Medical Sciences Commons^™

Synthesis And Design Of Clpp Activators As Novel Antibiotics, Schyler Odum

Theses and Dissertations (ETD)

Purpose. Design and synthesize novel compounds to treat Staphylococcus aureus infections by targeting the dysregulation of the Casein Protease P, ClpP. Methods. Utilize established chemical methods to synthesize ureadepsipeptides, small-molecule ClpP activators, and ureadepsipeptide hybrids. Assess their effectiveness by using minimum inhibitory concentration assays and in vitro biochemical assays for ClpP activation. Explore their potential as antibiotics through mitochondrial toxicity tests, glucose/galactose assays, and biophysical measurements related to metabolism and clearance, including thermal shift and surface plasmon resonance assays. Results. Synthesized and tested 33 novel compounds, comprising a total of 80 synthetic steps. Conclusion. The three-part conclusion from the dissertation …

The Impact Of Local Physiology On The Corrosion Of Orthopedic Alloys, Madison Nicole Brown

Theses and Dissertations (ETD)

Introduction. Total knee arthroplasty (TKA) is used in the treatment of end-stage osteoarthritis of the knee. It is one of the most common elective surgeries performed with predictions expecting significant increases in the number of procedures performed over the next decade. However, the patient satisfaction rate after TKA is as low as 80%. Cobalt-chromium-molybdenum (CoCrMo) is regularly used for TKA protheses due to the alloy’s mechanical strength, biocompatibility, and corrosion resistance. The corrosion resistance of this alloy relies on a passive oxide layer. This oxide layer can be impacted by phagocytic cells which can leave pits and craters on implant …

Biomechanical Outcomes Of Distinct Tka Surgical Alignments And Implant Designs, Alexis Kathleen Nelson-Tranum

Theses and Dissertations (ETD)

Introduction. Total knee arthroplasty (TKA) has advanced over the past two decades from traditional post-operative neutral alignment methods with an overall goal of implant longevity to ones that are more personalized to better replicate individual native knee kinematics. Personalizing TKA knee kinematics to better replicate a patient’s native knee kinematics has evolved in response to a reported 20% dissatisfaction by patients with their TKA. These personalization advancements include innovations in surgical alignment techniques include the kinematic alignment (KA) and joint line obliquity (JLO) restoration, in contrast to the mechanical alignment (MA) technique that places everyone into the same mold. Additionally, …

Characterizing The Cellular Response To Astrovirus Infection In The Central Nervous System, Amy E. Davis

Theses and Dissertations (ETD)

Central nervous system (CNS) diseases caused by infectious agents pose significant health challenges, often leading to severe neurological dysfunction with high morbidity and mortality rates. Astroviruses (AstVs), traditionally known for causing gastroenteritis, have recently been identified as neuroinvasive pathogens capable of inducing neurological diseases. This study explores the cellular and molecular mechanisms by which AstV, specifically non-classical VA1 and classical HAstV1 genotypes, induce CNS pathology in human neurons and astrocytes. Utilizing primary human neurons and astrocytes from various brain regions, this research investigates the cytotoxic effects, apoptotic pathways, and inflammatory responses triggered by these viruses. This study reveals that VA1 …

Pan-Cancer Genomic Characterization Of Human Papillomavirus Associated Tumors, Jeremiah Ray Holt

Theses and Dissertations (ETD)

Infection with high-risk human papillomavirus (HPV) accounts for nearly all cervical cancers (CESC), a subset of other anogenital squamous cancers, and increasing rates of head and neck squamous cell carcinomas (HNSC), with each cancer type having heterogenous outcomes due to a general lack of personalized care. Large scale genomic analyses have catalogued the somatic alterations occurring frequently among squamous tumor types including HNSC and CESC, but few studies have incorporated a thorough analysis of HPV genomics. High-risk HPVs are double-stranded DNA (dsDNA) viruses capable of integrating their genomes into host chromosomes, a phenomenon known to promote HPV-associated cancer formation. HPV …

Ftsk Regulates The Assembly Of The Division Machinery In The Ftsz-Less Chlamydia Trachomatis, Mckenna Katherine Harpring

Theses and Dissertations (ETD)

In evolving to obligate intracellular dependence, Chlamydia trachomatis serovar L2 (Ct), has eliminated several gene products essential for cell division in most other bacteria, including FtsZ, the central coordinator of divisome assembly. In the absence of FtsZ, we show that divisome assembly in Ct is initiated by FtsK, a chromosomal translocase. Chlamydial FtsK forms discrete foci at the septum and at the base of the progenitor mother cell, and our data indicate that FtsK foci at the base of the mother cell mark the location of nascent divisome complexes that form at the site where a daughter cell will emerge …

