Chemicals and Drugs Commons^™

Role Of Caveolin-1 In The Regulation Of The Vascular Shear Stress Response, Philippe G. Frank, Michael P. Lisanti

Department of Cancer Biology Faculty Papers

In blood vessels, endothelia are submitted to constant shear effects and are, under normal conditions, capable of responding to any variation in hemodynamic forces. Caveolae — 50- to 100-nm plasma membrane invaginations present at the surface of terminally differentiated cells and particularly enriched in ECs — are composed of a high sphingolipid and cholesterol content and the protein caveolin-1 (Cav-1). Previous studies have suggested that caveolae and endothelial Cav-1 may regulate the vascular response to altered shear stress. In this issue of the JCI, Yu et al. have examined the role of Cav-1/caveolae in the regulation of flow-induced alterations (i.e., …

Aspartyl-Trna Synthetase Is The Target Of Peptidenucleotide Antibiotic Microcin C, Anastasia Metlitskaya, Teymur Kazakov, Aigar Kommer, Olga Pavlova, Mette Praetorius-Ibba, Michael Ibba, Igor Krasheninnkov, Vyacheslav Kolb, Inessa Khmel, Konstantin Severinov

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Microcin C is a ribosome-synthesized heptapeptide that contains a modified adenosine monophosphate covalently attached to the C-terminal aspartate. Microcin C is a potent inhibitor of bacterial cell growth. Based on the in vivo kinetics of inhibition of macromolecular synthesis, Microcin C targets translation, through a mechanism that remained undefined. Here, we show that Microcin C is a subject of specific degradation inside the sensitive cell. The product of degradation, a modified aspartyl-adenylate containing an N-acylphosphoramidate linkage, strongly inhibits translation by blocking the function of aspartyl-tRNA synthetase.

C To U Editing Stimulates A To I Editing In The Anticodon Loop Of A Cytoplasmic Threonyl Trna In Trypanosoma Brucei, Mary Anne T. Rubio, Frank L. Ragone, Kirk W. Gaston, Michael Ibba, Juan D. Alfonzo

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Editing of tRNAs is widespread in nature and either changes the decoding properties or restores the folding of a tRNA. Unlike the phylogenetically disperse adenosine (A) to inosine (I) editing, cytosine (C) to uridine (U) editing has only been previously described in organellar tRNAs. We have shown that cytoplasmic tRNA^Thr(AGU) undergoes two distinct editing events in the anticodon loop: C to U and A to I. In vivo, every inosine-containing tRNA^Thr is also C to U edited at position 32. In vitro, C to U editing stimulates conversion of A to I at the wobble base. Although …

Linking Ligand-Induced Alterations In Androgen Receptor Structure To Differential Gene Expression: A First Step In The Rational Design Of Selective Androgen Receptor Modulators, Dmitri Kazmin, Tatiana Prytkova, C. Edgar Cook, Russell Wolfinger, Tzu-Ming Chu, David Beratan, J. D. Norris, Ching-Yi Chang, Donald P. Mcdonnell

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful selective AR modulators. To this end, we used combinatorial peptide phage display coupled with molecular dynamic structure analysis to identify the surfaces on AR that are exposed specifically in the presence of selected AR ligands. Subsequently, we …

Methods For The Study Of Signaling Molecules In Membrane Lipid Rafts And Caveolae, Rennolds S. Ostrom, Paul A. Insel

Pharmacy Faculty Articles and Research

Lipid rafts and caveolae are cholesterol- and sphingolipid-rich microdomains of the plasma membrane that concentrate components of certain signal transduction pathways. Interest in and exploration of these microdomains has grown in recent years, especially after the discovery of the biochemical marker of caveolae, caveolin, and the recognition that caveolin interacts with many different signaling molecules via its scaffolding domain. There are three major types of caveolins (1, 2, and 3), with some selectivity in their expression in different tissues. Results assessing lipid raft/caveolae co-localization of molecules in signal transduction pathways have provided support for the idea that signaling components are …

