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Quantum Computing for Machine Learning and Physics Simulation
Get PDFQuantum computing is widely thought to provide exponential speedups over classical algorithms for a variety of computational tasks. In classical computing, methods in artificial intelligence such as neural networks and adversarial learning have enabled drastic improvements in state-of-the-art performance for a variety of tasks. We consider the intersection of quantum computing with machine learning, including the quantum algorithms for deep learning on classical datasets, quantum adversarial learning for quantum states, and variational quantum machine learning for improved physics simulation.
We consider a standard deep neural network architecture and show that conditions amenable to trainability by gradient descent coincide with those necessary for an efficient quantum algorithm. Considering the neural network in the infinite-width limit using the neural tangent kernel formalism, we propose a quantum algorithm to train the neural network with vanishing error as the training dataset size increases. Under a sparse approximation of the neural tangent kernel, the training time scales logarithmically with the number of training examples, providing the first known exponential quantum speedup for feedforward neural networks. Related approximations to the neural tangent kernel are discussed, with numerical studies showing successful convergence beyond the proven regime. Our work suggests the applicability of the quantum computing to additional neural network architectures and common datasets such as MNIST, as well as kernel methods beyond the neural tangent kernel.
Generative adversarial networks (GANs) are one of the most widely adopted machine learning methods for data generation. We propose an entangling quantum GAN (EQ-GAN) that overcomes some limitations of previously proposed quantum GANs. EQ-GAN guarantees the convergence to a Nash equilibrium under minimax optimization of the discriminator and generator circuits by performing entangling operations between both the generator output and true quantum data. We show that EQ-GAN has additional robustness against coherent errors and demonstrate the effectiveness of EQ-GAN experimentally in a Google Sycamore superconducting quantum processor. By adversarially learning efficient representations of quantum states, we prepare an approximate quantum random access memory and demonstrate its use in applications including the training of near-term quantum neural networks.
With quantum computers providing a natural platform for physics simulation, we investigate the use of variational quantum circuits to simulate many-body systems with high fidelity in the near future. In particular, recent work shows that teleportation caused by introducing a weak coupling between two entangled SYK models is dual to a particle traversing an AdS-Schwarzschild wormhole, providing a mechanism to probe quantum gravity theories in the lab. To simulate such a system, we propose the process of compressed Trotterization to improve the fidelity of time evolution on noisy devices. The task of learning approximate time evolution circuits is shown to have a favorable training landscape, and numerical experiments demonstrate its relevance to simulating other many-body systems such as a Fermi-Hubbard model. For the SYK model in particular, we demonstrate the construction of a low-rank approximation that favors a shallower Trotterization. Finally, classical simulations of finite-N SYK models suggest that teleportation via a traversable wormhole instead of random unitary scrambling is achievable with O(20) qubits, providing further indication that such quantum gravity experiments may realizable with near-term quantum hardware.</p
Photo- and Electro-Chemistry Methods for Waterborne Pathogen Treatment and Detection in Environmental Water
Get PDFWaterborne disease is a global burden, which is mainly caused by waterborne pathogens disseminated through unsafe water, inadequate sanitation, and hygiene. Antibiotic resistance, which can also spread in water, has become an increasingly serious global health threat as it can prevent the effective treatment of infectious diseases. Improvements on water treatment and detection are the two critical strategies to control the surveillance of waterborne pathogens as well as antibiotic resistance bacteria and genes. The advancement in photo- and electro-chemical methods may provide more opportunities on decentralized water treatment and on-site pathogen monitoring under source-limited conditions. This thesis is dedicated to exploring the possible solutions to automatic, rapid, and easy-to-use in situ pathogen analysis for environmental water by adopting photo- or electro-chemical method, and to enhanced removal of antibiotic resistance bacteria (ARB) and antibiotic resistance genes (ARGs) from wastewater by combining photo- and electro-chemical techniques. These include removal of ARB and ARGs by UV-assisted electrochemical treatment, electrochemical cell lysis (ECL) for DNA extraction from bacteria, and sunlight-activated propidium monoazide (PMA) pretreatment for live/dead bacteria differentiation by quantitative real-time polymerase chain reaction (qPCR) detection. Both experimental approaches and computational modelling were used to evaluate the performance of the techniques and to bring more insights into the mechanism. Each study presents a demonstration on real environmental or wastewater to access the potential of their applications under complex environmental parameters.
