Digital Commons Network^™

Synthesis And Evaluation Of Conformationally Constrained Peptide Analogues As The Src Sh3 Domain Binding Ligands, Rakesh Tiwari, Alex Brown, Seetha Narramaneni, Gongqin Sun, Keykavous Parang

Pharmacy Faculty Articles and Research

Src kinase activity is regulated by the interaction of SH3 domain with protein sequences that are rich in proline residues. Identification of more potent SH3 domain binding ligands that can regulate Src kinase activity is a subject of major interest. Conformationally constrained peptides have been previously used for improving the binding potency of the Src SH2 domain binding peptide ligands and peptide substrates of the substrate-binding site of Src. A series of peptide analogues of Ac-VSLARRPLPPLP (1, Ac-VSL-12, Kd = 0.34 M) were synthesized by introducing conformational constraints to improve the binding affinity towards the Src SH3 domain. Peptides synthesized …

The Clinical And Polysomnographic Features In Complex Sleep Apnea Syndrome, Handan İnönü, Tansu Ulukavak Çi̇ftçi̇, Oğuz Köktürk

Turkish Journal of Medical Sciences

Complex sleep apnea syndrome (CompSAS) is characterized by the onset of central apneas or a Cheyne-Stokes breathing pattern in some patients with obstructive sleep apnea syndrome (OSAS) who were treated with continuous positive airway pressure (CPAP). The etiology of CompSAS is unclear, but derangement of respiratory control has been proposed. We sought to compare clinical and polysomnography (PSG) features of patients with CompSAS and OSAS. Materials and methods: Records of PSG were evaluated in a total of 270 patients, retrospectively. CPAP titration was prescribed in patients with an apnea-hypopnea index (AHI) of >=15. Patients who developed a central AHI of …

Structure Elucidation Of A Glycosylated Benzyl Ester Of Salicylic Acid From The North American Prairie Plant Oligoneuron Rigidum, Sarah Katherine Miesner

Honors Program Theses

The organic extract from Oligoneuron rigidum displayed anti-microbial activity, indicating a potential future use as a natural food preservative. Three novel compounds were isolated from the active extract. The skeletal structure of the three compounds was determined by spectral methods, and the final structural component that remained to be determined was the locations of the acetate groups. Neutral permethylations were performed on the compounds as the first step in determining the locations of the acetate groups; however, the permethylation technique proved to be ineffective, causing cleavage of the native compounds. The structure elucidation will be complete when a non-degradable method …

Effects Of Prenatal Dexamethasone On Hipopcampal Serotonin 1a Receptors In Adult Male Rats, Rahul Vijay

Master’s Theses

The main activation route for the stress response is the hypothalamo-pituitaryadrenal axis (HPA) and the sympatho-adrenomedullary system. The HPA axis is a neuroendocrine feedback loop mediated by an array of tissue specific hormones, receptors and neurotransmitters that regulate glucocorticoid (GC) release. GCs are steroidal hormones produced by the adrenal glands and are key players in a negativefeedback loop controlling HPA activity. They influence the HPA axis through glucocorticoid receptors in the hypothalamus and pituitary and through both glucocorticoid (GR) and mineralcorticoid receptors (MR) that are co-localized in the hippocampus. Repeated or chronic stress exerts a negative influence on these HPA …

Prospects And Pits On The Path Of Biomimetics: The Case Of Tooth Enamel, Vuk Uskoković

Pharmacy Faculty Articles and Research

This review presents a discourse on challenges in understanding and imitating the process of amelogenesis in vitro on the molecular scale. In light of the analysis of imitation of the growth of dental enamel, it also impends on the prospects and potential drawbacks of the biomimetic approach in general. As the formation of enamel proceeds with the protein matrix guiding the crystal growth, while at the same time conducting its own degradation and removal, it is argued that three aspects of amelogenesis need to be induced in parallel: a) crystal growth; b) protein assembly; c) proteolytic degradation. A particular emphasis …

Localization Of Angiotensin Converting Enzyme In Rabbit Cornea And Its Role In Controlling Corneal Angiogenesis In Vivo, Ajay Sharma, Daniel I. Bettis, John W. Cowden, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

Purpose: The renin angiotensin system (RAS) has been shown to modulate vascular endothelial growth factor and angiogenesis. In this study we investigated (i) the existence of the RAS components angiotensin converting enzyme (ACE) and angiotensin II receptors (AT1 and AT2) in the rabbit cornea using in vitro and ex vivo models and (ii) the effect of enalapril, an ACE inhibitor, to inhibit angiogenesis in rabbit cornea in vivo.