2,6-Hexadecadiynoic Acid And 2,6-Nonadecadiynoic Acid - Novel Synthesized Acetylenic Fatty Acids As Potent Antifungal Agents, Nestor Carballeira, David Sanabria, Clarisa Cruz, Keykavous Parang, Baojie Wan, Scott Franzblau

Pharmacy Faculty Articles and Research

The hitherto unknown 2,6-hexadecadiynoic acid, 2,6-nonadecadiynoic acid, and 2,9-hexadecadiynoic acid were synthesized in two steps and in 11–18% overall yields starting from either 1,5-hexadiyne or 1,8-nonadiyne. Among all the compounds 2,6-hexadecadiynoic acid displayed the best overall antifungal activity against both the fluconazole resistant Candida albicans strains ATCC 14053 and ATCC 60193 (MIC = 11 μM) and against Cryptococcus neoformans ATCC 66031 (MIC < 5.7 μM). The 2,9-hexadecadiynoic acid did not display any significant cytotoxicity against the fluconazole resistant C. albicans strains, but it showed fungitoxicity against C. neoformans ATCC 66031 with a MIC value of <5.8 μM. Other fatty acids, such as 2-hexadecynoic acid, 5-hexadecynoic acid, 9-hexadecynoic acid, and 6-nonadecynoic acid were also synthesized and their antifungal activities compared. The 2-hexadecynoic acid, a known antifungal fatty acid, exhibited the best antifungal activity (MIC = 9.4 μM) against the fluconazole resistant C. albicans ATCC 14053 strain, but it showed a MIC value of only 100 μM against C. albicans ATCC 60193. The fatty acids 2,6-hexadecadiynoic acid and 2-hexadecynoic acid also displayed a MIC of 140–145 μM towards Mycobacterium tuberculosis H37Rv in Middlebrook 7H12 medium. In conclusion, 2,6-hexadecadiynoic acid exhibited the best fungitoxicity profile compared to other analogues. This diynoic fatty acid has the potential to be further evaluated for use in topical antifungal formulations.

Loss Of Editing Activity During The Evolution Of Mitochondrial Phenylalanyl-Trna Synthetase, Hervé Roy, Jiqiang Ling, Juan D. Alfonzo, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Accurate selection of amino acids is essential for faithful translation of the genetic code. Errors during amino acid selection are usually corrected by the editing activity of aminoacyl-tRNA synthetases such as phenylalanyl-tRNA synthetases (PheRS), which edit misactivated tyrosine. Comparison of cytosolic and mitochondrial PheRS from the yeast Saccharomyces cerevisiae suggested that the organellar protein might lack the editing activity. Yeast cytosolic PheRS was found to contain an editing site, which upon disruption abolished both cis and trans editing of Tyr-tRNA^Phe. Wild-type mitochondrial PheRS lacked cis and trans editing and could synthesize Tyr-tRNA^Phe, an activity enhanced in …

Urotensin Ii Modulates Rapid Eye Movement Sleep Through Activation Of Brainstem Cholinergic Neurons, Salvador Huitron-Resendiz, Morten P. Kristensen, Stephen L. Grupke, Christopher Tyler, Olivier Civelli, Christopher S. Leonard, Luis De Lecea

NYMC Faculty Publications

Urotensin II (UII) is a cyclic neuropeptide with strong vasoconstrictive activity in the peripheral vasculature. UII receptor mRNA is also expressed in the CNS, in particular in cholinergic neurons located in the mesopontine tegmental area, including the pedunculopontine tegmental (PPT) and lateral dorsal tegmental nuclei. This distribution suggests that the UII system is involved in functions regulated by acetylcholine, such as the sleep-wake cycle. Here, we tested the hypothesis that UII influences cholinergic PPT neuron activity and alters rapid eye movement (REM) sleep patterns in rats. Local administration of UII into the PPT nucleus increases REM sleep without inducing changes …

Specific Functions Of Synaptically Localized Potassium Channels In Synaptic Transmission At The Neocortical Gabaergic Fast-Spiking Cell Synapse, Ethan Goldberg, Shigeo Watanabe, Su Ying Chang, Rolf Joho, Z Josh Huang, Christopher S. Leonard, Bernardo Rudy

