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Abl1/2 And Ddr1 Cooperate To Stabilize Braf/Craf To Drive Erk1/2 Reactivation And Promote Mek Inhibitor Resistance In Nras-Mutant Melanomas, Anastasia Lyon

Theses and Dissertations--Pharmacology and Nutritional Sciences

This study addresses the escalating incidence of NRAS-mutant melanomas, a type of skin cancer lacking FDA-approved targeted therapies. Despite ongoing research targeting the RAF/MEK/ERK pathway, existing drugs fail to enhance progression-free survival due to acquired resistance. This project identifies a novel role for ABL1/2 and DDR1 kinases in driving drug resistance and proliferation of NRAS-mutant melanoma cells. ABL1/2 and DDR1 cooperate to promote RAF homodimerization and protein stability in order to reactivate MEK/ERK signaling to drive MEK1/2 inhibitor (MEKi) resistance and promote survival of resistant cells. By targeting ABL1/2 and DDR1 with nilotinib, a FDA-approved anti-leukemic inhibitor, we …

Exenatide As Chronopharmacotherapy For T2dm Associated Complications: Targeting Nondipping Blood Pressure And Sleep Insufficiency, Aaron Chacon

Theses and Dissertations--Pharmacology and Nutritional Sciences

Although largely impacted by age, race and ethnicity, and socioeconomic factors, Type 2 Diabetes Mellitus (T2DM) is primarily driven by obesity, currently affecting ~30 million in the U.S and ~463 million globally. T2DM carries numerous complications, including high prevalence of hypertension and nondipping blood pressure (BP), sleep insufficiency and fragmentation. Nondipping BP is an inadequate drop in BP (≤ 10%) during sleeping hours compared with waking hours. Lending to this, sleep disturbance acts as both precursor and consequence of metabolic dysregulation, greatly impacting circadian rhythmicity. To model these conditions, we utilized diabetic (db/db) mice. These mice carry a point mutation …

Mitigating Risks For Dementia In Apoe4 Mice: Efficacy Of Prebiotic Inulin, Probiotics, And Fecal Microbiota Transplants, Ya-Hsuan Chang

Theses and Dissertations--Pharmacology and Nutritional Sciences

Apolipoprotein E4 allele (APOE4) carriers show early metabolic changes, heightening the genetic risk of late-onset Alzheimer's Disease (AD), characterized by amyloid-β and tau tangle plaques and neurodegeneration. Its development is influenced by age, environment, and genetics, with Mild Cognitive Impairment (MCI) often preceding AD, providing a crucial window for early intervention. Factors in AD progression include sex differences and gut microbiome imbalances, with women disproportionately affected and APOE4 carriers showing early metabolic and cognitive changes. This study explores the potential of prebiotic inulin, probiotic Bifidobacterium animalis, and fecal microbiota transplants (FMT) from healthy donors to mitigate AD …

Cell-Based Cardiac Repair And The Natural Cardiac Healing In Regenerative Adult Mammal, Hsuan Peng

Theses and Dissertations--Pharmacology and Nutritional Sciences

Heart failure (HF) following myocardial infarction (MI) remains a significant global health concern, with the initial ischemic injury often leading to microvascular damage and infarct expansion, exacerbating the overall cardiac impairment. Despite extensive research, there are currently no effective therapies to limit myocardial damage post-MI, resulting in a substantial number of patients progressing to HF. Stem cell therapy has emerged as a promising approach to modulate cardiac injury and promote healing. However, clinical trials have shown only modest success, underscoring the need for improved strategies to enhance efficacy. Additionally, the lack of significant ventricular regeneration highlights the necessity of targeting …

The Delineation Of Platelet Pathology In Cardiometabolic Disease, Chi Peng

Theses and Dissertations--Pharmacology and Nutritional Sciences

Obesity is a multifactorial disease with many comorbidities leading to multiorgan dysfunction. Current studies point towards dysregulation of platelet signaling as a driver for increased risk of cardiovascular disease and stroke. The exact mechanisms remain elusive due to the complex interplay of factors involved, warranting the need to further understand how platelets are affected. Our preliminary data evaluating changes in platelet and coagulation parameters from bariatric patients showed that obesity did not affect platelet count or clotting time as demonstrated in INR values. However, female patients had increased bleeding events before surgery that were decreased after surgery. Due to limitations …

Characterization Of Bowel Dysfunction After Spinal Cord Injury In Mice, Olivia Wireman

