京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19931号 / 医博第4151号 / 新制||医||1017(附属図書館) / 33017 / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 髙橋 良輔, 教授 大森 孝一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Le travail de thèse a consisté, en priorité, à s’approprier les technologies d’intégration verticale en usage dans l’industrie pour réaliser des mémoires à plusieurs étages, et à en évaluer l’apport pour les capteurs à pixel CMOS (CPS). Cette approche s’appuie sur la capacité de l’industrie à interconnecter des puces amincies empilées les unes sur les autres. Elle ouvre la perspective d’associer plusieurs microcircuits superposés à un même pixel, en dépits de sa taille réduite. L’interconnexion est donc réalisée au niveau du pixel. Ce saut technologique permet de lever la majorité des obstacles à l’obtention de performances optimales des CPS. On peut en particulier combiner des puces réalisées dans des technologies CMOS très différentes, chacune optimale pour une fonctionnalité précise. La collection des charges du signal peut ainsi être réalisée dans une couche dédiée, les microcircuits de conditionnement analogique des signaux peuvent être concentrés dans une autre couche, une troisième couche pouvant héberger les parties numériques assurant la compression puis la transmission des signaux, etc. Ce progrès se traduit notamment par la possibilité de combiner haute résolution spatiale et lecture rapide, avec une amélioration probable de la tolérance aux rayonnements intenses.On s’affranchit de cette manière des limitations provenant des paramètres de fabrication des fondeurs, qui ne permettent pas à l’heure actuelle, de pleinement exploiter le potentiel des CPS à l’aide d’une technologie CMOS unique. / The thesis has been a priority as taking ownership of vertical integration technologies used in the industry to realize a multistage development, and to evaluate the contributions on CMOS pixel sensors (CPS). 3D integration technologies (3DIT) provide a way to mitigate this hampering correlation between speed and resolution, since they allow to staple layers of readout circuitry on top of the sensing layer, which results in a drastic increase of the functionalities located in (the shadow of) each pixel. A multi-layer structure allows for a higher spatial resolution because more and more transistors may be integrated vertically in a relatively small pixel. Moreover, bringing the components of the sensor closer to each other translates in a faster readout, owing to the reduction in the average length of the inner connecting wires. Vertical integration also opens up the possibility of combining different technologies best suited to each of the sensor main functionalities (signal sensing, analog and digital signal processing and transmission). It overcomes the limitations in this way from the foundry manufacturing parameters, which do not allow to fully exploit the potential ofCPS with a single CMOS technology. 3D-CPS are thus expected to overcome most of the limitations of standard 2DCPS, and are therefore suspected to over new perspectives for the innermost layer of the ILC vertex detector.

Les interactions ADN-protéine sont fondamentales dans de nombreux processus biologiques tels que la régulation des gènes et la réparation de l'ADN. Cette thèse est centrée sur l'analyse des propriétés physiques et dynamiques des interfaces ADN-protéine. À partir de l'étude de quatre complexes ADN-protéine, nous avons montré que l'interface ADN-protéine est dynamique et que les ponts salins et liaisons hydrogène se forment et se rompent dans une échelle de temps de l'ordre de la centaine de picosecondes. L'oscillation des chaînes latérales des résidus est dans certains cas capable de moduler la spécificité d'interaction. Nous avons ensuite développé un modèle de protéine gros grains dans le but de décomposer les interactions ADN-protéine en identifiant les facteurs qui modulent la stabilité et la conformation de l'ADN ainsi que les facteurs responsables de la spécificité de reconnaissance ADN-protéine. Notre modèle est adaptable, allant d'un simple volume mimant une protéine à une représentation plus complexe comportant des charges formelles sur les résidus polaires, ou des chaînes latérales à l'échelle atomique dans le cas de résidus clés ayant des comportements particuliers, tels que les cycles aromatiques qui s'intercalent entre les paires de base de l'acide nucléique / DNA-protein interactions are fundamental in many biological processes such as gene regulation and DNA repair. This thesis is focused on an analysis of the physical and dynamic properties of DNA-protein interfaces. In a study of four DNA-protein complexes, we have shown that DNA-protein interfaces are dynamic and that the salt bridges and hydrogen bonds break and reform over a time scale of hundreds of picoseconds. In certain cases, this oscillation of protein side chains is able to modulate interaction specificity. We have also developed a coarse-grain model of proteins in order to deconvolute the nature of protein-DNA interactions, identifying factors that modulate the stability and conformation of DNA and factors responsible for the protein-DNA recognition specificity. The design of our model can be changed from a simple volume mimicking the protein to a more complicated representation by the addition of formal charges on polar residues, or by adding atomic-scale side chains in the case of key residues with more precise behaviors, such as aromatic rings that intercalate between DNA base pairs

