The CXC chemokine receptor 4 (CXCR4) and the atypical chemokine receptor 3 (ACKR3) are seven transmembrane receptors that are involved in numerous pathologies, including several types of cancers. Both receptors bind the same chemokine, CXCL12, leading to significantly different outcomes. While CXCR4 activation generally leads to canonical GPCR signaling, involving Gi proteins and β‐arrestins, ACKR3, which is predominantly found in intracellular vesicles, has been shown to signal via β‐arrestin‐dependent signaling pathways. Understanding the dynamics and kinetics of their activation in response to their ligands is of importance to understand how signaling proceeds via these two receptors. In this thesis, different Förster resonance energy transfer (FRET)‐based approaches have been combined to individually investigate the early events of their signaling cascades. In order to investigate receptor activation, intramolecular FRET sensors for CXCR4 and ACKR3 were developed by using the pair of fluorophores cyan fluorescence protein and fluorescence arsenical hairpin binder. The sensors, which exhibited similar functional properties to their wild‐type counterparts, allowed to monitor their ligand-induced conformational changes and represent the first RET‐based receptor sensors in the field of chemokine receptors. Additional FRET‐based settings were also established to investigate the coupling of receptors with G proteins, rearrangements within dimers, as well as G protein activation. On one hand, CXCR4 showed a complex activation mechanism in response to CXCL12 that involved rearrangements in the transmembrane domain of the receptor followed by rearrangements between the receptor and the G protein as well as rearrangements between CXCR4 protomers, suggesting a role of homodimers in the activation course of this receptor. This was followed by a prolonged activation of Gi proteins, but not Gq activation, via the axis CXCL12/CXCR4. In contrast, the structural rearrangements at each step of the signaling cascade in response to macrophage migration inhibitory factor (MIF) were dynamically and kinetically different and no Gi protein activation via this axis was detected. These findings suggest distinct mechanisms of action of CXCL12 and MIF on CXCR4 and provide evidence for a new type of sequential signaling events of a GPCR. Importantly, evidence in this work revealed that CXCR4 exhibits some degree of constitutive activity, a potentially important feature for drug development. On the other hand, by cotransfecting the ACKR3 sensor with K44A dynamin, it was possible to increase its presence in the plasma membrane and measure the ligand‐induced activation of this receptor. Different kinetics of ACKR3 activation were observed in response to CXCL12 and three other agonists by means of using the receptor sensor developed in this thesis, showing that it is a valuable tool to study the activation of this atypical receptor and pharmacologically characterize ligands. No CXCL12‐induced G protein activation via ACKR3 was observed even when the receptor was re-localized to the plasma membrane by means of using the mutant dynamin. Altogether, this thesis work provides the temporal resolution of signaling patterns of two chemokine receptors for the first time as well as valuable tools that can be applied to characterize their activation in response to pharmacologically relevant ligands. / Der CXC Chemokin‐Rezeptor 4 (CXCR4) und der atypische Chemokin‐Rezeptor 3 (ACKR3) sind heptatransmembranäre Rezeptoren, die in zahlreichen Krankheitsbildern eine Rolle spielen, wie in einigen Krebsarten. Beide Rezeptoren werden zwar von dem gleichen Chemokin CXCL12 aktiviert, allerdings mit unterschiedlichen Signalweiterleitungsmustern. Die Aktivierung von CXCR4 führt zu kanonischer GPCR Signaltransduktion über Gi‐Proteine und β‐Arrestine. Die Signalweiterleitung des Rezeptors ACKR3 hingegen, welcher hauptsächlich in intrazellulären Vesikeln vorliegt, erfolgt über ß‐Arrestinabhängige Signalwege. Es ist von großer Wichtigkeit die Dynamik und Kinetik dieser beiden Rezeptoren hinsichtlich der Aktivierung durch ihre Liganden und der Signalweiterleitung zu verstehen. In dieser Arbeit wurden verschiedene Förster‐Resonanzenergietransfer (FRET) Anwendungen kombiniert, um die frühen Phasen der Signal‐Kaskade von CXCR4 und ACKR3 zu untersuchen. Zur genaueren Aufklärung der Rezeptoraktivierung wurden intramolekulare FRET‐Sensoren entwickelt, hierzu wurden die Fluorophore Cyan‐fluoreszierendes Protein und engl. fluorescence arsenical hairpin binder verwendet. Die generierten Sensoren zeigten ähnliche funktionelle Eigenschaften wie die unveränderten Rezeptoren. Liganden‐induzierte Änderungen der Rezeptorkonformation können mittels dieser Sensoren beobachtet werden und stellen