VictorJuiz/thesis huggingface dataset:
3D Finite Element Cosserat Continuum Simulation of Layered Geomaterials

The goal of this research is to develop a robust, continuum-based approach for a three-dimensional, Finite Element Method (FEM) simulation of layered geomaterials. There are two main approaches to the numerical modeling of layered geomaterials; discrete or discontinuous techniques and an equivalent continuum concept. In the discontinuous methodology, joints are explicitly simulated. Naturally, discrete techniques provide a more accurate description of discontinuous materials. However, they are complex and necessitate care in modeling of the interface. Also, in many applications, the definition of the input model becomes impractical as the number of joints becomes large. In order to overcome the difficulties associated with discrete techniques, a continuum-based approach has become popular in some application areas. When using a continuum model, a discrete material is replaced by a homogenized continuous material, also known as an 'equivalent continuum'. This leads to a discretization that is independent of both the orientation and spacing of layer boundaries. However, if the layer thickness (i.e., internal length scale of the problem) is large, the classical continuum approach which neglects the effect of internal characteristic length can introduce large errors into the solution. In this research, a full 3D FEM formulation for the elasto-plastic modeling of layered geomaterials is proposed within the framework of Cosserat theory. The effect of the bending stiffness of the layers is incorporated in the matrix of elastic properties. Also, a multi-surface plasticity model, which allows for plastic deformation of both the interfaces between the layers and intact material, is introduced. The model is verified against analytical solutions, discrete numerical models, and experimental data. It is shown that the FEM Cosserat formulation can achieve the same level of accuracy as discontinuous models in predicting the displacements of a layered material with a periodic microstructure. Furthermore, the method is capable of reproducing the strength behaviour of materials with one or more sets of joints. Finally, due to the incorporation of layer thickness into the constitutive model, the FEM Cosserat formulation is capable of capturing complicated failure mechanisms such as the buckling of individual layers of material which occur in stratified media.

Keywords: Cosserat continuum
finite element
anisotropy
layered geomaterial
micropolar theory
explicit joint
discrete element modelling
Advisor: Curran, John H.
An Exploration of the Structural, Electronic, and Anion Binding Properties of 2-Indolylphosphines

2-Indolylphosphines are unique ligands which have the capability for further phosphine modification by introducing substituents on an indolyl nitrogen centre. Substituents can vary in electronics, sterics, chirality, and can contain amino or phosphino groups which result in a multidentate (P,N)- or (P,P)-2-indolylphosphine. X-ray crystallography was used predominantly to examine and analyze the structural features of 2-indolyphosphines and their metal complexes. While the cone angles could not be determined crystallographically, the sum of the <CPC bond angles provided some information on the steric crowding around a phosphorus atom in selected 2-indolylphosphines. The symmetric tris-2-(3-methylindolyl)phosphine demonstrated anion binding ability through its three indolyl NH sites. Titrations to a series of selected anions were carried out; it was determined that tris-2-(3-methylindolyl)phosphine binds to these selected anions in a 1 : 1 receptor to anion binding ratio. Crystal structures of the fluoride and acetate complexes confirm the binding stoichiometry, and demonstrate the cooperative interaction of all three indolyl NH sites with the anion guest. Synthetic routes to new anion receptors with three or two indolyl NH donors were explored. The second type yielded a molecular cleft that was used in anion binding studies. The net basicity of a 2-indolylphosphine was determined through formation of a Ni(CO)3L complex. Net basicity can be tuned by changing the substituents on phosphorus or on an indolyl nitrogen centre. The [Cu(tris-2-(3-methylindolyl)phosphine)(phenanthroline)]BF4 complex is a discrete ion pair complex, exhibiting coordination chemistry at the phosphorus centre of the phosphine, while simultaneously hydrogen bonding through the indolyl NH sites to the BF4- anion. Complexes of the type [Pd(L)Cl(mu-Cl)]2 were analyzed by crystallography and the effect of net basicity on Pd-P bond length examined. The solid-state structures of (P,N)- and (P,P)-2-indolylphosphines were evaluated. In general, the sum of the <CPC bond angles increased from the parent unfunctionalized 2-indolylphosphine. The metal complexes of (P,N)- and (P,P)-2-indolylphosphines were assessed by crystallography to find possible trends of trans-influence. Lastly, a tetradentate tripodal ligand was synthesized by furnishing diphenylphosphino substituents on the indolyl nitrogen centres of tris-2-(3-methylindolyl)phosphine. The coordination of the tetradentate tripodal ligand to Pt(II) or Rh(I) resulted in five-coordinate trigonal bipyramidal complexes.

