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Carbapenem-Resistant Enterobacteriaceae: Epidemiology, Genetics, In Vitro Activity, And Pharmacodynamic Modeling, Brandon Kulengowski

Theses and Dissertations--Pharmacy

Background: Infections caused by carbapenem-resistant Enterobacteriaceae (CRE) such as Escherichia coli and Klebsiella pneumoniae are among the most urgent threats of the infectious disease realm. The incidence of these infections has been increasing over the years and due to very limited treatment options, mortality is estimated at about 50%. By 2050, mortality from antimicrobial resistant infections is expected to surpass cancer at 10 million deaths annually.

Methods: We evaluated 18 contemporary antimicrobials against 122 carbapenem-resistant Enterobacteriaceae using a variety of antimicrobial susceptibility testing methods according to Clinical Laboratory Standards Institute guidelines. Time-kill studies were performed on clinical isolates with variable …

Pharmacokinetic And Pharmacodynamic Evaluation Of Cocaine Hydrolases For The Treatment Of Cocaine Overdose And Cocaine Addiction Using Rodent Models, Xirong Zheng

Theses and Dissertations--Pharmacy

Overdose and addiction are two medical complications of cocaine abuse. To date, there is no FDA approved pharmacotherapy specific for cocaine abuse. Cocaine hydrolases (CocHs) have been extensively investigated for its potential in anti-cocaine therapy. Previous studies have demonstrated that CocHs efficiently hydrolyze cocaine to generate biologically inactive metabolites both in vivo and in vitro. However, it has not been studied whether there is gender difference in the therapy using CocHs. In addition, the effectiveness of CocHs is unknown for treating cocaine toxicity when alcohol is co-administered.

The main purpose of this dissertation is to characterize and evaluate efficient …

Discovery Of Novel Pharmacotherapeutics For Substance Use Disorders, Na-Ra Lee

Theses and Dissertations--Pharmacy

Substance use disorders are serious health concerns in the United States. Furthermore, the National Survey on Drug Use and Health reports a continuous increase in substance use disorders in the United States during the last 10 years. However, there are not many effective pharmacotherapeutics available for substance use disorders. The current dissertation is focused on research aimed at discovering pharmacotherapeutics for substance use disorders. First part of dissertation focused on discovering methamphetamine (METH) use disorder therapeutics targeting specific mechanism of METH action on dopaminergic neurons. The second part of dissertation focused on opioids and cocaine use disorder therapeutics targeting rewarding …

Development Of Mithramycin Analogues With Improved Efficacy And Reduced Toxicity For Treatment Of Ets-Dependent Tumors In Ewing Sarcoma And Prostate Cancer, Joseph Michael Eckenrode

Theses and Dissertations--Pharmacy

Introduction: Genetic rearrangements in Ewing sarcoma, prostate, and leukemia cells result in activation of oncogenic ETS transcription factor fusions. Mithramycin (MTM) has been identified as an inhibitor of EWS-FLI1 transcription factor, a gene fusion product responsible for oncogenesis in Ewing sarcoma. Despite preclinical success, a phase I/II clinical trial testing MTM therapy in refractory Ewing sarcoma was terminated. Liver and blood toxicities resulted in dose de-escalation and sub-therapeutic exposures. However, the promise of selectively targeting oncogenic ETS transcription factors like EWS-FLI1 prompted us to undertake the discovery of more selective, less toxic analogues of MTM. MTM is a potent inhibitor …

Computational Modeling Guided Discovery Of Novel Inhibitors Of Mpges-1 And Butyrylcholinesterase As Drug Candidates, Shuo Zhou

Theses and Dissertations--Pharmacy

Ever since the advent of computer-aided drug design (CADD), in silico simulation methods have greatly accelerated the drug discovery process and lead to the discovery of numerous drug candidates. With the exponential growth of computational power, we nowadays simulate biologic systems at a scale unimaginable a decade ago and thus provides perspectives for drug design. In this dissertation research, combining in silico simulation methods like molecular docking and molecular dynamics (MD) simulation with organic synthesis, in vitro/in vivo experiments and clinical data mining, we developed new drug discovery strategies. These strategies were applied in our drug discovery projects and led …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Investigation Of Factors Influencing Protein Stability In Lyophilized Formulations Using Solid-State Nmr Spectroscopy, Ashley Lay-Fortenbery

Theses and Dissertations--Pharmacy

Many proteins are unstable in solution and must be formulated in the solid state. This has led to an increase in the use of lyophilized dosage forms. Lyophilization is a complicated processing method consisting of three major steps: freezing, primary drying, and secondary drying. This can lead to several formulation stability challenges including changes in ionization within the matrix, phase separation of the protein drug from added stabilizers, sufficient mobility within the system for movement of reactive species and protein side chains, and crystallization of excipients upon storage. Solid-State Nuclear Magnetic Resonance Spectroscopy (SSNMR) is used to characterize many important …

