Approaches and Considerations Towards a Safe and Effective Adeno-Associated Virus Mediated Therapeutic Intervention for GM1-Gangliosidosis: A Dissertation

GM1 gangliosidosis is a lysosomal storage disorder caused by a deficiency in the catabolizing enzyme β-galactosidase (βgal). This leads to accumulation of GM1-ganglioside (GM1) in the lysosome inducing ER stress and cell death. GM1 gangliosidosis is primarily a disorder of the central nervous system (CNS) with peripheral organ involvement. In this work we report two major findings, 1) systemic treatment of GM1 gangliosidosis with an adenoassociated virus (AAV9) encoding mouse-βgal (mβgal) in a GM1 gangliosidosis mouse model (βGal-/-), and 2) an investigation into an intracranial injection of a therapeutic AAVrh8 encoding mβgal. Systemic treatment of GM1 gangliosidosis with AAV9 resulted in a moderate expression of enzyme in the CNS, reduction of GM1 storage, significant retention of motor function and a significant increase in lifespan. Interestingly, the therapeutic effect was more robust in females. Intracranial injections of AAVrh8 vector expressing high levels of βgal resulted in enzyme spread throughout the brain, significant retention of motor function and a significant increase in lifespan. Histological alterations were also found at the injection site in both βGal-/- and normal animals. We constructed a series of vectors with a range of decreasing enzyme expression levels to investigate the cause for the unanticipated result. Microarrays were performed on the injection site and we showed that a lower expressing AAVrh8-mβgal vector mitigated the negative response. Intracranial injection of this newly developed vector was shown to clear lysosomal storage throughout the CNS of βGal-/- mice. Taken together, these studies indicate that a combined systemic and fine-tuned intracranial approach may be the most effective in clearing lysosomal storage completely in the CNS while providing therapeutic benefit to the periphery

Computational Study of Second- and Third-Harmonic Generation in Periodically Patterned 2D-3D Heteromaterials

Remarkable optical and electrical properties of graphene and other two-dimensional (2D) materials provide significant potential for novel optoelectronic applications and devices, many of which depend on nonlinear optical effects in these 2D materials. In this paper we use a theoretical and computational formalism we have recently introduced to efficiently and accurately compute the linear and nonlinear optical response of nanostructured 2D materials embedded in periodic structures containing regular three-dimensional (3D) materials, such as diffraction gratings or periodic metamaterials. Thus, we use the proposed method to demonstrate enhanced nonlinear optical interactions in periodically patterned photonic nanostructures via resonant excitation of phase-matched nonlinear waveguide modes, enhanced nonlinearity of nanostructures containing graphene and other 2D nanomaterials, such as WS2, and multi-continua Fano resonances for increasing the nonlinear efficiency of hybrid 2D-3D photonic heteromaterials

Theoretical and computational analysis of second- and third-harmonic generation in periodically patterned graphene and transition-metal dichalcogenide monolayers

Remarkable optical and electrical properties of two-dimensional (2D) materials, such as graphene and transition-metal dichalcogenide (TMDC) monolayers, offer vast technological potential for novel and improved optoelectronic nanodevices, many of which rely on nonlinear optical effects in these 2D materials. This paper introduces a highly effective numerical method for efficient and accurate description of linear and nonlinear optical effects in nanostructured 2D materials embedded in periodic photonic structures containing regular three-dimensional (3D) optical materials, such as diffraction gratings and periodic metamaterials. The proposed method builds upon the rigorous coupled-wave analysis and incorporates the nonlinear optical response of 2D materials by means of modified electromagnetic boundary conditions. This allows one to reduce the mathematical framework of the numerical method to an inhomogeneous scattering matrix formalism, which makes it more accurate and efficient than previously used approaches. An overview of linear and nonlinear optical properties of graphene and TMDC monolayers is given and the various features of the corresponding optical spectra are explored numerically and discussed. To illustrate the versatility of our numerical method, we use it to investigate the linear and nonlinear multiresonant optical response of 2D-3D heteromaterials for enhanced and tunable second- and third-harmonic generation. In particular, by employing a structured 2D material optically coupled to a patterned slab waveguide, we study the interplay between geometric resonances associated to guiding modes of periodically patterned slab waveguides and plasmon or exciton resonances of 2D materials

Mapping Itinerant Electrons around Kondo Impurities

We investigate single Fe and Co atoms buried below a Cu(100) surface using low temperature scanning tunneling spectroscopy. By mapping the local density of states of the itinerant electrons at the surface, the Kondo resonance near the Fermi energy is analyzed. Probing bulk impurities in this well-defined scattering geometry allows separating the physics of the Kondo system and the measuring process. The line shape of the Kondo signature shows an oscillatory behavior as a function of depth of the impurity as well as a function of lateral distance. The oscillation period along the different directions reveals that the spectral function of the itinerant electrons is anisotropic.Comment: 5 pages, 4 figures, accepted by Physical Review Letter

Double-resonant enhancement of third-harmonic generation in graphene nanostructures

Intriguing and unusual physical properties of graphene offer remarkable potential for advanced, photonics-related technological applications, particularly in the area of nonlinear optics at the deep-subwavelength scale. In this study, we use a recently developed numerical method to illustrate an efficient mechanism that can lead to orders of magnitude enhancement of the third-harmonic generation in graphene diffraction gratings. In particular, we demonstrate that by taking advantage of the geometry dependence of the resonance wavelength of localized surface-plasmon polaritons of graphene ribbons and discs one can engineer the spectral response of graphene gratings so that strong plasmonic resonances exist at both the fundamental frequency and third-harmonic (TH). As a result of this double-resonant mechanism for optical near-field enhancement, the intensity of the TH can be increased by more than six orders of magnitude