Keywords: X-ray crystallography
Phosphines
Advisor: Farrar, David
Surface-attached Biomolecules and Cells Studied by Thickness Shear Mode Acoustic Wave Sensor

The thickness shear mode acoustic wave (TSM) sensor, operated in a flow-through format, has been widely used in bioanalytical research. My research is mainly focused on the study of surface-attached biomolecules and cells using the TSM sensor, including lesions in DNA, conformational change of calmodulin, as well as the properties and attachment of rat aortic smooth muscle cells. Aldehydic apurinic or apyrimidinic sites (AP sites) that lack a nucleobase moiety are one of the most common forms of toxic lesions in DNA. In this work, synthesized oligodeoxyribonucleotides containing one, two, or three abasic sites were hybridized to complementary sequences immobilized on the gold electrode of the TSM device by affinity binding. The influence of AP sites on local base stacking energy and geometry caused a dramatic destabilization of the DNA duplex structure, which was detected by the TSM sensor. The signals detected by TSM correlated well with the thermostability of DNA duplexes in solution. The results indicate that both the number of sites and their localization in the double-stranded structure influence the stability of a 19 b.p. duplex. TSM was also used to detect the binding of ions or peptides to surface-attached calmodulin. The interaction between calmodulin and ions induced an increase in resonant frequency and a decrease in motional resistance. In addition, these signal changes were reversible upon washing with buffer. The response was interpreted as a decrease in surface coupling induced by exposure of hydrophobic domains on the protein, and an increase in the length of calmodulin by approximately 3 Å. In addition, the interaction of the protein with peptide together with calcium ions was detected successfully, despite the relatively low molecular mass of the 2-kDa peptide. In addition, the attachment of smooth muscle cells to various surfaces has been monitored by TSM. These surfaces include laminin, fibronectin and bare gold. The results of these experiments in terms of changes of frequency (fs) and resistance (Rm) were analyzed. The responses of the surface-bound cells to the introduction of various ions, depolarisation events and damage subsequent to exposure to hydrogen peroxide were also observed. Morphological changes in the cells, as confirmed by atomic force microscopy and scanning electron microscopy, are correlated with results from the TSM sensor.

Keywords: analytical chemistry
chemical sensor
bioanalytical chemistry
acoustic wave biosensor
Advisor: Thompson, Michael
Self-assembly of Elatin-like Peptides: Studies by Single Molecule Imaging

Understanding the basic mechanisms and dynamics that drive the assembly of molecules into functional structures is critically important in a diverse number of fields, ranging from materials science to drug delivery and biomaterials. In this work, we have focused on examining the self-assembly characteristics, both in solution and at surfaces, of a family of elastin-like peptides (EPs). In addition to directly observing the formation of ordered hexagonally arranged fibrillar EP structures on hydrophobic highly ordered pyrolytic graphite (HOPG), we have studied the dynamics of EP self-assembly process both within physically restricted domains using thermally etched HOPG, and in solution using detergent micelles. We have found that, at surfaces, EP fibril formation occurs via surface stabilization against the hydrophobic surface, while in solution, detergents inhibit EP aggregation at high temperatures and appear to enable the formation of an ordered crystalline structure at low temperatures. These model studies establish a framework for further investigations of peptide self-assembly and the role of hydrophobic interactions in controlling self-assembly.

