Deep brain stimulation (DBS) improves the quality of life for patients suffering from neurological disorders such as Parkinson’s disease and, more recently, psychiatric/cognitive disorders such as depression and addiction. This treatment option involves the implantation of an implantable pulse generator (or neurostimulator) and leads (or electrodes) implanted deep within the human brain. Magnetic resonance imaging (MRI) is a powerful diagnostic tool that offers superior soft tissue contrast and is routinely used in clinics for neuroimaging applications. MRI is advantageous in DBS pre-surgical planning as precise lead placement within the brain is essential for optimal treatment outcomes. DBS patients can also benefit from post-surgery MRI, and studies have shown that DBS patients are more likely to require MRI within 5-10 years post-surgery. However, imaging DBS patients is restricted by substantial safety concerns that arise from localized electric charge accumulation along the implanted device during resonant radiofrequency (RF) excitation, which can potentially lead to tissue heating and bodily damage. With the technological advancement of ultra-high field (UHF) MRI systems and a growing DBS patient population, DBS MRI safety will become increasingly problematic in the future and needs to be addressed. Parallel RF transmission (pTx) is a promising technology that utilizes multiple transmit channels to generate a desired electromagnetic profile during MRI RF excitation. Several proof-of-concept studies successfully demonstrated its efficacy in creating a "safe mode" of imaging that minimizes the localized RF heating effects. However, pTx MRI systems are not easily accessible and are often custom-built and integrated onto existing MRI systems. Consequently, it adds system characterization and verification complexity to the DBS MRI safety problem. System channel count is also an important consideration as implementation costs can be very high, and the impact of system transmit channel count remains unexplored. Furthermore, in practice, DBS patients with motor-related disorders will impact the pTx MRI system’s ability to precisely generate these safe mode electromagnetic profiles. Commercial DBS devices (i.e., the neurostimulator and leads) are manufactured with fixed dimensions, and the caring surgeon typically manages the surgical orientation of the implanted DBS device and leads. Therefore, lead trajectories can vary hospital-to-hospital. As a result, standard phantoms, i.e., the ASTM International Standard, used in safety verification experiments may not be suitable for DBS MRI applications. To advance DBS patient safety in MRI, this thesis studied the implant heating effects of pTx system uncertainty, system channel count, patient motion on a novel pTx MRI research platform and its associated safe mode of imaging. It developed a new anthropomorphic heterogeneous phantom to improve safety verification experiments. / Dissertation / Doctor of Philosophy (PhD)

The random-coil model has been dominant for unfolded proteins since the 1950’s; however, some experiments showed that the unfolded proteins were biased toward specific conformations in conflict with the random-coil model. Recently, residual dipolar couplings (RDCs) and paramagnetic relaxation enhancement (PRE) were applied to obtain a large amount of structural information on unfolded proteins. Typically, these data were interpreted in a framework of random-coil ensembles with a good agreement between experimental data and theoretical predictions. In this thesis, it was tested whether locally organized nonrandom ensembles could describe this agreement equally as well. Using a complete set of RDC and PRE data for denatured ubiquitin, it was revealed that there was no distinguishable difference between random-coil ensembles and ensembles containing 50% native structure. Thus, while it is important to measure as many RDCs or PRE as possible, even the best datasets may be insensitive to local organization in unfolded proteins.

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Yes / Magnetic Field Hyperthermia is a technique where tumours are treated through an increase in local temperature upon exposure to alternating magnetic fields (AMFs) that are mediated by magnetic nano-particles (MNPs). In an AMF, these particles heat-up and kill the cells. The relationship between an AMF and the heating-rate is complex, leading to confusion when comparing data for different MNP and AMF conditions. This work allows for the thermal-response to be monitored at multiple AMF amplitudes while keeping other parameters constant. An induction-heating coil was designed based on a Zero-Voltage-Zero-Current (ZVZC) resonant circuit. The coil operates at 93 kHz with a variable DC drive-voltage (12–30 V). NEC4 software was used to model the magnetic field distribution, and MNPs were synthesised by the coprecipitation method. The magnetic field was found to be uniform at the centre of the coil and ranged from 1 kAm−1 to 12 kAm−1, depending on the DC drive-voltage. The MNPs were found to have a specific absorption rate (SAR) of 1.37 Wg−1[Fe] and 6.13 Wg−1[Fe] at 93 kHz and 2.1 kAm−1 and 12.6 kAm−1, respectively. The measured SAR value was found to be directly proportional to the product of the frequency and field-strength (SARα f Ho). This leads to the recommendation that, when comparing data from various groups, the SAR value should be normalized following this relationship and not using the more common relationship based on the square of the field intensity (SARα f Ho2). / This work is partially supported by the UK Engineering and Physical Sciences Research Council (EPSRC) under grant EP/X039366/1, and HORIZON-MSCA-RISE ID: 101086492, Marie Skłodow-ska-Curie, Research and Innovation Staff Exchange (RISE), titled: FractuRe Orthopaedic Rehabilita-tion: Ubiquitous eHealth Solution (Robust).