die ersten RET‐basierten Sensoren auf dem Forschungsgebiet der Chemokin‐Rezeptoren dar. Weitere FRET‐basierte Methoden wurden zur Untersuchung von Interaktionen zwischen Rezeptor und G‐Protein, Neuanordnung von Dimeren, sowie der G‐Protein Aktivierung eingesetzt und für beide Chemokin‐Rezeptoren etabliert. CXCR4 zeigte einen komplexen Aktivierungsmechanismus nach Stimulation durch CXCL12, bei welchem zunächst eine Neuordnung der Rezeptor‐Transmembrandomäne gefolgt von Neuordnungen zwischen Rezeptor und G‐Protein und zuletzt eine Neuordnung zwischen CXCR4 Protomeren erfolgte. Dies impliziert, dass im Aktivierungsprozess des Rezeptors Homodimere eine Rolle spielen. Zudem wurde eine verlängerte Gi ‐Protein Aktivierung gegenüber der Gq‐Protein Aktivierung bei CXCL12 stimuliertem CXCR4 beobachtet. Hingegen zeigte eine Stimulierung mit dem Macrophage Migration Inhibitory Factor (MIF) bei jedem Schritt der frühen Singal‐Kaskade veränderte Dynamiken und Kinetiken im Vergleich zu CXCL12. Darüber hinaus konnte keine Gi ‐Protein Aktivierung festgestellt werden. Dieser Befund zeigt individuelle Mechanismen für MIF und CXCL12 am CXCR4‐Rezeptor und liefert Belege für eine neuer Art von sequenziellen Signalweiterleitungen an GPCRs. Eine wichtige Beobachtung dieser Arbeit für eine potentielle Medikamentenentwicklung ist das CXCR4 ligandenunabhängige Aktivität zeigt. Um die Aktivierung des ACKR3 Sensors messen zu können wurde durch eine Co‐Transfektion mit K44A Dynamin eine höhere Membranständigkeit erreicht. CXCL12 und drei weiteren Agonisten zeigten am hier entwickelten ACKR3‐Sensor unterscheidbare Kinetiken. Mit diesem wertvollen Werkzeug können Liganden an diesem atypischen Rezeptor pharmakologisch charakterisiert werden. Es konnte keine CXCL12‐induzierte G‐Protein Aktivierung gemessen werden, trotz der stärkeren Präsenz an der Plasmamembran mit Hilfe der Dynamin‐Mutante. In Summe liefert diese Arbeit zum ersten Mal eine zeitliche Auflösung von Signalweiterleitungsmustern von zwei Chemokin‐Rezeptoren sowie wertvolle Werkzeuge zur Charakterisierung der frühen Phase der Signal‐Kaskade durch andere pharmakologisch relevanten Liganden.

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Visualizing and interacting with engineering analysis results can provide valuable insights into a system's performance and aid in engineering decision-making. Currently, the majority of analysis codes are developed as isolated solutions focusing only on the most prominent physical influence to a system, such as thermal, structural, fluid, etc. Frequently, more than one of these physical influences combined to force engineers to evaluate complex, coupled systems. Coupled analysis codes are becoming more common place tools for engineers demanding high fidelity simulations of complex systems. External code coupling solutions are emerging to permit generic coupling of separate, world class CAE solvers thus providing a more general class of multidisciplinary simulations. The true value of an engineering analysis is determined by the accuracy of the analysis code and the ability to interpret all of the significant information contained in the analysis results. Post-processing visualization tools have long been valued for their ability to aid engineers in interpreting all of the significant information contained in non-coupled CAE analysis results. The tie between non-coupled CAE solvers and post-processing visualization tools is poorly defined and currently few general post-processing visualization tools exist capable of interpreting a wide range of differing CAE results. The few tools capable of general post-processing require extensive development of dozens of data readers or translators to accommodate the slew of varying CAE data formats. As coupled CAE solutions emerge, a need exists to standardize the data exchange between CAE solvers and post-processing visualization tools. A format for this standard CAE data exchange, similar to IGES for CAD/CAM data, is proposed. The object of this research is to bridge the gap between external code couplers and post-processing visualization tools to initiate visualization and interaction with these externally coupled results. This fusion of two dissimilar technologies affords a greater level of result interpretation to support engineering decision-making. A general integration architecture is presented and a proof of concept with industry leading tools is developed to demonstrate the benefits of a tight integration between external code couplers and post-processing visualization tools. Examples are presented of visualizing externally coupled results. This research lets the engineer significantly interact with and visualize more complex problems, solved in preferred world class tools, in a timely and streamlined manner.

