically quiet, such as the British Isles in which there are relatively few strong earthquakes. One of the possible applications of seismic interferometry is the ambient noise tomography method (ANT). ANT is a way of using interferometry to image subsurface seismic velocity variations using seismic (surface) waves extracted from the background ambient vibrations of the Earth. To date, ANT has been used to successfully image the Earth’s crust and upper-mantle on regional and continental scales in many locations and has the power to resolve major geological features such as sedimentary basins and igneous and metamorphic cores. In this thesis I provide a review of seismic interferometry and ANT and apply these methods to image the subsurface of north-west Scotland and the British Isles. I show that the seismic interferometry method works well within the British Isles and illustrate the usefulness of the method in seismically quiet areas by presenting the first surface wave group velocity maps of the Scottish Highlands and across the British Isles using only ambient seismic noise. In the Scottish Highlands, these maps show low velocity anomalies in sedimentary basins such as the Moray Firth and high velocity anomalies in igneous and metamorphic centres such as the Lewisian complex. They also suggest that the Moho shallows from south to north across Scotland, which agrees with previous geophysical studies in the region. Rayleigh wave velocity maps from ambient seismic noise across the British Isles for the upper and mid-crust show low velocities in sedimentary basins such as the Midland Valley, the Irish Sea and the Wessex Basin. High velocity anomalies occur predominantly in areas of igneous and metamorphic rock such as the Scottish Highlands, the Southern Uplands, North-West Wales and Cornwall. In the lower crust/upper mantle, the Rayleigh wave maps show higher velocities in the west and lower velocities in the east, suggesting that the Moho shallows generally from east to west across Britain. The extent of the region of higher velocity correlates well with the locations of British earthquakes, agreeing with previous studies that suggest British seismicity might be influenced by a mantle upwelling beneath the west of the British Isles. Until the work described in Chapter 6 of this thesis was undertaken in 2009, seismic interferometry was concerned with cross-correlating recordings at two receivers due to a surrounding boundary of sources, then stacking the cross-correlations to construct the inter-receiver Green’s function. A key element of seismic wave propagation is that of source-receiver reciprocity i.e. the same wavefield will be recorded if its source and receiver locations and component orientations are reversed. By taking the reciprocal of its usual form, in this thesis I show that the impulsive-source form of interferometry can also be used in the opposite sense: to turn any energy source into a virtual sensor. This new method is demonstrated by turning earthquakes in Alaska and south-west USA into virtual seismometers located beneath the Earth’s surface.

International Telemetering Conference Proceedings / October 17-20, 1994 / Town & Country Hotel and Conference Center, San Diego, California / The Aircraft Distance Measurement System (ADMS) could be used in Flight Test application to determine the aircraft position and speed during takeoff, landing and acceleration-stop performance test within runway limits using a microwave link.