Interplay Of Antibody Responses To Closely Related Viruses And Autoimmunity, Chun-Yang Lin

Theses and Dissertations (ETD)

Antibodies produced by B cells are crucial for eliminating infectious pathogens and preventing secondary infection. However, antibodies may also bind to self-antigens and contribute to autoimmune disease. While pathogen infections have been associated with development of autoimmune diseases, the precise contributions of viral infections to autoimmunity remain elusive. The presence of autoreactive antibodies is associated with an increased risk of developing autoimmune disease. Thus, analyzing the impact of viral infection and vaccination on the development of autoreactive antibodies will provide essential insight into mechanisms that contribute to autoimmune disease.

Examining How Non-Antifungal Medications Impact Host-Fungal Interactions, Parker Ryan Reitler

Theses and Dissertations (ETD)

Invasive fungal infections (IFIs) are estimated to kill 1.5 million people each year with mortality rates remaining high (around 30-70%), despite the availability of three major classes of antifungal drugs. Furthermore, millions more suffer debilitating infections of the mucosal membranes or destructive subcutaneous mycoses. One of the most common IFIs is invasive candidiasis, mostly commonly caused by Candida albicans infections, with mortality rates of approximately 30%. In addition, the population of susceptible individuals and the incidences of both mucosal and systemic mycoses continue to rise due to the widespread use of broad-spectrum antibacterial agents, cancer chemotherapies, and the immune suppressive …

Genotypes Of Snps Of Key Genes Regulate Susceptibility And Drug Sensitivity To Neovascular Amd, Jinglin Cui

Theses and Dissertations (ETD)

Age-related macular degeneration (AMD), particularly its neovascular form, stands as a leading cause of blindness globally, with its prevalence in our country on a steady rise. This underscores the critical impact of neovascular AMD (nAMD) management on patient quality of life and societal burden. Current optimal treatments hinge on anti-vascular endothelial growth factor (anti-VEGF) therapies, though their efficacy varies across different drugs and individuals, highlighting the importance of precise drug selection in clinical outcomes. Research suggests that factors such as baseline vision, age, disease duration, lesion size, central retina thickness, neovascularization type, and demographic differences influence nAMD prognosis. In addition, …

The Validity And Reliability Of Ultrasound As A Tool For Assessing Skeletal Muscle Characteristics In The Pediatric Population, Elizabeth Seewer

Theses and Dissertations (ETD)

Annually, around 5 million people in the U.S. are admitted to Intensive Care Units (ICU) due to critical conditions, with pediatric patients comprising 21% of these admissions. Approximately 40% of pediatric ICU (PICU) patients require mechanical ventilation and extended stays, and about 6% result in death. Survivors often face long-term disabilities, including loss of skeletal muscle mass (SMM), a risk factor for morbidity and mortality. Abdominal computed tomography (CT) scans, often performed during PICU admissions, can assess muscle mass but pose risks of increased cost and radiation exposure. While CT and Magnetic Resonance Imaging (MRI) are gold standards for muscle …

Anatomical And Physiological Characterization Of Striatal Activation Of The Cerebral Cortex, Yuhan Wang

Theses and Dissertations (ETD)

Purpose. The striatum receives excitatory glutamatergic input from nearly all parts of the cerebral cortex, and its output is delivered by direct pathway medium spiny neurons (dMSNs) expressing D1 type dopamine (DA) receptors (D1Rs) and indirect pathway MSNs (iMSNs) expressing D2 DA receptors (D2Rs). Loss of DA results in the imbalance between the activities of dMSNs and iMSNs in Parkinson’s disease (PD), leading to ab-normal interactions between the cerebral cortex and striatum. Thus, understanding the inter-actions between the cortex and striatum is important. The monosynaptic corticostriatal cir-cuit has been extensively studied. In contrast, due to the poly-synaptic nature of the …

Molecular Determinants Of Trp Channel Gating, Briar J. Bell

Theses and Dissertations (ETD)

Transient Receptor Potential (TRP) ion channels are a family of proteins that contribute to a myriad of physiological functions. They have been extensively studied since their discovery 35 years ago; however, there are still many questions regarding the mechanisms by which they function. This family of proteins is characterized by a generally shared structure: an intracellular N terminus featuring ankyrin repeats, six transmembrane helices including the pore domain, a re-entrant loop and TRP helix, and an intracellular C terminus with varying structure. Each of these regions has been implicated in the regular function of TRPs, while mutations that alter trafficking …