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has risen to among the top tier techniques for the direct analysis of solid samples. However, significant problems remain that must be solved to achieve the full analytical potential of LA-ICP-MS. Inefficient conversion of aerosol to ions within the ICP or transmission through the MS interface may decrease precision, sensitivity, and/or accuracy. Although fundamental mechanisms that govern ion production and transmission have been studied extensively in solution-nebulization (SN) ICP-MS instruments, significant gaps in our understanding remain. Furthermore, it is unclear to what extent differences between the aerosols generated during SN and LA influence either ion production or transmission. In this work, I initially investigated differences in the spatial distributions of Ca, Ba, and Sc ions generated by LA and SN using high-resolution LIF imaging. Ions formed from aerosol generated by LA at low fluence were distributed over much greater axial and narrower radial distances than SN aerosol. Additionally, I investigated the effects of solvent, laser fluence, and ablation atmosphere (He vs Ar) on ion distributions in the ICP. Unlike solvent, changing laser fluence and ablation atmosphere produced considerable changes in the ion signal intensity and spatial distribution during LA. At greater laser fluence, the radial distance over which ions were distributed dramatically increased. Surprisingly, when helium was mixed with argon as carrier gas, ion signals decreased. Many of these effects were assumed to be related to changes in the number and size of particles generated during LA. In a follow-up study, relative contributions to ion densities in the ICP from particles of different sizes were investigated. LIF images were recorded while filtering particles above a threshold size on-line. Micron-sized particles contributed the majority of ions formed in the ICP. For Ba, Ca, and Sc, differences in the axial position where nanometer- and micron-sized particles vaporized were 2, 1, and less than 1 mm, respectively. I also performed experiments to identify changes in the ion signal related to changing ablation conditions vs. changing ICP conditions associated with helium additions to the carrier gas. LIF images were recorded during different combinations of He/Ar added upstream and/or downstream of the ablation cell. Changes in the ion signal during ablation in helium vs argon did not always match expectations based on changes in particle numbers and sizes measured with SEM. The results force re-examination of some of the fundamental assumptions about the effect of carrier gas composition on the performance of LA-ICP-MS. The research described in this dissertation provides valuable insight into fundamental aspects of key ICP processes related to LA generated aerosol.

Antenna-coupled detectors provide uncooled, cost-effective solutions for infrared and millimeter-wave imaging. This work describes the design, fabrication, measurement, and optimization of several types of antenna-coupled detectors for LWIR (8 - 12 µm) and 94 GHz radiation. Two types of millimeter-wave antenna-coupled detectors were fabricated and tested: a slot antenna coupled to a bolometer, and a patch antenna coupled to a SiC Schottky diode. Electromagnetic modeling of the antennas helped guide the design of antennas with better impedance matching to the detectors. Schottky diodes are discussed as detectors for millimeter-wave and infrared radiation, with the goal of increasing the cutoff frequency to allow infrared detection. The magnitude of response of antenna-coupled bolometric detectors to infrared radiation is affected by the thermal-conduction properties of the sensor structure. Two fabrication processes were developed to improve the thermal isolation of the antenna-coupled bolometer from its substrate. The first process creates a membrane beneath the device. Measured results show a factor of 100 increase in responsivity over an identical device without a membrane. The second process thermally isolates the device from its substrate by suspending the metallic structure in air. Several factors for optimization of infrared antenna-coupled detectors are investigated. The complex dielectric function of the metal from which the antenna is constructed can affect the performance of the device. The use of a ground plane and dielectric standoff layer beneath the antenna can increase the sensor responsivity. Dielectric material properties and thicknesses are considered, and incorporated in device simulations. Finally, a potential fabrication process is presented for via connections from the antenna-coupled detector through a ground plane to bond pads to mitigate the effect of bias lines on antenna behavior.