Approved for public release, distribution is unlimited / This thesis is a continuation of the design and development of a three-dimensional 2.4 GHz digital phased array radar antenna. A commercial off-the-shelf quadrature modulator and demodulator were used as phase shifters in the digital transmit and receive arrays. The phase response characteristic of the demodulator was measured and the results show that the phase difference between the received phase and transmit phase is small. In order to increase the bandwidth of the phased array, a method of time-varying phase weights for linear frequency modulated signal was investigated. Using time-varying phase weights on transmit and receive give the best performance, but require the range information of the target. It is more practical to use time-varying phase weights on only one side (transmit or receive but not both), and constant phase weights on the other side. The simulation results showed that by using time-varying phase weights, the matched filter loss is not as severe as it is when using the conventional fixed weights technique. It was also found that this method is only effective for small scan angles when the time-bandwidth product is large. The approach to implement time-varying phase weights on transmit using commercial components such as direct digital synthesizer and quadrature modulator is discussed. / Civilian, Ministry of Defense, Singapore

A presente dissertação teve como finalidade avaliar a precisão e a discrepância das coordenadas (acurácia) obtidas por meio das observações GPS, no modo estático rápido, medidas com receptores de uma freqüência, empregando-se a técnica de suavização do código C/A pela fase da portadora para diferentes comprimentos de linha base (20, 50, 75, 100, 150, 200 e 300 Km), a partir da estação de monitoramento contínuo da EESC/USP. Essa técnica obteve boa repercussão no Brasil, a partir do momento em que foi permitida sua utilização para fins de georreferenciamento de imóveis rurais, conforme a norma técnica do INCRA, que permite a utilização da suavização do código pela fase da portadora, desde que esta apresente acurácia com valores iguais ou inferiores a 50 cm. Atualmente, trabalhos com tal técnica estão sendo desenvolvidos e aceitos para compor o banco de dados do cadastro rural nacional. Pelos resultados obtidos nesta dissertação, foi possível avaliar que a aplicação dessa técnica não atende à exigência requerida em 100% das medições e, ao mesmo tempo, verificar a diferença entre a precisão do pós-processamento, indicada pelos softwares comerciais e a acurácia dos pontos medidos comparados com os pontos de controle estabelecidos para esse fim. / The present dissertation has as objective to evaluate precision and discrepancies of coordinates (accuracy) obtained through GPS observations, in a rapid static method, measured by single frequency, which applies carrier-smoothed-code for different baseline length (20, 50, 75, 100, 150, 200 and 300 km), since continuous monitoring station from EESC/USP. This technique obtained a good repercussion in Brazil, since when its use was legitimate in rural property georeferencing, according to INCRA\'s norma técnica (technical rule), which allows the use of carrier-smoothed-code in view of the fact that presents accuracy with equal or inferior values to 50 cm. Currently, works using such technique are developed and accepted in order to compound database of national rural survey in Brazil. Based on the obtained results it was possible to evaluate that the technique does not guaranteed to requested requirement in 100% of measurements, and at the same time to verify the difference between post-processing precision, indicated by commercial software, as well as measured point accuracy compared with points established for this purposed.

Este trabalho consiste no estudo da estrutura sedimentar da Bacia do Paraná da região de Bebedouro utilizando função do receptor, ondas de superfície e sísmica de refração. Funções do Receptor (FR) mostram a resposta da estrutura geológica abaixo de uma estação sismográfica. Para diminuir a não unicidade na inversão do traço de uma FR, foram usadas curvas de dispersão de ondas de superfície como vínculos adicionais. Ondas de superfície foram também obtidas com a correlação cruzada de ruído sísmico ambiental. Esse método passivo permite a obtenção de dispersão em períodos intermediários entre os dados de telessismos e os dados de sísmica rasa auxiliando na determinação estruturas sedimentares. Foi utilizada a inversão conjunta de FR de alta e baixa frequência, dispersão de fase e grupo de períodos menores que 2 s e dispersão de ondas Love e Rayleigh continentais (períodos entre 10 e 100 s). Na inversão conjunta, foram usados vários modelos iniciais diferentes para garantir melhor cobertura do espaço de soluções possíveis. Os resultados mostram uma camada de basalto com uma espessura entre 200 e 400 m, sob uma camada superficial de arenito de 50 a 100m. O embasamento da bacia está torno de 2.5 3.0 km. A espessura e razão Vp/Vs crustal da região foi estimada em 40.0 (1.0) km e 1.78 (0.02). Foi possível identificar zonas de baixa velocidade dentro do pacote de basalto, possivelmente relacionadas a zonas de fraturas ou camadas de basalto alterado. Estas camadas de baixa