Computation predictions of organic crystal structure and thermodynamics are essential for material design, crystal engineering and drug development. However, accurate computational tools for organic crystal thermodynamics calculations are lacking, and experimental data set for validation of computational methods is limited. Most crystal structure predictions and stability calculations depend solely on potential energy, which is an insufficient representation of thermodynamics. This thesis proposes and validates both absolute and relative free energy calculation of small organic compounds, thus presenting an accurate computational tool that overcomes the shortcomings of potential-energy-based models. The solubility of organic molecules can be computed from a thermodynamic cycle that decomposes standard state solubility into the sum of solid-vapor sublimation, i.e. thermodynamic stability of the crystal, and vapor-liquid solvation free energies ΔG°solubility=ΔG°sub+ΔG°solv. Crystal polymorphs have different ΔG°sub thus different solubility, which of critical importance to the pharmaceutical industry, however, robust computational methods to predict this quantity from first principles are lacking. Over the past few decades, alchemical simulation methods to compute solvation free energy using classical force fields have become widely used. However, analogous methods for determining the free energy of the sublimation/deposition phase transition are currently limited. This thesis describes an absolute thermodynamics approach based on growth of the asymmetric unit into a crystal via alchemy (GAUCHE). GAUCHE computes deposition free energy ΔG°dep=-ΔG°sub=ΔG°Vol+ΔG°Au+ΔG°Au→UG as the sum of an entropic term to account for compressing a 1 M vapor into the molar volume of the crystal asymmetric unit (VAU) plus two simulation steps. In the first simulation step, the deposition free energy ΔG°AU for a system composed of only NAU asymmetric unit (AU) molecule(s) is computed beginning from an arbitrary conformation in vacuum. In the second simulation step, the change in free energy ΔG°AU�UG to expand the asymmetric unit degrees of freedom into a unit cell (UC) composed of NUC independent molecules is computed. This latter step accounts for the favorable free energy of removing the constraint that every symmetry mate of the asymmetric unit has an identical conformation and intermolecular interactions. The current work is based on NVT simulations, which requires knowledge of the crystal space group and unit cell parameters from experiment, but not a priori knowledge of crystalline atomic coordinates. GAUCHE was applied to 5 organic molecules whose sublimation free energy has been measured experimentally, based on the polarizable AMOEBA force field and more than a microsecond of sampling per compound. The mean unsigned and root-mean-square errors were only 1.6 and 1.7 kcal/mol, respectively, which indicates that GAUCHE is capable of accurately predicting sublimation thermodynamics. For polymorphic systems, we propose a relative thermodynamics approach, that is similar to the second simulation step of GAUCHE, where ΔG°P1→P2 is calculated instead of ΔG°AU→UG. A relative approach reduces statistical uncertainty upon convergence compared to an absolute calculation; thus, it is more appropriate due to the thermodynamic stability difference between polymorphs are often fairly small. For our paracetamol test system, the experimental free energy difference was only 0.93 kcal/mol. Although both quantum and AMOEBA potential calculations predict the form II of paracetamol as more stable crystal form than form I, our relative free energy calculation predict the opposite stability ranking, which agrees with the experiment. Decomposition of free energy into entropy and enthalpy indicates that the favorable entropy change contributes to the greater thermodynamic stability of form I over form II. Although the exact magnitude of entropy and enthalpy changes differs across literature data as well as our data, the favorable entropic contribution is consistent. Further calculations over the temperature range from 100 to 308 K show the temperature dependence of free energy, which follows the parabolic trend observed in experiments. Our results show that our relative polymorph stability methods can accurately capture temperature dependence of free-energy-based stability ranking and overcome the limitations of potential-energy-based ranking. Thus, the importance of crystal structure predictions based on free energy can be further emphasized.