Advisor: Yip, Christopher M.
Surface Intermediates, Mechanism, and Reactivity of Soot Oxidation

Factors that may govern diesel particulate matter (DPM) oxidation at low temperatures (~200°C) were studied using reactivity and TP-ToFSIMS analysis. Best-case scenarios that give maximum gasification rates were determined for DPM impregnated with KOH and non-catalyzed DPM using temperature programmed oxidation and isothermal experiments. Conditions of intimate catalyst-carbon contact (K/C molar ratio=1/50) and high NO2 concentrations (1%) to improve the reactivity of the carbon reactive sites were unable to meet the steady state gasification rate needed for particulate filter regeneration for a modern diesel engine at 200°C. Oxygen-free thermal annealing (>500°C) caused reactivity losses of a maximum of 40% that correspond to changes to surface morphology and/or concentration of oxygen-containing functional groups. TP-ToFSIMS identified surface functional group changes with temperature on non-dosed and NOX pre-dosed (1.5%NO, 1%NO2, 4.5%O2, balance helium) diesel soot and sucrose char. Detailed analysis of the NOX dosed sucrose char spectra using both inspection and principal component analysis techniques revealed that the 1200 ion fragments created could be reduced to five sets of ions that are chemically and kinetically distinct. These sets presumably represent surface functional groups on the carbon. For example, Set IV may represent carboxylic acid, lactone, or carboxylic anhydride functional groups. Based on these results a mechanism for the surface reaction of NO2 with carbon under vacuum conditions was postulated. At temperatures less than 200°C the ion fragments contain primarily carbon-NO2 type ions. As temperature increases between 200 and 400°C the ion fragments are primarily carbon-NO and carbon-N type fragments. At higher temperatures (>500°C) the surface is enriched with nitrogen containing functional groups. A surface reaction mechanism is proposed where NO2 is bonded to an armchair site and with increasing temperatures and molecular rearrangements the N is incorporated into the carbon ring. The initial surface composition of NOx containing functional groups changes within the area of relevance of low temperature soot regeneration (i.e. between 25° and 200°C). Further studies are needed to understand the effect of N-incorporation on carbon reactivity. No rate processes either in reactor studies or based on surface functional groups met the rate criteria for low temperature DPM oxidation.

Keywords: soot oxidation
TOFSIMS
particulate matter
Advisor: Mims, Charles A.
Self-assembled Polymeric Nanoparticles for Targeted Delivery of Anticancer Drugs

Targeted delivery of drugs to specific regions of the body, or even to specific regions of the cell, promises enhanced drug efficacy and reduced systemic toxicity. By covalently coupling targeting ligands, the smart drug delivery systems are capable of targeting specific cell types exclusively through ligand-receptor interactions. The main goal of the project is to create a polymeric nanoparticle drug delivery system from synthesized biodegradable polymers and modify the polymeric nanoparticles using targeting antibodies for targeted delivery of anticancer drugs. A new biodegradable copolymer poly(2-methyl, 2-carboxy trimethylene carbonate-co-D,L-lactide)-graft-poly(ethylene glycol)-furan (poly(TMCC-co-LA)-g-PEG-furan) was synthesized and characterized. The copolymers self-assembled into spherical nanoparticles in aqueous environments with the hydrodynamic diameters controlled over a broad size range. Immuno-polymeric nanoparticles were created by coupling maleimide-modified anti-human epidermal growth factor receptor 2 (anti-HER2) antibodies to the self-assembled nanoparticles through Diels-Alder (DA) chemistry. This new coupling methodology was demonstrated to be relatively rapid, highly efficient and specific under mild conditions. In vitro studies showed that the immuno-nanoparticles bound specifically and efficiently with SKBR3 breast cancer cells that overexpress HER2 receptors. Anticancer drugs were incorporated into the immuno-nanoparticle system and the drug delivery via an antibody-mediated targeting mechanism was investigated in vitro. First, a protein anticancer drug, interleukin-2 (IL-2), was physically encapsulated through polymer-drug association. The IL-2 encapsulated anti-HER2 immuno-nanoparticles exhibited a cell-binding associated IL-2 release in the extracellular space upon binding with HER2-overexpressing SKBR3 breast cancer cells. Second, a small molecule hydrophobic drug, doxorubicin (DOX), was chemically conjugated on the nanoparticle surface after the antibody coupling, using the same DA chemistry. The novel formulation localized DOX in the cell nucleus of HER2-overexpressing SKBR3 breast cancer cells and remained the biological function of conjugated DOX. Compared to the nanoparticles bearing DOX or anti-HER2 antibody alone, the nanoparticles having a combination of DOX and anti-HER2 antibody exhibited the most significant cytotoxicity and specificity against SKBR3 cells relative to healthy HMEC-1 endothelial cells, demonstrating the potential of the DOX-immuno-nanoparticles as a novel platform for intracellular DOX delivery. This work provides a novel means for the delivery of combination immunotherapy/chemotherapy to more effectively treat certain malignancies.