velocidade estão na parte sul, próximas à área de maior sismicidade induzida e também relativamente mais perto dos poços profundos de maior vazão. Isto corrobora com a hipótese de que a sismicidade local está associada à exploração de poços e estrutura de falhas pré -existentes. / A study of the seismic structure of the Paraná Basin in Bebedouro, SP, was carried out with Receiver Functions (RF). Both low frequency (with ~0.5 Hz low pass filter) and high-frequency (~10Hz) RFs were jointly inverted with surface wave dispersion curves. Surface-wave data included: long-period group velocities of Rayleigh and Love waves from continental-scale tomography in the period range 10-100 s (useful to control crustal scale structure and Moho depth), intermediate period group velocities near 1s period obtained from cross-correlation of ambient noise (useful to control sedimentary structure), phase velocities near 0.2-1.0 s obtained from local earthquakes, and phase velocities of Rayleigh waves from shallow seismic refraction data near ~0.1 s period (useful to control shallow layers). Joint inversion was obtained with several different initial models to better cover all possible solutions. The results indicate that the basalt layer is 200 to 400m thick, beneath sandstones of about 50 100m thick. The Basin basement was detected between 2.5 3.0 km depth, consistent with expected values from regional bore-hole data in the Paraná Basin. Beneath several stations a low-velocity zone was detected in the middle of the basalt pack which is interpreted as a zone of fractured or altered basalt. This anomalous low-velocity layer was detected near the most seismically active zone in the Andes district. It is also relatively close to the deep wells with larger outflow. The existence of this low-velocity zone in the middle of the basalt layer is consistent with the model proposed for the water-well induced seismicity.

Este trabalho consiste no estudo da estrutura sedimentar da Bacia do Paraná da região de Bebedouro utilizando função do receptor, ondas de superfície e sísmica de refração. Funções do Receptor (FR) mostram a resposta da estrutura geológica abaixo de uma estação sismográfica. Para diminuir a não unicidade na inversão do traço de uma FR, foram usadas curvas de dispersão de ondas de superfície como vínculos adicionais. Ondas de superfície foram também obtidas com a correlação cruzada de ruído sísmico ambiental. Esse método passivo permite a obtenção de dispersão em períodos intermediários entre os dados de telessismos e os dados de sísmica rasa auxiliando na determinação estruturas sedimentares. Foi utilizada a inversão conjunta de FR de alta e baixa frequência, dispersão de fase e grupo de períodos menores que 2 s e dispersão de ondas Love e Rayleigh continentais (períodos entre 10 e 100 s). Na inversão conjunta, foram usados vários modelos iniciais diferentes para garantir melhor cobertura do espaço de soluções possíveis. Os resultados mostram uma camada de basalto com uma espessura entre 200 e 400 m, sob uma camada superficial de arenito de 50 a 100m. O embasamento da bacia está torno de 2.5 3.0 km. A espessura e razão Vp/Vs crustal da região foi estimada em 40.0 (1.0) km e 1.78 (0.02). Foi possível identificar zonas de baixa velocidade dentro do pacote de basalto, possivelmente relacionadas a zonas de fraturas ou camadas de basalto alterado. Estas camadas de baixa velocidade estão na parte sul, próximas à área de maior sismicidade induzida e também relativamente mais perto dos poços profundos de maior vazão. Isto corrobora com a hipótese de que a sismicidade local está associada à exploração de poços e estrutura de falhas pré -existentes. / A study of the seismic structure of the Paraná Basin in Bebedouro, SP, was carried out with Receiver Functions (RF). Both low frequency (with ~0.5 Hz low pass filter) and high-frequency (~10Hz) RFs were jointly inverted with surface wave dispersion curves. Surface-wave data included: long-period group velocities of Rayleigh and Love waves from continental-scale tomography in the period range 10-100 s (useful to control crustal scale structure and Moho depth), intermediate period group velocities near 1s period obtained from cross-correlation of ambient noise (useful to control sedimentary structure), phase velocities near 0.2-1.0 s obtained from local earthquakes, and phase velocities of Rayleigh waves from shallow seismic refraction data near ~0.1 s period (useful to control shallow layers). Joint inversion was obtained with several different initial models to better cover all possible solutions. The results indicate that the basalt layer is 200 to 400m thick, beneath sandstones of about 50 100m thick. The Basin basement was detected between 2.5 3.0 km depth, consistent with expected values from regional bore-hole data in the Paraná Basin. Beneath several stations a low-velocity zone was detected in the middle of the basalt pack which is interpreted as a zone of fractured or altered basalt. This anomalous low-velocity layer was detected near the most seismically active zone in the Andes district. It is also relatively close to the deep wells with larger outflow. The existence of this low-velocity zone in the middle of the basalt layer is consistent with the model proposed for the water-well induced seismicity.

