Master of Science, Miami University, 2022, Chemical, Paper and Biomedical Engineering

The need for more efficient drug design and development has become more prevalent in just the last few years, leading to the development of the SAMPL challenges to promote exploration of methods to compute physical properties key to drug development. Blind predictions of octanol/water partition coefficients at 298.15 K for 22 drug-like compounds were made for the SAMPL7 challenge. The octanol/water partition coefficients were predicted using solvation free energies computed using molecular dynamics simulations, wherein we considered the use of both pure and water-saturated 1- octanol to model the octanol-rich phase. Water and 1-octanol were modeled using TIP4P and TrAPPE-UA, respectively, which have been shown to well reproduce the experimental mutual solubility, and the solutes were modeled using GAFF. After the close of the SAMPL7 challenge, we additionally made predictions using TIP4P/2005 water. We found that the predictions were sensitive to the choice of water force field. However, the effect of water in the octanol-rich phase was found to be even more significant and non-negligible. The effect of inclusion of water was additionally sensitive to the chemical structure of the solute.

Committee: Andrew Paluch (Advisor); Alim Dewan (Committee Member); Jason Boock (Committee Member) Subjects: Chemical Engineering

Master of Science in Engineering, Youngstown State University, 2024, Department of Civil/Environmental and Chemical Engineering

The 108-mile-long Mahoning River, historically one of the most contaminated rivers in the U.S., contains metals above the EPA aquatic criteria. This study identifies the contamination levels, spatiotemporal patterns, sources, speciation, and bioaccessibility of metals (As, Ba, Fe, Pb, Ni, Zn) in the water and sediment of the lower Mahoning River. Sediment analysis showed that all metals exceeded the Sediment Reference Value, except for Ba. Regression analysis showed a significant decrease of Pb and Fe (p < 0.05) in water from 1993-2021, suggests that the water quality of the river with respect to Pb and Fe is improving comparatively in the past three decades. The contamination factor indicated that metals in water were uncontaminated (< 1), while metals in sediment were moderately to highly polluted (3-15). Inverse distance weighting in sediments illustrated decreasing concentrations towards downstream for Ni, while increasing concentrations towards downstream for As, Ba, Fe, Pb, and Zn in sediment. The inverse distance weighting patterns may be associated with land use, as the river traversed the agricultural region upstream, the urbanized region downstream, and mixed-land areas in the last stretch. Speciation analysis revealed metals in water and sediments were in divalent forms (HM2+), except Pb (PbOH+, PbCO3), indicating high bioaccessibility and potential plant uptake in the aquatic environment.

Committee: Sahar Ehsani PhD (Advisor); Felicia Armstrong PhD (Committee Member); Rick Deschenes PhD (Committee Member); Bradley Shellito PhD (Committee Member) Subjects: Environmental Education; Environmental Engineering; Environmental Geology; Environmental Science; Environmental Studies; Geographic Information Science

Master of Science in Chemical Engineering, Cleveland State University, 2015, Washkewicz College of Engineering

Elastin-like polypeptides (ELPs) are a class of biopolymers with the potential to function as a novel drug delivery platform. These protein based polymers are composed of the repeating pentapeptide sequence (GαGβP)n where n is the number of pentapeptide repeats while α and β are guest amino acid residues. ELP constructs have been designed to respond to various external stimuli including temperature, pH, and ionic strength where their response to these stimuli results in the separation of the ELP from solution. This phase separation results in a two-phase system consisting of a protein poor supernatant phase and a protein rich coacervate phase. Under certain conditions select ELP constructs are able to self assemble into micellar structures of nanometer scale when raised above their transition temperature. The micellar architecture consists of an inner hydrophobic core, with a composition like that of the protein rich coacervate phase, surrounded by hydrophilic head groups. For the use of ELP micelles as a drug delivery platform these particles should possess the ability to encapsulate solute molecules. In this study, solute solubility within the micelle core was investigated by measuring the partition coefficients of several solutes in five different ELP two-phase systems, then all data was fit to a linear free energy relationship (LFER) model to provide insight into the dominate interactions governing solute partitioning in ELP systems. From the LFER it is shown that the cavity formation energy, solute size, and the solvents hydrogen bond acidity are important parameters governing solute partitioning in the ELP solvents investigated. Additionally, the partition coefficients provide a measurement of ELP phase hydrophobicity from which the development of future ELP constructs is possible.