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

Le objectif de ma thèse était la caractérisation moléculaire de la P des virus Nipah et Hendra (BL4) du genre Henipavirus. Le génome est encapsidé par la N qui sert de substrat pour la transcription et la réplication. La polymérase est composée par la L e son cofacteur la P. La P est composée d’un domaine N-terminal (PNT) désordonné et un domaine C-terminal (PCT) constitué d’une alternance de régions désordonnés et ordonnés (PMD domaine de multimerization). J'ai étudié PMD, PCT et PNT utilisant le «cross-linking», le CD, le SAXS, la RMN et la modélisation moléculaire. J'ai montré que le PMD du Hendra et Nipah sont un coiled-coil triméreric. La région PCT, est également un trimère en solution. Les protéines P des henipavirus constituent à ce jour le seul exemple de protéines P paramyxovirales ayant une organisation trimérique. En utilisant le SAXS, j'ai obtenu une description de Hendra PNT en tant qu’ensemble conformationnel. J'ai entrepris la caractérisation de la PNT par RMN. J’ai divisée la PNT avec l’approche divide et impera (PNT1,2,3,4). J’ai pu réaliser des expériences permettant l’attribution de PNT1, et j’ai également effectué des mesures de relaxation (R1, R2 et NOE) sur les fragments PNT1, PNT2 et PNT3. Les résultats issus des travaux effectués ont ouvert la voie vers l’obtention d’une description atomistique de la PNT en tant qu'ensemble conformationnel. Ces informations avec les informations structurales que j’ai sur PCT, PMD et XD, devraient conduire à une description atomistique de la P entière en tant qu’ensemble conformationnel. Ces informations structurales détaillées constitueront aussi un socle pour des approches antivirales rationnelles. / The objective of my PhD project was the molecular characterization of the P protein from the Nipah and Hendra viruses (BL4) belonging to the Henipavirus genus. The genome is encapsidated by the N that is the substrate for transcription and replication. The polymerase is made up the L and its cofactor the P. The P protein consists of an intrinsically disordered N-terminal domain (PNT), and a C-terminal domain (PCT) made of alternating disordered and ordered domain (PMD or P multimerization domain). I investigated the PMD, PCT and PNT regions, using cross-linking, AUC, CD, SAXS, NMR and molecular modeling. I showed that Hendra and Nipah PMD are a trimeric coiled-coil in solution. The Henipavirus proteins constitute so far the unique examples of a trimeric organization in paramyxoviral P proteins. The PCT is a trimer as well. Using SAXS, I obtained an ensemble description of PNT. To obtain site-specific information that improve SAXS-based models, I undertook the characterization of Hendra PNT by NMR. The latter was divided using the “divide et impera” approach to get four fragments (PNT1,2,3,4). Experiments for the assignment have been performed for PNT1. R1, R2 and NOE were carried out on PNT1,2,3. Altogether the results laid the basis for achieving an atomic-resolution conformational ensemble description of Hendra PNT. This information, combined with structural information that I collected on PCT, PMD and XD, is expected to lead an atomistic ensemble description of the full-length P, which would represent the first, such a description of a paramyxoviral P protein. This detailed structural information will also constitute an asset for rational antiviral approaches.

The aim of this thesis is to develop a computer program to design and simulate air conditioning-comfort application of a selected building, for a year period, on an hourly basis. In order to carry out this study, a computer program named AHUSIM.m, is prepared with Matlab computing language. The design and simulation procedure starts with preparing the inputs like indoor, outdoor design states, zone cooling and heating loads, along with the general data for conditioning-comfort equipment. The program, in light of these input data, performs the plotting of the psychrometric processes -including the design and off design processes- on psychrometric charts, air conditioning-comfort system selection and calculating the response of this selected system at varying load conditions for a year. The program also calculates the energy requirements of parts of the selected system throughout the year. Furthermore, it lists dimensions of the parts of the air conditioning-comfort unit, the outdoor supply air and total air flow rates, air and water inlet and exit states. Using numerical tools for heating, ventilating and air conditioning (HVAC) process design and simulation, can improve energy economy and comfort which are the main criteria of HVAC engineering. In such an attempt, major concern is the interaction between the comfort and energy consumption. The program, by designing the system and deciding its behavior throughout a year / provides a means of automatic control considering comfort and energy economy. This program also provides a tool for comparison of different techniques for putting limits to the relation between comfort and energy consumption.