NYMC Faculty Publications

Potassium (K+) channel subunits of the Kv3 subfamily (Kv3.1-Kv3.4) display a positively shifted voltage dependence of activation and fast activation/deactivation kinetics when compared with other voltage-gated K+ channels, features that confer on Kv3 channels the ability to accelerate the repolarization of the action potential (AP) efficiently and specifically. In the cortex, the Kv3.1 and Kv3.2 proteins are expressed prominently in a subset of GABAergic interneurons known as fast-spiking (FS) cells and in fact are a significant determinant of the fast-spiking discharge pattern. However, in addition to expression at FS cell somata, Kv3.1 and Kv3.2 proteins also are expressed prominently at …

Association Between Archaeal Prolyl- And Leucyl-Trna Synthetases Enhances TrnaPro Aminoacylation, Mette Praetorius-Ibba, Theresa E. Rogers, Rachel Samson, Zvi Kelman, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Aminoacyl-tRNA synthetase-containing complexes have been identified in different eukaryotes, and their existence has also been suggested in some Archaea. To investigate interactions involving aminoacyl-tRNA synthetases in Archaea, we undertook a yeast two-hybrid screen for interactions between Methanothermobacter thermautotrophicus proteins using prolyl-tRNA synthetase (ProRS) as the bait. Interacting proteins identified included components of methanogenesis, protein-modifying factors, and leucyl-tRNA synthetase (LeuRS). The association of ProRS with LeuRS was confirmed in vitro by native gel electrophoresis and size exclusion chromatography. Determination of the steady-state kinetics of tRNA^Pro charging showed that the catalytic efficiency (k_cat/K_m) of ProRS increased 5-fold …

Defensin In The Ticks Dermacentor Variabilis And Ixodes Scapularis, Shane Michael Ceraul

Theses and Dissertations in Biomedical Sciences

This dissertation presents the identification, molecular structure and expression of defensin, an antimicrobial peptide, in the ticks, Dermacentor variabilis and Ixodes scapularis. A 624 bp cDNA molecule for defensin was cloned and sequenced from hemocytes, fat body and midgut of unstimulated D. variabilis ticks. Defensin peptide was detected only in the hemocyte lysates. These results suggest that the defensin from D. variabilis is synthesized and stored in the hemocytes, although the role of other tissues is not excluded.

The ability of the juvenile stage ticks to express the defensin gene was confirmed. Detection of the defensin transcript in all …

Quality Control During Aminoacyl-Trna Synthesis, M. Praetorius-Ibba, S. Ataide, C. Hausmann, J. Levengood, J. Ling, S. Wang, H. Roy, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The fidelity of translation is determined at two major points: the accuracy of aminoacyl-tRNA selection by the ribosomes and synthesis of cognate amino acid/tRNA pairs by aminoacyl-tRNA synthetases (aaRSs) in the course of the aminoacylation reaction. The most important point in aminoacylation is the accurate recognition of cognate substrates coupled with discrimination of non-cognates. While this is generally accomplished by a single enzyme, we have recently found that discrimination against lysine analogues requires the existence of two unrelated lysyl-tRNA synthetases. For other amino acids, initial recognition is not sufficiently accurate with errors being corrected by an intrinsic editing activity. Recent …

Mouse Cytomegalovirus M33 Is Necessary And Sufficient In Virus-Induced Vascular Smooth Muscle Cell Migration, Ryan Melnychuk, Patsy Smith, Craig N. Kreklywich, Franziska Ruchti, Jennifer Totonchy, Laurel Hall, Lambert Loh, Jay A. Nelson, Susan L. Orloff, Daniel N. Streblow

Pharmacy Faculty Articles and Research

Mouse cytomegalovirus (MCMV) encodes two potential seven-transmembrane-spanning proteins with homologies to cellular chemokine receptors, M33 and M78. While these virus-encoded chemokine receptors are necessary for the in vivo pathogenesis of MCMV, the function of these proteins is unknown. Since vascular smooth muscle cell (SMC) migration is of critical importance for the development of atherosclerosis and other vascular diseases, the ability of M33 to promote SMC motility was assessed. Similar to human CMV, MCMV induced the migration of mouse aortic SMCs but not mouse fibroblasts. To demonstrate whether M33 was required for MCMV-induced SMC migration, we employed interfering-RNA technology to specifically …