This dissertation analyzes the fundamental limits for the determination of the network structure of loosely coupled oscillators based on observing the behavior of the network, specifically, node synchronization. The determination of the requisite characteristics and underlying behaviors necessary for the application of a theoretical mechanism for determining the underlying network topology in a network of loosely coupled natural oscillators are the desired outcome. To that end, this effort defines an analytical framework where key components of networks of coupled oscillators are isolated in order to determine the relationships between the various components. The relationship between the number of nodes in a network, the number of connections in the network, the number of connections of a given node, the distribution of the phases of the network, and the resolution of measurement of the components of the network, and system noise is investigated.

Electricity has become so ingrained in everyday life that the current generation has no knowledge of life without it. The majority of power generation in the United States is the result of turbines of some form. With such widespread utilization of these complex rotating machines, any increase in efficiency translates into improvements in the current cost of energy. These improvements manifest themselves as reductions in greenhouse emissions or possible savings to the consumer. The most important temperature regarding turbine performance is the temperature of the hot gas entering the turbine, denoted turbine inlet temperature. Increasing the turbine inlet temperature allows for increases in power production as well as increases in efficiency. The challenge with increasing this temperature, currently the hottest temperature seen by the turbine, is that it currently already exceeds the melting point of the metals that the turbine is manufactured from. Active cooling of stationary and rotating components in the turbine is required. Cooling flows are taken from bleed flows from various stages of the compressor as well as flow from the combustor shell. This cooling flow is considered wasted air as far as performance is concerned and can account for as much as 20% of the mass flow in the hot gas path. Lowering the amount of air used for cooling allows for more to be used for performance gain. Various technologies exist to allow for greater turbine inlet temperatures such as various internal channel features inside of turbine blades, film holes on the surface to cool the outside of the airfoil as well as thermal barrier coatings that insulate the airfoils from the hot mainstream iv flow. The current work is a study of the potential performance impact of coupling two effusion technologies, transpiration and discrete hole film cooling. Film cooling and transpiring flows are individually validated against literature before the two technologies are coupled. The coupled geometries feature 13 film holes of 7.5mm diameter and a transpiring strip 5mm long in the streamwise direction. The first coupled geometry features the porous section upstream of the film holes and the second features it downstream. Both geometries use the same crushed aluminum porous insert of nominal porosity of 50%. Temperature sensitive paint along with an ‘adiabatic’ Rohacell surface (thermal conductivity of 0.029W/m-K) are used to measure adiabatic film cooling effectiveness using a scientific grade high resolution CCD camera. The result is local effectiveness data up to 50 film hole diameters downstream of injection location. Data is laterally averaged and compared with the baseline cases. Local effectiveness contours are used to draw conclusions regarding the interactions between transpiration and discrete hole film cooling. It is found that a linear superposition method is only valid far downstream from the injection location. Both coupled geometries perform better than transpiration or the discrete holes far downstream of the injection location. The coupled geometry featuring the transpiring section downstream of the film holes matches the transpiration effectiveness just downstream of injection and surpasses both transpiration and film cooling further downstream.

