Human α-galactosidase (α-GAL; EC 3.2.1.22) is a lysosomal enzyme that hydrolyzes of terminal alpha-linked galactosyl residue of glycosphingolipids. Deficiencies in α-GAL leads to Fabry disease, which is characterized by the build-up of globotriaosylceramide and other neutral substrates in cells, ultimately leading to a multi-systemic organ failure in patients. Hundreds of distinct mutations have been found in the α-GAL gene of Fabry disease patients. One current treatment for Fabry disease is Enzyme Replacement Therapy (ERT), which restores the missing α-GAL function. An alternative treatment, called Pharmacological Chaperone Therapy (PCT), utilizes a small molecule substrate analogue, 1-deoxygalactonojirimycin (DGJ). In order to better understand molecular basis of Fabry disease, this work addresses structural and mechanistic studies of the α-GAL glycoprotein. First, we have determined crystal structures of each stage in the catalytic mechanism of the α-GAL enzymatic reaction. These studies reveal a novel strained conformation of the sugar when it is covalently bound to the enzyme. Second, we examine the molecular mechanism of chaperoning by pharmacological chaperones. A combination of biochemical and biophysical approaches reveals that the high potency of the DGJ chaperone is due to an interaction with α-GAL residue D170. Third, we have investigated mutant α-GAL proteins for their response to pharmacological chaperones, leading to a set of structure-based rules for predicting the effect of pharmacological chaperone on every Fabry disease patient. Fourth, we use rational design approaches to interconvert the specificity of α-GAL into that of a related enzyme, α-N-acetylgalactosaminidase (α-NAGAL). Structural and enzymatic experiments show that the engineered enzyme contains new substrate specificity, as predicted by the design. The structural and mechanistic details we present in this thesis provide better understanding of the catalysis of the human α-galactosidase enzyme as well as define the molecular basis for pharmacological chaperone therapy in Fabry patients. Since α-GAL is one of the best studied lysosomal storage disease, it might be used as a model to better understand other lysosomal storage diseases and as well as other diseases related to misfolded proteins, including Alzheimer's and Parkinson's diseases.

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The motivation of this research is to meet the growing demand for the measurand high-resolution, high-spatial resolution, attenuation insensitive and low-cost quasi-distributed temperature and strain sensors that can reliably work under harsh environment or in extended structures. There are two main drives for distributed fiber sensor research. The first is to lower cost-per-sensor so that the fiber sensors may become price-competitive against electrical sensors in order to gain widespread acceptance. The second is to obtain spatial distribution of the measurand. This dissertation presents detailed research on the design, modeling, analysis, system implementation, sensor fabrication, performance evaluation, sensor field test and noise analysis of a quasi-distributed intrinsic Fabry-Perot interferometric (IFPI) fiber sensor suitable for temperature and strain measurement. For the first time to our knowledge, an IFPI sensor using a different type of fiber spliced in between two single-mode fibers is proposed and tested. The proposed sensor has high measurement accuracy, excellent repeatability, a large working range and a low insertion-loss. It requests no annealing after the sensor is made, and the sensor is calibration-free. The sensor fabrication is low-cost and has a high yield rate. The goal for this research is to bring this sensor to a level where it will become commercially viable for quasi-distributed sensing applications. / Ph. D.

This dissertation proposes a miniaturized optical fiber based sensor system for the measurement of 3-dimensional vector magnetic fields. The operation of the sensor system is based on the detection of magnetostrictive dimensional changes in the sensor gage using a modified extrinsic Fabry-Perot Interferometer configuration. Because of the magnetostrictive reflector the gap length depends on the magnetic fields applied to the sensor. Since the diameter of the magnetostrictive sensor gage is 125 micrometer which is the same as that of the input/output fiber, the sensor is simply constructed by inserting the sensor gage and the input/output fiber into a small glass tube. The glass tube serves as both an aligner for the sensor gage and input/out fiber, and a passive temperature compensator. In addition, it also enhances the mechanical strength and compactness of the sensor. This sensor design shows 98 percent suppression of the thermally induced sensor output changes. The linear output of the sensor system is enhanced by transverse field annealing which increases magnetostrictive induction in the ferromagnetic sensor gage material and controls the sensor gage geometry. A 5-times increase in sensor sensitivity is obtained with the transverse field annealing and the use of a new magnetostrictive material. A modified sensor gage endface demonstrates 92 percent of fringe visibility, which further improves the performance of the interferometer. The signal fading in the interferometric sensors at the peak or bottom of a fringe is reduced by using a quadrature signal demodulation method. The system has been shown to have a resolution better than 100 nT over a measurement range from 100 to 40,000 nT. This research is supported financially by the Phillips Laboratory of the U.S. Air Force. / Ph. D.

