The study of the magnetic and structural properties of matter under extreme conditions is a fast developing field. With the emergence of new techniques and innovative instruments for measuring physical properties, the need for compatible pressure generating devices is constantly growing. The work described in this thesis is focused on development, construction and testing of several high pressure (HP) cells of novel design. One of the cells is intended for single crystal X-ray diffraction (SXD) studies at low temperature (LT) and the other three HP devices are designed for a Magnetic Property Measurement System (MPMS), two of which are suitable for dc susceptibility studies and the other one is aimed at high frequency ac susceptibility measurements. HP crystallographic studies are routinely carried out in diamond anvil cells (DAC) at room temperature while ambient pressure SXD studies are often conducted at LT to reduce atomic vibrations and obtain more precise structural data as well as to study LT phases. Combining HP with LT gives access to a whole new area on the phase diagrams but due to the size of the existing DACs this is generally achieved by cooling down the cells inside a cryostat and it is mainly possible at synchrotrons where dedicated facilities exist. A miniature DAC which can be used with commercially available laboratory cry-flow cooling systems and achieves pressures in excess of 10 GPa has been developed. The design of the pressure cell is based on the turnbuckle principle and therefore it was called TX-DAC. Its dimensions have been minimised using Finite Element Analysis (FEA) and the final version of the cell weighs only 2.4 g. The cell is built around a pair of 600 μm culet Boehler-Almax anvils which have large conical openings for the diffracted beam. The TX-DAC is made of beryllium copper (BeCu) alloy which has good thermal conductivity and allows quick thermal equilibration of the cell. The MPMS from Quantum Design is the most popular instrument for studies of magnetic properties of materials. It is designed to measure ac and dc magnetic susceptibility of sample with detectable signals as low as 10-8 emu. The MPMS has a sample chamber bore of 9 mm in diameter and this puts a constraint on the dimensions of the pressure cells. However, several types of clamp piston-cylinder cells and DACs have been designed for the MPMS. The former are used for measurements at pressure up to 2 GPa and the later can be used for studies at higher pressure. Taking advantage of the turnbuckle principle, a DAC (TM-DAC) and a piston-cylinder cell (TM-PCC) for dc magnetic studies were built. They allow HP measurements to be performed at the full sensitivity of MPMS. Both pressure cells are made of BeCu and their small dimensions combined with symmetrical design is the key to an ideal background signal correction. The TM-DAC is 7 mm long and 7 mm in diameter, it weighs 1.5 g and with 800 μm culet anvils it can generate a sample pressure of 10 GPa. Inherently the sample volume is limited to approximately 10-3 mm3 and the signal corresponding to this volume of some weakly magnetic material remains below the sensitivity of the MPMS. This constraint led us to the development of the TM-PCC – a piston-cylinder variant of the turnbuckle design. With a 4 mm3 sample volume it allows the study of weakly magnetic samples in the range 0-1.9 GPa. The TM-PCC uses two zirconia pistons of 2.5 mm in diameter; it is 10 mm long, 7 mm in diameter and weights 2.7 g. Conventional metallic pressure cells perform well in dc mode however in ac susceptibility measurements, the Eddy currents set in the cells’ body lead to a screening effect which can significantly obscure the signal from the sample. This problem was solved by designing a composite piston-cylinder cell made with Zylon fibre and epoxy resin. The sample is located in the middle of the cell in the 2.5 mm bore and the pressure is transmitted through zirconia pistons. Keeping the metallic parts away from the sample resolves any interference issue. The composite cell performs well in a pressure range of 0-1 GPa. The performance of the pressure cells developed within this project is illustrated by studies of various systems at high pressure.

