Digital Commons Network^™

Preclinical And Clinical Development Of The Lipophilic Camptothecin Analogue Ar-67, Eleftheria Tsakalozou

Theses and Dissertations--Pharmacy

AR-67 is a lipophilic third generation camptothecin analogue, currently under early stage clinical trials. It acts by targeting Topoisomerase 1 (Top1), a nuclear enzyme essential for DNA replication and transcription and is present in two forms, the pharmacologically active lipophilic lactone and the charged carboxylate. In oncology patients participating in a phase I clinical trial, AR-67 lactone was the predominant species in plasma. Similarly to other camptothecins, the identified dose-limiting toxicities for AR-67 were neutropenia, thrombocytopenia and fatigue. In addition, in vitro metabolism studies indicated AR-67 lactone as a substrate for CYP3A4/5 as well as the UGT1A7 and UGT1A8 enzymes …

The Pharmacokinetics Of Metal-Based Engineered Nanomaterials, Focusing On The Blood-Brain Barrier, Mo Dan

Theses and Dissertations--Pharmacy

Metal-based engineered nanomaterials (ENMs) have potential to revolutionize diagnosis, drug delivery and manufactured products, leading to greater human ENM exposure. It is crucial to understand ENM pharmacokinetics and their association with biological barriers such as the blood-brain barrier (BBB). Physicochemical parameters such as size and surface modification of ENMs play an important role in ENM fate, including their brain association. Multifunctional ENMs showed advantages across the highly regulated BBB. There are limited reports on ENM distribution among the blood in the brain vasculature, the BBB, and brain parenchyma.

In this study, ceria ENM was used to study the effect of …

Formulation Optimization For Pore Lifetime Enhancement And Sustained Drug Delivery Across Microneedle Treated Skin, Priyanka Ghosh

Theses and Dissertations--Pharmacy

Microneedle (MN) enhanced drug delivery is a safe, effective and efficient enhancement method for delivery of drug molecules across the skin. The “poke (press) and patch” approach employs solid stainless steel MN to permeablize the skin prior to application of a regular drug patch over the treated area. It has been previously shown that MN can be used to deliver naltrexone (NTX) at a rate that provides plasma concentrations in the lower end of the therapeutic range in humans. The drug delivery potential of this technique is, however, limited by the re-sealing of the micropores in a 48-72h timeframe. The …

Microglia Activation In A Rodent Model Of An Alcohol Use Disorder: The Importance Of Phenotype, Initiation, And Duration Of Activation, Simon A. Marshall

Theses and Dissertations--Pharmacy

Chronic ethanol exposure results in neuroadaptations that drive the progression of an alcohol use disorder (AUD). One such driving force is alcohol-induced neurodegeneration. Neuroinflammation has been proposed as a mechanism underlying this damage. Although neuroinflammation is a physiological response to damage, overactivation of its pathways can lead to neurodegeneration. A hallmark indicator of neuroinflammation is microglial activation, but microglial activation is a heterogeneous continuum of phenotypes that can promote or inhibit neuroinflammation. Furthermore acute microglial activation is necessary to restore homeostasis, but prolonged activation can exacerbate damage. The diversity of microglia makes both the level and timecourse of activation vital …

Polymer Micelles For Tunable Drug Release And Enhanced Antitumor Efficacy, Andrei G. Ponta

Theses and Dissertations--Pharmacy

Cancer remains a leading cause of death in the United States. The most common treatment options include chemotherapy, but poor solubility, adverse side effects and differential drug sensitivity hamper clinical applications. Current chemotherapy generally aims to deliver drugs at the limit of toxicity, assuming that higher dosage increases efficacy, with little attention paid to potential benefits of tunable release. Growing evidence suggests that releasing drugs at a constant rate will be as effective as a single bolus dose. To test this hypothesis, it is critical to develop drug delivery systems that fine-tune drug release and elucidate the impact of tunable …

Regulation Of 7-Dehydrocholesterol Reductase By Vitamin D3, Ling Zou

Theses and Dissertations--Pharmacy

7-Dehydrocholesterol (7-DHC) is the substrate of 7-dehydrocholesterol reductase (DHCR7) in the cholesterol synthesis pathway. Keratinocytes in human skin possess the enzymes necessary for cholesterol synthesis but are also responsible for vitamin D₃ synthesis from 7-DHC by exposure to UVB irradiation. It has been well established that DHCR7 is regulated by the SREBP pathway in the regulation of cholesterol synthesis, but little is known about the regulation of DHCR7 by the vitamin D pathway. In this study, the regulation of DHCR7 activity by vitamin D was explored. Treatment of adult human epidermal keratinocyte (HEKa) cells with vitamin D₃ resulted …