Suicide Attitudes And Terror Management Theory, Athena Kheibari

Theses and Dissertations--Social Work

Virtually every mental health problem carries stigma, but suicide appears to run so counter to our accumulative, achievement-oriented society, that it poses even greater threat of stigma. While suicide is inherently troubling in that it opposes the fundamental human instinct for self-preservation, the tendency to stigmatize and reject individuals affected by suicide appears to be counterproductive and excessive. Hence, the purpose of this three-manuscript dissertation is to gain a more nuanced understanding of suicide attitudes from an exploratory and terror management theory perspective. More specifically, this dissertation attempts to answer three general questions: (1) how do suicide attitudes differ from …

Quantification Of Myocardial Mechanics In Left Ventricles Under Inotropic Stimulation And In Healthy Right Ventricles Using 3d Dense Cmr, Zhan-Qiu Liu

Theses and Dissertations--Mechanical and Aerospace Engineering

Statistical data from clinical studies indicate that the death rate caused by heart disease has decreased due to an increased use of evidence-based medical therapies. This includes the use of magnetic resonance imaging (MRI), which is one of the most common non-invasive approaches in evidence-based health care research. In the current work, I present 3D Lagrangian strains and torsion in the left ventricle of healthy and isoproterenol-stimulated rats, which were investigated using Displacement ENcoding with Stimulated Echoes (DENSE) cardiac magnetic resonance (CMR) imaging. With the implementation of the 12-segment model, a detailed profile of regional cardiac mechanics was reconstructed for …

Quantification Of Papillary Muscle Motion And Mitral Regurgitation After Myocardial Infarction, Connor R. Ferguson

Theses and Dissertations--Mechanical and Aerospace Engineering

Change in papillary muscle motion as a result of left ventricular (LV) remodeling after posterolateral myocardial infarction is thought to contribute to ischemic mitral regurgitation. A finite element (FE) model of the LV was created from magnetic resonance images acquired immediately before myocardial infarction and 8 weeks later in a cohort of 12 sheep. Severity of mitral regurgitation was rated by two-dimensional echocardiography and regurgitant volume was estimated using MRI. Of the cohort, 6 animals (DC) received hydrogel injection therapy shown to limit ventricular remodeling after myocardial infarction while the control group (MI) received a similar pattern of saline injections. …

A Computational Study Of Patch Implantation And Mitral Valve Mechanics, Dara Singh

Theses and Dissertations--Mechanical and Aerospace Engineering

Myocardial infarction (i.e., a heart attack) is the most common heart disease in the United States. Mitral valve regurgitation, or the backflow of blood into the atrium from the left ventricle, is one of the complications associated with myocardial infarction. In this dissertation, a validated model of a sheep heart that has suffered myocardial infarction has been employed to study mitral valve regurgitation. The model was rebuilt with the knowledge of geometrical changes captured with MRI technique and is assigned with anisotropic, inhomogeneous, nearly incompressible and highly non-linear material properties. Patch augmentation was performed on its anterior leaflet, using a …

Pyocyanin, A Virulence Factor Produced By Sepsis-Causing Pseudomonas Aeruginosa, Promotes Adipose Wasting And Cachexia, Nika Larian

Theses and Dissertations--Pharmacology and Nutritional Sciences

Sepsis is a leading cause of death among critically ill patients that results in metabolic alterations including hypercatabolism, lipoatrophy, and muscle wasting, contributing to the development of cachexia. Septic cachexia is associated with loss of body weight, fat mass, and lean mass and dysregulated immune function. There are currently no efficacious treatment strategies for septic cachexia, and nutritional interventions have limited success in preventing hypercatabolic wasting. Pyocyanin is a virulence factor produced by sepsis-causing Pseudomonas aeruginosa that has been shown to activate the aryl hydrocarbon receptor (AhR), increase inflammation, and produce reactive oxygen species. Thus, pyocyanin represents a novel mechanistic …

The Role Of Endoplasmic Reticulum Stress In Ethanol-Induced Neurodegeneration, Yongchao Wang

Theses and Dissertations--Pharmacology and Nutritional Sciences

Heavy ethanol use causes neurodegeneration manifested by neuronal loss and dysfunction. It is becoming imperative to delineate the underlying mechanism to promote the treatment of ethanol-induced neurodegeneration. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases. This study aims to investigate the role of ER stress in ethanol-induced neurodegeneration. In experimental design, adult mice were exposed to binge ethanol drinking by daily gavage for 1, 5, or 10 days and the response of ER stress was examined. We found the induction of ER stress appeared at 5 days and remained at 10 days. Moreover, …

Azithromycin Therapy Reduces Cardiac Inflammation And Mitigates Adverse Cardiac Remodeling After Myocardial Infarction, Ahmed Hamish Neamah Al-Darraji

