[pt] Esta Tese tem por objetivo o desenvolvimento de um sistema destinado à medição de campo magnético com alta sensibilidade e resolução, baseado nas características de fase da impedância em sensores que apresentam o efeito GMI, e a otimização das características de desempenho por meio do uso de configurações em malha fechada. A metodologia empregada inicia com a avaliação experimental das características de fase da impedância de amostras de diferente estrutura e composição química, em função do campo magnético externo, a fim de selecionar aquelas com alta sensibilidade, baixa histerese e maior homogeneidade. Na sequência, são realizadas avaliações teórico-computacionais dos transdutores magnéticos em malha aberta e fechada (magnetômetro e gradiômetro). Da mesma forma, as principais características dos circuitos e controladores software dos transdutores desenvolvidos são detalhadas ao longo do texto. Por sua vez, as principais figuras de mérito dos protótipos desenvolvidos são detalhadamente analisadas, tais como: sensibilidade, linearidade, resposta em frequência, densidade espectral de ruído e resolução. As caracterizações e ensaios experimentais realizados evidenciaram o grande potencial dos transdutores GMI em malha fechada para a atenuação da interferência 1/f, aprimoramento da linearidade e ampliação da faixa de operação. O magnetômetro GMI em malha fechada apresentou sensibilidade em torno de 75,8 mV/microteslas, fundo de escala maior que mais ou menos 40 microteslas, banda de passagem de 45 Hz e resolução na banda de passagem de 27,74 nT. Por outro lado, o gradiômetro GMI em malha fechada desenvolvido apresentou sensibilidade em torno de 102 mV/microteslas, fundo de escala maior que mais ou menos 40 microteslas, banda de passagem de 30 Hz e resolução na banda de passagem de 28,41 nT. / [en] This Thesis aims to develop a system for magnetic field measurement with high sensitivity and resolution, based on the impedance phase characteristics of sensors that have the GMI effect and the performance characteristics optimization through closed-loop configurations. The methodology starts with the experimental evaluation of the phase characteristics of the impedance in samples of different chemical composition and structure as a function of the external magnetic field in order to select those with high sensitivity, low hysteresis, and higher homogeneity. Subsequently, theoretical-computational assessments of magnetic transducers in open and closed-loop (magnetometer and gradiometer) are carried out. Likewise, the main characteristics of the circuits and software controllers of the developed transducers are detailed throughout the text. In turn, the main figures of merit of the developed prototypes are analyzed in detail, such as sensitivity, linearity, frequency response, noise spectral density, and resolution. The characterizations and experimental tests carried out showed the great potential of GMI transducers in a closed-loop configuration for attenuation of interference 1/f, improving linearity and expanding the operating range. The closed-loop GMI magnetometer showed a sensitivity of around 75.8 mV/microteslas, a full-scale range greater than plus or minus 40 microteslas, a pass band of 45 Hz and a resolution in the pass band of 27.74 nT. On the other hand, the GMI closed-loop gradiometer developed had a sensitivity of around 102 mV/microteslas, a full scale greater than plus or minus 40 microteslas, a passband of 30 Hz and a resolution in the pass band of 28.41 nT.

Our study provided an analysis and comparison of specific blood values, dietary intake, body composition, and inflammatory markers (high sensitivity-C-reactive protein (HS-CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6)) between adults with type 2 diabetes mellitus (T2DM) and prediabetes (PDM) to adults without diabetes. A total of 22 participants (PDM/T2DM n=12, controls n=10) in the San Luis Obispo, CA area completed the study prior to our ending recruitment due to Covid-19. Body composition data were collected through DXA scans. Dietary intake was assessed using a 3-day food record survey and nutritional analysis conducted using ESHA food processing software. In addition, participants completed an overnight fast and early morning blood draw for evaluation of blood glucose regulation, blood lipid profile and inflammatory biomarkers. Analysis included a series of randomization tests that were conducted to determine possible statistical differences between the mean of basic characteristics (age, BMI, weight, HbA1C, fasting plasma glucose, fasting insulin, triglycerides, LDL, HDL, and total cholesterol levels) of the control group and the PDM/T2DM group. Secondly, 2-way ANOVA statistical analyses were conducted to determine the interaction between sex and diabetes status on caloric intake, macronutrient distribution, quality of fat intake, visceral adipose tissue (VAT), and inflammatory biomarkers. We found there was a significant difference in fasting plasma glucose (FPG) and hemoglobin A1C (HbA1C) between the control group and the PDM/T2DM group. We did not find a statistically significant difference in caloric intake, macronutrient distribution, quality of fat intake, visceral adipose tissue (VAT), and inflammatory biomarkers between the PDM/T2DM and control group. Due to the lack of studies that include adults with PDM, we concluded additional future research needs to focus on blood biochemistry values, dietary intake, body composition, and inflammatory markers health-risk factors in both adults with PDM and T2DM since these values can improve diagnosis and treatment of T2DM.