UV-assisted electrochemical treatment for ARB and ARGs was conducted using a blue TiO₂ nanotube array (BNTA) anode. The inactivation of tetracycline- and SMX-resistant E. coli and the corresponding plasmid coded genes (tetA and sul1) damage was measured by plate counting on selective agar and qPCR, respectively. As a comparison of UV treatment alone, the enhanced reduction of both ARB and ARGs was achieved by UV-assisted electrochemical oxidation (UV-EO) without Cl⁻ and was further facilitated with the presence of Cl⁻, which is attributed to the in-situ generated oxidants by electrochemical process. Significantly slower removal of ARG than ARB was observed for both UV irradiation alone and UV-EO treatment, wherein intracellular ARG generally reduced slower than extracellular ones, and short amplicons reduced significantly slower than long ones. The predominant nucleotide damage by UV irradiation and conformational change by UV-EO treatment was visualized by DNA gel electrophoresis for treated extracellular ARGs. The mechanism on ARB and ARGs damage was further understood by computational chemical modeling. The slower reduction was found for the native bacteria and genes, tetA and sul1, in the latrine wastewater than that in laboratory-prepared buffered samples. The result emphasizes that all the UV-based techniques may only apply after other treatments to avoid the impairment by the transmittance, color, and particulate material in environmental or wastewater.
A comprehensive investigation was conducted for ECL in terms of its performance on DNA extraction from gram-negative bacteria (Escherichia coli and Salmonella Typhi) and gram-positive bacteria (Enterococcus durans and Bacillus subtilis). A milliliter-output ECL device was developed based on the disruption of the cell membrane by OH⁻ that can be generated locally at the cathode and accumulated improvingly through a cation exchange membrane. Both gram-negative and gram-positive bacteria were successfully lysed within 1 min at a low voltage of ~5 V. To better understand the pH effects on cell lysis, the pH profile at the cathode surface and in bulk cathodic effluent was simulated via hydroxide transport in the cathodic chamber. The demonstration of ECL on various environmental water sample types (including pond water, treated wastewater, and untreated wastewater) showed its potential as a prelude to nucleic-acid based analyses of waterborne bacteria in the field.
Propidium monoazide (PMA), a nucleic acid-binding dye, has been used to distinguish live from dead cells prior to PCR-based detection. To explore the off-the-grid application of PMA, sunlight was investigated for PMA activation as an alternative light source to a typical halogen lamp. PMA was successfully activated by a solar simulator, and the pretreatment conditions were optimized with respect to the PMA concentration as 80 µM and the exposure time as 10 min. The optimal PMA pretreatment was tested on four different bacteria species (two gram-positive and two gram-negative), and the effects of sunlight intensity and multi-sequential treatment were studied. Sunlight-activated PMA pretreatment was eventually demonstrated on latrine wastewater samples with natural sunlight on both sunny and cloudy days. The results showed the potential of sunlight-activated PMA pretreatment to be integrated into a lab-on-a-chip (LOAC) PCR device for off-the-grid microbial detection and quantification.</p
Investigation of Transport Phenomena of Thermal Acoustic Excitations in Semi-Crystalline and Amorphous Materials Using Transient Grating Spectroscopy
Get PDFThe physics of transport of heat-carrying atomic vibrations in amorphous and semi-crystalline solids is a topic of fundamental interest. Diverse tools have been employed to study thermal transport in these materials, including cryogenic thermal conductivity measurements and various inelastic scattering tools. However, unambiguously identifying the damping mechanisms of few THz and smaller frequency excitations remains difficult owing to the lack of the experimental probes in the frequency band. As a result, debate has remained regarding the microscopic origin of weak acoustic damping in amorphous silicon (Si), the unusually high thermal conductivity of ultra-drawn polyethylene, and other topics.
In this thesis, we investigate the transport properties of heat-carrying acoustic excitations in semi-crystalline and amorphous solids using transient grating spectroscopy. This optical method permits the creation of thermal gradients over sub-micron length scales which may be comparable to the attenuation lengths of the excitations. We show how these measurements can be used to constrain the damping mechanisms in the sub-THz range that has been historically inaccessible by typical methods such as inelastic scattering.