Methods: New Zealand White rabbits were used. Cultured corneal fibroblasts and corneal epithelial cells were used for RNA isolation and cDNA preparation using standard molecular biology techniques. PCR was performed to …

Aav Serotype Influences Gene Transfer In Corneal Stroma In Vivo, Ajay Sharma, Jonathan C. K. Tovey, Arkasubhra Ghosh, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

This study evaluated the cellular tropism and relative transduction efficiency of three AAV serotypes, AAV6, AAV8 and AAV9, for corneal gene delivery using mouse cornea in vivo and donor human cornea ex vivo. The AAV6, AAV8 and AAV9 serotypes having AAV2 plasmid encoding for alkaline phosphatase (AP) gene were generated by transfecting HEK293 cell line with pHelper, pARAP4 and pRep/Cap plasmids. Viral vectors (109 vg/μl) were topically applied onto mouse cornea in vivo and human cornea ex vivo after removing the epithelium. Human corneas were processed for transgene delivery at day 5 after viral vector application. Mouse corneas were harvested …

Synthesis, Antiviral And Contraceptive Activities Of Nucleoside-Sodium Cellulose Sulfate Acetate And Succinate Conjugates, Hitesh K. Agarwal, Anil Kumar, Gustavo F. Doncel, Keykavous Parang

Pharmacy Faculty Articles and Research

Chemical conjugates between sodium cellulose sulfate (CS), displaying contraceptive and HIV-entry inhibiting properties, and nucleoside reverse transcriptase inhibitors (NRTIs) (3′-azido-2′,3′-dideoxythymidine (AZT), 3′-fluoro-2′,3′-dideoxythymidine (FLT), or 2',3'-dideoxy-3'-thiacytidine (3TC)) were designed to simultaneously provide contraceptive and anti-HIV activity. Two linkers, acetate and succinate, were used to conjugate the nucleoside analogs with CS. The conjugates containing cellulose sulfate-acetate (CSA) (e.g., AZT-CSA and FLT-CSA) were found to be more potent than CS and other conjugates (e.g., AZT-succinate-CS, and FLT-succinate-CS). The presence of both sulfate and the acetate groups on cellulose were critical for generating maximum anti-HIV activity. In addition to showing equal potency against wild-type …

Subcellular Localization Of The Non-Structural Proteins 3c And 3cd Of The Honeybee Virus Deformed Wing Virus, Cierra Nichole Danko

Honors Theses

Apis mellifera L., the European honeybee, is a crucial pollinator of many important agricultural crops in the United States. Recently, honeybee colonies have been affected by Colony Collapse Disorder (CCD), a disorder in which the colony fails due to the disappearance of a key functional group of worker bees. Though no direct causalrelationship has been confirmed, hives that experience CCD have been shown to have a high incidence of Deformed Wing Virus (DWV), a common honeybee virus. While the genome sequence and gene-order of DWV has been analyzed fairly recently, few other studies have been performed to understand the molecular …

Preclinical Pharmacology Of Novel Synthetic Iminoquinones As Anticancer Agents, Scharri Ezell

All ETDs from UAB

Prostate cancer is the most common male malignancy and the second leading cause of cancer related death in the United States. Despite recent advances in the detection, diagnosis, and treatment of prostate cancer, there is a need for more effective therapies. Unfortunately, most conventional therapeutic modalities, such as androgen ablation therapy, frequently result in androgen-independent cancers. These cancers are typically more aggressive, metastatic, and resistant to chemotherapeutic agents than androgen-dependent prostate cancer. Therefore, agents that are effective against both androgen-sensitive and androgen-independent, as well as genetically diverse cancers are critically needed. The objective of the dissertation research was to address …