Theses and Dissertations--Physiology

Most individuals who suffer a spinal cord injury (SCI) will experience some form of bowel dysfunction. Trauma to the spinal cord can result in severe constipation and/or incontinence, otherwise known as neurogenic bowel. Constipation requires extensive bowel routines typically involving the help of another person. Still, many living with SCI are hospitalized due to bowel complications such as fecal impaction. While neurogenic bowel has been well characterized in the clinic, pre-clinical models of neurogenic bowel after SCI are still in development. Most pre-clinical studies in bowel dysfunction after SCI are published in rat models. Studies existing in mice, to our …

Indoor Pests And Human Health: Characterizing Contaminants And Improving Mitigation, Johnalyn Gordon

Theses and Dissertations--Entomology

Much of the United States population spends the majority of their time indoors and within the home. Not only are indoor arthropod pests an unsightly nuisance in our homes, but they can have serious impacts on human health, especially with chronic exposure. In addition to negative health impacts, costs associated with these medical impacts can be tremendous. For these reasons, it is critical to develop comprehensive strategies for pest reduction and mitigation of associated health impacts. The work outlined in this dissertation represent examination of the distribution of a hypothesized bed bug allergen within the indoor environment, identification of a …

Practical Challenges In Delivering Dsrna For Woody Plant Protection, Zachary Bragg

Theses and Dissertations--Entomology

Unprecedented weather events associated with climate change, coupled with extensive anthropogenic stresses, have reduced the effectiveness of traditional forest pest management approaches, which can no longer keep pace with invasive species overwhelming naïve landscapes and native pests experiencing eruptive and expansive outbreaks. Double-stranded RNA-(dsRNA) mediated gene silencing, a type of RNA interference (RNAi), has been coopted for use as a biopesticide against a multitude of agricultural and horticultural pests and could serve as a powerful tool for woody plant protection. While effective initiation of gene silencing and subsequent mortality have been demonstrated in multiple tree pests, effective and efficient methods …

Consequences Of Abiotic And Anthropogenic Stressors In The Antarctic Midge, Belgica Antarctica, Jack J. Devlin

Theses and Dissertations--Entomology

The ability to tolerate stress is key to maintaining fitness in extreme environments such as the polar regions. Subject to a myriad of extreme year-round abiotic conditions, invertebrates inhabiting the terrestrial ecosystems of Antarctica provide an excellent system to investigate adaptations to stress. Understanding the response of these species to abiotic and novel stressors is crucial in a world with rapidly occurring climate change and increasing anthropogenic activity. In this dissertation, I investigated physiological and molecular responses to naturally occurring and human-derived stresses in the midge Belgica antarctica, which is Antarctica’s only endemic insect.

In my first research chapter, I …

Acting On Routine Outcome Monitoring, Virginia Courtney

Theses and Dissertations--Family Sciences

This thesis explores the application of an Acceptance and Commitment Therapy (ACT) informed approach in achieving clients’ therapeutic objectives via systematically tracking client progress over the therapy process. The study utilized the Marriage and Family Therapy Practice Research Network (MFT-PRN), a specific tool that aids the tracking of therapy progress, to gather relevant client data. The data consisted of therapy progress for 27 individuals the author worked with, 1,001 individuals from the Individual Relational and Finance Therapy Clinic, and 4,424 individuals from the MFT-PRN-Network. Upon collecting this data, progress trajectories were generated using Microsoft Excel to compare the author’s clients’ …

Sex Differences In Pediatric Hypertension: Obesity, Stress, And The Renin-Angiotensin System, Allyson Dyar

Theses and Dissertations--Nutrition and Food Systems

Pediatric hypertension, linked to long-term cardiovascular risks, shows increasing prevalence and varying patterns between boys and girls. This study explores sex-based differences in hypertension among 251 children aged 6-18 from Kentucky Children’s Hospital. Using 24-hour ambulatory blood pressure monitoring (ABPM) and assessing plasma renin, aldosterone, and cortisol, we examined blood pressure severity by sex. Girls showed a higher incidence of severe hypertension and elevated cortisol levels, whereas boys had higher mean systolic blood pressure. Aldosterone was associated with night systolic blood pressure in girls, while night diastolic blood pressure was linked to aldosterone in both sexes and renin in girls. …

Assessing Endophyte Frequency Distributions And The Effect Of Epichloë Brachyelytri In The Chemotypic And Genotypic Diversity Of Brachyelytrum Erectum, Rachel Ann Sneed

Theses and Dissertations--Plant Pathology

Seed-transmissible epichloid fungal endophytes are best known for their roles as defensive mutualists in cool-season grasses. Historically, the discovery of fungal endophytes was driven by investigations of plant toxicity to livestock, followed by extensive study of their alkaloids and protection against insects and nematodes. Epichloae can produce four classes of alkaloids: ergot alkaloids, lolines (saturated aminopyrrolizidines), indole–diterpenes, and peramine. It is increasingly evident that these hereditary symbionts have much more diverse chemical profiles both in individual populations and between them. To this end, differences in chemotypic profiles of these symbionts may translate to different evolutionary and environmental advantages across plant …