Improving Estimation Of Coronary Artery Disease Risk Using Haptoglobin Genotyping, Emily Kate Mewborn

Theses and Dissertations (ETD)

Atherosclerotic cardiovascular disease (ASCVD) continues to be the leading cause of death worldwide. While several risk factors contributing to disease progression are well-known, pitfalls and limitations exist for estimating if or when an individual will develop the disease. Coronary artery disease (CAD), a subtype of ASCVD, causes myocardial infarction, contributing to significant morbidity and mortality. Current ASCVD risk estimator calculators lack comprehensiveness and do not include genetic or social determinants of health information, which are known to affect ASCVD risk.

Haptoglobin (Hp) genotype also influences CAD risk. Hp is a protein that binds free hemoglobin released from physiologic or pathologic …

Development Of Novel, Brain Permeable, Mpges-1 Inhibitors For Inflammatory Conditions, Madison Sluter

Theses and Dissertations (ETD)

Prostaglandin E2 (PGE2) is a potent proinflammatory lipid signaling molecule produced downstream of the cyclooxygenase (COX) cascade. The COX pathway has long been implicated for its role in inflammation, with drugs like aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) non-selectively targeting the upstream COX enzymes to suppress inflammation. However, despite displaying potent anti-inflammatory effects it has been demonstrated that when taken chronically, NSAIDs can cause gastrointestinal bleeding. COX-2 selective inhibitors (COXIBs) were then developed to combat the gastrointestinal bleeding induced by nonselective NSAIDs by specifically inhibiting the COX enzyme most infamous for its role in inflammation. Yet, soon after entering …

Studies On The Leukocyte-Associated Ig-Like Inhibitory Receptor-1 Signaling Pathway In T Lymphocytes, Chidi Zacheaus

Theses and Dissertations (ETD)

Inflammation is a natural process in which the immune system concertedly responds to pathogens and abnormal cell growth to protect the host. For an efficient/effective immune response that circumvents tissue atrophy, a delicate balance between stimulatory and inhibitory mechanisms is essential for the proper functioning of the immune system. Immuno-receptor Tyrosine-based Inhibitory Motif (ITIM)-bearing receptors in immune cells, including T lymphocytes, play a major role in preventing autoimmune responses. Leukocyte-associated Ig-like Inhibitory Receptor 1 (LAIR-1) is one of ITIM-bearing receptors. The mechanism by which LAIR-1 attenuates T-cell response has yet to be completely understood. In this study, I investigated a …

The Interaction Between Host G3bp And Viral Nucleocapsid Protein Regulates Sars-Cov-2 Replication, Zemin Yang

Theses and Dissertations (ETD)

G3BP1/2 are RNA-binding proteins that promote condensation to form stress granules in response to various cellular stresses, including viral infection. G3BP1/2 are prominent interactors of the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the functional consequences of the G3BP-N interaction in the context of viral infection have remained unclear. Here we used structural and biochemical analyses to define the residues required for G3BP1-N interaction, followed by structure-guided mutagenesis of G3BP1 and N to selectively disrupt their interaction. We found that mutation of N-F17 led to selective loss of interaction with G3BP1 and consequent failure of …

Tcf4 Is A Key Mediator Of Cell Identity And Oncogenesis In Neuroblastoma, Nour Aljouda

Theses and Dissertations (ETD)

Neuroblastomas (NB) are embryonal childhood tumors that derive from the multipotent neural crest cells (NCCs) of the peripheral nervous system. NB accounts for more than 15% of all childhood cancer-related deaths. Despite the most intensive multimodal therapy, more than 50% of patients with high-risk NB relapse with often fatal, resistant disease. Novel therapies are desperately needed to improve cure rates. Previous studies proposed that the deregulation of normal neural crest developmental programs contributes to NB oncogenesis by retaining the highly migratory and proliferative traits of NCCs. Thus, activation or repression of neural crest developmental pathways have been implicated in NB …

Cytochrome P450 1b1 And 12/15 Lipoxygenase Interaction In Paraventricular Nucleus In Angiotensin Ii-Induced Hypertension In Females, Shubha Ranjan Dutta

Theses and Dissertations (ETD)