Committee: Nolan B Holland PhD (Advisor); Rolf Lustig PhD (Committee Member); David Anderson PhD (Committee Member) Subjects: Analytical Chemistry; Chemical Engineering; Chemistry; Engineering; Pharmaceuticals; Polymer Chemistry; Polymers

Doctor of Philosophy (PhD), Wright State University, 2015, Biomedical Sciences PhD

Organophosphates (OPs) are highly toxic insecticides and nerve agents that have been designed to inhibit the hydrolysis of acetylcholine by binding to the serine active site of acetylcholinesterase (AChE). They are one of the most common causes of human poisoning worldwide and are frequently intentionally used in suicides in agricultural areas. For this reason, there is a need for therapeutics to rescue those from intoxication. Obvious ethical concerns prevent humans from being subjected to OP exposure for therapeutic efficacy and safety testing. Therefore, animal surrogates for humans must be appropriately selected. A new paradigm, described herein, incorporating both in silico and in vitro techniques may be able to reduce the use of animals in biomedical research. Historically, the guinea pig (Cavia porcellus) has been believed to be the best non-primate model for OP toxicology and therapeutic development because, similarly to humans, guinea pigs have low amounts of OP metabolizing carboxylesterase (CaE) in blood and tissues. To explore the hypothesis that guinea pigs are the most appropriate human substitute for studying OP toxicology and therapeutic development, I cloned, purified and enzymatically compared a recombinant guinea pig acetylcholinesterase (gpAChE) with the human and mouse enzyme variants. The guinea pig, mouse and human apparent inhibition constants for diisopropyl fluorophosphate were found to be 8.4+/-0.6 uM, 4.9+/-0.6 uM and 0.42+/-0.01 uM, respectively, indicating that species differences exist for OP inhibition. Furthermore, I developed a mechanistic quantitative structure-property relationship (QSPR) to predict OP and therapeutic tissue: plasma partition coefficient (Kt:pl) parameters for each species. Differences in tissue lipid, water and protein content contributed to species specific Kt:pl. For example, guinea pig and human lung Kt:pl predictions for paraoxon were found to be 0.3 and 0.17, respectively. Biological and chemical (open full item for complete abstract)

Committee: Jeffery Gearhart Ph.D. (Advisor); Adrian Corbett Ph.D. (Committee Member); James Lucot Ph.D. (Committee Member); Mateen Rizki Ph.D. (Committee Member); Gerald Alter Ph.D. (Committee Member) Subjects: Biochemistry; Molecular Biology; Pharmacology; Toxicology

Master of Science (MS), Wright State University, 2008, Earth and Environmental Sciences

Using batch and stream recirculating flume experiments to compare and contrast one clayey sediment (Warden Ditch) and two analytical grade clay minerals (montmorillonite and kaolinite), the dynamic interactions between two aquatic stressors (suspended solids and nickel) were explored. Aldrich humic acid was incorporated to demonstrate the mitigating effects of dissolved organic carbon (DOC) on Ni toxicity. The flux of Ni between compartments (dissolved and sorbed) was quantified as a partition/distribution coefficient. The USEPA test organism Daphnia magna (neonates, < 24 h) was utilized to evaluate toxicity in dynamic non-renewal, short-term bioassays. Generally, toxicity showed a linear relationship with turbidity level. Conversely, sorption coefficients were experiment specific, making them difficult to predict and assess. Clay functioned as an adsorbent, scavenging Ni. Results support the hypotheses that solids and metals act as stressors in streams, DOC attenuates the toxicity of Ni, and Ni fluxes quickly between system compartments.