The effect of pressure on a number of magnetically interesting compounds such as single-molecule magnets and dimeric copper and manganese molecules has been investigated to probe the validity of ambient magneto-structural correlations. The first chapter is an introduction to the equipment and methodologies that have been adopted to carry out the experimental high-pressure work. The second chapter reports the first combined high-pressure single crystal X-ray diffraction and high pressure magnetism study of four single-molecule magnets (SMMs). At 1.5 GPa the structures [Mn6O2(Et-sao)6(O2CPh(Me)2)2(EtOH)6] (1) – an SMM with a record effective anisotropy barrier of ~86 K – and [Mn6O2(Etsao) 6(O2C-naphth)2(EtOH)4(H2O)2] (2) both undergo significant structural distortions of their metallic skeletons which has a direct effect upon the observed magnetic response. Up to 1.5 GPa pressure the effect is to flatten the Mn-N-O-Mn torsion angles weakening the magnetic exchange between the metal centres. In both compounds one pairwise interaction switches from ferro- to antiferromagnetic, with the Jahn-Teller (JT) axes compressing (on average) and re-aligning differently with respect to the plane of the three metal centres. High pressure dc χMT plots display a gradual decrease in the low temperature peak value and slope, simulations showing a decrease in |J| with increasing pressure with a second antiferromagnetic J value required to simulate the data. The “ground states” change from S = 12 to S = 11 for 1 and to S = 10 for 2. Magnetisation data for both 1 and 2 suggest a small decrease in |D|, while out-of-phase (χM //) ac data show a large decrease in the effective energy barrier for magnetisation reversal. The third SMM is the complex [Mn3(Hcht)2(bpy)4](ClO4)3·Et2O·2MeCN (3·Et2O·2MeCN) that at 0.16 GPa loses all associated solvent in the crystal lattice, becoming 3. At higher pressures structural distortions occur changing the distances between the metal centres and the bridging oxygen atoms making |J| between the manganese ions weaker. No significant variations are observed in the JT axis of the only MnIII present in the structure. Highpressure dc χMT plots display a gradual decrease in the low temperature peak value and slope. Simulations show a decrease in J with increasing pressure although the ground state is preserved. Magnetisation data do not show any change in |D|. The fourth SMM, [(tacn)6Fe8O2(OH)12](ClO4)3.9Br4.1⋅6H2O, (4) is the largest inorganic compound ever studied at high-pressure. Up to 2.0 GPa the conformation of the complex remains largely unaffected, with the counter ions and water molecules moving around to accommodate a compression of the unit cell volume. High pressure magnetic susceptibility data collected up to 0.93 GPa confirm minimal changes in the intra-molecular exchange interactions. The third chapter focuses on three hydroxo-bridged CuII dimers: [Cu2(OH)2(H2O)2(tmen)2](ClO4)2 (5), [Cu2(OH)2(tben)2](ClO4)2 (6) and [Cu2(OH)2(bpy)2](BF4)2 (7) have been structurally determined up to 2.5, 0.9 and 4.7 GPa, respectively. 6 and 7 have never been reported before. Pressure imposes important distortions in the structures of all three complexes, particularly on the bond distances and angles between the metal centres and the bridging hydroxo groups. 5 undergoes a phase transition between 1.2 and 2.5 GPa caused by the loss of a coordinated water molecule. This leads to a loss of symmetry and dramatic changes in the molecular structure of the complex. The structural changes are manifested in different magnetic behaviours of the complexes as seen in dc susceptibility measurements up to ~0.9 GPa: J becomes less antiferromagnetic in 5 and 6 and more ferromagnetic in 7. The fourth chapter shows the compression of two oxo-bridged MnII/MnIII mixed valence dimers: [Mn2O2(bpy)4](ClO4)3⋅3CH3CN, (8) has been squeezed up to 2.0 GPa whilst [Mn2O2(bpy)4](PF6)3⋅2CH3CN⋅1H2O, (9) could be measured crystallographically up to 4.55 GPa. 9 has never been reported before, while 8 has been reported in a different crystallographic space group. The application of pressure imposes significant alterations in the structures of both complexes. In particular, in 8 the Mn-Mn separation is reduced by the contraction of some of the Mn-O bond distances, 9 shows essentially analogous behaviour: the Mn-Mn distance and nearly all the Mn-N bonds shrink significantly. The magnetic behaviour of the complexes has been measured up to 0.87 GPa for 8 and 0.84 GPa for 9, but neither display any significant differences with respect to their ambient data.