Theses and Dissertations--Pharmacology and Nutritional Sciences

Introduction: Myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Induced by cardiomyocyte death, MI initiates a prolonged and uncontrolled inflammatory response which impairs the healing process. Immune cells, such as macrophages, play a central role in organizing the early post-MI inflammatory response and the subsequent repair phase. Two activation states of macrophages have been identified with distinct and complementary functions (inflammatory vs. reparatory). This bimodal pattern of macrophage activation is an attractive therapeutic target to favorably resolve post-MI inflammation and enhance recovery. It has been demonstrated that azithromycin (AZM), a commonly used antibiotic with immunomodulatory effects, …

Pathological Tau As A Cause, And Consequence, Of Cellular Dysfunction, Shelby Meier

Theses and Dissertations--Physiology

Tauopathies are a group of neurodegenerative diseases characterized by the abnormal deposition of the protein tau, a microtubule stabilizing protein. Under normal physiological conditions tau is a highly soluble protein that is not prone to aggregation. In disease states alterations to tau lead to enhanced fibril formation and aggregation, eventually forming neurofibrillary tangles (NFTs). The exact cause for NFT deposition is unknown, but increased post-translational modifications and mutations to the tau gene can increase tangle formation.

Tauopathic brains are stuck in a detrimental cycle, with cellular dysfunction contributing to the development of tau pathology and the development of tau pathology …

Development And Evaluation Of Nonradioactive Methods For Monitoring T Lymphocyte Response To Equine Arteritis Virus (Eav) In Horses, Annet Kyomuhangi

Theses and Dissertations--Veterinary Science

Target cell lysis is the hallmark of immune effector responses of cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and monocytes. The most commonly used assay to measure target cell lysis is the 51Cr release assay and is considered the ‘gold standard’. However, this assay has many disadvantages that limit its use by most laboratories. Thus, several alternative assays have been developed. Some of these alternative assays are more sensitive, easy to perform and do not use radioactive elements.

In this study, four of these assays were evaluated for their ability to detect antigen- specific CTL responses in equine blood. …

Effects Of Pituitary Pars Intermedia Dysfunction And Prascend® Treatment On Endocrine And Immune Function In Senior Horses, Ashton B. Miller

Theses and Dissertations--Veterinary Science

Pituitary pars intermedia dysfunction (PPID) is one of the most common endocrine diseases affecting senior horses. PPID causes abnormally high concentrations of adrenocorticotropic hormone (ACTH) in the plasma and a very distinct, long, shaggy haircoat (hypertrichosis). At present, the recommended treatment for PPID is daily oral administration of pergolide mesylate. Due to the increased ACTH levels associated with PPID, it is commonly thought that these horses are immunosuppressed and at increased risk of opportunistic infections, although current research in this area is sparse. Additionally, it is not well-understood how treatment with Prascend^® (pergolide tablets) affects endocrine measures other than …

Effects Of A Systemic High Urea Concentration On The Endometrial And Embryonic Transcriptomes Of The Mare, Yatta Linhares Boakari

Theses and Dissertations--Veterinary Science

Pregnancy loss remains a major source of economic cost to the equine industry. Frequently, the exact causes of pregnancy loss remain unknown. It has been shown, in other species, that increased dietary protein leading to elevated blood urea nitrogen concentrations (BUN) can be a factor in decreased survival of the early embryo. Our studies provided novel information regarding the effects of elevated BUN on endometrium and embryos from mares as well as insights on changes in their gene expression. Our first objective was to develop an experimental model to elevate BUN during diestrus using intravenous urea infusion. We analyzed the …

Anthelmintic Resistance In Equine Parasites: Mechanisms And Treatment Approaches, Jessica Scare Kenealy

Theses and Dissertations--Veterinary Science

Anthelmintic resistance of parasites infecting livestock animals is a global problem resulting in decreased animal welfare and production losses. Horses are not exempt from this issue as wide-spread anthelmintic resistance exists among the equine cyathostomins and Parascaris spp. Of the three drug classes available for treating equine intestinal helminths anthelmintic resistance, defined as less than 90-95% drug efficacy, exist to all three. New pharmaceutical control regimens and the elucidation of parasite drug response mechanisms are needed.