Committee: G. Allen Burton PhD (Committee Chair); David Dominic PhD (Committee Member); Songlin Cheng PhD (Committee Member); Chad Hammerschmidt PhD (Committee Member) Subjects: Earth; Environmental Science; Geology; Toxicology

Master of Science, The Ohio State University, 2012, Environmental Science

Growth promoters (GPs) are antibiotic or hormone compounds given to livestock at sub-therapeutic levels in order to promote growth rates and feed efficiency. Many GPs have limited bioavailability, meaning that a fraction of the compound will pass through the target animal without being metabolized. The application of manure containing the unmetabolized fraction as fertilizer can result in the introduction of GPs to the environment. The subsequent transport and environmental fate of GPs is largely controlled by the underlying soil matrix. Tylosin (a macrolide antibiotic) and progesterone (a naturally produced hormone) are both GPs with limited bioavailability that have been detected in surface waters in the United States. Despite their widespread use, the interactions of both of these compounds with soils are poorly understood. The purpose of this work was to help elucidate the fate of these two compounds in soil systems. Batch sorption experiments were conducted with five different sterilized soils and both tylosin and progesterone in order to determine their interactions with soils. Kinetics experiments were completed in order to determine the amount of time required to reach quasi-equilibrium between the sorbed and aqueous phase. Sorption isotherms were also completed, with initial aqueous concentrations ranging from 0.05-5.0 µM and 0.5-5.0 µM for progesterone and tylosin, respectively. Analysis of the aqueous concentration after quasi-equilibrium was reached was conducted via reverse phase high performance liquid chromatography (RP-HPLC). Both tylosin and progesterone were found to undergo strong non-linear sorption based upon Freundlich transformations of the isotherm data. Concentration dependent partition coefficients were calculated for both compounds using the Freundich isotherm fits and an initial aqueous concentration of Caq=0.5 µM. This resulted in average log Koc=2.94 ¿¿¿¿ 0.10 for progesterone and log Koc=2.95 ¿¿¿¿0.18 for tylosin. While no work has be (open full item for complete abstract)

Committee: Yu-Ping Chin Ph.D (Advisor); Roman P. Lanno (Committee Member); Dick Warren (Committee Member) Subjects: Agricultural Chemicals; Environmental Science; Soil Sciences

Master of Sciences, Case Western Reserve University, 2008, Materials Science and Engineering

Direct methanol fuel cell operation with uniaxially pre-stretched recast Nafion® membranes (draw ratio of 4) was investigated and compared to that with commercial (un-stretched) Nafion. The effects of membrane thickness (60-250 μm) and methanol feed concentration (0.5-10.0 M) on fuel cell power output were quantified for a cell temperature of 60°C, ambient pressure air, and anode/cathode catalyst loadings of 4.0 mg/cm2. Pre-stretched recast Nafion in the 130-180 μm thickness range produced the highest power at 0.4 V (84 mW/cm2), as compared to 58 mW/cm2 for Nafion 117. MEAs with pre-stretched recast Nafion consistently out-performed Nafion 117 at all methanol feed concentrations, with 33-48% higher power densities at 0.4 V, due to a combination of low area-specific resistance (the use of a thinner pre-stretched membrane, where the conductivity was the same as that for commercial Nafion) and low methanol crossover (due to low methanol solubility in the membrane). Very high power was generated with a 180 μm thick pre-stretched recast Nafion membrane by increasing the cell temperature to 80°C, increasing the anode/cathode catalyst loading to 8.0 mg/cm2, and increasing the cathode air pressure to 25 psig. Under these conditions the power density at 0.4 V for a 1.0 M methanol feed solution was 240 mW/cm2 and the maximum power density was 252 mW/cm2. Water uptake and mobility data were collected and analyzed for pre-stretched films with draw ratios ranging from 1 to 7 in order to better understand the transport characteristics and fuel cell performance of these materials. Macroscopic gravimetric water uptake and the water self diffusion coefficient (by NMR) in pre-stretched films were found to be identical to that in commercial Nafion 117 films, regardless of the extent of elongation. The ratio of freezable/nonfreezable water in pre-stretched recast Nafion, the water electro-osmotic drag coefficient, and the spin-lattice relaxation time constant of deuterated water, howev (open full item for complete abstract)

Committee: Dr. Peter Pintauro (Committee Chair); Dr. Joe Payer (Committee Chair); Dr. Gerhard Welsch (Committee Member) Subjects: Chemical Engineering