Enterotoxin B Subunit Lectins As Adjuvants For Improvement Of Mucosal Vaccine, Nak-Won Choi

Loma Linda University Electronic Theses, Dissertations & Projects

In comparison with whole organism vaccines, subunit vaccines may be safer for immunization but may lack sufficient immunogenicity to provide complete immunity to the pathogen. To resolve this problem, bacterial and plant enterotoxin B subunit adjuvants containing a variety of receptor-binding properties were used to enhance the immunogenicity of rotavirus subunit vaccines. Enterotoxin B subunit adjuvants were employed to enhance protection against virus infection. Pentameric cholera toxin B subunit (CTB), shiga toxin-1 B subunit (STB) and monomeric ricin toxin B subunit (RTB) molecules were genetically linked to a 90 amino acid peptide from the simian rotavirus (SA11) nonstructural protein NSP4 …

The Potential Role Of Ledgf/P75 In Prostate Cancer, Tracy Ruth Daniels

Loma Linda University Electronic Theses, Dissertations & Projects

The serum autoantibody repertoire from cancer patients is currently being exploited for the identification of tumor associated antigens (TAA) and the design of TAA arrays. Such arrays would facilitate autoantibody profiling and potentially aid in the serological diagnosis and prognosis of tumors. The goal of this study was to identify and characterize prostate-specific TAA. We observed that while the general frequency and titers of autoantibodies in PCa patients were relatively similar to those in matched controls, significant differences could be detected between the two groups in the autoantibody response to the lens epithelial-derived growth factor p75 (LEDGF/p75). LEDGF/p75 is a …

Photoreactive Bicyclic Amino Acids As Substrates For Mutant Escherichia Coli Phenylalanyl-Trna Synthetases, Thomas Bentin, Ramin Hamzavi, Jahan Salomonsson, Hervé Roy, Michael Ibba, Peter E. Nielsen

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Unnatural amino acids carrying reactive groups that can be selectively activated under non-invasive biologically benign conditions are of interest in protein engineering as biological tools for the analysis of protein-protein and protein-nucleic acids interactions. The double ring system phenylalanine analogues benzofuranylalanine and benzotriazolylalanine were synthesized, and their photolability was tested by UV irradiation at 254, 320, and 365 nm. Although both showed photo reactivity, benzofuranylalanine appeared as the most promising compound because this amino acid was activated by UVA (long wavelength) irradiation. These amino acids were also tested for in vitro charging of tRNA^Phe and for protein mutagenesis via …

Divergence In Non-Cognate Amino Acid Recognition Between Class I And Class Ii Lysyl-Trna Synthetases, Jeffrey D. Levengood, Sandro F. Ataide, Hervé Roy, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Lysine insertion during coded protein synthesis requires lysyl-tRNA^Lys, which is synthesized by lysyl-tRNA synthetase (LysRS). Two unrelated forms of LysRS are known: LysRS2, which is found in eukaryotes, most bacteria, and a few archaea, and LysRS1, which is found in most archaea and a few bacteria. To compare amino acid recognition between the two forms of LysRS, the effects of l-lysine analogues on aminoacylation were investigated. Both enzymes showed stereospecificity toward the l-enantiomer of lysine and discriminated against noncognate amino acids with different R-groups (arginine, ornithine). Lysine analogues containing substitutions at other positions were generally most effective as …

Nitric Oxide Inhibition Of Adenylyl Cyclase Type 6 Activity Is Dependent Upon Lipid Rafts And Caveolin Signaling Complexes, Rennolds S. Ostrom, Richard A. Bundey, Paul A. Insel