Nanomaterials (NMs) are materials in which the size of at least one dimension is less than 100 nm. Examples include quantum dots, nanoparticles, “Buckminsterfullerene (C60)”, carbon nanotubes, graphene and TiO2 thin films. Many research groups have investigated the properties of NMs, and they have reported that some of them are clearly different to those of the bulk materials, and depend on the size of the NMs. Examples include melting temperatures, phase transition pressures, fluorescence spectra, catalytic properties and magnetic properties. Recently, a high-pressure study of Te nano-cylinders revealed compressibility effects that are different to those observed in bulk-Te. Although this study reported an elevation of phase transition pressure compared to the bulk, the authors did not investigate the structures of the high-pressure phases, and it is unclear whether the incommensurate phase found at high pressures in bulk-Te was observed or not. Indeed, it is completely unknown whether the incommensurate phases observed in a number of elements at high pressure also exist in nanoparticle samples of the same materials. The search for, and study of, such phases forms the subject of this thesis. Initial studies of commercial selenium nanoparticles (nano-Se) revealed that the incommensurate phase of bulk selenium (Se-IV) is also found in nano-Se. The transition pressures in nano-Se are slightly higher than those of bulk-Se. However, the nano-Se samples were subsequently found not to have the sizes, shapes, and properties claimed by the vendor, which was confirmed by transmission and scanning electron microscopy. Further commercial samples of nano-Se and nano-Bi were also found to be of extremely poor quality. It was clear, therefore, that a detailed study of incommensurate phases in NMs would require us to make our own samples. Bismuth nanoparticles (nano-Bi) with dimensions 51(6), 52(15), 92(13), 128(45), and 138(27) nm have been successfully synthesised by the author in collaboration with the Hybrid Nano Collods group at the University of St. Andrews. On compression, the nano-Bi samples were found to have the same order of phases Bi-I, Bi-II, Bi-III, and Bi-V and phase transitions as found in bulk-Bi, but were found to exhibit larger phase coexistence. The phase transition pressures on pressure increase were higher than those of the bulk materials, and the smaller the diameter of nano-Bi, the higher the phase-transition pressure. This behaviour is similar to, but more extreme than, that found in CdSe nanoparticles. The incommensurate Bi-III structure has been found in nano-Bi under increases in pressure. However, the di↵raction patterns from Bi-III contain additional unaccounted-for peaks, and this phase is referred to as complex Bi-III. The Debye- Scherrer rings from complex Bi-III are smooth, and do not exhibit the spottiness observed in the diffraction patterns of Bi-III obtained from bulk-Bi. This enables full Rietveld refinement of Bi-III in the nano-samples. Complex Bi-III exists from 3 GPa up to 30 GPa, compared to the stable range of only 2.7 to 7.7 GPa of Bi-III in the bulk material. While such a large range of pressure enables the structure of nano-Bi-III to be studied over a much wider pressure range than bulk-Bi-III, such studies were hampered by the existence of the unaccounted-for peaks. In order to get clean, single-phase patterns of Bi-III, samples of this phase were first prepared on pressure decrease from the higher-pressure Bi-V phase, before recompressing them. Single-phase samples of Bi-III were obtained and were found to be stable up to 14-18 GPa. However, because of phase coexistence, diffraction peaks from Bi-III were still visible at pressures as high as ~30 GPa, which is ~3 times larger than the upper limit pressure of existence of bulk-Bi-III. On pressure re-increase, nano-Bi-III has a higher bulk modulus than bulk-Bi-III. The bulk modulus was found to be size-dependent as it is higher when size decreases. Moreover, nano-Bi has a smaller value of the incommensurate wave vector, which is almost pressure independent, but is found to be particles size dependent. The incommensurate wave vector thus becomes another of the structural and physical properties of nanomaterials that is found to be sample-size dependent.