Background: Angiotensin (Ang) II releases arachidonic acid (AA) from tissue phospholipids that is metabolized by 12/15-lipoxygenase (ALOX15) generating 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE) which have been implicated in cardiovascular and renal diseases. This study was conducted to investigate a) the contribution of ALOX15 to Ang II-induced hypertension and associated pathogenesis in female mice, and b) the interaction between the cytochrome P450 (CYP)1B1-generated metabolite of 17β-estradiol (E2) (2-methoxyestradiol, 2-ME) and ALOX15 in the paraventricular nucleus (PVN) as a mechanism that protects against Ang II-induced hypertension and its associated pathogenesis in female mice. Methods: Experiments were conducted in intact and ovariectomized (OVX) …

A Design, Development, And Evaluation Of Bio-Patch For Myocardial Tissue Repair, Yaya Zhang

Theses and Dissertations (ETD)

Introduction. Ischemic heart disease (IHD) is a major concern of human health issue. The structural repair and functional recovery of injured hearts is a major challenge in the clinical setting. Preclinical studies over last 10 years have demonstrated the potential of using stem cells to treat IHD, but the efficacy of this therapy is jeopardized by uncontrollable migration and low survival of the injected stem cells. An approach based on tissue engineering enabling target-specific stem cell delivery such as cardiac patches has emerged as an alternative solution for stem cell therapy for IHD. It employs scaffold materials to engulf various …

Investigation Of Clinically Relevant Fluconazole Resistance Mechanisms In The Fungal Pathogen Candida Parapsilosis, Laura Anne Doorley

Theses and Dissertations (ETD)

Invasive candidiasis is a severe fungal infection associated with significant morbidity and mortality, particularly among the critically ill and immunocompromised. Candida parapsilosis is the most common non-albicans species causing invasive Candida infections in pediatric and neonatal populations worldwide and is particularly common in the countries of South America, Western Asia, Mediterranean Europe, and Southern Africa. For many of these countries, fluconazole and other triazoles are the first line antifungal agents used for effective treatment of invasive Candida infection. Until recently, rates of fluconazole resistance among C. parapsilosis isolates were relatively low, therefore the determination of clinically relevant resistance mechanisms in …

Vascular Mechanisms Of Rhabdomyolysis-Induced Acute Kidney Injury, Jeremiah Moyinolu Afolabi

Theses and Dissertations (ETD)

In patients with rhabdomyolysis, the overwhelming release of myoglobin into circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Myoglobin stimulated endothelin-1 (ET-1) production in proximal tubular cells, an effect driven by NADPH oxidase-dependent oxyradical generation. Rats subjected to glycerol-induced rhabdomyolysis also …

Modulation Of Cerebral Artery Smooth Muscle Bk Channel Function By Neurosteroids, Kelsey Caroline Cleland North

Theses and Dissertations (ETD)

Voltage-gated and Ca2+ activated K+ channels of large conductance (BK) channels are essential for many key physiological processes, such as controlling the contraction of smooth muscle, including cerebrovascular smooth muscle. Importantly, BK channels are made up of a homotetramer of α subunits which associate with accessory β subunits. These β subunits alter the activity of the channel; this modulation is subunit-specific. Moreover, these accessory subunits have tissue-specific expression, such that the β1 subunit is highly expressed within cerebrovascular smooth muscle and greatly increases the open probability of BK channels. Increased BK channel open probability is linked to increased dilation of …

Transmission Competence Of B. Burgdorferi Infected Ixodes Ticks And Development Of An Ospc-Based Lyme Disease Vaccine, Samanta Kamalika

Theses and Dissertations (ETD)

Introduction. Lyme disease, otherwise called Lyme borreliosis, is a vector-borne infectious disease caused by the spirochete Borrelia burgdorferi (Bb). Studying the increase in overall Lyme disease incidence requires understanding the role of the vector Ixodes scapularis (I. scapularis) as the agent that carries the spirochete which is important to limit the occurrence of Lyme disease. Once we understand the vector-pathogen response, it also becomes important to determine the remedies for Lyme disease. Lyme disease can be treated with antibiotics if detected early, but the major obstacle lies in the early detection process. Therefore, it is important to investigate alternative preventive …

Physiologically-Based Pharmacokinetic (Pbpk) Modeling For The Preclinical Development Of Spectinamide Antibiotics, Keyur R. Parmar

Theses and Dissertations (ETD)

Despite being an ancient disease caused by Mycobacterium tuberculosis (Mtb) and after decades of research, tuberculosis (TB) still affects millions of people every year worldwide. In 2018, the World Health Organization (WHO) reported that 10 million people developed tuberculosis and 1.5 million died of the disease. With the increase in the multidrug-resistant (MDR) and extensively drug-resistant (XDR) cases, the treatment for TB with the standard first and second-line therapy is becoming increasingly difficult. Therefore, there is an urgent need to find new anti-TB drugs as combination partners of existing and experimental classes of antimicrobial agents to shorten and simplify the …