In this report, detailed and systematic theoretical and experimental study of low-finesse extrinsic Fabry-Perot interferometric (EFPI) fiber optic sensors together with their signal processing methods for white-light systems are presented. The work aims to provide a better understanding of the operational principle of EFPI fiber optic sensors, and is useful and important in the design, optimization, fabrication and application of single mode fiber(SMF) EFPI (SMF-EFPI) and multimode fiber (MMF) EFPI (MMF-EFPI) sensor systems. The cases for SMF-EFPI and MMF-EFPI sensors are separately considered. In the analysis of SMF-EFPI sensors, the light transmitted in the fiber is approximated by a Gaussian beam and the obtained spectral transfer function of the sensors includes an extra phase shift due to the light coupling in the fiber end-face. This extra phase shift has not been addressed by previous researchers and is of great importance for high accuracy and high resolution signal processing of white-light SMF-EFPI systems. Fringe visibility degradation due to gap-length increase and sensor imperfections is studied. The results indicate that the fringe visibility of a SMF-EFPI sensor is relatively insensitive to the gap-length change and sensor imperfections. Based on the spectral fringe pattern predicated by the theory of SMF-EFPI sensors, a novel curve fitting signal processing method (Type 1 curve-fitting method) is presented for white-light SMF-EFPI sensor systems. Other spectral domain signal processing methods including the wavelength-tracking, the Type 2-3 curve fitting, Fourier transform, and two-point interrogation methods are reviewed and systematically analyzed. Experiments were carried out to compare the performances of these signal processing methods. The results have shown that the Type 1 curve fitting method achieves high accuracy, high resolution, large dynamic range, and the capability of absolute measurement at the same time, while others either have less resolution, or are not capable of absolute measurement. Very different from SMF-EFPI sensors, MMF-EFPI sensors with high fringe visibility usually are more difficult to obtain in practice because the fringe visibility of a MMF-EFPI sensor is much more sensitive to gap-length change and sensor head imperfections. %Previously, only geometric-optics are available to analyze MMF-EFPI sensors which approximate the light in MMF as rays propagating in different directions. Geometric-optics theory has fundenmental limitations because it is approximate and only valid for limited conditions. Moreover, geometric-optics theory is not capable of poviding the exact fringe pattern which is important in the signal processing of white light MMF-EFPI sensor systems. In this report, Previous mathematical models for MMF-EFPI sensors are all based on geometric optics; therefore their applications have many limitations. In this report, a modal theory is developed that can be used in any situations and is more accurate. The mathematical description of the spectral fringes of MMF-EFPI sensors is obtained by the modal theory. Effect on the fringe visibility of system parameters, including the sensor head structure, the fiber parameters, and the mode power distribution in the MMF of the MMF-EFPI sensors, is analyzed. Experiments were carried out to validate the theory. Fundamental mechanism that causes the degradation of the fringe visibility in MMF-EFPI sensors are revealed. It is shown that, in some situations at which the fringe visibility is important and difficult to achieve, a simple method of launching the light into the MMF-EFPI sensor system from the output of a SMF could be used to improve the fringe visibility and to ease the fabrication difficulties of MMF-EFPI sensors. Signal processing methods that are well-understood in white-light SMF-EFPI sensor systems may exhibit new aspects when they are applied to white-light MMF-EFPI sensor systems. This report reveals that the variations of mode power distribution (MPD) in the MMF could cause phase variations of the spectral fringes from a MMF-EFPI sensor and introduce measurement errors for a signal processing method in which the phase information is used. This MPD effect on the wavelength-tracking method in white-light MMF-EFPI sensors is theoretically analyzed. The fringe phases changes caused by MPD variations were experimentally observed and thus the MFD effect is validated. / Ph. D.