The Aldo-Keto Reductases (AKR) are a group of oxidoreductase enzymes structurally and mechanistically distinct from the Alcohol Dehydrogenases (ADH). The AKRs are of importance for their ability to produce industrially useful compounds including chiral secondary alcohols. The ADH family have traditionally been exploited for chiral alcohol production; the AKR family have currently been underexploited for chiral alcohol production and present the opportunity to search for novel oxidoreductases with properties and substrate specificities distinct from the ADH enzymes. The AKR studied here, from the hyperthermophilic bacteria Thermotoga maritima has been characterised with respect to its biochemical and structural properties, and its potential as a biocatalyst evaluated. This enzyme is the second example of a thermophilic AKR to have its three dimensional structure solved, the other also being from Thermot. maritima. The AKR studied exhibits high stability with respect to temperature and moderate amounts of organic solvents. A large preference for the reduction reaction compared to the oxidation reaction was found, which has previously been observed in other AKRs. The X-ray crystal structure was solved to 2.6Å resolution in the apo form. The final structure has three loop sections which were not located due to disorder within the crystal, which are expected to become ordered upon cofactor and substrate binding. A section of one of these missing loops was found to bind at the active site of the enzyme, with a glutamate occupying the site of substrate carbonyl binding. The formation of a dimer, increased helix-dipole stabilisation and long distance ion pair interactions all act to increase thermostability of the AKR with respect to its mesophilic homologues. The X-ray crystal structure of Escherichia coli bacterioferritin has also been solved to 1.9Å resolution, which was co-purified along with the recombinant AKR enzyme. This structure shows the symmetrical binding of a heme molecule on the local two-fold axis between subunits and the binding of two metal atoms to each subunit at the ferroxidase centre. These metal atoms have been identified as zinc by the anaylsis of the structure and X-ray data and confirmed by microPIXE experiments. For the first time the heme has been shown to be linked to the internal and external environments via a cluster of waters positioned above the heme molecule. This information has provided a greater insight into the function and mechanism of bacterioferritin.

This thesis is concerned with describing a novel technique for characterizing the (spectrally resolved) spatial properties of light. The new approach, known as Scanning Interference Method for Integrated Transverse Analysis of Radiation (SCIMITAR), is a specific implementation of a variable-separation two-pinhole interferometer. Evaluation of the series of interference patterns produced by a SCIMITAR measurement allows the transverse profiles of intensity and spatial phase to be retrieved, while at the same time characterizing the spatial coherence of light. Including a diffraction grating in the simple experimental arrangement permits the spectral dependence of the aforementioned quantities to be measured. The SCIMITAR technique was demonstrated by characterizing the spatial properties of high harmonic generation (HHG). Excellent agreement with an alternate characterization technique known as SWORD was observed. The spectral dependence of the harmonic spatial properties was also investigated. Evidence suggesting absorption may play a role in shaping the harmonic intensity and spatial coherence was presented. Treating the harmonic radiation as either a fully coherent or partially coherent beam allowed the intensity width, spatial phase curvature and coherence width of the harmonic radiation source to be deduced. Measurement of the fine variation of the harmonic complex coherence factor (CCF) with pinhole separation revealed distinctive modulations. The Van Cittert-Zernike theorem was modified by including a Gerchberg-Saxton inspired improvement, allowing data missing from the SCIMITAR measurement to be inferred. The harmonic equivalent incoherent source intensity profile was found to be asymmetric with low intensity features isolated away from the optical axis. Calculations of the diffraction pattern produced by illumination of a non-redundant array of pinholes showed that the modulated harmonic properties could adversely influence lensless imaging-type experiments.