First, we report measurements of the bulk thermal conductivity and elastic properties of MoS₂ thin films. Specifically, we use TG to measure the in-plane longitudinal sound velocity and thermal conductivity. We do not observe any size effects of thermal conductivity with grating period, indicating that the propagating distance of heat-carrying acoustic phonons are smaller than the thermal length scale accessible in the experiment. This result is consistent with the mean free paths predicted from ab-initio numerical methods.
Second, we utilize the capability of TG to resolve the microscopic heat transport properties of phonons in highly oriented semi-crystalline polyethylene (PE). Earlier experimental studies have reported thermal conductivities of up to ~ 100 Wm⁻¹ K⁻¹ crystalline polyethylene, orders of magnitude larger than the bulk value of ~ 0.4 Wm⁻¹ K⁻¹. However, the microscopic origin of the high thermal conductivity remains unclear. We address this question by applying TG to highly oriented polyethylene to show that mean free paths on micron length scales are the dominant heat carriers. Using a low-energy anisotropic Debye model to interpret these data, we find evidence of one-dimensional phonon density of states for excitations of frequency less than ~ 2 THz. This transition frequency is consistent with the unique features of ultradrawn PE, in particular the stiff longitudinal branch leading to wavelengths of 8 nm at 2 THz frequency; and fiber diameters < 10 nm observed in prior structural studies of ultradrawn polymers; so that the wavelength does indeed exceed the fiber diameter at the relevant frequencies.
Finally, we report the measurements of the frequency-resolved mean free path of heat-carrying acoustic excitation in amorphous silicon (aSi), for the first time. The heat-carrying acoustic excitations of amorphous silicon are of interest because their mean free paths approach the micron scale at room temperature. Despite extensive investigation, the origin of the weak acoustic damping in the heat-carrying frequencies remains a topic of debate for decades. A prior study suggested a framework of classifying the vibrations into propagons, diffusons, and locons. Propagons were considered phonon-like, delocalized, propagating vibrations; locons as localized vibrations, and diffusons as delocalized yet non-propagating vibrations. Following the framework, numerous works have predicted mechanism of acoustic damping in aSi, but the predictions have contradicted to observations in experiments. In this work, we obtained measurements of the frequency-dependent mean free path in amorphous silicon thin films from ~0.1-3 THz and over temperatures from 60 - 315 K using picosecond acoustics (PSA) and transient grating spectroscopy. We first describe our PSA experiments to resolve the attenuation of 0.1 THz acoustic excitations in aSi. We then present our table-top approach to resolve MFP of heat-carrying acoustic excitation between ~ 0.1-3 using TG spectroscopy. The mean free paths are independent of temperature and exhibit a Rayleigh scattering trend over most of this frequency range. The observed trend is inconsistent with the predictions of numerical studies based on normal mode analysis, but agrees with diverse measurements on other glasses. The micron-scale MFPs in amorphous Si arise from the absence of Akhiezer and two-level system damping in the sub-THz frequencies, leading to heat-carrying acoustic excitations with room-temperature damping comparable to that of other glasses at cryogenic temperatures. Our results allow us to establish a clear picture for the origin of micron-scale damping in aSi by understanding vibrations as acoustic excitation rather than propagons, diffusons, and locons.</p
Therapeutic Microparticles and Biolistic Drug-Delivery to the Cornea
Get PDFThe ability to deliver therapeutic compounds to the cornea using high-velocity microparticles is assessed and a method to synthesize therapeutic particles suitable for the cornea is demonstrated. Using a commercial gene gun (BioRad; PDS1000), a pneumatic capillary gun, and custom biolistic technology, microparticles were accelerated and made to embed in target materials: either homogeneous gels or corneal tissue. In homogeneous gels, penetration was shown to be directly proportional to particle size and density. In contrast, penetration of microparticles into the cornea is insensitive to particle size and density: varying the sectional density by 680% failed to penetrate beyond the epithelium (ca. 50 microns). The corneal epithelium exhibits two distinct kinetic energy thresholds that must be exceeded to first embed particles in the epithelium (rather than stopping on its anterior surface) and second to embed particles in the stroma (rather than stopping at the posterior surface of the epithelium). Penetration profiles show that the stroma is a highly effective stopping medium for high velocity microparticles. Despite the high water content of corneal tissue (76 w%) compared to the stratum corneum of skin (40 w%), the resistance to penetration of the cornea is comparable to literature values for skin. Ideal particles for drug delivery to the cornea would dissolve away completely, leaving no residue that might scatter light. With a vibrating orifice aerosol generator and a temperature-controlled column, 30-50 µm particles were composed of 1% Eosin Y with poly(ethylene glycol). Using low density polymer particles with a therapeutic agent payload, it was demonstrated that bulk material can be ballistically delivered to the central 1 cm² of the corneal epithelium rapidly, in an even, quantifiable layer
Matching Waveform Envelopes for Earthquake Early Warning
Get PDFCurrent earthquake early warning (EEW) algorithms are continuously optimized to strive for fast, accurate source parameter estimates for the rupturing earthquake (i.e. magnitude, location), which are then used to predict ground motions expected at a site. However, they may still struggle with challenging cases, such as offshore events and complex sequences. An envelope-based two-part search algorithm is developed to handle such cases. This algorithm matches different templates to the incoming observed ground motion envelopes to find the optimal earthquake source parameter estimates.