Methylphenidate And Atomoxetine Treatment During Adolescence In The Spontaneously Hypertensive Rat: Mechanisms Underlying High Cocaine Abuse Liability In Attention Deficit/Hyperactivity Disorder, Sucharita S. Somkuwar

Theses and Dissertations--Pharmacy

Effects of pharmacotherapies for Attention Deficit/Hyperactivity Disorder (ADHD) on cocaine abuse liability in ADHD are not understood. Spontaneously Hypertensive Rats (SHR), an ADHD model, exhibited greater cocaine self-administration than control Wistar-Kyoto and Wistar rats. Methylphenidate, but not atomoxetine during adolescence enhanced cocaine self-administration in adult SHRs compared to controls. The mesocortical dopaminergic system, including medial prefrontal (mPFC) and orbitofrontal (OFC) cortices, is important for ADHD and cocaine addiction. Dopamine and norepinephrine transporter (DAT and NET) are molecular targets for methylphenidate, atomoxetine and cocaine action.

In the current studies, SHR, Wistar-Kyoto and Wistar were administered methylphenidate (1.5 mg/kg/day, p.o.), atomoxetine (0.3 …

Cellular And Molecular Aspects Of The Interaction Betwen Maize And The Anthracnose Pathogen Colletotrichum Graminicola, Maria F. Torres

Theses and Dissertations--Plant Pathology

Maize anthracnose, caused by the fungus Colletotrichum graminicola, is an economically important species contributing to major yield losses. C. graminicola is a hemibiotroph; initially it invades its host while it is alive, and then it switches to destructive necrotrophic growth and the host is killed. Establishment of compatible interactions by biotrophic pathogens is usually associated with suppression of host defenses and cell death, while necrotrophic pathogens typically secrete phytotoxic compounds and induce cell death. To understand the relationship of hemibiotrophy in C. graminicola to biotrophy and necrotrophy, I compared a compatible and an incompatible interaction, utilizing a non-pathogenic …

Overexpression/Silencing Of Selected Soybean Genes Alters Resistance To Pathogens, Mohamed H. El-Habbak

Theses and Dissertations--Plant Pathology

Plant diseases remain a major obstruction to meeting the world’s increased demand for soybean oil and protein. Reducing the losses caused by diseases in order to improve crop production is a high priority for agricultural research. The need for novel strategies for plant disease control cannot be overstated. In the present study, selected defense-related genes were silenced and/or overexpressed in soybean using a virus-based vector and the resultant plants were tested for their responses to pathogens. The first part of the study focused on Rps1k (Resistance to Phytophthora sojae) gene. The two conserved domains encoding ‘P-Loop NTPase’ and ‘PLN03210’ …

Equine Protozoal Myeloencephalitis: Investigation Of Genetic Susceptibility And Assessment Of An Equine Infection Method, Breanna M. Gaubatz

Theses and Dissertations--Veterinary Science

Equine protozoal myeloencephalitis (EPM) is a progressive neurological disease of horses caused by Sarcocystis neurona. Two projects were conducted to identify factors involved in the development of EPM. The first study explored a possible genetic susceptibility to EPM by attempting a genome-wide association study (GWAS) on formalin-fixed, paraffin-embedded (FFPE) tissue from 24 definitively-positive EPM horses. DNA extracted from tissues older than 14 months was inadequate for SNP analysis on the Illumina Equine SNP50 BeadChip probably due to degradation and formalin cross-linking. Results were inconclusive as analysis was not possible with the small sample set. The second study evaluated an …

Determination Of Farm-Specific Lawsonia Intracellularis Seroprevalence In Central Kentucky Thoroughbreds And The Identification Of Factors Contributing To Equine Proliferative Enteropathy, Allen E. Page

Theses and Dissertations--Veterinary Science

Lawsonia intracellularis and the disease it causes in horses, equine proliferative enteropathy (EPE), is an emerging pathogen of increasing importance to the horse industry from both an economic and welfare standpoint. Long recognized as an economically important disease of swine, the hallmark of EPE is a protein-losing enteropathy, where affected horses suffer weight loss and some ultimately succumb to the disease despite aggressive treatment. There are currently no known EPE preventative measures and the epidemiology of the disease remains poorly defined. While EPE is a sporadic disease affecting less than 25% of exposed horses, some farms experience clinical cases year …

Evidence For The Maturation Of Cellular Immune Responses In Equine Infectious Anemia Virus-Infected Ponies, Chong Liu

