<p> We show that a combination of different theoretical methods is a viable approach to calculate and explain the relative binding affinities of inhibitors of the human butyrylcholinesterase enzyme. We probe structural properties of the enzyme-inhibitor complex in the presence of dialkyl phenyl phosphates and derivatives that include changes to the aromatic group and alkane-to-cholinyl substitutions that help these inhibitors mimic physiological substrates. Monte Carlo docking allowed for the identification of three regions within the active site of the enzyme where substituents of the phosphate group could be structurally stabilized. Computational clustering was used to identify distinct binding modes and their relative stabilities. Molecular dynamics suggest an essential asparagine residue not previously characterized as strongly influencing inhibitor strength which may serve as a crucial component in catalytic and inhibitory activity. This study provides a framework for suggesting future inhibitors that we expect will be effective at sub-micromolar concentrations. </p><p>

<p> The nervous system encodes information about external stimuli through sophisticated computations performed by vast networks of sensory neurons. Since the space of all possible stimuli is much larger than the space of those that are ultimately meaningful, dimensionality reduction techniques were developed to identify the subspace of stimulus space relevant to neural activity. However, dimensionality reduction methods provide limited insight into the nonlinear functions that build the nervous system&rsquo;s internal model of the world. In Chapter 2, the <i>functional basis</i> is introduced that transforms the relevant subspace to a basis that describes the computational function of the subunits that make up the neural circuitry. This functional basis is used to uncover novel insights about the computations performed by neurons in low-level vision and, later on, high-level auditory circuitry. For the latter, significant barriers are found in the capability of current dimensionality reduction methods to recover the relevant subspaces of high-level sensory neurons. This barrier is caused by the relative difficulty of stimulating high-level sensory neurons, which are often unresponsive to noise stimuli, while still maintaining a thorough exploration of the stimulus distribution. In response, a new approach to dimensionality reduction is formulated in Chapter 3 called the <i>low-rank maximum noise entropy method</i> that makes it possible to overcome challenges presented by high-level sensory systems. In Chapter 4, functional bases derived from the relevant subspaces recovered by the low-rank maximum noise entropy method are employed to study the neural computations performed by high-level auditory neurons.</p><p>

This dissertation concerns the planning, implementation, and results from a highly sensitive, automated search for new pulsars. This research effort was begun with a study of the relevant signal detection theory, and the conclusions reached are presented. The general procedures developed were specifically tailored for use on a high speed minicomputer, and produced a search relatively free from observational selection effects. The actual computer coding of these procedures is also described, with emphasis on how the required speed and efficiency of these routines was obtained. The final system applied over half a million different matched digital filters to the data obtained from each successive telescope beam area. These filters correspond to a similar number of discrete combinations of possible pulsar parameters, within the approximate bounds: 0 ≤ DM ≤ 1280 cm-3 pc, 0.033< P <3.9 s, and 0.016< (w/P) <0.125. Here DM is the dispersion measure to the pulsar (the column density of free electrons), P is the pulsation period, and (w/P) is the ratio of pulse width to period, or duty cycle. Use of this search system at the 1000 foot telescope of the Arecibo Observatory resulted in the detection of 50 pulsars, 40 of which were not previously known. Parameters are presented for these new pulsars. The relatively limited range in dispersion measure exhibited by this pulsar sample is used, along with other evidence, to infer a reduced number density of pulsars at distances beyond approximately 10 kpc from the galactic center.

<p>There are many different codes available for making molecular dynamic simulation. Most of these are focused on high performance mainly. We have moved that focus towards modularity, flexibility and user friendliness. Our goal has been to design a software that is easy to use, can handle many different kind of simulations and is easily extendable to meet new requirements.</p><p>In the report we present you with the theory that is needed to understand the principles of a molecular dynamics simulation. The four different potentials we have used in the software are presented. Further we give a detailed description of the design and the different design choices we have made while constructing the software.</p><p>We show some examples of how the software can be used and discuss some aspects of the performance of the implementation. Finally we give our thoughts on the future of the software.</p>

There are many different codes available for making molecular dynamic simulation. Most of these are focused on high performance mainly. We have moved that focus towards modularity, flexibility and user friendliness. Our goal has been to design a software that is easy to use, can handle many different kind of simulations and is easily extendable to meet new requirements. In the report we present you with the theory that is needed to understand the principles of a molecular dynamics simulation. The four different potentials we have used in the software are presented. Further we give a detailed description of the design and the different design choices we have made while constructing the software. We show some examples of how the software can be used and discuss some aspects of the performance of the implementation. Finally we give our thoughts on the future of the software.