Identification And Validation Of Biodosimetry Markers In Multiple Models Of Radiation Exposure, Ashley Nicole Filiano

All ETDs from UAB

Following a radiological or nuclear disaster, radiation dose assessment is imperative to minimize morbidity and mortality through rationally directed medical intervention. Current methods of retrospective dosimetry are not amenable to mass exposure scenarios and remain limited to monitoring of clinical symptoms (nausea/vomiting and lymphocyte depletion) and cytogenetic analysis. The goal of this study was to identify radiation biomarkers capable of qualitative (non-irradiated/irradiated) and quantitative (dose) assessment of radiation exposure. Initial analyses revealed 17 radiation-responsive cytokine/chemokine genes in blood samples from 6 pediatric cancer patients undergoing fractionated total body irradiation (TBI). These 17 genes were combined with 29 additional IR-inducible genes …

A Model For Understanding Epilepsy In Peromyscus, Kevin Ryan, Gabor Szalai

Journal of the South Carolina Academy of Science

No abstract provided.

Molecular Staging Estimates Occult Tumor Burden In Colorectal Cancer, Alex Mejia, Stephanie Schulz, Terry Hyslop, David S. Weinberg, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Tumor cells in regional lymph nodes are a key prognostic marker of survival and predictive marker of response to adjuvant chemotherapy in colorectal cancer. However, clinicopathologic techniques to detect lymph node metastases remain imperfect, and ~30% of patients with lymph nodes negative by histology (pN0) develop recurrent disease, reflecting occult metastases that escape detection. These observations underscore an unmet clinical need for accurate approaches to identify occult nodal metastases in colorectal cancer patients. GUCY2C is a receptor whose expression normally is restricted to intestinal epithelial cells, but is universally over-expressed by colorectal cancer cells. A prospective, multicenter, blinded clinical trial …

Selection Of Optimal Reference Genes For Normalization In Quantitative Rt-Pcr., Inna Chervoneva, Yanyan Li, Stephanie Schulz, Sean Croker, Chantell Wilson, Scott A Waldman, Terry Hyslop

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: Normalization in real-time qRT-PCR is necessary to compensate for experimental variation. A popular normalization strategy employs reference gene(s), which may introduce additional variability into normalized expression levels due to innate variation (between tissues, individuals, etc). To minimize this innate variability, multiple reference genes are used. Current methods of selecting reference genes make an assumption of independence in their innate variation. This assumption is not always justified, which may lead to selecting a suboptimal set of reference genes. RESULTS: We propose a robust approach for selecting optimal subset(s) of reference genes with the smallest variance of the corresponding normalizing factors. …

The Interictal State In Epilepsy And Behavior, Daniel Tice Barkmeier

Wayne State University Dissertations

Epilepsy is one of the most common neurological diseases, affecting up to 1% of the world population. Epilepsy remains poorly understood and there are currently no medications to cure it. Patients with epilepsy have both seizures as well as another type of abnormal activity between seizures, known as interictal spikes. Interictal spikes have thus far been poorly researched, yet growing evidence supports an important role for them in epilepsy. In this project, we first show the high variability between reviewers in marking interictal spikes on intracranial EEG, and then develop and test an automated detection method to solve this problem. …

Neuroaids In Africa, Kevin Robertson, Jeff Liner, James Hakim, Jean-Louis Sankalé, Igor Grant, Scott Letendre, David Clifford, Amadou Gallo Diop, Assan Jaye, Georgette Kanmogne, Alfred Njamnshi, T. Dianne Langford, Tufa Gemechu Weyessa, Charles Wood, Mwanza Banda, Mina Hosseinipour, Ned Sacktor, Noeline Nakasuja, Paul Bangirana, Robert Paul, John Joska, Joseph Wong, Michael Boivin, Penny Holding, Betsy Kammerer, Annelies Van Rie, Prudence Ive, Avindra Nath, Kathy Lawler, Clement Adebamowo, Walter Royal Iii, Jeymohan Joseph