<p>X-ray computed tomography (CT) imaging constitutes one of the most widely used diagnostic tools in radiology today with nearly 85 million CT examinations performed in the U.S in 2011. CT imparts a relatively high amount of radiation dose to the patient compared to other x-ray imaging modalities and as a result of this fact, coupled with its popularity, CT is currently the single largest source of medical radiation exposure to the U.S. population. For this reason, there is a critical need to optimize CT examinations such that the dose is minimized while the quality of the CT images is not degraded. This optimization can be difficult to achieve due to the relationship between dose and image quality. All things being held equal, reducing the dose degrades image quality and can impact the diagnostic value of the CT examination. </p><p>A recent push from the medical and scientific community towards using lower doses has spawned new dose reduction technologies such as automatic exposure control (i.e., tube current modulation) and iterative reconstruction algorithms. In theory, these technologies could allow for scanning at reduced doses while maintaining the image quality of the exam at an acceptable level. Therefore, there is a scientific need to establish the dose reduction potential of these new technologies in an objective and rigorous manner. Establishing these dose reduction potentials requires precise and clinically relevant metrics of CT image quality, as well as practical and efficient methodologies to measure such metrics on real CT systems. The currently established methodologies for assessing CT image quality are not appropriate to assess modern CT scanners that have implemented those aforementioned dose reduction technologies.</p><p>Thus the purpose of this doctoral project was to develop, assess, and implement new phantoms, image quality metrics, analysis techniques, and modeling tools that are appropriate for image quality assessment of modern clinical CT systems. The project developed image quality assessment methods in the context of three distinct paradigms, (a) uniform phantoms, (b) textured phantoms, and (c) clinical images.</p><p>The work in this dissertation used the “task-based” definition of image quality. That is, image quality was broadly defined as the effectiveness by which an image can be used for its intended task. Under this definition, any assessment of image quality requires three components: (1) A well defined imaging task (e.g., detection of subtle lesions), (2) an “observer” to perform the task (e.g., a radiologists or a detection algorithm), and (3) a way to measure the observer’s performance in completing the task at hand (e.g., detection sensitivity/specificity).</p><p>First, this task-based image quality paradigm was implemented using a novel multi-sized phantom platform (with uniform background) developed specifically to assess modern CT systems (Mercury Phantom, v3.0, Duke University). A comprehensive evaluation was performed on a state-of-the-art CT system (SOMATOM Definition Force, Siemens Healthcare) in terms of noise, resolution, and detectability as a function of patient size, dose, tube energy (i.e., kVp), automatic exposure control, and reconstruction algorithm (i.e., Filtered Back-Projection– FPB vs Advanced Modeled Iterative Reconstruction– ADMIRE). A mathematical observer model (i.e., computer detection algorithm) was implemented and used as the basis of image quality comparisons. It was found that image quality increased with increasing dose and decreasing phantom size. The CT system exhibited nonlinear noise and resolution properties, especially at very low-doses, large phantom sizes, and for low-contrast objects. Objective image quality metrics generally increased with increasing dose and ADMIRE strength, and with decreasing phantom size. The ADMIRE algorithm could offer comparable image quality at reduced doses or improved image quality at the same dose (increase in detectability index by up to 163% depending on iterative strength). The use of automatic exposure control resulted in more consistent image quality with changing phantom size.</p><p>Based on those results, the dose reduction potential of ADMIRE was further assessed specifically for the task of detecting small (<=6 mm) low-contrast (<=20 HU) lesions. A new low-contrast detectability phantom (with uniform background) was designed and fabricated using a multi-material 3D printer. The phantom was imaged at multiple dose levels and images were reconstructed with FBP and ADMIRE. Human perception experiments were performed to measure the detection accuracy from FBP and ADMIRE images. It was found that ADMIRE had equivalent performance to FBP at 56% less dose.</p><p>Using the same image data as the previous study, a number of different mathematical observer models were implemented to assess which models would result in image quality metrics that best correlated with human detection performance. The models included naïve simple metrics of image quality such as contrast-to-noise ratio (CNR) and more sophisticated observer models such as the non-prewhitening matched filter observer model family and the channelized Hotelling observer model family. It was found that non-prewhitening matched filter observers and the channelized Hotelling observers both correlated strongly with human performance. Conversely, CNR was found to not correlate strongly with human performance, especially when comparing different reconstruction algorithms.