Systemic Signaling In Plants: Role Of Cuticle, Salicylic Acid, Rna, And Vitamins, Huazhen Liu

Theses and Dissertations--Plant Pathology

Systemic acquired resistance (SAR) is a form of broad-spectrum resistance induced in response to local infection that protects uninfected parts against subsequent secondary infections. Several diverse chemical signals contributing to SAR have been isolated and characterized, including glycerol-3-phosphate (G3P) and pipecolic acid (Pip), both of which play an important role in human and plant disease physiologies. In addition to these, salicylic acid (SA) also regulates SAR and normal transport of SA and G3P is required for de novo biosynthesis of Pip in the distal leaves. Pip is catabolized via multiple pathways, and this in turn regulates vitamin homeostasis. A normal …

Current And New Perspectives On Equine Protozoal Myeloencephalitis Therapeutics, Izabela De Assis Rocha

Theses and Dissertations--Veterinary Science

Equine protozoal myeloencephalitis (EPM) is an important neurologic disease of horses in the Americas. It is caused by the apicomplexan parasite Sarcocystis neurona and less commonly by the related parasite Neospora hughesi. Current antiprotozoal treatment relies on the use of either folate inhibitors (sulfadiazine/pyrimethamine) or triazine drugs (diclazuril/ponazuril), with a success rate of 60-70% regardless of the drug of choice. Successful treatment is defined as the improvement of at least one ataxia grade following the modified Mayhew scale, which often is not enough for the horse to return to the previous level of performance. The goals of this dissertation …

Impact Of Short-Distance Road Transportation On Horse Health, Erica Jacquay

Theses and Dissertations--Veterinary Science

Horses are regularly transported across the United States; however, the reasons for travel, trip lengths, and management practices are not well characterized. While long distance transportation has been associated with increased incidences of health-related problems, the impact of short distance transportation on horse health is less understood. Notably, aged horses ( > 15 years) have an altered immune response following short-distance transportation, but this has yet to be compared to young horses. It is also unknown whether transportation stress would alter endocrine responses of horses with metabolic disorders, such as insulin dysregulation (ID) or pituitary pars intermedia dysfunction (PPID).

The objectives …

Determining Population Structure In Kentucky Parascaris Univalens Specimens, Constance Finnerty

Theses and Dissertations--Veterinary Science

Parascaris univalens is a highly pathogenic nematode that affects the gastrointestinal system of young horses. When unaddressed, this parasite causes severe intestinal impactions and even death. Parascaris univalens is also found to have an emergence of anthelmintic resistances, causing a concern for horse owners. Despite its clinical significance, very little work has been done on Parascaris univalens to identify its population structure. This study aimed to determine the population structure of Parascaris univalens through Illumina next generation sequencing (NGS) on three hierarchical categorizations: within a horse, within an isolated herd, and within horses in the state of Kentucky. A total …

Genomic Studies Of The Equine Bloodworm, Strongylus Vulgaris, Nichol Ripley

Theses and Dissertations--Veterinary Science

Strongylus vulgaris is the most pathogenic nematode parasite of grazing horses worldwide. This gastrointestinal parasitic nematode is in the family Strongylidae under the subfamily Strongylinae, or Strongylins. While the epidemiology, complete life cycle, and high pathogenicity of the fourth and fifth larval stages of S. vulgaris are well established, we understand very little about its biology. This parasite is renowned for its unique life cycle and capacity to cause arterial damage, leading to significant health and economic impacts for the equine industry. It also is the most intensively documented Strongylin; however, S. vulgaris has yet to gain drug resistance as …

Temporal Changes In The Genome Of Apicomplexan Parasite Sarcocystis Neurona Sn3, Jamie Norris

Theses and Dissertations--Veterinary Science

Sarcocystis neurona is an apicomplexan parasite and the main etiologic agent behind Equine Protozoal Myeloencephalitis (EPM), the most diagnosed neurologic disease in horses living in the Americas. Technical advances that arose from the human genome project between 1990 and 2003 and the corresponding “omics” revolution in research have allowed scientists novel approaches to study organisms. Herein, we sought to leverage bioinformatic advances and new sequencing platforms to provide an improved understanding of the biology of S. neurona. At the outset of this project, reference genomes from two different S. neurona strains (SN3.e1 and So SN1) were available. A new and …