Keywords: drug delivery
polymeric nanoparticle
Advisor: Shoichet, Molly
Genetic and Chemical Genetic Analysis of the Cell Cycle

Proper progression through the cell cycle is critical for cell growth and survival. Disruption of cell cycle progression can lead to cell cycle arrest and cell death. In addition, uncontrolled cell cycle progression can lead to cancer. Cells have evolved complex mechanisms to regulate each phase of the cell cycle to ensure proper cell cycle progression. In the presence of cellular stress, cells will respond promptly to arrest the cell cycle and allow repair. In order to study this complex process, it is important to identify the complete complement of proteins involved. I took two large-scale approaches to study the cell cycle. First, I down-regulated the majority of essential genes in Saccharomyces cerevisiae, and determined how depletion of individual gene product affected progression through the cell cycle. I determined that over 65% of essential genes I tested are most important at a specific cell cycle phase. In addition, I found that two genes, Smc4 and Cse1, have novel roles in S-phase of the cell cycle. In the second approach, I discovered two anti-proliferative compounds. Both compounds caused cell cycle delay in G1 phase of the cell cycle. Chemical genetic screens in yeast allowed me to determine the pathways most sensitive to each of these two compounds. By studying the response of cells to these compounds, I confirmed that compound 13 causes mitochondrial dysfunction in cells and compound 15 causes nuclear DNA damage. Furthermore, I found that both compounds are toxic in mammalian cells and that the responses that they elicit in mammalian cells are similar to those observed in yeast cells.

Keywords: cell cycle
Advisor: Brown, Grant
Probing Septin Function Through Interaction Screens: Identification of Novel Septins and Possible Regulatory Mechanisms

Septins are a family of guanine nucleotide-binding proteins that function in eukaryotic cell division, where they form a high-order cortical structure at the site of division, which is essential in most eukaryotes. Expanded roles have evolved for septins in metazoans, where they also have essential functions in terminally-differentiated cell types, such as neurons and spermatozoa. Specific details of septin function are lacking in most roles described, due at least in part to the limited number of characterized binding partners. In this work, yeast two-hybrid screens and pull-downs from tissue homogenate were used to identify novel septin binding partners for subsequent characterization. The neuron-enriched septin, SEPT5, interacted directly with SUMO E3 ligases of the PIAS family. However, I was not able to demonstrate endogenous sumoylation of SEPT5 and SUMO isoforms did not concentrate with the septins during cytokinesis. SEPT5 also interacted with a novel septin, SEPT12, which I further characterized to be testis-specific and localized to the annulus in mature spermatozoa. Further, using SEPT12-specific reagents, I determined that the annulus forms via sequestration and subsequent segregation from the Golgi during spermiogenesis. SEPT9 pull-downs identified another novel testis-specific septin, SEPT14. Reagents specific to SEPT2 and SEPT9 also revealed a septin-rich structure in the seminiferous epithelium in close association with the ectoplasmic specialization. The specific role of septins in this structure awaits further characterization. Several other intriguing candidate septin-interaction partners were identified and the further study of their possible in vivo interaction with septins may provide substantial insight into the mechanisms of septin function in eukaryotes.