No description available.

Une grande ‘Chambre à Projection Temporelle’ (TPC) est un candidat pour la détection et la mesure des traces chargées auprès de l’ILC, collisionneur linéaire d’électrons et de positons de 31 km permettant d’atteindre des énergies dans le centre de masse de 250 GeV à 1 TeV. Le travail de R&D décrit dans cette thèse porte sur un type nouveau de TPC, dont la lecture est assurée par des Micromégas à anode résistive. Ce dispositif permet de répartir le signal électrique sur plusieurs carreaux, même lorsque la charge est déposée sur un seul carreau. Il permet aussi de protéger l’électronique, ce qui est utilisé dans notre prototype pour miniaturiser les cartes de lecture. Dans ce travail, des modules Micromégas ont été testés et caractérisés, dans un premier temps, en faisceau, un par un au centre de la chambre, puis 7 modules montés en même temps de façon à couvrir la surface. Egalement, des tests sur un banc équipé d’une source de ⁵⁵Fe ont permis de caractériser les 7 modules utilisés. Une résolution en position de 60 microns par ligne de carreaux est obtenue à petite distance de dérive. L’uniformité est aussi évaluée, et des distorsions pouvant atteindre environ 500 microns sont observées. L’ensemble des résultats démontre l’adéquation de ce type de lecture à la TPC pour l’ILC. La fraction de retour des ions est également mesurée à l’aide d’un détecteur de même géométrie et avec le même gaz que ceux utilisés dans ces tests, et la loi en rapport inverse des champs est validée à nouveau dans ces conditions. La même technique est appliquée à la réalisation d’un imageur neutron, consistant en une TPC Micromégas ‘plate’ précédée d’un film convertisseur de 1mm d’épaisseur. Les protons éjectés par les neutrons sont ‘suivis à la trace’ dans le volume gazeux, ce qui permet de reconstruire avec une précision meilleure que le millimètre le point d’origine du neutron. / The study of the fundamental building blocks of matter necessitates always more powerful accelerators. New particles are produced in high energy collisions of protons or electrons. The by-Products of these collisions are detected in large apparatus surrounding the interaction point. The 125 GeV Higgs particle discovered at LHC will be studied in detail in the next e⁺e⁻ collider. The leading project for this is called ILC. The team that I joined is working on the R&D for a Time Projection Chamber (TPC) to detect the charged tracks by the ionization they leave in a gas volume, optimised for use at ILC. This primary ionization is amplified by the so-Called Micromegas device, with a charge-Sharing anode made of a resistive-Capacitive coating. After a presentation of the physics motivation for the ILC and ILD detector, I will review the principle of operation of a TPC (Chapter 2) and underline the advantages of the Micromegas readout with charge sharing. The main part of this PhD work concerns the detailed study of up to 12 prototypes of various kinds. The modules and their readout electronics are described in Chapter 3. A test-Bench setup has been assembled at CERN (Chapter 4) to study the response to a ⁵⁵Fe source, allowing an energy calibration and a uniformity study. In Chapter 5, the ion backflow is studied using a bulk Micromegas and the gas gain is measured using a calibrated electronics chain. With the same setup, the electron transparency is measured as a function of the field ratio (drift/amplification). Also, several beam tests have been carried out at DESY with a 5 GeV electron beam in a 1 T superconducting magnet. These beam tests allowed the detailed study of the spatial resolution. In the final test, the endplate was equipped with seven modules, bringing sensitivity to misalignment and distortions. Such a study required software developments (Chapter 6) to make optimal use of the charge sharing and to reconstruct multiple tracks through several modules with a Kalman filter algorithm. The results of these studies are given in Chapter 7. The TPC technique has been applied to neutron imaging in collaboration with the University of Lanzhou. A test using a neutron source has been carried out in China. The results are reported in Chapter 8.