Two studies were carried out evaluating combination deworming regimens. A population of cyathostomins with known resistance to the benzimidazole (BZ) and pyrimidine drug classes …

Quantifying White-Tailed Deer Density And Its Impacts On Agricultural Systems, Jonathan A. Matthews

Theses and Dissertations--Forestry and Natural Resources

White-tailed deer (Odocoileus virginianus) commonly consume row crops, with yield losses often attributed to their browsing. Deer density and field morphology may predict yield losses within local areas. We sought to 1) determine the effects of deer browsing on corn and soybean yields and investigate if deer density or field morphology correlated to yield loss in western Kentucky, and 2) compare pellet-based distance sampling to game camera surveys to determine if a distance sampling technique could accurately estimate deer density during the growing season. Overall, deer reduced corn and soybean yields on one-half of surveyed properties. Deer density …

Modulation Of Inflammatory Cytokine, Chemokine, And Toll-Like Receptor Genes And Transcriptome Analysis Of Equine Endothelial Cells Following Infection With Equid Herpesvirus-1, And Equine Arteritis Virus., Saranajith Wangisa Dunuwille

Theses and Dissertations--Veterinary Science

EHV-1 is a double-stranded DNA virus whereas EAV is a positive sense, single-stranded RNA virus. Therefore, genetically, they are very different from one another. However, both these viruses are endotheliotropic and thus, infect and replicates in equine endothelial cells resulting in vasculitis. Vasculitis is central to the pathogenesis of these two viruses. Thus, the main objective of this thesis was to investigate the inflammatory and innate immune responses of EECs that contribute towards the development of vasculitis following infection with EHV-1 and EAV in-vitro. Since proinflammatory cytokines and chemokines produced by endothelial cells play a significant role in the …

Evaluating Reforestation Options For Surface Mines In Appalachia, Joseph Frederick

Theses and Dissertations--Forestry and Natural Resources

During the last century coal extraction has degraded ecosystems in Appalachia, converting forested land into other cover types that have a diminished capacity to naturally progress to later stages of succession. This projects objective was to examine two options for land-use that can assist in returning the reclaimed surface mines to forested cover types, with increased ecosystem services, and a potential for economic gain.

This project examined a biomass plantation and an American chestnut trial. In the biomass trial, greatest heights for American sycamore (12.3 m) and black locust (8.0 m) were found in the fertilizer plots. Mean individual tree …

Mechanisms Of Type-I Ifn Inhibition: Equine Herpesvirus-1 Escape From The Antiviral Effect Of Type-1 Interferon Response In Host Cell, Fatai S. Oladunni

Theses and Dissertations--Veterinary Science

Equine herpesvirus-1 (EHV-1) is one of the most important and prevalent viral pathogens of horses causing a major threat to the equine industry throughout most of the world. EHV-1 primarily causes respiratory disease but viral spread to distant organs enables the development of more severe sequelae; abortion and neurologic disease. In order to produce disease, EHV-1 has to overcome the innate barrier of the type-I interferon (IFN) system in host cells. However, the underlying mechanisms employed by EHV-1 to circumvent the type-I IFN response in host cells are not well understood. In this project study, using molecular techniques, we explored …

News - Screven-Jenkins Regional Library, Sharon Blank

Georgia Library Quarterly

No abstract provided.

California Livestock Owners: An Assessment Of Familiarity With New Antimicrobial Rules And Access To Educational Outreach, Philip Theodor Paulson

Master's Theses

The purpose of this research is to support the California Department of Food & Agriculture (CDFA) with education and outreach about recent changes regarding antimicrobial use in livestock, and to enhance their emergency communications network. This was done by characterizing a population of small-scale livestock owners underserved with regards to educational outreach about animal health issues, such as antimicrobial use rules. The project also seeks to enhance public understanding of the importance of responsible antimicrobial use in animal and human health.

To accomplish this, the study used a survey administered in person at local farm supply stores and online to …

A Review Of The Use Of Positive Reinforcement In Drug Courts, Katherine Bascom

PCOM Psychology Dissertations

There is a need to provide effective treatment for drug-abusing offenders, as evidenced by the explicitly supported relationship between drug use and crime (Anglin & Perrochet, 1998; Tonry & Wilson, 1990; McBride & McCoy, 1993). Drug policy in the United States has viewed drug abuse as a public safety concern or a public health concern (Marlowe, 2002). In 1989, the Miami Drug Court in Dade County, Florida developed a drug court system that is currently used nationwide. The model embodies a very strong behavioral orientation with clear expectations, as well as graduated sanctions and rewards for successive infractions and accomplishments. …

“Right This Way: A Potential Artificial Intelligence-Based Solution For Complying With Article 13 Of The Eu’S 2018 Copyright Directive”, Vincent Ferrer

Student Works

No abstract provided.

Strong, Cheap, And Ready Access To Body-Worn Camera Footage Under New Jersey’S Open Public Records Act (Opra) Will Promote Police Accountability And Transparency, Nicholas Delaney

Student Works

No abstract provided.

Wire-Tapping Criminal Suspects: Should The Scope Of Attorney-Client Privilege Extend That Far?, Jenna Ventola

Student Works

No abstract provided.

Patent Eligibility Of Emerging Computer Technologies In The Aftermath Of Alice Corp. V. Cls Bank, Michael Campolongo

Student Works

No abstract provided.