Keywords: septin, GTP, sperm, annulus, SUMO
Advisor: Trimble, William S.
The Role of Ligand Induced Stabilization in the Allosteric Mechanism of Tetracycline Repressor

Allosteric regulation of proteins by reversible ligand binding is essential for regulation of fundamental biological processes. The mechanism by which a binding event alters the function of a distant site in a protein is only poorly understood. In this thesis, I use the Tetracycline Repressor (TetR) as a model system to study ligand induced allostery. The transcription of genes encoding the resistance to the antibiotic, tetracycline (Tc), is repressed by TetR, which is a homodimeric alpha-helical protein possessing a small N-terminal DNA binding domain (DNB domain) and a larger C-terminal tetracycline binding and dimerization domain (TBD domain). Based on previous structural and thermodynamic studies, the DNB domains are thought to exist in two stable, distinct conformations. One conformation is able to bind the Tc resistance operator sequence (tetO) with high affinity, while the other, which is induced by Tc binding, binds very weakly. While most previous studies on TetR have focused on the effects of Tc binding on the DNB domain conformation, here I have investigated the role of the DNB domain in modulating Tc binding. By introducing destabilizing mutations into the DNB domain I ascertained that the conformation and stability of the DNB domain plays an important role in determining Tc binding affinity. I also discovered that in the absence of ligand, the DNB domain exists in an unstable and flexible state with respect to the TBD domain. However, Tc binding to the TBD domain stabilizes the DNB domain, causing it to fold cooperatively with the TBD domain. I have discovered that the behavior of previously isolated non-inducible mutants is caused by the inability of Tc to stabilize the DNB domain in these mutants. Furthermore, reverse TetR mutants, which bind DNA better in the presence of Tc have an unfolded DNB domain that is only partially stabilized by Tc binding. My work suggests a new comprehensive, Tc induced stabilization and domain cooperativity model that can describe the mechanism of allostery in TetR and previously unexplainable mutants. A practical outcome of this research is the creation of a Tc induced folding switch that can be exploited to control the in vivo degradation of a protein of interest.

Keywords: TetR
allostery
tetracycline
stabilization
Advisor: Davidson, Alan R.
Airfoil Optimization for Unsteady Flows with Application to High-lift Noise Reduction

The use of steady-state aerodynamic optimization methods in the computational fluid dynamic (CFD) community is fairly well established. In particular, the use of adjoint methods has proven to be very beneficial because their cost is independent of the number of design variables. The application of numerical optimization to airframe-generated noise, however, has not received as much attention, but with the significant quieting of modern engines, airframe noise now competes with engine noise. Optimal control techniques for unsteady flows are needed in order to be able to reduce airframe-generated noise. In this thesis, a general framework is formulated to calculate the gradient of a cost function in a nonlinear unsteady flow environment via the discrete adjoint method. The unsteady optimization algorithm developed in this work utilizes a Newton-Krylov approach since the gradient-based optimizer uses the quasi-Newton method BFGS, Newton's method is applied to the nonlinear flow problem, GMRES is used to solve the resulting linear problem inexactly, and last but not least the linear adjoint problem is solved using Bi-CGSTAB. The flow is governed by the unsteady two-dimensional compressible Navier-Stokes equations in conjunction with a one-equation turbulence model, which are discretized using structured grids and a finite difference approach. The effectiveness of the unsteady optimization algorithm is demonstrated by applying it to several problems of interest including shocktubes, pulses in converging-diverging nozzles, rotating cylinders, transonic buffeting, and an unsteady trailing-edge flow. In order to address radiated far-field noise, an acoustic wave propagation program based on the Ffowcs Williams and Hawkings (FW-H) formulation is implemented and validated. The general framework is then used to derive the adjoint equations for a novel hybrid URANS/FW-H optimization algorithm in order to be able to optimize the shape of airfoils based on their calculated far-field pressure fluctuations. Validation and application results for this novel hybrid URANS/FW-H optimization algorithm show that it is possible to optimize the shape of an airfoil in an unsteady flow environment to minimize its radiated far-field noise while maintaining good aerodynamic performance.

Keywords: unsteady discrete adjoint
unsteady optimization
hybrid acoustic predictions
computational fluid dynamic
airframe-generated noise
optimal control
gradient-based optimization
Ffowcs Williams and Hawkings equation
Advisor: Zingg, David W.