The algorithm consists of two methods. Method I is the standard grid search, and it uses Cua-Heaton ground motion envelopes as its templates; Method II is the extended catalog search, and its templates are waveform envelopes from past real and synthetic earthquakes. The grid search is intended for robustness and provides approximate average solutions, whereas the extended catalog search matches envelopes considering the station’s specific site and path effects. In parallel execution, Methods I and II work together – either by confirming each other’s solutions or accepting the solution with stronger fits – to provide the best parameter estimates based on waveform-based data.
The main advantage of the two-part search algorithm is its ability to find parameter estimates of reduced uncertainties using the P-wave data from a single station. Many algorithms wait until multiple stations are triggered to reduce tradeoffs between the magnitude and location. This waiting time, however, is detrimental in EEW, for it jeopardizes the warning time that can be issued to nearby regions expected to experience strong shaking. The use of a single station would virtually eliminate this waiting time, maximizing the warning time without the cost in accuracy of the estimates.
Because EEW is a race against time, further actions are taken for more rapid estimation of the earthquake source parameters. A Bayesian approach using prior information has the potential to reduce uncertainties that arise in the initial time points due to tradeoffs between the magnitude and location. This essentially increases the confidence of the initial parameter estimates, allowing alerts to be issued faster. A KD tree nearest neighbor search is also introduced to reduce latency in the time it takes to find the best-fitting solutions. In comparison to an exhaustive, brute-force search, it cuts the searching time by only examining through a fraction of the total database.
An envelope-based algorithm examines the shape and relative frequency content and makes appropriate judgments, just as a human seismologist would; it also addresses the issue of data transmission latencies. Overall, this algorithm is able to interpret the complexity of earthquakes and assess the features they hold to ultimately communicate information of significant ground shaking to different regions.</p
Multiscale Mechanical Characterization of Subcellular Structures in Living Walled Cells
Get PDFThe physiology of walled cells is dramatically different from that of human cells, but the biomechanics of walled cells are far less studied. Most bacterial, fungal, and plant cells have a strong cell wall (CW), which allows them to withstand large hydrostatic pressures in the cytoplasm, called turgor. Turgor pressure conflates the mechanics of subcellular components and complicates the characterization of the cell. In this dissertation, new models are introduced and explored for single cells to investigate the multiscale mechanics of plant and bacterial cells using micro- and nano-indentation experiments.
A multi-scale biomechanical assay is used to study the mechanical properties of plant cells. The plant CW is typically around 5% of the width of the entire cell, and is thought to carry most of the mechanical load. Large-scale indentations using a micro-indentation system probe the behavior of the overall cell structure, and atomic-force microscopy (AFM) nano-scale indentations are used to isolate the CW response. To determine the effect of external osmotic pressure, indentations are performed on cells in different osmotic conditions: hypotonic, isotonic, and hypertonic. The cell is idealized as two springs acting in series, one to represent the CW and one to represent the cytoplasm. The model uses the experimentally determined initial stiffnesses as input to the model to determine the relative stiffness contributions of the CW and the cytoplasm.