<p> A general formulation of the analysis of plane coupled shear walls is presented. The "continuous method" of analysis of coupled shear walls is reformulated in terms of deflection variables. The assumption that midpoints of the connecting beams are points of contraflexure is relaxed so that the resulting theory is applicable to the general case where the lateral loading on the piers can be arbitrarily distributed. The governing equation of the structural system under static loading with the appropriate boundary conditions are given. The effect of asymmetry of the structure is discussed. As an application of the derived theory, the problem of shear walls subjected to differential foundation settlement and rotation is studied. Solutions to deflections and internal stresses, under such conditions, are given. Evaluation of the internal stresses was performed on a practical shear wall structure and the results analysed. Through the use of deflection variables, the formulation is extended into the regime of dynamics. The governing equation of motion with appropriate boundary conditions are given. The free vibration of coupled shear walls is studied and design curves for the fundamental natural frequency are presented. The use of substitutive symmetric systems and its effects on the fundamental frequency of asymmetric systems are examined. Theoretical natural frequencies were verified by dynamic testing on two models to show that the proposed theory is sufficiently accurate to provide information for dynamic analysis in seismic design. / Thesis / Master of Engineering (ME)

<p> This thesis presents the results of an investigation of an integrated direct coupled grounded gyrator. A complete analysis is presented for the gyrator using components available in integrated circuit form. Integrated circuit layout and fabrication procedures are discussed. </p> <p> Close agreement between theoretical and experimental results is shown. The Q factor of a simulated inductor shows good stability over a wide range of frequency, temperature, and voltage supply. </p> / Thesis / Master of Engineering (ME)

Optical and spectroscopic molecular properties are key to characterizing the behavior of molecules interacting with an applied electromagnetic field of light. Response theory has been used for a long time to calculate such properties in the frequency domain. Real-time (RT) methods solve for the frequency-dependent properties in the time domain by explicitly propagating the time-dependent wave function. Various quantum chemical methods can be incorporated with the RT formalism, including Hartree-Fock, density functional theory, configurational interaction, coupled cluster, etc. Among these, coupled cluster (CC) methods provide high accuracy for systems with strong electron correlation, making RT-CC implementations intriguing. All applications of CC methods face a substantial challenge due to their high-order polynomial scaling. For RT-CC methods, two aspects may be explored to improve the efficiency, the numerical techniques regarding the RT propagation and the reduced-scaling methods regarding CC itself. In this work, we start with the exploration of the hardware used for the calculations and the numerical integration methods for propagating the wave function parameters. Firstly, a GPU-enabled Python implementation has been developed by conducting the tensor contractions on GPUs utilizing PyTorch, a machine learning package, that has similar syntax as NumPy for tensor operations. A speedup of a factor of 14 is obtained for the RT-CCSD/cc-pVDZ absorption spectrum calculation of the water tetramer. Furthermore, to optimize the performance on GPUs, single-precision arithmetic is added to the implementation to achieve an additional speedup of a factor of two. Lastly, a group of integrators for solving differential equations are introduced to the RT framework, including regular explicit integrators, adaptive integrators, and a mixed-step-size approach customized for strong-field simulations. The optimal choice of the integrator depends on the requiring accuracy, stability and efficiency. In addition to being highly accurate, CC methods are also systematically improvable and provide a hierarchy of accuracy. Based upon the RT-CCSD implementation, the coupled cluster singles, doubles and approximate triples (CC3) method, favorable for calculating frequency-dependent properties, is tailored to the RT framework for high excitation and approximate orbital relaxation. The calculation is tested on both CPUs and GPUs, with a significant speedup gained from GPUs for the water cluster test cases. To further expand the range of applications of our RT-CC implementation, dynamic polarizabilities, first hyperpolarizabilities, and the G' tensor are calculated from induced electric and magnetic dipole moments using finite-difference methods. A discussion has also been conducted to compare RT-CC3 with RT-CCSD, and time-dependent nonorthogonal orbital-optimized coupled cluster doubles (TDNOCCD) method. Additionally, electron dynamics, including the Rabi oscillation and exited state to excited state transitions, have also been explored utilizing the well-developed RT-CC framework. / Doctor of Philosophy / Theoretical studies aim to match experiments, but more importantly, provide insights to interpret and predict experimental data. Calculating optical properties related to light-matter interactions is one of the most crucial tasks for characterizing molecular properties. In experiments, electromagnetic radiation in the form of light is applied to the system. The absorption or emission of light can be measured to identify, for example, the electronic structure of the molecule. In theoretical simulations, this applied radiation is represented by a perturbation operator that is added to the Hamiltonian in the Schrödinger equation. Quantum chemists are dedicated to developing methods that provide a better description of the spectroscopy. In the current work, the frequency, shape and the intensity of the radiation can all be finely-tuned, similar to experimental setups. The framework for extracting optical properties from time-dependent trajectories of induced dipole moments is established for accurate and efficient simulations. To improve efficiency and make the method feasible for real-world applications, a strong understanding of light-matter interactions on a quantum level and proper utilization of computational resources are both necessary. Improvements achieved and presented in this dissertation demonstrate a powerful tool for a better understanding of the nature of the interaction between the system and the electromagnetic radiation.