Theses and Dissertations--Veterinary Science

Equine infectious anemia virus (EIAV) has been used as a model to investigate protective mechanisms against lentiviruses. Unlike other lentiviruses, EIAV replication can be eventually controlled in most infected horses leading to an inapparent carrier state free of overt clinical signs which can last for many years. Maintenance of this carrier state is absolutely dependent on active immune responses as evidenced by the fact that immunosuppressive drugs can induce the recurrence of disease. However, the immune mechanisms that are responsible for this control of infection are not yet identified. As the resolution of the initial infection is correlated with the …

Effects Of Streamside Management Zone Timber Harvest On Salamander Communities In Robinson Forest, Thomas Maigret

Theses and Dissertations--Forestry and Natural Resources

Salamanders are critical components of forest ecosystems, in terms of total biomass, as well as for their value as indicators of ecosystem stress. Considering the worldwide decline in amphibian populations, the known effects of timber harvest on salamander populations, and the importance of the forest products industry in Kentucky and elsewhere, the impacts of silvicultural operations on salamander communities cannot be overlooked. The objective was to investigate the effects of three different silvicultural treatments, each involving different streamside management zone (SMZ) characteristics, on salamander communities in ephemeral streams. Data were collected by regular checks of pitfall traps, coverboards, and transect …

Chondrodysplasia-Like Dwarfism In The Miniature Horse, John E. Eberth

Theses and Dissertations--Veterinary Science

Dwarfism is considered one of the most recognized congenital defects of animals and humans and can be hereditary or sporadic in cause and expression. There are two general morphologic categories within this vastly diverse disease. These categories are disproportionate and proportionate dwarfism and within each of these there are numerous phenotypes which have been extensively described in humans, and to a lesser extent in dogs, cattle, mice, chickens, and other domestic species. Ponies and Miniature horses largely differ from full size horses only by their stature. Ponies are often defined as those whose height is not greater than 14.2 hands; …

Equine Serum Antibody Responses To Streptococcus Equi And Streptococcus Zooepidemicus, Rafaela De Negri

Theses and Dissertations--Veterinary Science

Streptococcus zooepidemicus (Sz) and Streptococcus equi (Se) share 98% DNA sequence homology, but display different pathogenic properties. Infection by one organism does not cross-protect against the other. To better understand pathogenic differences between these organisms and gain information about which proteins are expressed in horses infected experimentally with Se, intrauterine Sz or naturally with respiratory Sz we compared antibody specificities of convalescent sera using ELISA. These comparisons were based on sets of 8 and 14 immunoreactive recombinant proteins of Se strain CF32 and Sz strain NC78, respectively. Sera from donkeys that were previously naturally affected with strangles and later developed …

Development Of A New Allelic Discrimination Real-Time Pcr Assay For The Diagnosis Of Equine Herpesvirus-1 And Characterization Of The Virulence Determinants Of The Virus, Kathryn L. Smith

Theses and Dissertations--Veterinary Science

Equine herpesvirus-1 (EHV-1) can cause acute upper respiratory tract disease, abortion, neonatal death and neurological disease in horses. Rapid, accurate and timely diagnosis of EHV-1 infection in horses is important to curtail the spread of this pathogen. It has been reported that the neuropathogenic phenotype of EHV-1 can result from a single non-synonymous nucleotide substitution at position 2254 (A→G₂₂₅₄) in open reading frame 30 (ORF30). This was the basis for the development of an allelic discrimination, real-time PCR assay to distinguish between potential neuropathogenic and non-neuropathogenic EHV-1 strains. However, PCR analysis of a panel of EHV-1 abortion isolates …

Selective Utilization Of Microhabitats By Web-Building Spiders, Kelton D. Welch

Theses and Dissertations--Entomology

Natural enemies are members of complex ecological communities, and their ability to contribute to the biological control of pest organisms is strongly influenced by a convoluted network of ecological interactions with many other organisms within these communities. Researchers must develop an understanding of the mechanisms that shape trophic webs to predict and promote top-down effects of predators. The behavior of predators can have a strong influence on their potential as biological control agents.