Immunoassays are analytical methods that use the highly specific binding of antibodies in order to detect and quantify an analyte. The technique has become a staple in modern biopharmaceutical research and diagnostics, however the measurement of biomarkers like dysregulated cytokines require ultra-sensitive immunoassays that can detect molecules at sub pg/mL concentrations. One such method is the Exazym® signal amplification. Based on a method called Binding Oligo Ladder Detection (BOLD), it is a set of add-on reagents where a primer is conjugated to a detection antibody which is then combined with a template, polymerase and modified DNA nucleotides to generate a oligonucleotide ladder that is detected with a secondary detection antibody; this amplifies the signal by a factor of 10-100 in an existing immunoassay.  By applying this method to the Gyrolab® microfluidic immunoassay system, a sensitivity increase of 880x-1800x was achieved between a pre-synthesised BOLD product and the polymerised BOLD product. Several key factors for successful polymerisation in the microfluidic system were identified: adding the template separately before the polymerase and using a buffer with low ionic strength for the secondary detection antibody. Applying the BOLD amplification to an existing Gyrolab TNF-α assay only resulted in similar sensitivity as previous methods however. This report demonstrates that BOLD amplification can be successfully performed in a flow-through format on miniaturized affinity columns in the Gyrolab system to increase the sensitivity by orders of magnitude, where both the immunoassay and the amplification steps are automated in the system. However, further optimisation is needed for application in biomarker assays.

This thesis focuses on improving the performance of the THz time-domain spectroscopy system using second-order nonlinear crystals for THz generation and detection in terms of bandwidth, sensitivity, and THz field strength. The theories for the THz generation based on optical rectification and detection technique, electro-optical sampling, based on Pockels effect are introduced in Chapter 2. In Chapter 3, some experiments are presented to characterize the performances of the THz system based on a 180 fs Yb:KGW femtosecond laser amplifier operating at 1035 nm. The Yb-based femtosecond laser is becoming increasingly popular due to its robustness, high repetition rate, and high average power. However, the NIR bandwidth of these femtosecond lasers is limited by the gain bandwidth of the gain medium, and achieving pulse durations shorter than 180 fs is challenging. Consequently, the full bandwidth of THz time-domain spectroscopy systems is constrained by such laser systems. In order to broaden the THz bandwidth of such THz time-domain spectroscopy systems, our work in Chapter 4 combines the Yb:KGW femtosecond laser amplifier with an argon-filled hollow-core photonic crystal fiber pulse shaper to spectrally broaden the near-infrared pulses from 3.5 to 8.7 THz, increasing the measured THz bandwidth correspondingly from 2.3 THz to 4.5 THz. This is one of the first works to have broadband THz system based on Yb-based femtosecond lasers in the year of 2018. In Chapter 5, the tilted-pulse-front phase matching in the THz generation and detection scheme is demonstrated using the same surface-etched phase gratings on the front surfaces of the 2 mm-thick GaP generation and detection crystals. This scheme overcomes the THz generation and detection bandwidth limit of thick crystals imposed by the traditional collinear phase matching, while allowing the long nonlinear interaction length. This results in a THz spectral range from 0.1 to 6.5 THz with a peak at 3 THz and a peak dynamic range of 90 dB. In the range between 1.1 and 4.3 THz, the system dynamic range exceeds 80 dB. Based on this contact grating-based