Dynamic Patterns Of Resource Selection In Northern Bobwhite Across The Annual Cycle In A Region With Poor Edaphic Conditions, Autumn S. Randall

Theses and Dissertations--Forestry and Natural Resources

Developing successful management strategies requires an understanding of how an organism's resource needs change over the course of its life cycle. For almost a century, northern bobwhite (Colinus virginianus) populations have been declining range-wide, mostly as a result of habitat loss and degradation. Resource selection studies conducted at coarse-temporal resolutions and in areas with fertile soils form the majority of current management recommendations for bobwhites. In this thesis, we quantified resource selection patterns for 1,302 bobwhites in a region with poor soil conditions with respect to several common management practices (fire, fallow fields, supplemental feeding, and brush management …

Autism In Agricultural Education: A Case Study Of An Adolescent With Autism Spectrum Disorder And Their Parent On Career And Technical Education, Grace Miller

Theses and Dissertations--Community & Leadership Development

Autism spectrum disorder (ASD) is a unique and often misunderstood diagnosis. Little is known about the experiences of adolescents with ASD. As students with ASD graduate high school, many are under- and unemployed. Career and technical education (CTE) in U.S. schools is intended to prepare all students for careers post-secondary. Agricultural education is one of the predominate career clusters within CTE. This qualitative single case study sought to create a platform for both a student and their parent to share their experiences in agricultural education and CTE. Participants were an adolescent with ASD who had taken at least one year …

Development Of Lignin Derived Hydrophobic Deep Eutectic Solvents As Sustainable Solvents And Their Applications, Yuxuan Zhang

Theses and Dissertations--Biosystems and Agricultural Engineering

The development of green solvents is a pivotal endeavor in achieving the goals of green chemistry. Ionic liquids (ILs) and deep eutectic solvents (DESs) have emerged as promising green alternatives to conventional organic solvents due to their low toxicity, potential biodegradability, low volatility, and high tunability. Compared to ILs, DESs have attracted more attention recently as they are easier and less expensive to produce. Hydrophobic DESs (HDESs), a new generation of DESs introduced in 2015, have gained considerable interest for their ability to overcome the instability issues of traditional DESs when exposed to water. This advancement extensively broadens the application …

The Characterization, Assessment, And Shear Strength Of Turfgrass Soil In North American Thoroughbred Racing, Peter Schmitt

Theses and Dissertations--Biosystems and Agricultural Engineering

Minimizing catastrophic injuries to racehorses, which also protects the riders, is critical for the future of the Thoroughbred racing industry. While the causes of catastrophic injuries are multifactorial, the condition of the racing surface is one of only a few factors that affects all horses in competition. Horse racing surfaces must retain enough shear strength to support the hoof of a Thoroughbred at a gallop. Turfgrass racing surfaces also require healthy turf to reinforce the footing while also achieving a high infiltration rate to allow races to run on the turf soon after or even during rain. This research is …

The Efficacy Of Wetland Treatment Systems Used To Treat Runoff Mixtures From Different Landscapes Across Kentucky, Emily Nottingham

Theses and Dissertations--Biosystems and Agricultural Engineering

The overarching goal was to improve our understanding of the cumulative effect of increased use and occurrence of commonly detected contaminants of potential concern (CPCs) on nitrogen (N) transformation processes in wetlands. The central hypothesis was that those various mixtures of nutrients and CPCs entering treatment wetlands impact N removal pathways. The first study assessed the current state of the literature on the implications to N removal in wetlands in the presence of pesticides and antibiotics. 181 primary studies were identified. Removal efficiencies for nitrate varied widely across the studies, with CPCs impacting microbial communities. A knowledge gap remains in …

Valorization Of Bourbon Distilling Waste Using Thermal Conversion Processes For Nutrient-Rich Food Products, Tosin Olayemi Olanrewaju

Theses and Dissertations--Biosystems and Agricultural Engineering

The Commonwealth of Kentucky accounts for over 95% of global bourbon production. A primary byproduct of bourbon production is stillage, which has a very high moisture content (91–94%) and high biochemical oxygen demand, making it challenging to manage. The recent expansion of the bourbon industry has heightened environmental concerns regarding the best methods to handle this byproduct. Dewatering and drying of stillage produce distillers' spent grains (DSG-B), which are rich in dietary fiber and protein and could serve as an excellent source of functional fiber in human nutrition.

