Chemicals and Drugs Commons^™

Differential Modulation Of Functional Dynamics And Allosteric Interactions In The Hsp90-Cochaperone Complexes With P23 And Aha1: A Computational Study, Kristin Blacklock, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Allosteric interactions of the molecular chaperone Hsp90 with a large cohort of cochaperones and client proteins allow for molecular communication and event coupling in signal transduction networks. The integration of cochaperones into the Hsp90 system is driven by the regulatory mechanisms that modulate the progression of the ATPase cycle and control the recruitment of the Hsp90 clientele. In this work, we report the results of computational modeling of allosteric regulation in the Hsp90 complexes with the cochaperones p23 and Aha1. By integrating protein docking, biophysical simulations, modeling of allosteric communications, protein structure network analysis and the energy landscape theory we …

A Novel Selective Lipid Uptake Pathway Contributing To Ldl-Induced Macrophage Foam Cell Formation, Jason M. Meyer

Theses and Dissertations--Molecular and Cellular Biochemistry

Atherosclerosis is a disease characterized by cholesterol-rich plaques within the intima of medium and large arteries. Cholesterol deposition is thought to occur by infiltration of low-density lipoprotein (LDL) into lesions followed by uptake into macrophages, generating lipid-loaded “foam cells.” Foam cells can also be generated in vitro by treatment of macrophages with LDL or oxidized LDL (oxLDL). The purpose of the current investigation was to determine the contribution of selective cholesteryl ester (CE) uptake versus whole-particle uptake during LDL-induced foam cell formation in cultured macrophages. Murine bone marrow-derived macrophages (BMMs) exhibited significant cholesterol accumulation when treated with LDL as indicated …

The Mesocorticolimbic Dopamine Pathway Reconstituted In Vitro: Glutamate Receptors And Corticosteroid-Methamphetamine Neurotoxicity, Jennifer N. Berry

Theses and Dissertations--Psychology

Stress promotes the use of methamphetamine and other recreational substances and is often implicated in relapse to stimulant use. Thus, it is of critical importance to examine the consequences of the co-occurance of stress and methamphetamine use. Activity of the glutamatergic N-methyl D-aspartate (NMDA) receptor system appears to be involved in the neurotoxic effects of both chronic stress and methamphetamine exposure. The current studies investigated the hypothesis that chronic pre-exposure to the stress hormone corticosterone (CORT) results in an increase of NMDA receptor activity and that this will potentiate the neurotoxic effects of methamphetamine (METH). Co-cultures of the …

High Fat Diet Induced Obesity In A Mouse Model For Colorectal Cancer, Kennerly Clinton Patrick

Theses and Dissertations

Obesity is widely correlated with the incidence of colorectal cancer (CRC). The exact mechanisms that link obesity to CRC risk have not yet been fully established, and only a limited number of animal models are available to study pathways involved in obesity-related colon carcinogenesis. The objective of this study was to determine the influence of HFD-induced obesity on AOM/DSS-mediated colorectal tumorigenesis, tumor proliferation, and symptom severity. Male C57BL/6 mice were fed a novel high fat diet, designed to mimic the standard American diet (12 % saturated fat & 28 % unsaturated fat), at 4 weeks of age until 16 weeks …

Development Of Proteomic Characterization And Speciation Techniques Utilizing Tryptic Peptides With Maldi-Tof Ms And Lc-Esi Ms-Ms, Jennifer Marie Kooken

Theses and Dissertations

The characterization of microbes which can be opportunists and pathogens (e.g., methicillin resistant Staphylococcus aureus (MRSA)) is important in understanding and potentially treating diseases caused by various bacterial species. Common genera found in the human skin micro-biome include Micrococcus and Staphylococcus, but there only a limited number of tests to differentiate these genera and/or species. My research reflects methods development from distinguishing one closely related genera from another and then expanded to species identification. Tryptic peptides were analyzed by MALDI TOF MS and the mass profiles compared with those of a reference strain in both genus and species identification. Aconitate …