<p>In modern medicine, the measurement of electrophysiological signals play a key role in health monitoring and diagnostics. Electrical activity originating from our nerve and muscle cells conveys real-time information about our current health state. The two most common and actively used techniques for measuring such signals are electrocardiography (ECG) and electroencephalography (EEG).</p><p>These signals are very weak, reaching from a few millivolts down to tens of microvolts in amplitude, and have the majority of the power located at very low frequencies, from below 1 Hz up to 40 Hz. These characteristics sets very tough requirements on the electrical circuit designs used to measure them. Usually, measurement is performed by attaching electrodes with direct contact to the skin using an adhesive, conductive gel to fixate them. This method requires a clinical environment and is time consuming, tedious and may cause the patient discomfort.</p><p>This thesis investigates another method for such measurements; by using a non-contact, capacitively coupled sensor, many of these shortcomings can be overcome. While this method relieves some problems, it also introduces several design difficulties such as: circuit noise, extremely high input impedance and interference. A capacitively coupled sensor was created using the bottom layer of a printed circuit board (PCB) as a capacitor plate and placing it against the signal source, that acts as the opposite capacitor plate. The PCB solder mask layer and any air in between the two acts as the insulator to create a full capacitor. The signal picked up by this sensor was then amplified by 60 dB with a high input impedance amplifier circuit and further conditioned through filtering.</p><p>Two measurements were made of the same circuit, but with different input impedances; one with 10 MΩ and one with 10 GΩ input impedance. Additional filtering was designed to combat interference from the main power lines at 50 Hz and 150 Hz that was discovered during initial measurements. The circuits were characterized with their transfer functions, and the ability to amplify a very low-level, low frequency input signal. The results of these measurements show that high input impedance is of critical importance for the functionality of the sensor and that an input impedance of 10 GΩ is sufficient to produce a signal-to-noise ratio (SNR) of 9.7 dB after digital filtering with an input signal of 25 μV at 10 Hz.</p>

Hybrid pixel detectors have been demonstrated to provide excellent quality detection of ionising photon radiation, particularly in X-ray imaging. Recently, there has been interest in developing a hybrid pixel detector specifically for photon dosimetry. This thesis is on the design, implementation, and preliminary characterisation of the Dosepix readout chip. Dosepix has 256 square pixels of 220 mm side-length, constituting 12.4 mm2 of photo-sensitive area per detector. The combination of multiple pixels provides many parallel processors with limited input flux, resulting in a radiation dose monitor which can continuously record data and provide a real-time report on personal dose equivalent. Energy measurements are obtained by measuring the time over threshold of each photon and a state machine in the pixel sorts the detected photon event into appropriate energy bins. Each pixel contains 16 digital thresholds with 16 registers to store the associated energy bins. Preliminary measurements of Dosepix chips bump bonded to silicon sensors show very promising results. The pixel has a frontend noise of 120 e-. In low power mode, each chip consumes 15 mW, permitting its use in a portable, battery-powered system. Direct time over threshold output from the hybrid pixel detector assembly reveal distinctive photo-peaks correctly identifying the nature of incident photons, and verification measurements indicate that the pixel binning state machines accurately categorise charge spectra. Personal dose equivalent reconstruction using this data has a flat response for a large range of photon energies and personal dose equivalent rates.