Nebraska Center for Virology: Faculty Publications

In July 2009, the Center for Mental Health Research on AIDS at the National Institute of Mental Health organized and supported the meeting “NeuroAIDS in Africa.” This meeting was held in Cape Town, South Africa, and was affiliated with the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Presentations began with an overview of the epidemiology of HIV in sub-Saharan Africa, the molecular epidemiology of HIV, HIV-associated neurocognitive disorders (HANDs), and HAND treatment. These introductory talks were followed by presentations on HAND research and clinical care in Botswana, Cameroon, Ethiopia, The Gambia, Kenya, Malawi, Nigeria, Senegal, South Africa, Uganda, …

Towards An Understanding Of The Herpes Simplex Virus Type 1 Latency-Reactivation Cycle, Guey-Chuen Perng, Clinton Jones

School of Veterinary and Biomedical Sciences: Faculty Publications

Infection by herpes simplex virus type 1 (HSV-1) can cause clinical symptoms in the peripheral and central nervous system. Recurrent ocular shedding can lead to corneal scarring and vision loss making HSV-1 a leading cause of corneal blindness due to an infectious agent. The primary site of HSV-1 latency is sensory neurons within trigeminal ganglia. Periodically, reactivation from latency occurs resulting in virus transmission and recurrent disease. During latency, the latency-associated transcript (LAT) is abundantly expressed. LAT expression is important for the latency-reactivation cycle in animal models, in part, because it inhibits apoptosis, viral gene expression, and productive infection. A …

Effect Of L-Carnitine On Diabetic Neuropathy And Ventricular Dispersion In Patients With Diabetes Mellitus, Hizir Ulvi̇, Recep Aygül, Recep Demi̇r

Turkish Journal of Medical Sciences

Diabetes is a common cause of polyneuropathy. Cardiac arrhythmias and markedly increased mortality rate have been demonstrated in patients with diabetic neuropathy and also demonstrated that abnormally prolonged QT dispersion interval (QTd) is associated with a higher risk of ventricular arrhythmias and sudden death. We investigated the efficacy and tolerability of L-carnitine (LC) in the treatment of diabetic neuropathy and ventricular dispersion, mainly by evaluating the effects of treatment on electrophysiological parameters. Materials and methods: We recruited 30 patients with type I or type II diabetes (mean age: 60 ± 9 years, range: 36-75; 18 males, 12 females) meeting clinical …

Effect Of Telmisartan On Vascular Endothelium In Hypertensive And Type 2 Diabetic Hypertensive Patients, Burcu Barutçuoğlu, Zuhal Parildar, M. Işil Mutaf, Di̇lek Özmen, Emi̇n Ali̇oğlu, Sara Habi̇f, Oya Bayindir

Turkish Journal of Medical Sciences

Hypertension and type 2 diabetes mellitus (DM) cause endothelial dysfunction and may result in cardiovascular disease. The aim of this study was to assess endothelial dysfunction in essential hypertensives, and normotensive and hypertensive type 2 diabetics and to evaluate the effect of telmisartan on endothelium in hypertensives. Materials and methods: Eighteen essential hypertensives (group 1), 16 type 2 diabetic hypertensives (group 2), 10 type 2 diabetic normotensives (group 3), and 10 control subjects (group 4) were included in this study. Groups 1 and 2 received 40 mg/day telmisartan for 12 weeks and were evaluated at the beginning and end. Groups …

Serum Lipid And Lipoprotein Levels, Dyslipidemia Prevalence, And The Factors That Influence These Parameters In A Turkish Population Living In The Province Of Tokat*, İlhan Çeti̇n, Beytullah Yildirim, Şemsetti̇n Şahi̇n, İdri̇s Şahi̇n, İlker Eti̇kan