Impact Of Physical Activity In The Prevention Of Colorectal Cancer, Sarah Ashley Barnes

Theses and Dissertations

This review evaluates the current understanding of research on the impact of physical activity in the prevention of colorectal cancer. Current biological mechanisms implicated in physical activity and colorectal cancer risk reduction are blood glucose regulation, insulin sensitivity, leptin and adiponectin profiles, inflammation as well as secreted protein acidic and rich in cysteine (SPARC), an exercise induced myokine. Recent literature indicates that 30-60 minutes of moderate to vigorous activity a day is effective against colorectal cancer development, and there is convincing evidence of aerobic exercise as differently beneficial in recruiting mechanisms identified as preventative against colorectal cancer. This article provides …

Linking Obesity To Colorectal Cancer: Recent Insights Into Plausible Biological Mechanisms, Catherine Guffey

Theses and Dissertations

Obesity has emerged as a leading environmental risk factor for the development of CRC. However, the mechanisms underlying this relationship have not yet been fully explained. Recent literature has focused on 1) inflammatory processes, 2) adipokines, and 3) estrogen. Obesity-enhanced inflammation is largely orchestrated by increases in adipose tissue macrophages leading to the secretion of TNF-alpha, MCP-1, and IL-6, all of which are linked to CRC. Adiponectin is decreased with obesity and has been reported to be negatively associated with CRC, while leptin, which is increased, is positively associated with the disease. Estrogen has been shown to influence CRC, although …

Resveratrol Attenuates The Development Of Trans-Aortic Constriction (Tac) Induced Heart Failure In Mice, Prakash Kumar Gupta

Theses and Dissertations

Heart failure (HF) still remains the leading cause of morbidity and mortality and imposes severe global affliction and enormous cost on the healthcare system. Although current pharmacological therapies have shown to slow down the progression of HF, but seems to have reached their limits in improving overall patient prognosis. Thus, an immediate call for novel alternate therapies are needed which act independently as well as in conjunction with current treatment modality. Studies were performed in the well-established transverse aortic constriction (TAC) model of chronic pressure overload (PO) in mice. In the first series of studies, Male C57BL6 mice (26-28 g) …

Mass Spectrometry And Tandem Mass Spectrometry Characterization Of Protein Patterns, Protein Markers And Whole Proteomes For Pathogenic Bacteria, Jennifer Intelicato-Young

Theses and Dissertations

There have been many recent reviews published on MALDI-TOF MS (matrix assisted laser desorption/ionization time-of-flight) MS (mass spectrometry) for identification of bacteria particularly with relevance to clinical microbiology. MALDI-TOF MS is now a mature technique for bacterial identification with great promise. The purpose of this review is to put into perspective MALDI-TOF MS and other widely used mass spectrometry methods for characterization of proteins. MALDI-TOF MS is used for rapid determination of a mass pattern of proteins for bacterial characterization; these proteins

are generally not identified. Alternatively, after gel separation, MALDI TOF-TOF MSMS (tandem mass spectrometry) or on-line LC-ESI MS-MS …

Turning Stealth Liposomes Into Cationic Liposomes For Anticancer Drug Delivery, Vijay Gyanani

University of the Pacific Theses and Dissertations

Targeting the anticancer agents selectively to cancer cells is desirable to improve the efficacy and to reduce the side effects of anticancer therapy. Previously reported passive tumor targeting by PEGylated liposomes (stealth liposomes) have resulted in their higher tumor accumulation. However their interaction with cancer cells has been minimal due to the steric hindrance of the PEG coating. This dissertation reports two approaches to enhance the interaction of stealth liposomes with cancer cells. First, we designed a lipid-hydrazone-PEG conjugate that removes the PEG coating at acidic pH as in the tumor interstitium. However, such a conjugate was highly unstable on …