The first type of walled cells investigated is the xylem vessel element of Arabidopsis thaliana. The xylem is responsible for transporting water through the stem of any vascular plant (more commonly known as a land plant), and hence it must maintain structural integrity against high internal pressures while transporting water from the roots to the leaves. For extra structural support, xylem vessel elements develop secondary cell walls (SCWs), which are known to be a key component for mediating mechanical strength and stiffness in vascular plants. The structure and biomechanics of cultured plant cells are investigated during the cellular developmental stages associated with SCW formation using the multi-scale biomechanical assay described above. To determine the effect of morphological changes during differentiation, micro- and nano-indentations are performed on cells in different observed stages of the differentiation process.Prior to triggering differentiation, cells in hypotonic pressure conditions are significantly stiffer than cells in isotonic or hypertonic conditions, highlighting the dominant role of turgor pressure. Plasmolyzed cells with a SCW reach similar levels of stiffness as cells with maximum turgor pressure. Analysis using the two-spring model shows that the stiffness of the primary CW in all of these conditions is lower than the stiffness of the fully-formed SCW. These results provide the first experimental characterization of the mechanics of SCW formation at the single-cell level in plant cells.
Next, the mechanical response of individual Nicotiana tabacum cells from a suspension culture is studied using the same multi-scale biomechanical assay. The role played by the microtubules (MTs) and actin filaments (AFs) is determined through the use of drug treatments which selectively remove MTs and AFs. A generative statistical model is added to the two-spring model to quantify the stiffnesses of the CW, cytoplasm, turgor pressure, MTs, and AFs. Analysis of the initial stiffness and energy dissipation calculated from micro-indentation experiments indicates that the MTs and AFs contribute significantly to the mechanical response of a cell under compression. Micro- and nano-indentation tests confirm that turgor pressure is the most significant contributor to the stiffness response of turgid cells in compression. Finally, the results reveal that turgor pressure exerts stress on the CW, which leads to a measurable stiffening of the CW.
The studies described above focused on developing a discrete model to describe the mechanics of a cell in indentation experiments. However, the most common type of model used to evaluate the mechanics of a cell are continuum models. Continuum models are also necessary to decouple the material properties of subcellular components from their structure. In the final section, AFM indentations are simulated on a gram-negative bacterium, Escherichia coli, and a sensitivity study and inverse analysis are performed to solve for the CW elastic modulus and turgor pressure simultaneously. Sensitivity study results reveal that uncertainty in turgor pressure and CW elasticity indeed contribute the most to variability in force spectra from AFM measurements. The parameter space of possible values for CW elastic modulus and turgor pressure is discretized using triangular elements. "Simulated experiments" are tested throughout the parameter space, and correlations between the CW elastic modulus and turgor pressure, which depend on the type of objective function, are investigated. Two unique objective functions are tested in the inverse analysis, and a third objective function, which is a weighted sum of the first two, is found to reduce errors in estimated CW elastic modulus and turgor pressure by 20% and 11%, respectively. The use of this type of inverse analysis has the potential to elucidate the material properties of CWs using a single indentation measurement and reliably decouple these properties from the high turgor pressures inside walled cells.</p
Road to Equilibrium: Stable Isotope Distribution in Gaseous Alkanes and Thermal History of Geological Hydrocarbons
Get PDFNaturally occurring hydrocarbon fluids have economic, geological, and environmental significance. Most of the natural hydrocarbon on Earth is formed by thermal alteration of organic matter in the sedimentary basin. My dissertation study is motivated by this question: can we track generation, transformation, storage, and destruction of these subsurface hydrocarbon fluids with isotopic proxies? The conventional geochemical toolkit includes relative compositional abundances, such as wetness and C1/(C2+C3) ratio, and stable isotope ratios of 13C/12C and 2H/1H, on both the bulk (material-average) and compound-specific (molecular-average) levels. However, these signatures often rely on empirical categorizations and calibrations, so they can be prone to ambiguities, errors, and inconsistencies. This thesis presents a series of work that develops and refines stable isotope proxies of gaseous hydrocarbon (C1-C5) molecules. My approaches overcome the problems in mainly two ways. (1) I add new analytical techniques to acquire isotopologue ratios of compounds. I establish two new analytical proxies, multiply substituted isotopologues (clumped isotopes) of methane, and position-specific isotope ratios of propane, using recently advanced high-resolution