In modern medicine, the measurement of electrophysiological signals play a key role in health monitoring and diagnostics. Electrical activity originating from our nerve and muscle cells conveys real-time information about our current health state. The two most common and actively used techniques for measuring such signals are electrocardiography (ECG) and electroencephalography (EEG). These signals are very weak, reaching from a few millivolts down to tens of microvolts in amplitude, and have the majority of the power located at very low frequencies, from below 1 Hz up to 40 Hz. These characteristics sets very tough requirements on the electrical circuit designs used to measure them. Usually, measurement is performed by attaching electrodes with direct contact to the skin using an adhesive, conductive gel to fixate them. This method requires a clinical environment and is time consuming, tedious and may cause the patient discomfort. This thesis investigates another method for such measurements; by using a non-contact, capacitively coupled sensor, many of these shortcomings can be overcome. While this method relieves some problems, it also introduces several design difficulties such as: circuit noise, extremely high input impedance and interference. A capacitively coupled sensor was created using the bottom layer of a printed circuit board (PCB) as a capacitor plate and placing it against the signal source, that acts as the opposite capacitor plate. The PCB solder mask layer and any air in between the two acts as the insulator to create a full capacitor. The signal picked up by this sensor was then amplified by 60 dB with a high input impedance amplifier circuit and further conditioned through filtering. Two measurements were made of the same circuit, but with different input impedances; one with 10 MΩ and one with 10 GΩ input impedance. Additional filtering was designed to combat interference from the main power lines at 50 Hz and 150 Hz that was discovered during initial measurements. The circuits were characterized with their transfer functions, and the ability to amplify a very low-level, low frequency input signal. The results of these measurements show that high input impedance is of critical importance for the functionality of the sensor and that an input impedance of 10 GΩ is sufficient to produce a signal-to-noise ratio (SNR) of 9.7 dB after digital filtering with an input signal of 25 μV at 10 Hz.

This thesis presents the development of high resolution, wide dynamic range sigma-delta type readout circuits for capacitive MEMS accelerometers. Designed readout circuit employs fully differential closed loop structure with digital output, achieving high oversampling ratio and high resolution. The simulations of the readout circuit together with the accelerometer sensor are performed using the models constructed in Cadence and Matlab Simulink environments. The simulations verified the stability and proper operation of the accelerometer system. The sigma-delta readout circuit is implemented using XFab 0.6 &micro / m CMOS process. Readout circuit is combined with Silicon-On-Glass (SOG) and Dissolved Wafer Process (DWP) accelerometers. Both open loop and closed loop tests of the accelerometer system are performed. Open loop test results showed high sensitivity up to 8.1 V/g and low noise level of 4.8 &micro / g/&amp / #61654 / Hz. Closed loop circuit is implemented on a PCB together with the external filtering and decimation electronics, providing 16-bit digital output at 800 Hz sampling rate. High acceleration tests showed &plusmn / 18.5 g of linear acceleration range with high linearity, using DWP accelerometers. The noise tests in closed loop mode are performed using Allan variance technique, by acquiring the digital data. Allan variance tests provided 86 &micro / g/&amp / #61654 / Hz of noise level and 74 &micro / g of bias drift. Temperature sensitivity tests of the readout circuit in closed loop mode is also performed, which resulted in 44 mg/&ordm / C of temperature dependency. Two different types of new adaptive sigma-delta readout circuits are designed in order to improve the resolution of the systems by higher frequency operation. The two circuits both change the acceleration range of operation of the system, according to the level of acceleration. One of the adaptive circuits uses variation of feedback time, while the other circuit uses multi-bit feedback method. The simulation results showed micro-g level noise in closed loop mode without the addition of the mechanical noise of the sensor.