Magnetic Resonance Imaging (MRI) is a powerful non-invasive reconstruction tool used primarily in the medical community to produce high quality images of the human anatomy. Surface coils are Radio Frequency (RF) systems typically deployed for receiving the MR signals. Multiple surface coils, or an array of coils, are employed to obtain a localized improvement in the signal-to-noise ratio without limiting the field of view. In this research, a novel modeling and design method for decoupling RF surface coils in a phased array is investigated. This method employs an impedance transformation interface circuit along with a high input reflection coefficient preamplifier to decouple the coil. In this research report both the theory and design methodology are discussed in detail.

Les RTKs sont impliqués dans le dialogue au sein des tissus par la régulation de nombreuses réponses cellulaires dont la survie, la prolifération ou la mobilité. Dans les cancers, ces récepteurs sont fréquemment dérégulés notamment par des mutations activatrices. Ainsi, la suractivation des RTKs induit la transformation cellulaire et la tumorigenèse en favorisant par exemple la survie cellulaire. Depuis le début des années 2000, le développement de molécules inhibitrices de l’activité tyrosine kinase (TKI) et d’anticorps bloquant l’interaction ligand/récepteur ont montré que les RTKs représentent des cibles thérapeutiques majeures dans le traitement des cancers.MET est un RTK exprimé par les cellules épithéliales, dont le ligand est l’Hepatocyte Growth Factor/Scatter Factor (HGF/SF). En plus de son rôle pro-survie, MET peut également favoriser l’apoptose en absence de ligand et sous l’effet d’un stress. MET est alors clivé par les caspases et libère dans le cytosol un fragment de 40 kDa nommé p40MET. Ce fragment active la voie intrinsèque de l’apoptose en causant la perméabilisation des mitochondries. Cependant, les mécanismes moléculaires responsables de cette perméabilisation et l’impact physiologique de la fonction pro-apoptotique de MET étaient encore inconnus.Mon travail de thèse a permis de démontrer que le fragment p40MET se localise dans la région des MAMs, constituant l’interface entre le réticulum endoplasmique et les mitochondries, où il favorise un transfert de calcium entre les deux organites. Ce transfert déclenche une surcharge de calcium dans les mitochondries, responsable de leur perméabilisation. De plus, nous avons développé une lignée de souris transgéniques dans lesquelles MET est muté sur l’un des sites caspases. Ces souris sont incapables de produire le fragment p40MET pro-apoptotique. Ce modèle nous a permis de démontrer l'importance du clivage de MET dans l’amplification de l’apoptose in vivo. Ainsi, nos travaux apportent les premières preuves de la fonction de MET en tant que récepteur à dépendance au sein d’un organisme et décrivent un nouveau mécanisme de signalisation pro-apoptotique par la dérégulation des flux calciques.Ces dernières années, la découverte de mutations touchant les RTKs dans les cancers a augmenté de façon exponentielle. Toutefois, pour une grande majorité de mutations, leurs conséquences fonctionnelles sont totalement inconnues. Ainsi, en parallèle de mon principal sujet de thèse nous avons évalué la pertinence biologique et clinique des mutations de RTK identifiées par séquençage haut débit à partir d’échantillons de patients. Le séquençage de tissus sains, de tumeurs colorectales et de métastases hépatiques de 30 patients a permis d'identifier de nombreuses mutations somatiques. Parmi elles, certaines affectent le domaine kinase des récepteurs et sont présentes à la fois dans les tumeurs et les métastases. L’analyse fonctionnelle que j’ai menée sur 7 de ces mutations révèle qu’elles ne provoquent ni la suractivation de la kinase ni la transformation des fibroblastes NIH3T3. Au contraire, deux mutations de RTKs provoquent une inhibition drastique de leur activité kinase. Ces résultats démontrent que ces variants de RTK ne sont pas des cibles appropriées