Turkish Journal of Medical Sciences

To determine the mean total LDL and HDL cholesterol values and trigliseride levels as well as dyslipidemia and the factors that influence the parameters mentioned above in the population living in the province of Tokat located in the Middle Black Sea (Northeastern) region of Turkey. Materials and methods: The study was performed in 58 rural and 12 urban residential areas. The 58 rural regions were selected using a cluster sampling method. A total of 1095 subjects were selected through a random sampling method. Results: The total serum cholesterol level was 186 ± 42 mg/dL with 33.7% of the participants having …

The Development Of Humoral And Cellular Responses To Plasmodium Falciparum Malaria In The Hypoendemic Peruvian Amazon And Potential Clinical Protection, Eva Helen Clark

All ETDs from UAB

Each year 300-500 million cases of Plasmodium falciparum malaria occur, leading to more than 1 million deaths. In high malaria transmission regions, development of immunity from severe infection requires 2-10 years of persistent parasitemia. This delay has been attributed to difficulties in the development of protective humoral responses. Indeed, anti-malarial antibody responses tend to be short-lived, and immunologic memory seems to be dysfunctional in high-transmission regions. In contrast, in the low-transmission Peruvian Amazon >60% of infections are asymptomatic, suggesting that clinical immunity occurs despite low parasite exposure. To analyze more precisely the naturally-acquired humoral responses to malarial antigens and their …

Small Molecule Inhibitors Of Acid Sensing Ion Channel-1, Yawar J. Qadri

All ETDs from UAB

Acid Sensing Ion Channel 1 is one of the many proteins in the Epithelial Sodium Channel/Degenerin family. The proteins in this family interact to form cation channels with unique biophysical properties and can all be inhibited by the small molecule amiloride. Their expression in many different cell types underlies their involvement in a large variety of physiological and pathophysiological processes. ASIC-1 containing channels, specifically, are an important therapeutic target for ischemic stroke, nociception, the invasiveness of glioblastoma cells, and many other processes including anxiety and memory formation. Of the members of the ENaC/Deg family, chicken ASIC-1 is the only protein …

Investigation Of Residues Of The Vesicular Stomatitis Virus Nucleocapsid Protein That Affect Transcription And Rna Replication, Djamila Harouaka

All ETDs from UAB

The template for transcription and RNA replication for vesicular stomatitis virus (VSV) and other negative-strand RNA viruses is a ribonucleoprotein (RNP) complex consisting of the viral RNA genome and associated nucleocapsid (N) protein. The structure of the RNP-like complex of VSV showed that the RNA is sequestered between two lobes of the N protein, and adjacent N monomers are linked by an extensive network of interactions. Long-range interactions mediated by the N-terminal arm and C-terminal loop of the N protein stabilize the side-to-side contacts between adjacent N monomers, and are required for RNA encapsidation. It is unclear how the polymerase …

Mechanisms Of Major Outer Membrane Protein (Momp)-Vaccine Induced Protective Immunity Against Chlamydia Muridarum Genital Infection, Christina M. Farris

All ETDs from UAB

Urogenital infection with Chlamydia trachomatis is the most common bacterial sexually transmit-ted disease with an estimated 90 million new infections occurring each year worldwide. In women infection with C. trachomatis can result in serious complications including ectopic pregnancy, pelvic inflammatory disease and tubal factor infertility. Despite very effective antimicrobial chemotherapy, control of the infection will likely require an effective vaccine. We have assessed the protective effect of an outer membrane based vaccine using a murine model of chlamydial genital tract infection. Female mice were vaccinated with C. muridarum major outer membrane protein (MOMP) plus the immunostimulatory adjuvants CpG-1826 and Montanide …

The Role Of Gli1 In Eralpha-Negative Breast Cancer: Promoting Survival, Migration, Invasion, And Metastasis, Yeon-Jin Kwon

All ETDs from UAB

Glioma-associated oncogene homolog 1 (Gli1) is a well-known oncogene and a transcription factor that mediates several signaling pathways important for tumor progression, such as hedgehog, TGFß, Ras, and EGFR. Although Gli1 is known to play an important role in cancers of brain, skin, prostate, and the pancreas, the role of Gli1 in breast cancer was not previously well-defined. Therefore, this dissertation focuses on defining the role of Gli1 and the mechanism underlying Gli1-mediated transcription in breast cancer. Interestingly, the major findings of the dissertation clearly indicate that Gli1 promotes cell survival and is predictive of a poor outcome in Estrogen …