</p><p>The uniform background phantoms used in the previous studies provided a good first-order approximation of image quality. However, due to their simplicity and due to the complexity of iterative reconstruction algorithms, it is possible that such phantoms are not fully adequate to assess the clinical impact of iterative algorithms because patient images obviously do not have smooth uniform backgrounds. To test this hypothesis, two textured phantoms (classified as gross texture and fine texture) and a uniform phantom of similar size were built and imaged on a SOMATOM Flash scanner (Siemens Healthcare). Images were reconstructed using FBP and a Sinogram Affirmed Iterative Reconstruction (SAFIRE). Using an image subtraction technique, quantum noise was measured in all images of each phantom. It was found that in FBP, the noise was independent of the background (textured vs uniform). However, for SAFIRE, noise increased by up to 44% in the textured phantoms compared to the uniform phantom. As a result, the noise reduction from SAFIRE was found to be up to 66% in the uniform phantom but as low as 29% in the textured phantoms. Based on this result, it clear that further investigation was needed into to understand the impact that background texture has on image quality when iterative reconstruction algorithms are used.</p><p>To further investigate this phenomenon with more realistic textures, two anthropomorphic textured phantoms were designed to mimic lung vasculature and fatty soft tissue texture. The phantoms (along with a corresponding uniform phantom) were fabricated with a multi-material 3D printer and imaged on the SOMATOM Flash scanner. Scans were repeated a total of 50 times in order to get ensemble statistics of the noise. A novel method of estimating the noise power spectrum (NPS) from irregularly shaped ROIs was developed. It was found that SAFIRE images had highly locally non-stationary noise patterns with pixels near edges having higher noise than pixels in more uniform regions. Compared to FBP, SAFIRE images had 60% less noise on average in uniform regions for edge pixels, noise was between 20% higher and 40% lower. The noise texture (i.e., NPS) was also highly dependent on the background texture for SAFIRE. Therefore, it was concluded that quantum noise properties in the uniform phantoms are not representative of those in patients for iterative reconstruction algorithms and texture should be considered when assessing image quality of iterative algorithms.</p><p>The move beyond just assessing noise properties in textured phantoms towards assessing detectability, a series of new phantoms were designed specifically to measure low-contrast detectability in the presence of background texture. The textures used were optimized to match the texture in the liver regions actual patient CT images using a genetic algorithm. The so called “Clustured Lumpy Background” texture synthesis framework was used to generate the modeled texture. Three textured phantoms and a corresponding uniform phantom were fabricated with a multi-material 3D printer and imaged on the SOMATOM Flash scanner. Images were reconstructed with FBP and SAFIRE and analyzed using a multi-slice channelized Hotelling observer to measure detectability and the dose reduction potential of SAFIRE based on the uniform and textured phantoms. It was found that at the same dose, the improvement in detectability from SAFIRE (compared to FBP) was higher when measured in a uniform phantom compared to textured phantoms.</p><p>The final trajectory of this project aimed at developing methods to mathematically model lesions, as a means to help assess image quality directly from patient images. The mathematical modeling framework is first presented. The models describe a lesion’s morphology in terms of size, shape, contrast, and edge profile as an analytical equation. The models can be voxelized and inserted into patient images to create so-called “hybrid” images. These hybrid images can then be used to assess detectability or estimability with the advantage that the ground truth of the lesion morphology and location is known exactly. Based on this framework, a series of liver lesions, lung nodules, and kidney stones were modeled based on images of real lesions. The lesion models were virtually inserted into patient images to create a database of hybrid images to go along with the original database of real lesion images. ROI images from each database were assessed by radiologists in a blinded fashion to determine the realism of the hybrid images. It was found that the radiologists could not readily distinguish between real and virtual lesion images (area under the ROC curve was 0.55). This study provided evidence that the proposed mathematical lesion modeling framework could produce reasonably realistic lesion images.