Vitamin B12 Bioconjugates In Pharmaceutical Design

Abstract This thesis addresses several questions focused on the vitamin B12 (B12) dietary uptake pathway, in particular that of the enteric B12 transport protein intrinsic factor (IF) and its receptor cubilin, and the expression and exploitation of IF/cubilin in pharmaceutical development. Q1: (Chapter 2) Does an 89Zr-B12 conjugate allow for improved background/noise ratio, relative to 99mTc and 64Cu B12 conjugates, in in vivo tumor uptake? Goal: Conduct positron emission tomography (PET) imaging and biodistribution studies in mice bearing MDA-MB-453 breast cancer tumors using a new 89Zr-B12 conjugate. Q2: (Chapter 3) What is the uptake of systemically administered holo-intrinisic factor bound to 89Zr-B12 in vivo? Goal: Conduct PET imaging and biodistribution studies in healthy mouse models using IF-89Zr-B12 and assign organ distribution to target receptors. Q3: (Chapter 4) Are functional cubilin and megalin receptors expressed in human fetal small intestinal cells? Goal: Design a fluorescent assay to establish functional cubilin and megalin expression and conduct western blotting to complement observations. Q4: (Chapter 4) Does B12-Exendin-4, a conjugate of B12 and the diabetes drug exendin-4 (Ex-4; a peptide agonist of the glucagon like peptide receptor 1) show reduced central nervous system (CNS) penetrance, thus reducing the common side effect of nausea that is observed in patients taking Ex-4? Goal: Systemically administer fluorescently labeled Ex-4, B12, and B12-Ex4 and observe CNS uptake in rats through immunohistochemistry and confocal microscopy. Q5: (Chapter 5) Does systemically administered holo-IF prevent aminoglycoside antibiotic induced hearing loss in guinea pigs? Goal: Induce hearing loss in guinea pigs with the aminoglycoside kanamycin and prevent such loss with co-administration of holo-IF

Air commando Intel: optimizing specialization training for Air Force Special Operations Command Intelligence Officers

Since 1999, Air Force Intelligence officers have been trained, managed, and assigned in accordance with a 'generalist' approach to intelligence disciplines. Specialization is the exception, and intelligence officers are assigned to a variety of missions, disciplines, and commands in an attempt to "broaden" their experience and maximize exposure to various disciplines. Because of this approach, specialization training after completion of the Air Force Intelligence Officer Course has become crucial to intelligence officer success at the unit level. This research examines specialization training provided to intelligence officers assigned to Air Force Special Operations Command (AFSOC) flying squadrons. Information gathered through surveys and interviews of AFSOC squadron leadership, weapons officers, and intelligence officers, coupled with a detailed analysis of AFSOC Intelligence Officer responsibilities and training, was utilized to develop a web-based survey designed to measure intelligence officer performance at unit level AFSOC flying squadrons. The survey results were analyzed to determine areas of strength and weakness, and recommendations for optimizing specialization training were created from the survey results. Recommendations include actions to enhance intelligence at the individual and team level in AFSOC flying squadrons, minor modifications to specialization training, and an alternative intelligence career path which allows increased specialization is discussed.http://archive.org/details/aircommandointel1094510715US Air Force (USAF) autho

Retrospective study of treatment outcome for individuals with aphasia

Measurement of outcomes subsequent to treatment and documentation of the efficiency with which outcomes are achieved is critical information for healthcare policy makers and third-party payers. This study employed the ASHA Functional Communication Measure (FCM) scales to retrospectively analyse charts of 20 aphasic patients. By discharge, both severe and moderate groups gained a median (across modalities) of 1 FCM level. The severe group remained dependent for communication, while the moderately impaired group typically achieved independent communication levels. Efficiency (amount of FCM level gain relative to number of treatment sessions) was greater for the moderate group; average number of treatment sessions was 40 for the severe group and 22 for the moderate group

An evaluation of the effectiveness of PROMPT therapy in improving speech production accuracy in six children with cerebral palsy