isotope ratio mass spectrometry. (2) I use rigorous thermodynamic and kinetic constraints of isotope distribution in hydrocarbon molecules to interpret isotopic data in natural samples. These constraints are determined by theories and experiments. For thermodynamic control, I conducted catalytic exchange experiments to calibrate equilibrium isotope effect for propane position-specific hydrogen isotopes (Chapter 2) and compound-specific hydrogen isotope fractionation between alkanes (Chapter 4) and tested quantum chemical calculations. For expression of kinetic isotope effects, I implemented a statistical approach, the kinetic Monte Carlo method, to calculate the intramolecular and intermolecular stable isotope composition of alkanes generated by radical cracking mechanism in catagenesis (Chapter 6). I measured position-specific hydrogen isotopes of propane (Chapter 3) and methane clumped isotopes (Chapter 5) in natural gas samples from global reservoirs, and compiled compound-specific isotope data in the literatures (Chapter 5 and 6). Results show similarities in isotope ordering of these molecules, which is that gas formed at lower temperature/depth expresses kinetic isotope effects, but gas formed or buried at higher temperature for longer times is in equilibrium. The switch from kinetic control to thermodynamic control is likely a result of thermally-activated hydrogen exchange. This trend provides the foundation for tracking generation and thermal evolution of subsurface hydrocarbons with stable isotope proxies.</p
Hybrid Frequency-Time Analysis and Numerical Methods for Time-Dependent Wave Propagation
Get PDFThis thesis focuses on the solution of causal, time-dependent wave propagation and scattering problems, in two- and three-dimensional spatial domains. This important and long-lasting problem has attracted a great deal of interest reflecting not only its use as a model problem but also the prevalence of wave phenomena in diverse areas of modern science, technology and engineering. Essentially all prior methods rely on "time-stepping" in one form or another, which involves local-in-time approximation of the evolution of the solution of the partial differential equation (PDE) based on the immediate time history and temporal finite-difference approximation. In addition to the need to manage the accumulation of (dispersion) error and the burdensome increase in computational cost over time, there are additionally difficult issues of stability, time-domain boundary conditions, and absorbing boundary conditions which often need to be addressed.
To sidestep many of these problems, this thesis develops a novel highly-efficient approach for time-dependent wave scattering problems employing the global-in-time techniques of Fourier transformation and leading to a frequency/time hybrid method for the time-dependent wave equation. Thus, relying on Fourier Transformation in time and utilizing a fixed (time-independent) number of frequency-domain solutions, the method evaluates the desired time-domain evolution with errors that both, decay faster than any negative power of the temporal sampling rate, and that, for a given sampling rate, are additionally uniform in time for all time. The fast error decay guarantees that high accuracies can be attained on the basis of relatively coarse temporal and frequency discretizations. The uniformity of the error for all time with fixed sampling rate, a property known as dispersionlessness, plays a crucial role, together with other properties of the Fourier transform, in enabling the evaluation of solutions for long times at O(1) cost. In particular, this thesis demonstrates the significant advantages enjoyed by the proposed methods over alternative approaches based on volumetric discretizations, time-domain integral equations, and convolution-quadrature.
The approach relies on two main elements, namely, 1) A smooth time-windowing methodology that enables accurate band-limited representations for arbitrarily-long time signals, and 2) A novel Fourier transform approach which, in a time-parallel manner and without causing spurious periodicity effects, delivers numerically dispersionless spectrally-accurate solutions. A similar hybrid technique can be obtained on the basis of Laplace transforms instead of Fourier transforms, but we do not consider in detail the Laplace-based method, and only briefly point out its essential features and associated challenges.
The proposed frequency/time Fourier-transform methods for obstacle scattering problems are easily generalizable to any linear partial differential equation in the time domain for which frequency-domain solutions can readily be obtained, including e.g. the time-domain Maxwell equations, the linear elasticity equations, inhomogeneous and/or frequency-dependent dispersive media, etc. Further, the proposed approach can tackle complex physical structures, it enables parallelization in time in a straightforward manner, and it allows for time leaping—that is, solution sampling at any given time T at O(1)-bounded sampling cost, for arbitrarily large values of T, and without requirement of evaluation of the solution at intermediate times. In particular, effective algorithms are introduced that, relying on use of time-asymptotics, compute two-dimensional solutions at O(1) cost despite the very slow time-decay that takes place in the two-dimensional case.