THz generation, the next step involves generating high-field THz above 2 THz. For high-field THz generation, the most renowned technique is the tilted-pulse-front technique, which generates high-field THz below 2 THz in a LiNbO₃ crystal. Most nonlinear optics experiments in the THz regime rely on such THz sources. To generate high-field THz above 2 THz, one promising candidate is organic THz crystals. However, most organic crystals require a pump laser with a wavelength exceeding 1200 nm, necessitating a more complex laser system. Additionally, the low damage threshold of these crystals are susceptible to compromise the stability of the measurements. Other techniques, such as air plasma and metallic spintronics, can generate ultra-broadband high-field THz from 0.1 to 30 THz, but the pulse energy within certain frequency windows is relatively low, rendering these THz sources less effective for nonlinearly driving specific optical transitions. On the other hand, semiconductor crystals as THz generation crystals, have a high damage threshold and can achieve good phase matching at wavelength around 800 or 1000 nm. In Chapter 6, high-field THz generation with a peak field of 303 kV/cm and a spectral peak at 2.6 THz is achieved with a more homogenous grating on the surface of a 1 mm-thick GaP generation crystal in a configuration collimating the near-infrared generation beam with a pulse energy of 0.57 mJ onto the generation crystal. The experiments also show that the system operates significantly below the GaP damage threshold and THz generation saturation regime, indicating that the peak THz field strength can approach 1 MV/cm, with a 5 mJ near-infrared generation pulse. This is the first high-field THz source based on semiconductor crystals capable of generating high-field THz above 2 THz. With such a THz source, we can conduct nonlinear optics experiments above 2 THz, including the study of phonon-assisted nonlinearities, coherent control of Bose-Einstein condensation of excitons and polaritons in semiconductor cavities, and saturable absorption in molecular gases.

No description available.

Control and analysis of protein aggregation is an increasing challenge to biopharmaceutical research and development. Therefore it is important to understand the interactions, causes and analysis of particles in order to control protein aggregation to enable successful biopharmaceutical formulations. This work investigates the role of different non-ionic surfactants on protein conformational stability, as assessed by HSDSC, and on protein size stability as assessed by Dynamic Light Scattering (DLS), HIAC and MFI. BSA and IgG2 were used as model proteins. Thermal unfolding experiments indicated a very weak surfactant-immunoglobulin IgG2 interaction, compared to much stronger interactions for the BSA surfactant systems. The DLS results showed that BSA and IgG2 with different surfactants and concentration produced different levels of particle size growth. The heat treatment and aging of samples in the presence of Tween 20, Tween 80, Brij 35 and Pluronic F-68 surfactants led to an increase in the populations of larger particles for BSA samples, whereas IgG2 systems did not notably aggregate under storage conditions MFI was shown to be more sensitive than HIAC technique for measuring sub-visible particles in protein surfactant systems. Heat treatment and storage stress showed a significant effect on BSA and IgG2 protein sub-visible particle size stability. This work has demonstrated that both proteins with different Tween 20, Tween 80, Brij 35 and Pluronic F-68 concentrations, have different level of conformational and size stability. Also aging samples and heating stress bears the potential to generate particles, but this depends on surfactant type. Poor predictive correlations between the analytical methods were determined.