Pharmacy Faculty Articles and Research

Several cell types, including cardiac myocytes and vascular endothelial cells, produce nitric oxide (NO) via both constitutive and inducible isoforms of NO synthase. NO attenuates cardiac contractility and contributes to contractile dysfunction in heart failure, although the precise molecular mechanisms for these effects are poorly defined. Adenylyl cyclase (AC) isoforms type 5 and 6, which are preferentially expressed in cardiac myocytes, may be inhibited via a direct nitrosylation by NO. Because endothelial NO synthase (eNOS and NOS3), β-adrenergic ( AR) receptors, and AC6 all can localize in lipid raft/caveolin-rich microdomains, we sought to understand the role of lipid rafts in …

The Evolving Role Of Lipid Rafts And Caveolae In G Protein-Coupled Receptor Signaling: Implications For Molecular Pharmacology, Rennolds S. Ostrom, Paul A. Insel

Pharmacy Faculty Articles and Research

The many components of G-protein-coupled receptor (GPCR) signal transduction provide cells with numerous combinations with which to customize their responses to hormones, neurotransmitters, and pharmacologic agonists. GPCRs function as guanine nucleotide exchange factors for heterotrimeric (α, β, γ) G proteins, thereby promoting exchange of GTP for GDP and, in turn, the activation of ‘downstream’ signaling components. Recent data indicate that individual cells express mRNA for perhaps over 100 different GPCRs (out of a total of nearly a thousand GPCR genes), several different combinations of G-protein subunits, multiple regulators of G-protein signaling proteins (which function as GTPase activating proteins), and various …

Aminoacyl-Trnas: Setting The Limits Of The Genetic Code, Michael Ibba, Dieter Söll

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Aminoacyl-tRNAs (aa-tRNAs) are simple molecules with a single purpose—to serve as substrates for translation. They consist of mature tRNAs to which an amino acid has been esterified at the 3′-end. The 20 different types of aa-tRNA are made by the 20 different aminoacyl-tRNA synthetases (aaRSs, of which there are two classes), one for each amino acid of the genetic code (Ibba and Söll 2000). This would be fine if it were not for the fact that such a straightforward textbook scenario is not true in a single known living organism. aa-tRNAs lie at the heart of gene expression; they interpret …

Phosphoproteomic Studies Of Smooth Muscle Contraction: Investigation Of Differential Phosphorylation In Relaxed/Contracted Rat Aortic Smooth Muscle Tissue Using Maldi-Tof Ms, Tonya M. Pekar

Theses, Dissertations and Capstones

Many human disorders are associated with the malfunction of smooth muscle tissue, or are related to the capabilities of its proper function—asthma, glaucoma, renal inefficiency, hypertension, and cardiovascular disease. Dysfunctional proteins are frequently implicated as the source of such disorders. As the second highest cause of death in the United States, the epidemic of cardiovascular disease makes the study of smooth muscle of utmost concern.

The capabilities of proteomics and mass spectrometry allow the entire proteome complement of a cell or tissue type to be analyzed at once. This investigation employs such techniques in an effort to better understand the …

Hypertonic Stress Co-Stimulates T Cell Il-2 Expression Through A Feedback Mechanism Involving Atp Release And P2 Receptor Activation Of P38 Map Kinase, William H. Loomis, Sachiko Namiki, Rennolds S. Ostrom, Paul A. Insel, Wolfgang G. Junger

Pharmacy Faculty Articles and Research

Hypertonic stress (HS) can alter the function of mammalian cells. We have reported that HS enhances differentiated responses of T cells by increasing their ability to produce interleukin (IL)-2, a finding of clinical interest because hypertonic infusions may modulate immune function in patients. HS shrinks cells and mechanically deforms membranes, which results in ATP release from many cell types. Here we investigate if ATP release is an underlying mechanism through which HS augments T cell function. We found that mechanical stress and HS induced rapid ATP release from Jurkat T cells. HS and exogenous ATP mobilized intracellular Ca2+, activated p38 …

Determination Of The Substrate-Docking Site Of Protein Tyrosine Kinase C-Terminal Src Kinase, Sungsoo Lee, Xiaofeng Lin, Nguyen Hai Nam, Keykavous Parang, Gongqin Sun