A significant portion of this thesis is devoted to a theoretical study of the validity of a certain stopping criterion used by the algorithm, which guarantees that certain field contributions can safely be neglected after certain stopping times. Roughly speaking, the theoretical results guarantee that, after the incident field is turned off, the magnitude of the future scattering density (and thus the magnitudes of the fields) can be estimated by the magnitude of the integral density over a time period comparable to the time required by a wave to travel a distance equal to the diameter of the scatterer. The criterion, which is crucial in ensuring the O(1) computational cost of the algorithm, is closely related to the well-known scattering theory developed in the 1960s and '70s by Lax, Morawetz, Phillips, Strauss and others. Our approach to the decay problem is based on use of frequency-domain estimates (developed previously in the context of numerical analysis of frequency-domain problems) on integral operators in the high-frequency regime for obstacles of various trapping classes. In particular, our theory yields, for the first time, decay estimates for a class of connected trapping obstacles: all previous estimates of scattered-field decay for connected obstacles are restricted to nontrapping structures.
In all, the proposed approach leverages the power of the Fourier transformation together with a range of newly developed spectrally convergent numerical methods in both the frequency and time domain and a variety of novel theoretical results in the general area of scattering theory to produce a radically-new framework for the solution of time-dependent wave propagation and scattering problems.</p
In Vivo Activity of Rhodium Metalloinsertors and Exploration of Drug Delivery Systems
Get PDFRhodium metalloinsertors are octahedral complexes developed to selectively target the mismatches and insertions/deletions (indels) that result from mismatch repair (MMR) deficient cancers. By incorporating particularly wide, aromatic, inserting ligands, these complexes are able to detect thermodynamically destabilized mismatch sites via a binding mode known as metalloinsertion, in which the inserting ligand binds DNA via the minor groove and results in ejection of the destabilized mismatched base pair. In vitro analyses of metalloinsertors have found that these complexes are selectively cytotoxic towards MMR-deficient cancer cells compared to MMR-proficient cells. Furthermore, the newest family of Rh-O metalloinsertors, which includes [Rh(phen)(chrysi)(PPO)]²⁺ (Rh-PPO), displays preferential cytotoxicities in the nanomolar range, which is significantly more potent than first generation metalloinsertors and many standard of care chemotherapeutics. Given the high level of potency and selectivity of Rh-O metalloinsertors, further clinical development of these complexes has been pursued.
Here, we present the first preclinical mouse evaluation of a rhodium metalloinsertor as an anticancer agent. The Rh-O metalloinsertor Rh-PPO was evaluated in the HCT116 colorectal cancer xenograft tumor model alongside saline and oxaliplatin controls. Intraperitoneal studies with Rh-PPO showed significant decreases in tumor volumes over time and final tumor weights, indicating Rh-PPO has notable anticancer activity. Additionally, Rh-PPO treatment resulted in a noteworthy increase in the length of mouse survival that was on par with the FDA approved chemotherapeutic oxaliplatin. Pharmacokinetic analyses revealed rapid absorption of Rh-PPO in plasma with notable accumulation in the liver compared to tumors. Importantly, intratumoral metalloinsertor administration resulted in enhanced anticancer effects, which points to a need for more selective delivery methods in order to further metalloinsertor development.
In order to target cancerous cells with still higher selectivity, routes to metalloinsertor antibody drug conjugate (ADC) designs were explored. By attaching Rh-O metalloinsertors to an antibody specific to cancer-associated antigens, our complexes may become even more specifically directed to induce selective cytotoxicity in diseased cells. Three ADC drug linkers that incorporate maleimide groups into the N^O coordinating ligand of a Rh-O metalloinsertor were designed, synthesized, and characterized. These complexes were evaluated for their cellular potency and selectivity toward MMR-deficient cancer cells. Studies revealed that functionalization of the hydroxyl-containing ancillary ligand resulted in decreased potency and abolished preferential cytotoxicity, contrary to previous studies that assessed modifications of this ligand.