Optical fiber sensor multiplexing reduces cost per sensor by designing a system that minimizes the expensive system components (sources, spectrometers, etc.) needed for a set number of sensors. The market for multiplexed optical sensors is growing as fiberoptic sensors are finding application in automated factories, mines, offshore platforms, air, sea, land, and space vehicles, energy distribution systems, medical patient surveillance systems, etc. Optical path length multiplexing (OPLM) is a modification to traditional white-light interferometry techniques to multiplex extrinsic Fabry-Perot interferometers and optical path length two-mode sensors. Additionally, OPLM techniques can be used to design an optical fiber sensor to detect pressure/force/acceleration and temperature simultaneously at a single point. While power losses and operating range restrictions limit the broadscale applicability of OPLM, it provides a way to easily double or quadruple the number of sensors by modifying the demodulation algorithm. The exciting aspect of OPLM is that no additional hardware is needed to multiplex a few sensors. In this way OPLM works with conventional technology and algorithms to drastically increase their efficiency. [1] / Master of Science

This dissertation focuses on developing new technologies for ultra-low-cost sapphire fiber-optic high-temperature sensors. The research is divided into three major parts, the souceless sensor, the simple Fabry-Perot (F-P) interrogator, and the sensor system. Chapter 1 briefly reviews the background of thermal radiation, fiber optic F-P sensors, and F-P signal demodulation. The research goal is highlighted. In Chapter 2, a temperature sensing system is introduced. The environmental thermal radiation was used as the broadband light source. A sapphire wafer F-P temperature sensor head was fabricated, with an alumina cap designed to generate a stable thermal radiation field. The radiation-induced optical interference pattern was observed. We demodulated the temperature sensor by white-light-interferometry (WLI). Temperature resolution better than 1°C was achieved. Chapter 3 discusses a novel approach to demodulate an optical F-P cavity at low-cost. A simple interrogator is demonstrated, which is based on the scanning-white-light-interferometry (S-WLI). The interrogator includes a piece of fused silica wafer, and a linear CCD array, to transform the F-P demodulation from the optical frequency domain to the spatial domain. By using the light divergence of an optical fiber, we projected a tunable reference F-P cavity onto an intensity distribution along a CCD array. A model for S-WLI demodulation was established. Performance of the new S-WLI interrogator was investigated. We got a good resolution similar to the well-known traditional WLI. At last, we were able to combine the above two technologies to a sapphire-wafer-based temperature sensor. The simple silica wafer F-P interrogator was optimized by focusing light to the image sensor. This approach improves the signal to noise ratio, hence allows the new integrator to work with the relatively weak thermal radiation field. We, therefore, proved in the experiment, the feasibility of the low-cost sourceless optical Fabry-Perot temperature sensor with a simple demodulation system. / PHD

This dissertation addresses several theoretical issues in low-finesse fiber optic Fabry-Perot Interferometric (FPI) sensors. The work is divided into two levels: modeling of the sensors, and signal processing based on White-Light-Interferometry (WLI). In the first chapter, the technical background of the low-finesse FPI sensor is briefly reviewed and the problems to be solved are highlighted. A model for low finesse Extrinsic FPI (EFPI) is developed in Chapter 2. The theory is experimentally proven using both single-mode and multimode fiber based EFPIs. The fringe visibility and the additional phase in the spectrum are found to be strongly influenced by the optical path difference (OPD), the output spatial power distribution and the working wavelength; however they are not directly related to the light coherence. In Chapter 3, the Single-Multi-Single-mode Intrinsic FPI (SMS-IFPI) is theoretically and experimentally studied. Reflectivity, cavity refocusing, and the additional phase in the sensor spectrum are modeled. The multiplexing capacity of the sensor is dramatically increased by promoting light refocusing. Similar to EFPIs, wave-front distortion generates an additional phase in the interference spectrogram. The resultant non-constant phase plays an important role in causing abrupt jumps in the demodulated OPD. WLI-based signal processing of the low-finesse FP sensor is studied in Chapter 4. The lower bounds of the OPD estimation are calculated, the bounds are applied to evaluate OPD demodulation algorithms. Two types of algorithms (TYPE I & II) are studied and compared. The TYPE I estimations suffice if the requirement for resolution is relatively low. TYPE II estimation has dramatically reduced error, however, at the expense of potential demodulation jumps. If the additional phase is reliably dependent on OPD, it can be calibrated to minimize the occurrence of such jumps. In Chapter 5, the work is summarized and suggestions for future studies are given. / Ph. D.