<p>The Short Time Fourier transform and the S-transform are among the most used methods of spectral decomposition to localize spectra in time and frequency. The S-transform utilizes a frequency-dependent Gaussian analysis window that is normalized for energy conservation purposes. The STFT, on the other hand, has a selected fixed time window that does not depend on frequency. In previous literature, it has been demonstrated that the S-transform distorts the Fourier spectra, shifting frequency peaks, and could result in misleading frequency attributes. Therefore, one way of making the S-transform more appropriate for quantitative seismic signal analysis is to ignore the conservation of energy over time requirement. This suggests a hybrid approach between the Short Time Fourier transform and the S-transform for seismic interpretation purposes. In this work, we introduce the Multi-Scale Boxcar transform that has temporal resolution comparable to the S-transform while giving correct Fourier peak frequencies. The Multi-Scale Boxcar transform includes a special analysis window that focusses the analysis on the highest amplitude portion of the Gaussian window, giving a more accurate time-frequency representation of the spectra in comparison with the S-transform. Post-stack seismic data with a strong well logs control was used to demonstrate the differences of the Multi-Scale Boxcar transform and the S-transform. The analysis area in this work is the Pennsylvanian and Lower Permian Horseshoe Atoll Carbonate play in the Midland Basin, a sub-basin in the larger Permian Basin. The Multi-Scale Boxcar transform spectral decomposition method improved the seismic interpretation of the study area, showing better temporal resolution for resolving the layered reservoirs? heterogeneity. The time and depth scale values on the figures are shifted according to the sponsor request, but the relative scale is correct.

Extensive information can be obtained on wave-particle interactions and wave fields by direct measurement of perturbed ion distribution functions using laser-induced fluorescence (LIF). For practical purposes, LIF is frequently performed on metastable states that are produced from neutral gas particles and ions in other electronic states. If the laser intensity is increased to obtain a better LIF signal, then optical pumping can produce systematic effects depending on the collision rates which control metastable population and lifetime. We numerically simulate the ion velocity distribution measurement and wave-detection process using a Lagrangian model for the LIF signal. The simulations show that optical pumping broadening affects the ion velocity distribution function (IVDF) $f_0(v)$ and its first-order perturbation $f_1(v,t)$ when laser intensity is increased above a certain level. The results also suggest that ion temperature measurements are only accurate when the metastable ions can live longer than the ion-ion collision mean free time. For the purposes of wave detection, the wave period has to be significantly shorter than the lifetime of metastable ions for a direct interpretation. Experiments are carried out to study the optical pumping broadening and metastable lifetime effects, and the results are compared with the simulation in order to validate the Lagrangian model for LIF. It is more generally true that metastable ions may be viewed as test-particles. As long as an appropriate model is available, LIF can be extended to a range of environments.

<p> We introduce an elastic constitutive model of gravity that enables the interpretation of cosmological observations in terms of established ideas from Solid Mechanics and multi-scale modeling. The behavior of physical space is identified with that of a material-like medium called "cosmic fabric," which exhibits constitutive behavior. This cosmic fabric is a solid hyperplate that is broad in the three ordinary spatial dimensions and thin in a fourth hyperspatial dimension. Matter in space is treated as fabric inclusions that prescribe in-plane (three-dimensional) strain causing the transverse bending of the fabric into the fourth hyperspatial dimension. The linearized Einstein-Hilbert action, which governs the dynamics of physical space, is derived from postulating Hooke's Law for the fabric, and the Schwarzschild metric is recovered from investigating matter-fabric interactions. At the continuum length scale, the Principle of Relativity is shown to apply for both moving and stationary observers alike, so that the fabric's rest reference frame remains observationally indistinguishable at such a length scale. Within the Cosmic Fabric paradigm, the structural properties of space at different hierarchical length scales can be investigated using theoretical notions and computational tools from solid mechanics to address outstanding problems in cosmology and fundamental physics. For example, we propose and offer theoretical support for the "Inherent Structure Hypothesis", which states that the gravitational anomalies currently attributed to dark matter may in fact be manifestations of the inherent (undeformed) curvature of space. In addition, we develop a numerical framework wherein one can perform numerical "experiments" to investigate the implications of said hypothesis. </p><p>