Web-building spiders are a useful example organism for the study of natural enemy behavior because of the experimentally tractable nature of their foraging behavior. Specifically, patterns in …

An Assessment Of The Invasive Poison Hemlock And Its Insect Associates In Kentucky, Christine D. Allen

Theses and Dissertations--Entomology

Poison hemlock, Conium maculatum (Apiaceae), is an invasive plant in North America with a unique toxic chemistry. Previous research on this plant has focused on identifying herbivores as potential biological control agents or describing the toxic plant alkaloids. However, none have examined the role of higher trophic levels in the food web surrounding poison hemlock. Generalist predators and food web interactions are an important component of studies investigating invasion effects, as plant or animal introductions can alter ecosystem functioning. In this study, predators in poison hemlock were sampled at the foliar and epigeal levels, resulting in 956 Carabidae and 321 …

Enhancing Beneficial Insect Biodiversity And Biological Control In Turf: Mowing Height, Naturalized Roughs, And Operation Pollinator, Emily Dobbs

Theses and Dissertations--Entomology

The goal of this study was to evaluate several sustainable turf maintenance techniques for their potential to increase beneficial insect populations, which could then provide ecosystem services including pest suppression and pollination. The three techniques in question were 1) raising mowing height in commercial and residential lawns, 2) establishing naturalized roughs on golf courses, and 3) creating pollinator refuges on golf courses through the program Operation Pollinator. We found that raising mowing heights did increase populations of some predators such as spiders and staphylinids, but did not increase predation, which was ubiquitously high because ant populations were unaffected by mowing …

Endosymbiotic Prevalence And Reproductive Manipulation Of The Spider Mermessus Fradeorum, Meghan M. Curry

Theses and Dissertations--Entomology

Spiders are host to a plethora of heritable endosymbiotic bacteria. Broad-taxa screening studies indicate that endosymbionts are particularly common among spiders, however, little is known about how these bacteria affect their spider hosts. In insects these bacteria ensure vertical transmission by either conveying a benefit to the host or manipulating host reproduction to eliminate males that serve as evolutionary dead-ends for maternally-inherited bacteria. Common modes of reproductive manipulation include parthenogenesis, male killing, feminization, and cytoplasmic incompatibility. Screening an assemblage of Mermessus genus spiders, I detected a high frequency and diversity of endosymbiont infection. Within a single species, M. fradeorum …

Entrepreneurship On The Farm: Kentucky Growers’ Perceptions Of Benefits And Barriers, Amy L. Camenisch

Theses and Dissertations--Nutrition and Food Systems

This study analyzed the perceptions of Kentucky Homebased Processors and Microprocessors of the benefits of and barriers to developing and selling value-added products. The final sample consisted of 141 participants, 60.5% (n=72) of which were from Central KY, 26.9% (n=32) were from Western KY, and 12.6% (n=15) were from Eastern KY. Overall, participants seemed to feel that their value-added products were successful in many different benefit categories. The primary barriers to developing value-added products were lack of time, lack of funding, and lack of legal knowledge. The primary barriers to utilizing program resources for farmers were not having enough time, …

Evaluation Of Handling Equipment Sound Pressure Levels As Stressors In Beef Cattle, Christina M. Lyvers

Theses and Dissertations--Biosystems and Agricultural Engineering

Sound pressure level (SPL) is known to cause stress in cattle but is often overlooked as a potential source of fear for cattle when designing handling equipment. Current literature does not offer guidelines for the design of equipment with regard to SPL. It is, however, recommended that handling equipment should be designed to minimize the SPL during handling. The purpose of this experiment was to measure stress levels in a group of cattle which were subjected to a series of varying sounds in order to determine a design threshold limit for handling equipment. Treatments included two frequencies, 1 kHz and …

Using Gis To Delineate Headwater Stream Origins In The Appalachian Coal-Belt Region Of Kentucky, Jonathan A. Villines

Theses and Dissertations--Biosystems and Agricultural Engineering

Human activity such as surface mining can have substantial impacts on the natural environment. Performing a Cumulative Hydrologic Impact Assessment (CHIA) of such impacts on surface water systems requires knowing the location and extent of these impacted streams. The Jurisdictional Determination (JD) of a stream’s protected status under the Clean Water Act (CWA) involves locating and classifying streams according to their flow regime: ephemeral, intermittent, or perennial. Due to their often remote locations and small size, taking a field inventory of headwater streams for surface mining permit applications or permit reviews is challenging. A means of estimating headwater stream location …

Automatic Performance Level Assessment In Minimally Invasive Surgery Using Coordinated Sensors And Composite Metrics, Sami Taha Abu Snaineh

Theses and Dissertations--Computer Science

Skills assessment in Minimally Invasive Surgery (MIS) has been a challenge for training centers for a long time. The emerging maturity of camera-based systems has the potential to transform problems into solutions in many different areas, including MIS. The current evaluation techniques for assessing the performance of surgeons and trainees are direct observation, global assessments, and checklists. These techniques are mostly subjective and can, therefore, involve a margin of bias.