This study evaluates perceptual changes in speech production accuracy in six children (3 – 11 years) with moderate-to-severe speech impairment associated with cerebral palsy before, during, and after participation in a motor-speech intervention program (Prompts for Restructuring Oral Muscular Phonetic Targets). An A1BCA2 single subject research design was implemented. Subsequent to the baseline phase (phase A1), phase B targeted each participant’s first intervention priority on the PROMPT motor-speech hierarchy. Phase C then targeted one level higher. Weekly speech probes were administered, containing trained and untrained words at the two levels of intervention, plus an additional level that served as a control goal. The speech probes were analysed for motor-speech-movement-parameters and perceptual accuracy. Analysis of the speech probe data showed all participants recorded a statistically significant change. Between phases A1 – B and B – C 6/6 and 4/6participants, respectively, recorded a statistically significant increase in performance level on the motor speech movement patterns targeted during the training of that intervention. The preliminary data presented in this study make a contribution to providing evidence that supports the use of a treatment approach aligned with dynamic systems theory to improve the motor-speech movement patterns and speech production accuracy in children with cerebral palsy

Familial Amyotrophic Lateral Sclerosis with a focus on C9orf72 Hexanucleotide GGGGCC Repeat Expansion Associated ALS with Frontotemporal Dementia

Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disorder resulting in the loss of motor neurons from the spinal cord and frontal cortex. The patterns of neurodegeneration, affected regions, age of onset, and time course of disease progression are all highly variable between and within variants of the disease. Familial ALS (fALS), inherited versions of ALS due to genetic changes, accounts for between 5-20% of all ALS cases, while the rest are sporadic, with either no causative mutation identified or no familial history of ALS. Recently, the discovery of C9orf72 hexanucleotide repeat expansions have been identified as one of the most common causes of familial ALS, with some patients presenting with dual phenotypes of ALS and frontotemporal dementia, leading to new hypotheses about the nature of neurodegenerative diseases. Despite the continued discovery of new ALS causative genes, little is known about the pathogenesis of the disease. While almost all variants include the presence of intracellular protein inclusions, the site of the protein plaques and involved proteins varies between genetic and phenotypic variants of this disease. Due to the lack of clear pathogenic mechanisms, several hypotheses have been developed to explain the process of neurodegeneration. Autophagy, the process of self-eating, leading to destruction of damaged or excess proteins and organelles, has been implicated as being altered in ALS. Multiple variants have demonstrated altered mitochondrial morphology and cellular energetic dynamics, which could explain previous observations that implicate the process of apoptosis in cellular death. Many of the involved proteins in ALS have functional roles for intracellular, nucleocytoplasmic, and axonal transport of various proteins or RNA. These three competing hypotheses are currently the most prominent hypotheses in the pathogenesis of ALS, and have largely been considered as separate and competing in past research. Is there a chance that the true pathogenesis leading to neuronal destruction via apoptosis involve all three hypotheses? Altered protein and RNA transport dynamics could lead to changes in cellular stress responses or overload autophagy pathways, leading to exacerbated cellular stress responses, leading to alterations in mitochondrial morphology and eventually cell death via apoptosis

Master's Recitals

Recital presented at the UNT College of Music Voertman Hall in partial fulfillment of the Master of Music (MM) degree

Challenges in the Diagnosis of Magnesium Status

Magnesium is a critical mineral in the human body and is involved in ~80% of known metabolic functions. It is currently estimated that 60% of adults do not achieve the average dietary intake (ADI) and 45% of Americans are magnesium deficient, a condition associated with disease states like hypertension, diabetes, and neurological disorders, to name a few. Magnesium deficiency can be attributed to common dietary practices, medications, and farming techniques, along with estimates that the mineral content of vegetables has declined by as much as 80–90% in the last 100 years. However, despite this mineral’s importance, it is poorly understood from several standpoints, not the least of which is its unique mechanism of absorption and sensitive compartmental handling in the body, making the determination of magnesium status difficult. The reliance on several popular sample assays has contributed to a great deal of confusion in the literature. This review will discuss causes of magnesium deficiency, absorption, handling, and compartmentalization in the body, highlighting the challenges this creates in determining magnesium status in both clinical and research settings