<p> This work presents a novel polytopal finite-element framework that addresses the collective issues of discretization sensitivity and mesh generation for computational solid mechanics problems. The use of arbitrary polygonal and polyhedral shapes in place of canonical isoparametric elements seeks to remediate issues pertaining to meshing and mesh quality (particularly for irregularly shaped elements), while maintaining many of the desirable features of a traditional finite element method. </p><p> A general class of <i>partitioned element methods</i> (PEM) is proposed and analyzed, constituting a family of approaches for constructing piecewise polynomial approximations to harmonic shape functions on arbitrary polytopes. Such methods require a geometric partition of each element, and under certain conditions will directly yield integration consistency. Two partitioned element methods are explored in detail, including a novel approach herein referred to as the <i>discontinuous Galerkin partitioned-element method</i> (DG-PEM). An implementational framework for the DG-PEM is presented, along with a discussion of its associated numerical challenges. </p><p> The numerical precision of the PEM is explored via classical patch tests and single element tests for a representative sampling of polygonal element shapes. Solution sensitivity with respect to element shape is examined for a handful of problems, including a mesh convergence study in the nearly incompressible regime. Finally, the efficacy of the DG-PEM is assessed for a number of benchmark problems involving large deformations and nonlinear material behavior.</p><p>

<p> We use non-adiabatic <i>ab initio</i> molecular dynamics to study the influence of substituent side groups on the photoactive unit (Z)-hexa-1,3,5-triene (HT). The Time-Dependent Density Functional Theory Surface Hopping method (TDDFT-SH) is used to investigate the influence of substituted isopropyl and methyl groups on the excited state dynamics. The 1,4 and 2,5-substituted molecules are simulated: 2,5-dimethylhexa-1,3,5-triene (DMHT), 2-isopropyl-5-methyl-1,3,5-hexatriene (2,5-IMHT), 3,7-dimethylocta-1,3,5-triene (1,4-IMHT), and 2,5-diisopropyl-1,3,5-hexatriene (DIHT). We find that HT and 1,4-IMHT have the lowest ring-closing branching ratios of 5.3% and 1.0%, respectively. For the 2,5-substituted derivatives, the branching ratio increases with increasing size of the substituents, exhibiting yields of 9.78%, 19%, and 24% for DMHT, 2,5-IMHT, and DIHT, respectively. The reaction channels are shown to prefer certain conformation configurations at excitation, where the ring-closing reaction tends to originate from the gauche-Z-gauche (gZg) rotamer almost exclusively. In addition, there is a conformational dependency on absorption, gZg conformers have on average lower S₁ &larr; S₀ excitation energies that the other rotamers. Furthermore, we develop a method to calculate a predicted quantum yield that is in agreement with the wavelength-dependence observed in experiment for DMHT. In addition, the quantum yield method also predicts DIHT to have the highest CHD yield of 0.176 at 254 nm and 0.390 at 290 nm. </p><p> Additionally, we study the vitamin D derivative Tachysterol (Tachy) which exhibits similar photochemical properties as HT and its derivatives. We find the reaction channels of Tachy also have a conformation dependency, where the reactive products toxisterol-D1 (2.3%), previtamin D (1.4%) and cyclobutene toxisterol (0.7%) prefer cEc, cEt, and tEc configurations at excitation, leaving the tEt completely non-reactive. The rotamers similarly have a dependence on absorption as well, where the cEc configuration has the lowest energy S₁ &larr; S₀ excitation of the rotamers. The wavelength dependence of the rotamers should lead to selective properties of these molecules at excitation. An excitation to the red-shifted side of the maximum absorption peak will on average lead to excitations of the gZg rotamers more exclusively. </p><p>