</p><p>Based on that result, two studies were conducted which demonstrated the utility of the lesion models. The first study used the modeling framework as a measurement tool to determine how dose and reconstruction algorithm affected the quantitative analysis of liver lesions, lung nodules, and renal stones in terms of their size, shape, attenuation, edge profile, and texture features. The same database of real lesion images used in the previous study was used for this study. That database contained images of the same patient at 2 dose levels (50% and 100%) along with 3 reconstruction algorithms from a GE 750HD CT system (GE Healthcare). The algorithms in question were FBP, Adaptive Statistical Iterative Reconstruction (ASiR), and Model-Based Iterative Reconstruction (MBIR). A total of 23 quantitative features were extracted from the lesions under each condition. It was found that both dose and reconstruction algorithm had a statistically significant effect on the feature measurements. In particular, radiation dose affected five, three, and four of the 23 features (related to lesion size, conspicuity, and pixel-value distribution) for liver lesions, lung nodules, and renal stones, respectively. MBIR significantly affected 9, 11, and 15 of the 23 features (including size, attenuation, and texture features) for liver lesions, lung nodules, and renal stones, respectively. Lesion texture was not significantly affected by radiation dose.</p><p>The second study demonstrating the utility of the lesion modeling framework focused on assessing detectability of very low-contrast liver lesions in abdominal imaging. Specifically, detectability was assessed as a function of dose and reconstruction algorithm. As part of a parallel clinical trial, images from 21 patients were collected at 6 dose levels per patient on a SOMATOM Flash scanner. Subtle liver lesion models (contrast = -15 HU) were inserted into the raw projection data from the patient scans. The projections were then reconstructed with FBP and SAFIRE (strength 5). Also, lesion-less images were reconstructed. Noise, contrast, CNR, and detectability index of an observer model (non-prewhitening matched filter) were assessed. It was found that SAFIRE reduced noise by 52%, reduced contrast by 12%, increased CNR by 87%. and increased detectability index by 65% compared to FBP. Further, a 2AFC human perception experiment was performed to assess the dose reduction potential of SAFIRE, which was found to be 22% compared to the standard of care dose. </p><p>In conclusion, this dissertation provides to the scientific community a series of new methodologies, phantoms, analysis techniques, and modeling tools that can be used to rigorously assess image quality from modern CT systems. Specifically, methods to properly evaluate iterative reconstruction have been developed and are expected to aid in the safe clinical implementation of dose reduction technologies.</p> / Dissertation

The Notch receptor family plays a key role in development and disease. In cancer, Notch can act either as an oncogene or as a tumour suppressor, and possibly as a cancer stem-cell factor. Whereas most research has focused on downstream signalling events, little is known about the cell surface organisation of Notch and its ligands. The extracellular part of Notch consists mainly of 36 epidermal growth factor-like domains (EGF-domains), many of which bind calcium. Studies have shown that tandem repeats of calcium-binding EGF domains form a rigid linear arrangement; however, the lack of calcium binding in EGF6, EGF10 and EGF22 led to the hypothesis that these might be sites of flexibility. This thesis addresses the effect of these domains on the organisation of the extracellular region of Notch and provides further insight into the calcium-binding properties of Notch. NMR residual dipolar coupling (RDC) measurements of these regions are presented, together with the X-ray crystallographic data obtained in collaboration. The crystal structure of the human Notch-1 construct EGF4-7 shows a tilt angle of 90° at the EGF5-6 interface which is much larger than the tilt angles of 10-20° observed for the EGF11-13 crystal structure. RDC measurements demonstrated an angle of ~70° in solution. The crystal structures of EGF21-23 and EGF20-23 showed a rod-shaped interface for the EGF21-22 domain, in which a cis-proline forms the packing interaction to a tyrosine at the β-turn in the major β-sheet of EGF22. These two interfaces are novel and demonstrate the possibility of interface formation without Ca²⁺. Crystallisation was unsuccessful for the EGF8-11 construct. However, RDC measurements indicate interdomain motion between EGF9 and EGF10 demonstrating a flexible interface. These data establish new information on the structural organisation and calcium-binding properties of the extracellular region of Notch and identify flexible and rigid interfaces within multiple tandem repeats of EGF domains. This information will be invaluable in constructing models of Notch-ligand complexes for testing in future functional experiments.

L- and M-shell x-ray production cross sections have been measured for thin solid targets of neodymium, gadolinium, holmium, ytterbium, gold, and lead by 25 MeV 12/6C^q+ (q=4,5,6) and by 32 MeV 16/8O^q+ (q=5,7,8). The cross sections were determined from measurements made with thin targets (< 2.5 μg/cm2). For projectiles with one or two K-shell vacancies, the target x-ray production cross sections were found to be enhanced over those for projectiles without a K-shell vacancy. The sum of direct ionization to the continuum (DI) plus electron capture (EC) to the L, M, N... shells and EC to the K-shell of the projectile have been extracted from the data. The results are compared to the predictions of first Born theories, i.e., plane wave Born approximation for DI and Oppenheimer-Brinkman-Kramers formula of Nikolaev for EC and to the ECPSSR approach that accounts for Energy loss and Coulomb deflection of the projectile as well as for Relativistic and Perturbed Stationary States of inner shell electrons.