This study examined the approach for dewatering, drying, inclusion of DSG-B as …

Precision Application Of Water To Equine Racing Surfaces, Sydney Rae Cannon

Theses and Dissertations--Biosystems and Agricultural Engineering

As the horseracing industry has come under more scrutiny as of late, horse and rider safety has become a priority. The best was to keep a rider safe is to keep them on their horse, and the best way to do that is to keep the horse upright. This all comes down to consistency both between tracks and across a single track. The most important method of managing track consistency is through moisture content. This study examined how track design can impact moisture application, how moisture content can impact the surface material, and what design elements can be implemented to …

Development Of Fungal Hydrogels For 3d Bioprinting And Cellular Agriculture, Lauren E. Doyle

Theses and Dissertations--Biosystems and Agricultural Engineering

Hydrogel scaffolds are an important component to cellular agriculture. There is a need for a sustainable alternative to the commonly used gelatin-sodium-alginate hydrogels. Specific edible fungus species may provide a suitable alternative. Many fungi possess high protein contents, ease of cultivation, and strong functional properties. However, functional characterizations and application of fungal flour and protein extracts in cellular agriculture are lacking in the literature. Therefore, this study’s objectives were to 1) Develop processes to create functional fungal protein fractions from different fungal strains and evaluate their characteristics, and 2) Quantify the printability of the resulting fungal gels for the creation …

Inflammation And Tumor Progression: The Differential Impact Of Saa In Breast Cancer Models, Daniel Wilhelm Olivier, Carla Eksteen, Manisha Du Plessis, Louis De Jager, Lize Engelbrecht, Nathaniel Wade Mcgregor, Preetha Shridas, Frederick C. De Beer, Willem J. S. De Villiers, Etheresia Pretorius, Anna-Mart Engelbrecht

Saha Cardiovascular Research Center Faculty Publications

Background: Previous research has shown that the Serum Amyloid A (SAA) protein family is intricately involved in inflammatory signaling and various disease pathologies. We have previously demonstrated that SAA is associated with increased colitis disease severity and the promotion of tumorigenesis. However, the specific role of SAA proteins in breast cancer pathology remains unclear. Therefore, we investigated the role of systemic SAA1 and SAA2 (SAA1/2) in a triple-negative breast cancer mouse model.

Methods: Syngeneic breast tumors were established in wild-type mice, and mice lacking the SAA1/2 (SAADKO). Subsequently, tumor volume was monitored, species survival determined, the inflammatory profiles of mice …

Disorganization Of Actin Within The Shafts Of Stereocilia Is A Key Difference Between Temporary And Permanent Noise-Induced Hearing Loss (Nihl), Shadan Hadi

Theses and Dissertations--Physiology

During sound stimulation, mechanosensory stereocilia of the auditory hair cell pivot around their bases, where their actin cores become denser and form rootlets protruding into the cuticular plate. It is believed that actin-based cuticular plate provides a stable mechanical support for stereocilia, while rootles are responsible for their pivotal flexibility and life-long resilience to mechanical stimuli. Not surprisingly, damage to the stereocilia bundles is known as a hallmark of permanent noise-induced hearing loss (NIHL). Yet, despite decades of NIHL studies, it is still unknown which ultrastructural changes in the stereocilia bundles are evoked directly by mechanical overstimulation.

Here, we explored …

Differential Effects Of Traumatic Brain Injury On Preinjury And Postinjury Born Hippocampal Neural Precursor Cells, Hannah Downing

Theses and Dissertations--Physiology

Moderate contusive traumatic brain injury (TBI) results in neuronal cell death in the cortex as well as cell death and damage in underlying structures, including the hippocampus. The hippocampus is critically involved in learning and memory and is one of two regions in the brain capable of undergoing neurogenesis throughout adulthood. Adult hippocampal neurogenesis is a complex sequence of events necessary for a neural progenitor cell (NPC) to differentiate into a mature granule cell neuron located in the granule cell layer of the dentate gyrus. TBI results in a preferential loss of immature neurons in the granule cell layer of …

Profiling The Molecular And Clinical Landscape Of Glioblastoma Utilizing The Oncology Research Information Exchange Network Brain Cancer Database, Alexandra N. Demetriou, Frances Chow, David W. Craig, Michelle G. Webb, D. Ryan Ormond, James Battiste, Arnab Chakravarti, Howard Colman, John L. Villano, Bryan P. Schneider, James K. C. Liu, Michelle L. Churchman, Gabriel Zada

Markey Cancer Center Faculty Publications

Background. Glioblastoma exhibits aggressive growth and poor outcomes despite treatment, and its marked var- iability renders therapeutic design and prognostication challenging. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling of 206 glio- blastoma patients, providing opportunities to identify novel associations between molecular features and clinical outcomes.

Methods. Survival analyses were performed using the Logrank test, and clinical features were evaluated using Wilcoxon and chi-squared tests with q-values derived via Benjamini-Hochberg correction. Mutational analyses util- ized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test …