由於可攜式行動裝置近年來快速成長，隨著行動裝置與地理資訊的結合發展出的適地性服務 (Location-Based Service, LBS)，也呈現越來越多的應用方式。LBS最基本的功能為定位，定位精度好壞也影響著LBS的應用面，越高的定位精度應用面越廣。常見的定位方式便是用GPS導航定位，但是在都會地區越是繁榮的地方往往過多的建物使衛星訊號被阻擋，導致GPS的定位會受到影響，造成平面誤差量會在15公尺以上，或是無法定位。利用都市區域有Wi-Fi訊號分布的特性，藉由區分不同的Wi-Fi訊號來源與接收強度，做出定位判斷，可以使原本GPS無法定位的區域，也可以利用Wi-Fi訊號來做定位。本研究嘗試使用高感度GPS接收器，在建物周邊定位，及在GPS無法運作時使用Wi-Fi訊號來做定位依據，提高整體的定位成功率，並嘗試利用Wi-Fi定位與GPS協同運作來提高整體精度。Wi-Fi定位採用訊號紋辨識法，欲使用訊號紋辨識法必先建立Wi-Fi訊號資料庫，包含地理坐標與對應的訊號來源與強度分布。實驗區為政治大學山下校區綜合院館四周面積約1.76公頃區域，模擬被遮蔽狀況下的GPS導航定位精度，配合Wi-Fi定位來輔助GPS定位結果。結果顯示利用兩種定位系統，可使平面平均定位誤差小於10公尺，高程平均定位誤差小於1.5公尺。 / The positioning accuracy is an important issue for Location-Based Service (LBS). LBS has many products, and its applications are usually based on Global Positioning System (GPS), because GPS navigation has been very mature. GPS has a typical outdoor positioning error of up to 15 meters for civilian users. Hence it has become a viable method for civilian to carry out coarse positioning. However, it has its shortcomings. GPS is available only in outdoors with a clear view of the sky. Since Wi-Fi (Wireless Fidelity) has become another positioning technology which is capable of performing positioning in indoor environments and urban canyons. Wi-Fi positioning is using fingerprinting in this study. This study is desirable to integrate GPS and Wi-Fi positioning technologies for ubiquitous positioning. The related issues of Wi-Fi/GPS technologies, such as database quality, analysis of algorithms, and database processing procedures were studied. Test data sets from National Chengchi University (NCCU) campus will be used to test the proposed algorithms. By using those two positioning system , it is revealed that the positioning accuracy made at the test sites resulted that the 2D coordinate average error is less than 10 meters, elevation positioning average error is less than 1.5 meters.

La Magneto-Impédance Géante (GMI) consiste en une forte variation de l’impédance d’un matériau ferromagnétique doux parcouru par un courant d’excitation alternatif haute fréquence lorsqu’il est soumis à un champ magnétique extérieur. Ce travail de thèse introduit de nouvelles techniques numériques et les pistes d’optimisation associées pour les capteurs GMI à haute sensibilité. L'originalité réside dans l'intégration d'un synthétiseur de fréquence et d'un récepteur entièrement numérique pilotés par un processeur de traitement de signal. Ce choix instrumental se justifie par le souhait de réduire le bruit de l’électronique de conditionnement qui limite le niveau de bruit équivalent en champ. Ce dernier caractérise le plus petit champ mesurable par le capteur. Le système de conditionnement conçu est associé à la configuration magnétique off-diagonal pour accroître la sensibilité intrinsèque de l’élément sensible. Cette configuration magnétique consiste en l’utilisation d’une bobine de détection autour du matériau ferromagnétique. Cette association permet en outre d’obtenir une caractéristique impaire de la réponse du capteur autour du champ nul, et par conséquent de pouvoir mettre en œuvre et d’utiliser le capteur sans avoir recours à une polarisation magnétique. Ce choix permet ainsi d’éliminer, ou au moins de minimiser les problématiques liées aux offsets des dispositifs GMI, tout en validant l’intérêt de cette configuration magnétique, notamment sur le choix du point de fonctionnement. Une modélisation des performances en bruit de toute la chaîne de mesure, incluant le système de conditionnement numérique, est réalisée. Une comparaison entre les niveaux de bruit équivalent en champ attendus par le modèle et mesurés est effectuée. Les résultats obtenus ont permis de dégager des lois générales d’optimisation des performances pour un capteur GMI numérique. Partant de ces pistes d’optimisation, un prototype de capteur complet et optimisé a été implémenté sur FPGA. Ce capteur affiche un niveau de bruit équivalent en champ de l’ordre de 1 pT/√Hz en zone de bruit blanc. En outre, ce travail permet de valider l’intérêt des techniques numériques dans la réalisation de dispositifs de mesure à haute sensibilité. / The Giant Magneto-Impedance (GMI) is a large change of the impedance of some soft ferromagnetic materials, supplied by an alternating high-frequency excitation current, when they are submitted to an external magnetic field. This thesis presents the design and performance of an original digital architecture for high-sensitivity GMI sensors. The core of the design is a Digital Signal Processor (DSP) which controls two other key elements: a Direct Digital Synthesizer (DDS) and a Software Defined Radio (SDR) or digital receiver. The choice of these digital concepts is justified by the will to reduce the conditioning electronics noise that limits the