Exploring Risk Factors Of Alzheimer’S Disease Using Mouse Models, Xian Han

Theses and Dissertations (ETD)

Mouse models of Alzheimer’s disease (AD) that accurately recapitulate pathology and molecular changes are crucial for understanding disease mechanisms and subsequent therapeutic development. We examined five commonly used mouse models of AD (5xFAD, J20, APPNL-F, APPNL-G-F, Tau P301S) and compared their whole- and phosphoproteomes with human AD (the integration of three published datasets) to study whether they can mimic protein/RNA expression discrepancies, molecular changes, and enriched pathways found in human AD cases. The mouse models especially 5xFAD and APPNL-G-F show proteomic signatures similar to human AD but lack human-specific AD progressions, such as dysregulation of synaptic pathways and networks. Integration …

A Cloning-Free Recyclable System For Crispr-Cas9 Mediated Mutant And Reversion Construction In Candida Albicans Clinical Isolates, Amanda K. Vogel

Theses and Dissertations (ETD)

Candida albicans is a ubiquitous opportunistic fungal pathogen and one of the most prevalent causes of fungal diseases worldwide. The reference isolate SC5314 is one of the most widely used strains for both experimental and genetic studies, but it is becoming increasingly evident that genetic diversity in clinical isolates plays an important role in antifungal resistance, virulence, and pathogenicity. These recent discoveries highlight the need for genetic tools that are capable of investigating genes in multiple strain backgrounds. Here we build on the SAT1-flipper method and combine it with CRISPR-Cas9 technology to achieve cloning-free homozygous deletion in a single transformation …

Computer-Aided Drug Discovery For Helicobacter Pylori, Nicole Ann Vita

Theses and Dissertations (ETD)

Helicobacter pylori is a high-priority drug-resistant pathogen and is currently the only bacteria considered to be a class I carcinogen and there is a critical need to identify novel chemical matter to treat H. pylori infections. Hp is responsible for greater than 60% of gastric cancer related deaths and 89% of all gastric cancer morbidities. In a previous study, our lab identified novel Hp thienopyrmidine inhibitors that target respiratory complex I, an essential enzyme in respiration. Respiratory complex I is a large asymmetric multidomain and membrane bound enzyme and due to these innate features, it is not practical for biophysical …

Methods Development In Inflammatory Bowel Disease, Andrew B. Steimke

Theses and Dissertations (ETD)

Inflammatory bowel disease (IBD) is a disease that is classified into two subtypes: ulcerative colitis (UC) and Crohn’s disease (CD). Symptoms can range from mild discomfort to requiring surgical intervention and affects approximately 1-in-200 adults in America alone, with global incidence rates increasing. While many treatments exist for IBD, perhaps the main reason for the lack of a cure is that there are many different pathogeneses that all lead to a very similar expression of symptoms. Over 240 IBD loci have been identified to date, yet the causative allele that drives the association has only been identified in ~60 of …

Olfactory Processing In The Piriform Cortex Of Awake, Freely Moving Mice, Ian F. Chapman

Theses and Dissertations (ETD)

The piriform cortex (PC) has long been established as the primary cortical recipient of olfactory information in the mammalian brain. In rodents, information extracted from recordings of PC neurons can accurately decode the identity of odors, leading to delineation of PC as the primary cortical region involved in the formation of odor perception. Unfortunately, due to technical limitations, many of the prior studies establishing these coding principles were performed without the ability to track the responses of the same cells over time. Additionally, recordings have often relied on head-fixation to minimize diffusion of odor stimuli, limiting movement range and natural …

Cerebellar Coordination Of Neuronal And Behavioral Rhythms, Brittany Correia Chapman

Theses and Dissertations (ETD)

Long known for its role in motor control, it is increasingly clear that the cerebellum is also involved in numerous cognitive and affective behaviors. Though the neuronal mechanism for the role of the cerebellum in cognition is still unclear, there is a consensus that it involves cerebellar interactions with the cerebral cortex. Recent studies suggest that the cerebellum monitors, and possibly coordinates, the precise phase alignment or coherence of neuronal oscillations in cerebral cortical areas. Here, we asked how loss of cerebellar function affects respiratory rhythms and the interactions of local field potential (LFP) oscillations between the lobulus simplex (LS) …