The current automated approaches are all implemented using mechanical or electromagnetic sensors, which suffer limitations and influence the surgeon’s motion. Thus, evaluating the skills of the MIS surgeons and trainees …

Context Aware Privacy Preserving Clustering And Classification, Nirmal Thapa

Theses and Dissertations--Computer Science

Data are valuable assets to any organizations or individuals. Data are sources of useful information which is a big part of decision making. All sectors have potential to benefit from having information. Commerce, health, and research are some of the fields that have benefited from data. On the other hand, the availability of the data makes it easy for anyone to exploit the data, which in many cases are private confidential data. It is necessary to preserve the confidentiality of the data. We study two categories of privacy: Data Value Hiding and Data Pattern Hiding. Privacy is a huge concern …

A Novel Computational Framework For Transcriptome Analysis With Rna-Seq Data, Yin Hu

Theses and Dissertations--Computer Science

The advance of high-throughput sequencing technologies and their application on mRNA transcriptome sequencing (RNA-seq) have enabled comprehensive and unbiased profiling of the landscape of transcription in a cell. In order to address the current limitation of analyzing accuracy and scalability in transcriptome analysis, a novel computational framework has been developed on large-scale RNA-seq datasets with no dependence on transcript annotations. Directly from raw reads, a probabilistic approach is first applied to infer the best transcript fragment alignments from paired-end reads. Empowered by the identification of alternative splicing modules, this framework then performs precise and efficient differential analysis at automatically detected …

The Impairment Of Macrophage-To-Feces Reverse Cholesterol Transport During Inflammation Does Not Depend On Serum Amyloid A, Maria C. De Beer, Joanne M. Wroblewski, Victoria P. Noffsinger, Ailing Ji, Jason M. Meyer, Deneys R. Van Der Westhuyzen, Frederick C. De Beer, Nancy R. Webb

Saha Cardiovascular Research Center Faculty Publications

Studies suggest that inflammation impairs reverse cholesterol transport (RCT). We investigated whether serum amyloid A (SAA) contributes to this impairment using an established macrophage-to-feces RCT model. Wild-type (WT) mice and mice deficient in SAA1.1 and SAA2.1 (SAAKO) were injected intraperitoneally with ³H-cholesterol-labeled J774 macrophages 4 hr after administration of LPS or buffered saline. ³H-cholesterol in plasma 4 hr after macrophage injection was significantly reduced in both WT and SAAKO mice injected with LPS, but this was not associated with a reduced capacity of serum from LPS-injected mice to promote macrophage cholesterol efflux in vitro. Hepatic accumulation of ^{3 …}

Simulacro, Hiperrealidad Y Pos-Humanismo: La Ciencia Ficción En Argentina Y España En Torno Al 2000, Mirta Rímolo De Rienzi

Theses and Dissertations--Hispanic Studies

This project focuses on science fiction literature of Spain and Argentina produced in the last twenty years (1990-2010). It hypothesizes that in this period a change of perspective substantially modified science fiction productions in both countries and converges into a new model of narrative. As a consequence of this reformulated vision, a new narrative perspective immerses readers in an era of simulation, hyperreality, and post-humanism. When advanced technology is able to modify the basic human anatomy, and persons are trapped between virtual and real universes, simulacra facilitate control of people in an effective and impersonal manner. Simultaneously, fictional scenarios show …

Injury Establishes Constitutive Μ-Opioid Receptor Activity Leading To Lasting Endogenous Analgesia And Dependence, Gregory F. Corder

Theses and Dissertations--Physiology

Injury causes increased pain sensation in humans and animals but the mechanisms underlying the emergence of persistent pathological pain states, which arise in the absence of on-going physical damage, are unclear. Therefore, elucidating the physiological regulation of such intractable pain is of exceptional biomedical importance. It is well known that endogenous activation of µ-opioid receptors (MORs) provides relief from acute pain but the consequences of prolonged endogenous opioidergic signaling have not been considered. Here we test the hypothesis that the intrinsic mechanisms of MOR signaling promote pathological sensitization of pain circuits in the spinal cord. We found that tissue inflammation …

Veterinary Specialty Certification: Analyzing The Value Of Certification Through The American Board Of Veterinary Practitioners, Jeff Allen

MPA/MPP/MPFM Capstone Projects

When it comes to professional certification a number of potential benefits can be cited by the organizations that offer them. Self-improvement, recognition by peers, public benefit and enhanced career opportunities are just a few of the frequently mentioned values associated with certification programs. This study was conducted to identify the primary benefits of certification for the American Board of Veterinary Practitioners (ABVP) by recording and analyzing the perceived value of ABVP certification within the veterinary community. An online survey was developed to collect data from ABVP certified and non-certified veterinarians, relying heavily on the Perceived Value of Certification Tool (PVCT). …