equivalent magnetic noise level. The latter characterizes the smallest measurable field by the sensor. The developed conditioning system is associated with the off-diagonal magnetic configuration in order to increase the intrinsic sensitivity of the sensitive element. This magnetic configuration consists of the use of an additional a pick-up coil wound around the ferromagnetic material. This association also makes it possible to obtain an asymmetrical characteristic (odd function) of the sensor response near the zero-field point and to consequently allow for sensor implementation and use without any bias magnetic field. Thus, this choice eliminates, or at least minimizes, the problems related to the offset cancelling of the GMI devices. Also, it validates the advantage of this magnetic configuration, especially the choice of the operating point. Modeling of the noise performance of the entire measurement chain, including the digital conditioning, is performed. A comparison between the expected and measured equivalent magnetic noise levels is then carried out. The results yield general optimization laws for a digital GMI sensor. Using these laws, an optimized prototype of a GMI sensor is designed and implemented on FPGA. An equivalent magnetic noise level in a white noise zone region of approximately 1 pT/√ Hz is obtained. Furthermore, this work also makes it possible to validate the interest of digital techniques in the realization of a high-sensitivity measuring devices.

Introduction: Type 2 diabetes continues to be one of the most common non-communicable diseases worldwide and complications due to type 2 diabetes, such as cardiovascular disease (CVD) can cause severe disability and even death. Despite advances in the development and validation of cardiovascular risk scores, those used in clinical practice perform inadequately for people with type 2 diabetes. Research has suggested that particular non-traditional biomarkers and novel omics data may provide additional value to risk scores over-and-above traditional predictors. Aims: To determine whether a small panel of non-traditional biomarkers improve prediction models based on a current cardiovascular risk score (QRISK2), either individually or in combination, in people with type 2 diabetes. Furthermore, to investigate a set of 228 metabolites and their associations with CVD, independent of well-established cardiovascular risk factors, in order to identify potential new predictors of CVD for future research. Methods: Analyses used the Edinburgh Type 2 Diabetes Study (ET2DS), a prospective cohort of 1066 men and women with type 2 diabetes aged 60-75 years at baseline. Participants were followed for eight years, during which time 205 had a cardiovascular event. Additionally, for omics analyses, four cohorts from the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium were combined with the ET2DS. Across all studies, 1005 (44.73%) participants had CVD at baseline or experienced a cardiovascular event during follow-up. Results: In the ET2DS, higher levels of high sensitivity cardiac troponin (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) and lower levels of ankle brachial pressure index (ABI) were associated with incident cardiovascular events, independent of QRISK2 and pre-existing cardiovascular disease (odds ratios per one SD increase in biomarker 1.35 (95% CI: 1.13, 1.61), 1.23 (1.02, 1.49) and 0.86 (0.73, 1.00) respectively). The addition of each biomarker to a model including just QRISK2 variables improved the c-statistic, with the biggest increase for hs-cTnT (from 0.722 (0.681, 0.763) to 0.732 (0.690, 0.774)). When multiple biomarkers were considered in combination, the greatest c-statistic was found for a model which included ABI, hs-cTnT and gamma-glutamyl transpeptidase (0.740 (0.699, 0.781)). In the combined cohorts from the UCLEB consortium, a small number of high-density lipoprotein (HDL) particles were found to be significantly associated with CVD: concentration of medium HDL particles, total lipids in medium HDL, phospholipids in medium HDL and phospholipids in small HDL. These associations persisted after adjustment for a range of traditional cardiovascular risk factors including age, sex, blood pressure, smoking and HDL to total cholesterol ratio. Conclusions: In older people with type 2 diabetes, a range of non-traditional biomarkers increased predictive ability for cardiovascular events over-and-above the commonly used QRISK2 score, and a combination of biomarkers may provide the best improvement. Furthermore, a small number of novel omics biomarkers were identified which may further improve risk scores or provide better prediction than traditional lipid measurements such as HDL cholesterol.