Role Of Heme Oxygenase-1 In Acute Kidney Injury, Subhashini Bolisetty

All ETDs from UAB

Acute kidney injury (AKI), defined as the rapid loss of kidney function, is often seen in the setting of multiple organ failure in critically ill patients. Lack of established therapeutic approaches to overcome AKI has lead to unacceptably high incidence of morbidity and mortality in these patients. The molecular mechanisms that lead to AKI often have oxidative stress as a common pathogenic event. The kidney responds by prompt induction of its own anti-oxidant machinery including the highly inducible, anti-inflammatory and anti-apoptotic gene-heme oxygenase-1 (HO-1). This microsomal enzyme degrades pro-oxidant heme, which is released from heme proteins. The cytoprotective properties of …

Evolution Of Pneumococcal Serogroup 6, Preston Eugene Bratcher

All ETDs from UAB

Serogroup 6 of Streptococcus pneumoniae has been known to contain three serotypes, named 6A, 6B and 6C, with highly homologous capsule gene loci. The 6A and 6B capsule gene loci consistently differ from each other by only one nucleotide in the wciP gene. The 6A capsule gene locus has a galactosyltransferase (wciNα), which has been replaced with a glucosyltransferase (wciNß) in the 6C capsule gene locus. We considered that a new serotype, 6D, would be possible if the glucosyltransferase found in 6C strains was combined with the wciP gene from a 6B strain. We demonstrate that this gene combination yields …

The Role Of Wnt5a In Mammary Gland Development, Sarah Baxley

All ETDs from UAB

Transforming growth factor-beta (TGF-beta) negatively regulates mammary gland development and requires Wnt5a to exert some of these effects on mammary gland development. Wnt5a is a non-canonical signaling Wnt that is expressed in all stages of mammary gland development except lactation. Using slow release pellets containing Wnt5a, as well as Wnt5a null tissue, we previously showed that Wnt5a also acts to limit mammary development. Initial studies revealed a potential role for TGF-beta and Wnt5a in regulating mammary gland progenitor cells, indicating they may act to regulate the stem and progenitor cell population. In order to study the role of Wnt5a on …

Canonical Wnt Signaling By The Proteolytic Processing Of Lrp6, Brandon Richard Beagle

All ETDs from UAB

Low density Lipoprotein receptor Related 6 (LRP6) functions as an essential co-receptor for Wnt/Beat;-catenin signaling as pathway activation, reflected by cytosolic Beta-catenin stabilization and TCF/LEF-1 transactivation, requires Glycogen Synthase Kinase 3Beta(GSK3Beta)-mediated phosphorylation of multiple PPP(S/T)P motifs within the membrane anchored LRP6 intracellular domain. Additionally, LRP6 undergoes a proteolytic cleavage event resulting in the formation of a soluble LRP6 intracellular domain (LRP6-ICD). LRP6-ICD can function within the Wnt/Beta-catenin pathway by interacting with GSK3Beta and attenuating the phosphorylation of GSK3Beta substrates such as cytosolic Beta-catenin as well as stimulate TCF/LEF-1 activity. However, LRP6-ICD's role(s) within the Wnt/Beta-catenin pathway and the mechanism(s) that …

Pneumococcal Vaccine Response And Aging In Human, Saeyoung Park

All ETDs from UAB

Streptococcus pneumoniae is a major human pathogen, especially for young children and older adults. To protect from pneumococcal diseases, 23-valent pneumococcal polysaccharide vaccine (PPV23) has been used clinically since 1983. However, PPV23 is not so effective among old adults with its protective efficacy diminishing with age. We confirmed that young and old adults, who were immunized with PPV23, have comparable pneumococcal polysaccharide (PS) specific IgG levels. Interestingly, we found that old adults had lower IgA and IgM antibody levels than young adults for three serotypes (serotype 14, 18C and 23F). Consistent with the previous results, opsonic capacities of immune sera …