The optimization of powder x-ray diffraction (PXRD) for the study of cheese crystals was the focus of this study. A survey was conducted of various manifestations of calcium lactate crystals on the rindless surface and within mechanical openings of Cheddar cheese using PXRD. The diffraction reference card database contained a card that was entitled calcium lactate pentahydrate and corresponded to some of the crystalline material found on the cheeses. Diffractions patterns generated from other samples of crystalline material revealed the existence of an unknown crystal that resembled and behaved similarly to calcium lactate pentahydrate, but did not match the reference card. The existence of two enantiomeric variants of calcium lactate pentahydrate had been firmly established; an experiment was thus designed to determine if the unknown diffraction pattern represented one enantiomeric form, and if the ambiguously named reference card represented the other. This experiment demonstrated that the existing reference card corresponded to calcium DL-lactate pentahydrate and that the unknown diffraction pattern was generated from calcium L-lactate pentahydrate. This study resulted in the proposal of a new reference card for calcium L-lactate pentahydrate and the proposed renaming of the existing card to calcium DL-lactate pentahydrate. This discovery allows the rapid identification of both forms of calcium lactate that form in and on cheese. In order to conduct the survey and experiment that are described above, the PXRD method needed to be adjusted for use with cheese crystals. Samples of cheese crystals pose a particular challenge because they are often composed of high proportions of moisture, fat, protein, and other amorphous material; these all disrupt the efficient diffraction of crystals and thus needed to be removed or minimized. The removal of water from samples is a particular challenge because some cheese crystals contain water of hydration that may be driven off in the process, thereby destroying the crystals. A protocol for the preparation of cheese samples for PXRD was consequently developed.

A novel geometry for powder X-ray diffraction (XRD), termed ‘focal construct geometry’ (FCG) is introduced and developed with both non-ideal samples and non-ideal sample conditions. FCG utilises an annular beam that has the unique feature of ‘focusing’ scattering maxima at single loci along a primary axis, hence offering diffraction data of enhanced intensity. This main advantage of FCG can be used within fields in need of rapid material identification, such as security screening in airports. A theoretical comparison between FCG and conventional transmission mode XRD showed that even though FCG suffers from broader diffraction peaks, an alternative approach to FCG data interpretation has the potential to provide narrower scattering maxima than conventional XRD. However, in order to employ this approach, discrimination between converging and diverging FCG scattering maxima is essential. Peak broadening was investigated by altering various aspects of FCG instrumentation components by either pencil beam XRD or FCG, indicating broad diffraction peaks independent of the beam geometry employed. Development of FCG resulted in the successful analysis of non-ideal samples, such as non-crystalline liquid samples, samples exhibiting preferred orientation and samples with large grain size, demonstrating advantages over conventional XRD. Furthermore, ideal samples (in terms of crystallinity, preferred orientation and grain size) were analysed by FCG under non-ideal conditions. This involved randomly orientating a single planar sample with respect to the primary axis, contrary to previous research that present FCG with a single planar sample normal to the primary axis. Sample rotation resulted in FCG scattering maxima with different xyz coordinates depending on the degree, axis and direction of rotation. Moreover, FCG analysis of multiple samples (normal to the primary axis) showed that as with all XRD arrangements, a priori knowledge of the samples’ position along the primary axis is required for effective data analysis. Investigation into the ability of FCG’s annular beam to act as a pre-sample coded aperture demonstrated an alternative method to interpret FCG images by recovering conventional XRD data. Additionally, two novel post-sample encoders (linear wire and Archimedean spiral) were considered. This enabled spatial discrimination of unknown samples along a primary axis and material identification for conventional XRD techniques. Combination of FCG with an absorbing edge post-sample encoder indicated discrimination between converging and diverging FCG scattering maxima. This ability can enable interpretation of single FCG images, as well as depth information of unknown samples within an inspection volume (e.g. airport luggage), hence enabling material identification.