La communauté de la chimie atmosphérique souffre d'un manque de mesures rapides, fiables résolues spatialement et temporellement pour un large éventail de molécules réactives (radicaux tels que NO2, OH, BrO, IO, etc). En raison de leur forte réactivité, ces molécules contrôlent largement la durée de vie et la concentration de nombreuses espèces clés dans l'atmosphère, et peuvent avoir un impact important sur le climat. Les concentrations de ces radicaux sont extrêmement faibles (ppbv ou moins) et très variable dans le temps et dans l'espace, ce qui impose un véritable défi lors de la détection. Dans la première partie de cette thèse, un spectromètre UV robuste, compacte et transportable est développé, exploitant la technique ML-CEAS pour mesurer à des niveaux très faibles (pptv et même en dessous) des molécules réactives d'importance atmosphérique, en particulier, les radicaux d'oxyde d'halogènes, afin de répondre aux besoins émergents. La technique ML-CEAS est basée sur le couplage d'un laser femtoseconde à blocage de modes à une cavité optique de haute finesse, qui agit comme un piège à photons pour augmenter l'interaction entre la lumière et l'échantillon de gaz intracavité. Cela permet d'améliorer fortement la sensibilité d'absorption. La limite de détection obtenue pour le radical IO est de 20 ppqv pour un temps d'acquisition de 5 minutes, ce qui est un résultat impressionnant. Dans la deuxième partie de cette thèse, une nouvelle technique spectroscopique est développée appelée effet Vernier, qui est également basé sur l'interaction entre un laser femtoseconde à blocage de mode et une cavité optique de haute finesse. Cette technique fournit une sensibilité de détection similaire à la technique ML-CEAS, mais l'avantage est que le nombre des éléments spectraux est donné par la finesse de la cavité optique et donc peut atteindre plusieurs dizaines de milliers. De plus, cette configuration simplifie le montage expérimental par la suppression du spectrographe qui est remplacé par une simple photodiode. Le temps d'acquisition d'un spectre peut être aussi réduit à moins d' 1 ms. / The atmospheric chemistry community suffers a lack of fast, reliable and space resolved measurements for a wide set of reactive molecules (e.g. radicals such as OH, NO3, BrO, IO, etc). Due to their high reactivity, these molecules largely control the lifetime and concentration of numerous key atmospheric species, and may have an important impact on the climate. The concentrations of such radicals are extremely low (ppbv or less) and highly variable in time and space, which imposes a real challenge during the detection. In the first part of this thesis, a compact, robust and transportable UV spectrometer is developed, exploiting the Mode-Locked Cavity Enhanced Absorption Spectroscopy (ML-CEAS) technique to measure pptv and sub-pptv levels of atmospherically important reactive molecules, in particular, halogen oxide radicals, to respond to the emerging needs. The ML-CEAS technique is based on coupling a Mode-Locked femtosecond laser to a high finesse optical cavity, which acts as a photon trap to increase the interaction between the light and the intracavity gas sample, which highly enhances the absorption sensitivity. The detection limit obtained for the IO radical is 20 ppqv (part per quadrillion), which is an impressive result. In the second part of this thesis, a new spectroscopic technique is developed, called Vernier effect, which is also based on the interaction between a mode-locked femtosecond laser with a high finesse optical cavity. This technique provides detection sensitivity similar to that of ML-CEAS technique, but the advantage is that the number of the spectral elements is given by the cavity finesse, so it can reach ten thousands, as well as this technique has a simple setup, where the spectrograph is replaced by a photodiode. Additionally, the time required to measure one output absorption spectrum can be less than 1 ms.