(R)-Β-Lysine Modified Elongation Factor P Functions In Translation Elongation, Tammy J. Bullwinkle, S. Betty Zou, Andrei Rajkovic, Steven J. Hersch, Sara Elgamal, Nathaniel Robinson, David Smil, Yuri Bolshan, William Wiley Navarre, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Post-translational modification of bacterial elongation factor P (EF-P) with (R)-β-lysine at a conserved lysine residue activates the protein in vivo and increases puromycin reactivity of the ribosome in vitro. The additional hydroxylation of EF-P at the same lysine residue by the YfcM protein has also recently been described. The roles of modified and unmodified EF-P during different steps in translation, and how this correlates to its physiological role in the cell, have recently been linked to the synthesis of polyproline stretches in proteins. Polysome analysis indicated that EF-P functions in translation elongation, rather than initiation as proposed previously. This was …

Circularized Synthetic Oligodeoxynucleotides Serve As Promoterless Rna Polymerase Iii Templates For Small Rna Generation In Human Cells, Christine I. Seidl, Lodoe Lama, Kevin Ryan

Publications and Research

Synthetic RNA formulations and viral vectors are the two main approaches for delivering small therapeutic RNA to human cells. Here we report findings supporting an alternative strategy in which an endogenous human RNA polymerase (RNAP) is harnessed to make RNA hairpin-containing small RNA from synthetic single-stranded DNA oligonucleotides. We report that circularizing a DNA template strand encoding a pre-microRNA hairpin mimic can trigger its circumtranscription by human RNAP III in vitro and in human cells. Sequence and secondary structure preferences that appear to promote productive transcription are described. The circular topology of the template is required for productive transcription, at …

Applications Of Weak Ion Association Between Symmetrical Tetraalkylammonium Ions And Inorganic Anions, Julius Mbuna

Journal of Humanities and Social Sciences

Interactions between tetraalkylammonium ions and inorganic anions can be used to develop methods of separation for inorganic anions by any separation technique. From the ion association and thermodynamic data, capillary electrophoretic (CE) technique can be easily designed to effect separation of inorganic anions samples. Using CE mode such as capillary zone electrophoresis (CZE) to investigate weak ion association between inorganic anions and the pairing cations also furnishes data to evaluate association theories like Bjerrum’s theory. Findings show that the increase in association constant Kass as the dielectric constant decreased is not exponential as maintained by the Bjerrum’s theory. The increase …

Selection Of Trna Charging Quality Control Mechanisms That Increase Mistranslation Of The Genetic Code, Srujana S. Yadavalli, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Mistranslation can follow two events during protein synthesis: production of non-cognate amino acid:transfer RNA (tRNA) pairs by aminoacyl-tRNA synthetases (aaRSs) and inaccurate selection of aminoacyl-tRNAs by the ribosome. Many aaRSs actively edit non-cognate amino acids, but editing mechanisms are not evolutionarily conserved, and their physiological significance remains unclear. To address the connection between aaRSs and mistranslation, the evolutionary divergence of tyrosine editing by phenylalanyl-tRNA synthetase (PheRS) was used as a model. Certain PheRSs are naturally error prone, most notably a Mycoplasma example that displayed a low level of specificity consistent with elevated mistranslation of the proteome. Mycoplasma PheRS was found …

Neuroanatomical Substrates Of The Disruptive Effect Of Olanzapine On Rat Maternal Behavior As Revealed By C-Fos Immunoreactivity, Changjiu Zhao, Ming Li

Department of Psychology: Faculty Publications

Olanzapine is one of the most widely prescribed atypical antipsychotic drugs in the treatment of schizophrenia. Besides its well-known side effect on weight gain, it may also impair human parental behavior. In this study, we took a preclinical approach to examine the behavioral effects of olanzapine on rat maternal behavior and investigated the associated neural basis using the c-Fos immunohistochemistry. On postpartum Days 6–8, Sprague-Dawley mother rats were given a single injection of sterile water or olanzapine (1.0, 3.0 or 5.0 mg/kg, sc). Maternal behavior was tested 2 h later, after which rats were sacrificed and brain tissues were collected. …