pour l’utilisation de TKI à des fins thérapeutiques et démontre l’intérêt de coupler la recherche de variants à des études fonctionnelles [...] / RTKs are involved in tissue dialogue by regulating many cellular mechanisms such as survival, proliferation or mobility. In cancers, these receptors are frequently deregulated, as a result of various molecular alterations leading to their activation. RTKs overactivation induces cell transformation and tumorigenesis notably by promoting survival. Since the early 2000s, the development of tyrosine kinase inhibitors (TKI) demonstrated that RTKs represent major therapeutic targets in cancer treatment.MET receptor and its ligand the Hepatocyte Growth Factor/Scatter Factor (HGF/SF) are known to promote survival of many epithelial structures during embryogenesis and later during adulthood. Besides pro-survival role of the ligand-activated MET, the receptor is also able to promote apoptosis, which has led to classify it within the dependence receptor family. Indeed, in absence of its ligand and under stress conditions, MET is cleaved by caspases leading to the production of an intracellular fragment of nearly 40 kDa named p40MET able to amplify apoptosis. This fragment activates the intrinsic pathway of apoptosis by causing mitochondrial permeabilization. However, the molecular mechanisms involved in this permeabilization and the physiological impact of the pro-apoptotic function of MET were still unknown.My PhD work has evidenced p40MET localization at the MAM microdomain and characterized a calcium transfer from the endoplasmic reticulum to the mitochondria triggered by p40MET. This calcium transfer triggers a calcium overload in mitochondria leading to their membrane permeabilization and apoptosis. In addition, we engineered a knock-in mouse model expressing mutated MET at the C-terminal caspase site. These mice are unable to produce the pro-apoptotic p40MET fragment. This model allowed us to assess the importance of MET cleavage in physiological apoptosis in vivo. Altogether, our work brings the first evidence for MET function as a dependence receptor in an organism and demonstrates a new signaling mechanism involved in apoptosis amplification by p40MET through calcium flux deregulation. This process may be relevant in the physio-pathology of organs where MET is expressed.In recent years, the discovery of mutations affecting RTKs in cancers has increased exponentially. However, for a large majority of mutations, their functional consequences are totally unknown. Thus, in parallel of my main thesis topic, we evaluated the biological and clinical relevance of RTKs mutations identified by high throughput sequencing from patient samples. Sequencing of healthy tissues, colorectal tumours and liver metastases of 30 patients has identified many somatic mutations. Some of them affect the receptor kinase domain and are present in both tumors and metastases. Functional analysis of 7 of these mutations shows that they do not cause neither kinase overactivation nor transformation of NIH3T3 fibroblasts. On the contrary, two RTK mutations cause drastic inhibition of the corresponding kinase activity. These findings indicate that these RTK variants are not suitable targets for TKI. Therefore, it appears important to set up reliable functional assays to interpret identified variants and classify them as pathogenic or neutral.In conclusion, my work opens up new perspectives on therapeutic strategies targeting RTKs in cancers. First of all, the pro-apoptotic capacities of some RTKs are undoubtedly a brake to tumorigenesis, and their stimulations could reinforce the effectiveness of anti-cancer therapies. On the other hand, we have shown that RTKs mutations in the kinase domain do not necessarily lead to overactivation of the receptor suggesting that they are probably not involved in tumorigenesis and that treatment with TKIs targeting them would be ineffective. This functional information could notably influence the choice of a suitable targeted therapy.