Solid polymer-drug dispersions are used to prepare and stabilize amorphous forms of poorly soluble drugs as a means of improving drug solubility, dissolution and bioavailability. Despite many reports on this subject, solid dispersion dissolution mechanisms have not been well understood. An early study was reported by Simonelli, Mehta and Higuchi (SMH) in 1969 and has served as a model for dispersion dissolution behavior. These authors proposed a dissolution model (SMH) which gave good agreement between their experimental results and model predictions for one drug and one type of PVP. Few researchers have applied this traditional approach (SMH) in a systematic fashion to solid dispersion systems. One difficulty is obtaining parameters needed for predictions such as polymer diffusion coefficient, diffusion layer thickness or other pertinent parameters. In this work, a general model has been developed based on the concepts in the traditional approach (SMH) and simulations with this model were performed to show how dispersion dissolution rates change with system variables. Such simulations showed underestimation of dissolution rates resulted when compounds had low solubility. In this work, solid dispersion dissolution behavior was studied systematically with a homologous compound series (alkyl-p-aminobenzoate esters, or PABA esters) and three polyvinylpyrrolidone (PVP) molecular weights (K15, K30 and K90). The PABA esters with varying solubility used in this study were methyl PABA (MePABA), ethyl PABA (EtPABA), propyl PABA (PrPABA) and butyl PABA (BuPABA). Six solid dispersions for each PABA ester and PVP (weight ratios of PVP:PABA ester 20:1, 10:1, 6:1, 3:1, 4:1 and 2:1) were prepared by a solvent evaporation method. Solid dispersions were obtained and their amorphous character confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Intrinsic dissolution rates for these dispersions were obtained in water with a rotating disc dissolution system. Both dissolution rate of drug (PABA ester) and carrier (PVP) were measured to obtain more information on which to evaluate the release behavior. Measuring the dissolution of the polymer (dispersion agent) and drug is unique in this work and has not been done in most other reported studies. For the more soluble PABA esters (i.e., MePABA, EtPABA and PrPABA), as drug loading increased, PABA ester dissolution rates first increased and then decreased to that of the pure drug for PVP K15 and K30 dispersions. For K90 systems, drug dissolution rates were below pure drug rates and increased steadily as drug loading increased, eventually reaching that of the pure drug. On the other hand, PVP dissolution rates decreased constantly as drug content increased for all three PVP grades. However, the decrease in polymer dissolution was more pronounced for the lower molecular weight PVPs (K15 and K30) than the higher molecular weight PVP (K90). Comparison of drug and polymer dissolution behavior indicated that congruent release of both components occurred when drug loading was low (< 15%). As drug loading increased, more deviation from congruent release behavior was observed. For BuPABA, the least soluble PABA ester, precipitated BuPABA solid accumulated on the disc surface during dissolution. PABA ester relative dissolution rates were calculated and compared with the predictions from the developed general model (based on assumptions in the traditional approach). Such predictions correlated well with experimental results at high drug loadings (i.e., >25%) but at low drug loadings (i.e.,

Painting and Intermedia arts

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Non-uniform rational basis spline (NURBS) is a geometric language which has been commonly used in computer graphics and Computer Aided Design over years, due to its great flexibility and precision for handling modeled shapes. In computer-aided design, NURBS has become part of industry standards. In most CAD programs every solid model is described by NURBS and stored in NURBS data structure. Recently, the geometric basis function of NURBS is directly used in analysis, leading to the birth of a new area of computational mechanics called isogeometric analysis (IGA). Compared with the traditional finite element analysis, IGA eliminates the disconnection between analysis and design at the geometric level, showing superiority on efficiency and accuracy over the traditional finite element method. This thesis focuses on the development of an IGA preprocessor for converting an original CAD model (2D-NURBS model) to an ASG (analysis suited geometry) model. ASG means models with mesh quality suitable for analysis. Core technologies utilized during the development include the well-developed NURBS algorithm of knot insertion and knot removal, and a self-developed technology of constructing and utilizing “multi-patch tree”. The developed IGA preprocessor is utilized to process a body armour model consisting of multiple NURBS patches with overly dense meshes. After the processing, the output model has a relatively reasonable elements distribution; the uniformity of the mesh across presumably contact patch boundaries is rebuilt.