Specifically binding ions induce the transition of anionic polyacrylate coils from extended conformation to collapsed globules passing through a cascade of intermediate states when solution conditions approach the L-type precipitation threshold. It is the conformation of these intermediate states on surfaces and in solution which is at the focus of this thesis. In comparing the surface and solution conformations of intermediate states, we were able to qualitatively and quantitatively underline the effects of sample history. Two types of quantitative comparisons have been emphasized. In real space, the radius of gyration values of adsorbed molecules have been evaluated incorporating fully the x, y and z axes. These values have been compared with radius of gyration values of the very same sample solution obtained using SLS. In reciprocal space, a novel image processing protocol has been used to generate the 2D form factor curve wherein the correlation maxima have been compared with corresponding maxima obtained for the very same sample solution using small angle scattering techniques like the SANS. The influence of bivalent ions, respectively, Strontium, Lead and Calcium, on the shape of polyacrylate coils is studied. In the last case, temperature has been introduced as a secondary parameter to shed further light on the mechanism by which polyelectrolytebivalent ion complexation takes place. Both scattering and AFM experiments reveal formation of necklace-like structures as intermediates for NaPA-Sr2+ system. Since the mol. wt. of the NaPA coils used was relatively large in this case, adsorption on mica surfaces was strong. Under such conditions, the molecules undergo a z collapse upon flux drying but do not get altered in x and y directions. The ratio Rg(AFM)/Rg(SLS) was found to be in the range 0.7-0.9. The remaining (insignificant) differences in the Rg Abstract ii values arise due to the fact that AFM gives the square root of number averaged mean squared radius of gyration while SLS gives the square root of z-averaged mean squared radius of gyration. The differences in radius of gyration values observed in solution and on surfaces were more prominent for NaPA-Pb2+ system. Again, although both scattering and AFM reveal necklace-like structures as intermediates, the ratio Rg(AFM)/Rg(SLS) was now found to be nearly 0.6. The fact that Rg(AFM) is the square root of number averaged and Rg(SLS) is the square root of z-averaged mean squared radius of gyration, alone cannot explain this low value. Since the mol. wt. of NaPA coils used in this case was quite low, adsorption on mica surfaces was weak. Under such conditions, the molecule does not only undergo a z collapse upon flux drying, but also shrinks in the x and y directions due to capillary forces. Finally, with NaPA-Ca2+ system, the picture did not show a one-to-one correspondence between solution and surface conformations at all. In fact, it showed a one-step-ahead correspondence. As already stated, the coil to globule transition was induced by increasing the equilibration temperature from 15°C to 30°C in this case. SANS could not identify any necklace-like intermediates in solution at the equilibration temperature of 15°C while AFM scans at this temperature showed the beginning of formation of pearls. Likewise, at the equilibration temperature of 30°C, SANS could identify necklace-like intermediates in solution with a large majority of dumbbells while AFM scans at this temperature showed a mix of dumbbells, sausage-like structures and globules. Indeed, we were witnessing an accelerated coil to globule transition on surfaces as compared to the situation in solution resulting in a pre-emption in the formation of intermediate states on surfaces. Since the ratio Rg(AFM)/Rg(SLS) (given the square root of number averaged and the square root of z-averaged mean Abstract iii squared values respectively) at the equilibration temperature of 30°C showed a range of 0.7-0.9 indicating strong adsorption of the relatively high mol. wt. NaPA coil on mica surfaces, our suspect were the substrate-sample interaction forces. The AFM scans were therefore analysed with 2D form factor curves, a better protocol when no assumptions about the shape of adsorbed molecules are made a priori, to trace the effects of sample history. The thesis establishes the general utility of AFM to capture the essential features of a collapsing coil which the very coil exhibits in solution. The shape of the coil on surface and in solution may not be exactly the same, yet reveal the same characteristics. The comparative advantages and disadvantages of salt pre-treated mica surfaces and chemically modified mica surfaces have been brought out. Finally, a definitive new insight is gained as regards the mechanism of coil collapse induced by specifically binding ions. The entropic nature of the process as well as the visualized shape of the collapsing intermediates does not support a mechanism along an electrostatically driven shrinking with linear, rod-like arrays of pearls as intermediates. On a molecular level, it is the liberation of water molecules and Na+ ions which promotes binding of bivalent ions to COO- residues. This binding in turn increases the hydrophobicity of the polyacrylate chains. As a consequence, the chains shrink due to an increased propensity for polymerpolymer contacts (and finally precipitate).