The Morbidity & Mortality Of Prevalent Heart Failure, Jennifer Kwon

Loma Linda University Electronic Theses, Dissertations & Projects

The first study population included 292 unselected consecutive patients from the LLUMC heart failure clinic who were enrolled in the study from January to July 2006 and were followed up through the end of December 2010. The treatment policy at the clinic was to uptitrate dosages of beta-adrenergic blockade (β-blockers), angiotensin-converting-enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) to the most tolerable levels in order to reach target dosages, as recommended by the Heart Failure Society of America (HFSA). Patients were classified into systolic heart failure (ejection fraction (EF) < 40%) or diastolic heart failure (EF≥40%). All dosages of β-blockers, ACEi and ARB were extracted through chart reviews and were used as the main predictors of the patients' survival. Results from analyses showed that reaching target dosages of β-blockers and ACEi/ARB may increase survival when compared to not reaching target among the systolic HF population (HR_{β_biockers}= 0.64, 95% CI 0.26-1.56 and HR_ACEi/ARB=0.50, …

Mrp4 Is A Crucial Regulator Of Testosterone Biosynthesis, Jessica Ann Morgan

Theses and Dissertations (ETD)

The physiological role of multidrug resistance protein 4 (Mrp4) in the testes is unknown. It was discovered that Mrp4 is expressed primarily in mouse and human Leydig cells; however, there is no current evidence that Mrp4 regulates testosterone biosynthesis. The role of Mrp4 was investigated in Leydig cells where testosterone production is regulated by cAMP, an intracellular second messenger formed when the luteinizing hormone (LH) receptor (Lhr) is activated. As Mrp4 regulates cAMP, we compared testosterone levels in our Mrp4 WT and KO mice. Prepubertal KO mice had significantly reduced testicular testosterone, impaired gametogenesis, and disrupted cAMP homeostasis, resulting in …

Sociosexuality, Mate Preferences, And Sex Steroid Hormone Levels Among Breastfeeding Women In Manila, Michelle Escasa

UNLV Theses, Dissertations, Professional Papers, and Capstones

This project investigates the influence of lactation on female sociosexuality and mate preferences in urban Manila, a population with long-term breastfeeding, low contraceptive use, and quick return to ovulatory cycling. Physiological and evolutionary considerations suggest that lactating women face important life history allocation trade-offs between mating and parenting effort that may be manifest in their sociosexual behavior and mate preferences. Breastfeeding (n=155) and control (n=105) women were recruited to provide a saliva sample (for testosterone and estradiol analyses), complete a questionnaire, and complete a face and voice preference task to determine preferences for masculinity. Breastfeeding women reported differences in commitment …

Frictional Forces Of A Fixed, Esthetic Orthodontic Appliance System, Brady Michael Nance

UNLV Theses, Dissertations, Professional Papers, and Capstones

Purpose: The demands of an all esthetic fixed orthodontic appliance system are ever increasing in today's world. Frictional values of an esthetic, fixed orthodontic appliance system are needed to evaluate their clinical effectiveness for orthodontic treatment. The aim of this study is to evaluate the frictional values of various esthetic orthodontic archwires ligated to an esthetic orthodontic bracket.

Methods: Three types of stainless steel and nickel titanium alloy (niti) esthetic orthodontic archwires (epoxy, poly, plastic) in four sizes (.016, .018, .017 x .025, .019 x .025 inches) were ligated to both a stainless steel bracket system and a ceramic (esthetic) …

Pharmacokinetics And Brain Uptake In The Rhesus Monkey Of A Fusion Protein Of Arylsulfatase A And A Monoclonal Antibody Against The Human Insulin Receptor, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui, Rachita K. Sumbria, William M. Pardridge

Pharmacy Faculty Articles and Research

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder of the brain caused by mutations in the gene encoding the lysosomal sulfatase, arylsulfatase A (ASA). It is not possible to treat the brain in MLD with recombinant ASA, because the enzyme does not cross the blood-brain barrier (BBB). In the present investigation, a BBB-penetrating IgG-ASA fusion protein is engineered and expressed, where the ASA monomer is fused to the carboxyl terminus of each heavy chain of an engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, …