Dehn surgery and the notion of reducible manifolds are both important tools in the study of 3-manifolds. The Cabling Conjecture of Francisco González-Acuña and Hamish Short describes the purported circumstances under which Dehn surgery can produce a reducible manifold. This thesis extends the work of James Allen Hoffman, who proved the Cabling Conjecture for knots of bridge number up to four. Hoffman built upon the combinatorial machinery used by Cameron Gordon and John Luecke in their solution to the knot complement problem. The combinatorial approach starts with the graphs of intersection of a thin level sphere of the knot and the reducing sphere in the surgered manifold. Gordon and Luecke's proof then proceeds by induction on certain cycles. Hoffman provides more insight into the structure of the base case of the induction (i.e. in an innermost cycle or a graph containing no such cycles). Hoffman uses this structure in a case-by-case proof of the Cabling Conjecture for knots of bridge number up to four. We find trees with specific properties in the graph of intersection, and use them to provethe existence of structure which provides lower bounds on the number of the aforementioned innermost cycles. Our results combined with a recent lower bound on the number of vertices inside the innermost cycles succinctly prove the conjecture for bridge number up to five and suggests an approach to the conjecture for knots of higher bridge number.

It is the goal of this paper to document through written description the personal approach that I would take in creating a role for the theatre. It will also describe what I feel to be valuable attributes and traits that make successful theatrical performance. Through the dissection of these two areas, I will glean a valuable personal insight into my work, how I've grown within it, and where I need to continually push to learn more.

Glacial Warm investigates romantic, human relationships and our collective commitment to the environment we inhabit. A couple travels and settles into polar and tropical landscapes, gathering, taking shelter, and finding sustenance together. They build their climate, adapting to continuous change. Through glaciers melting, volcanoes hissing, whales breaching, and nude bodies touching and holding, I develop a painted mythology. Partnership is embodied through separate entities working together. Everyday tasks become intimate gestures. The tenderness of these gestures is rooted in their separation as individuals. Paint application is direct. What melts, drips. What freezes is preserved in cloudy impasto. A kiss is an oily smudge.

This work is regarded as casting symbolic spells: spells for the health of degraded prairie remnants, the thriving of bats, fearlessness, romantic love. Spells are a call for transformation, and images of transformation occur throughout the work - snakes molting, mummies decaying, insects in metamorphosis. Whether examining a construction site or the end of a relationship, the author is asking herself "when is change good and when is it catastrophic?" Right now the author is looking closely at punk, witchy contemporary artists like Rosy Keyser, Maria Loboda, Marisa Merz, Victor Man, and Sterling Ruby. The author is also influenced by artists who smash a lot of pictures together, or have an overwhelming "Google Image Search" aesthetic like Isa Genzken, Anne de Vries, and Camille Henrot. At the same time, the author is drawn to old, mysterious, precious things (Viking runes, Taureg amulets, Hilma af Klint paintings, archaeological digs) and have an abiding love of altarpieces, medieval objects, Botticelli, and Van der Weyden. Depictions of the Expulsion from the Garden serve as regular references. In them, the author finds an entwinement of her interest in ecological and romantic upheaval and a relationship to the body and touch that is both tender and precarious. The author wants to make the work that's about all the inexhaustible things: love, death, history, sex, mysticism, family, nature. It's not there yet, but she is working to make them happen.

Contrary to the previous belief that any presence of supraglottic activity indicates presence of hyperfunctional vocal pathology, Stager et al. (2000, 2002) found out that supraglottic compressions do occur in normal subjects. In fact, dynamic false vocal fold compressions during production of phrases with a great number of glottal stops were noted. The present study hypothesized that a similar pattern s would be observed at sentence level, where at least 50% or higher incidence of dynamic FVF compressions would be observed at aurally perceived glottal stops and other linguistic markers, such as vowel-initial words, /t/ final words, punctuations and phrase boundaries, where glottal stops were likely to occur. Nasendoscopic recordings were obtained from 8 healthy subjects (2M; 6F) during production of selected sentence stimuli.. Their audio recordings were rated by two judges to detect the location of glottal stops. Then, the video images were analyzed to categorize the presence and absence of dynamic and static false vocal folds (FVF) or anterior posterior (AP) compressions. Results indicated that the incidence of dynamic FVF compressions was 30%. Nevertheless, the average incidence was elevated at aurally perceived glottal stops and at the linguistic contexts that are known to be associated with glottal stops compared to other contexts.