Theoretical and computational insights into the nonlinear optics of nanostructured bulk and 2D materials

In this thesis, a comprehensive analytical and computational study of linear and nonlinear optical response of nanostructured two-dimensional (2D) and bulk materials is presented. The new numerical methods developed in this thesis facilitate the efficient and accurate design of new artificial optical materials and novel nonlinear optical devices. Moreover, the presented results and conclusions can provide a deeper theoretical understanding of different resonant, nonlinear optical phenomena in photonic nanostructures. Two computational electromagnetic methods to calculate the interaction of light with linear and nonlinear diffraction gratings and more general periodic structures have been developed. An efficient formulation of the rigorous coupled-wave analysis (RCWA), a modal frequency domain method, for accurate near-field calculations and for complex oblique structures has been proposed. This method has been implemented into a powerful commercial software tool and applied to calculate diffraction in several nanophotonic devices highly relevant to practical applications. Beyond this commercial implementation, the RCWA has been extended to describe linear and nonlinear optical effects in nanostructured 2D materials, with second- and third-harmonic generation being the most important nonlinear processes. A key feature of this formulation is that it is independent of the height of the 2D material, and only requires knowledge of its linear and nonlinear optical properties. Using this method, plasmon resonances of nanostructured graphene have been investigated, and tuneable Fano resonances have been explored to increase the nonlinear efficiency of heterostructures containing transition metal dichalcogenide monolayers and nanopatterned slab waveguides. The second thrust of the thesis was devoted to extending the so-called generalised source method (GSM) to the area of nonlinear optics. In particular, its mathematical formulation has been extended to incorporate second- and third-order nonlinear optical effects, and the proposed nonlinear GSM has been used to design and optimise multi-resonant photonic devices made of nonlinear optical materials. In addition, this advanced computational method facilitated the understanding of strong nonlinear optical activity in plasmonic nanostructures, and explained the multipolar nonlinear optical response of certain nonlinear metasurfaces

Best Practices for Retaining Public Speaking Students

This article draws on existing communication research and praxes to share the best practices for retaining students enrolled in the introductory public speaking course. Among the many important pedagogical practices that communication scholars have documented, this article highlights the value of 10 best practices: instructor use of immediacy and confirmation; instructor inclusion of written prescriptive feedback, peer feedback workshops, low-stakes assignments, applied assignments, and individual speech preparation tools; and instructor participation in out-of-class communication, online office hours, and classroom-connectedness

Benefactors, Bonds, and Beholders: The Beliefs and Reality Behind Beethoven’s Behavior

This paper will explore the relationships which Beethoven had during the years he composed and premiered his Eroica Symphony. Some of the individuals who will be discussed in this paper include Prince Lobkowitz, Ferdinand Ries, and Franz Wegeler. After learning about the nature of these relationships, the reader should begin to realize that Beethoven’s notoriously irrational or ill-tempered behavior was only one facet of his life

Long-range Kondo signature of a single magnetic impurity

The Kondo effect, one of the oldest correlation phenomena known in condensed matter physics, has regained attention due to scanning tunneling spectroscopy (STS) experiments performed on single magnetic impurities. Despite the sub-nanometer resolution capability of local probe techniques one of the fundamental aspects of Kondo physics, its spatial extension, is still subject to discussion. Up to now all STS studies on single adsorbed atoms have shown that observable Kondo features rapidly vanish with increasing distance from the impurity. Here we report on a hitherto unobserved long range Kondo signature for single magnetic atoms of Fe and Co buried under a Cu(100) surface. We present a theoretical interpretation of the measured signatures using a combined approach of band structure and many-body numerical renormalization group (NRG) calculations. These are in excellent agreement with the rich spatially and spectroscopically resolved experimental data.Comment: 7 pages, 3 figures + 8 pages supplementary material; Nature Physics (Jan 2011 - advanced online publication

Generalized source method for modeling nonlinear diffraction in planar periodic structures

We present a new numerical method for the analysis of second-harmonic generation (SHG) in one-and twodimensional (1D, 2D) diffraction gratings with arbitrary profile made of non-centrosymmetric optical materials. Our method extends the generalized source method (GSM), which is a highly efficient alternative to the conventional Fourier modal method, to quadratically nonlinear diffraction gratings. The proposed method consists of a two-stage algorithm. Initially, the electromagnetic field at the fundamental frequency is computed in order to obtain the second-harmonic polarization using the known second-order nonlinear susceptibility. Then the optical field at the second-harmonic frequency is computed using this polarization as an additional source term in the GSM. We show how to integrate this source term into the GSM framework without changing the structure of the basic algorithm. We use the proposed algorithm to investigate a doubly resonant mechanism that leads to strong enhancement of SHG in a nonlinear 2D circular GaAs grating mounted on top of a GaAs slab waveguide. We design this optical device such that slab waveguide modes at the fundamental and second-harmonic are simultaneously excited and phase matched by the grating. The numerically obtained resonance frequencies show good agreement with analytically computed resonance frequencies of the unperturbed slab waveguide. © 2014 SPIE