Liposomal formulations of Rh-PPO were also explored to further target metalloinsertors to malignant cells. Liposomal drug encapsulations have a demonstrated ability to decrease systemic toxicity and increase tumor drug uptake; therefore, the biological activity of Rh-PPO liposomal formulations was explored. Four distinct Rh-PPO liposome formation methods were developed and the resulting liposomes were assessed for their encapsulation efficiency, cellular toxicity, and stability. Remote loaded Rh-PPO liposomes were found to display the most promising chemical and biological characteristics, although additional optimization of encapsulation procedures is necessary for further preclinical evaluation of this metalloinsertor drug delivery approach.
As metalloinsertors continue preclinical assessment and development, a greater understanding of their mechanism of action is imperative. Biological studies with Rh-PPO and the fluorescent analogue RhPPO-Cy3 have shown that DNA damage from metalloinsertor treatment involves the formation of DNA double strand breaks near metalloinsertor-mismatch binding sites. Furthermore, the DNA damage response, including recruitment of pH2AX and Rad51 proteins, becomes activated in response to Rh-PPO treatment. In order to further elucidate the unique mechanism of action of Rh-O metalloinsertors, which involves both metalloinsertor enantiomers binding to DNA mismatches and displaying biological activity, structural studies are ongoing. X-ray crystallography and microelectron diffraction (microED) techniques have been used in attempts to obtain a high resolution structure of Rh-O metalloinsertors bound to DNA mismatch sites. Gaining these structural insights will be critical to understanding the increased cytotoxic selectivity and uniquely high potency of these second generation metalloinsertor complexes.
The experiments detailed in this thesis have advanced the preclinical development of rhodium metalloinsertors. The ability of Rh-O metalloinsertors to decrease tumor growth in vivo has been established. Additionally, liposomal and ADC metalloinsertor drug formulations have been pursued as drug delivery systems, and the biological mechanisms relevant to metalloinsertor activity have been analyzed. Additional efforts to study rhodium metalloinsertors will continue to advance these promising chemotherapeutics as novel, targeted treatments for MMR-deficient cancers.</p
Provenance, Structural Geology, and Sedimentation of the Miocene and Pliocene Californias
Get PDFThe first chapter of this thesis documents a provenance study, in which orthoquartzite clasts deposited in the Miocene Sespe Formation are linked to the Mesoproterozoic Shinumo Quartzite. The Sespe Formation outcrops in the Santa Monica Mountains and the Santa Ana Mountains, both in California. The Shinumo Quartzite outcrops only in Grand Canyon. We determine that the Shinumo Quartzite can be distinguished from other sources that may feed the Sespe Formation through its unique combination of a moderate paleomagnetic inclination and 1.2, 1.4, and 1.7 Ga detrital zircon spectrum peaks. This provenance link places an important constraint on the drainage of a paleo-Colorado River from Grand Canyon during Miocene time.
The second and third chapters of this thesis are hinged upon a geologic mapping project on Isla Ángel de la Guarda, a microcontinental block, in Baja California, Mexico. A plate reorganization at the end of the late Miocene andesitic arc marks the transfer of Baja California and the not-yet-rifted Isla Ángel de la Guarda to the Pacific plate from the North American plate. Between 3 and 2 Ma, the plate boundary jumped again, northward along the Ballenas Transform fault. In this Pliocene time, units mapped in this study were deposited.
The oldest units mapped are Miocene-Pliocene volcanic flows, for which we have no lower age constraint. The oldest volcanic flow dated is a Pliocene andesite lava (3.916 ± 0.088 Ma from 40Ar/39Ar). We map Miocene to Pliocene volcanic flows and Pliocene to Quaternary sedimentary units in two field areas. The sedimentary units are probably results of Pliocene rifting-related basin subsidence. Geochemical data from X-ray fluorescence indicate that lavas are compositionally similar to ~12 Ma arc-related rocks mapped in the Puertecitos Volcanic Province. In the southern field area, the sedimentary units are overlain by a Pliocene basaltic andesite with an 40Ar/39Ar age of 2.754 ± 0.021 Ma. We map several NNE-striking faults throughout both field areas, which cut NNW-striking bedding in Pliocene units. The Pliocene volcanic flows and sedimentary units were probably tilted before faulting, and the faults are likely linked to the Northern Salsipuedes Basin, offshore of the island in the Ballenas Channel. Both of these events may be results of 3-2 Ma rifting.</p