Pharmacy Faculty Articles and Research

Protein tyrosine kinases (PTK) are key enzymes of mammalian signal transduction. For the fidelity of signal transduction, each PTK phosphorylates only one or a few proteins on specific Tyr residues. Substrate specificity is thought to be mediated by PTK–substrate docking interactions and recognition of the phosphorylation site sequence by the kinase active site. However, a substrate-docking site has not been determined on any PTK. C-terminal Src kinase (Csk) is a PTK that specifically phosphorylates Src family kinases on a C-terminal Tyr. In this study, by sequence alignment and site-specific mutagenesis, we located a substrate-docking site on Csk. Mutations in the …

Angiotensin Ii Enhances Adenylyl Cyclase Signaling Via Ca2+/Calmodulin. Gq-Gs Cross-Talk Regulates Collagen Production In Cardiac Fibroblasts, Rennolds S. Ostrom, Jennifer E. Naugle, Miki Hase, Caroline Gregorian, James S. Swaney, Paul A. Insel, Laurence L. Brunton, J. Gary Meszaros

Pharmacy Faculty Articles and Research

Cardiac fibroblasts regulate formation of extracellular matrix in the heart, playing key roles in cardiac remodeling and hypertrophy. In this study, we sought to characterize cross-talk between Gq and Gs signaling pathways and its impact on modulating collagen synthesis by cardiac fibroblasts. Angiotensin II (ANG II) activates cell proliferation and collagen synthesis but also potentiates cyclic AMP (cAMP) production stimulated by β-adrenergic receptors (β-AR). The potentiation of β-AR-stimulated cAMP production by ANG II is reduced by phospholipase C inhibition and enhanced by overexpression of Gq. Ionomycin and thapsigargin increased intracellular Ca2+ levels and potentiated isoproterenol- and forskolin-stimulated cAMP production, whereas …

Human Cytomegalovirus Chemokine Receptor Us28-Induced Smooth Muscle Cell Migration Is Mediated By Focal Adhesion Kinase And Src, Daniel N. Streblow, Jennifer Totonchy, Patsy Smith, Ryan Melnychuk, Laurel Hall, Dora Pancheva, Martine Smit, Paola Casarosa, David D. Schlaepfer, Jay A. Nelson

Pharmacy Faculty Articles and Research

The human cytomegalovirus-encoded chemokine receptor US28 induces arterial smooth muscle cell (SMC) migration; however, the underlying mechanisms involved in this process are unclear. We have previously shown that US28-mediated SMC migration occurs by a ligand-dependent process that is sensitive to proteintyrosine kinase inhibitors. We demonstrate here that US28 signals through the non-receptor protein-tyrosine kinases Src and focal adhesion kinase (FAK) and that this activity is necessary for US28-mediated SMC migration. In the presence of RANTES (regulated on activation normal T cell expressed and secreted), US28 stimulates the production of a FAK Src kinase complex. Interestingly, Src co-immunoprecipitates with US28 in …

Il-10 And Alveolar Bone Loss, Abdulaziz Saud Al-Rasheed

Loma Linda University Electronic Theses, Dissertations & Projects

Interleukin-10 (IL-10) is a cytokine with anti-inflammatory activities. IL-10 knockout (KO) mice exhibit severe intestinal inflammation in the presence of normal gut flora. We hypothesized that IL-10 KO mice would also be susceptible to inflammatory periodontal disease resulting in alveolar bone loss (ABL). The purpose of this study was to compare naturally occurring ABL in IL-10 KO and wild type (WT) mice. Twelve IL-10 KO and 12 WT mice, age-(7 months) and sex-(male) matched, were used. Half of the mice were on 129/SvEv and half on C57BL/6J background. Animal heads were defleshed and treated to remove all organic material. ABL …

Protein-Protein Interactions And Muscle Cell Signaling Via Syntrophin, Shilpa A. Oak

Theses and Dissertations (ETD)

Absence of dystrophin results in Duchenne muscular dystrophy (DMD), a lethal neuromuscular d isorder that afflicts 1 in 3500 live male births. In the sarcolemma, dystrophin is associated with a complex of proteins and glycoproteins, known as the dystrophin glycoprotein complex. The DGC constituents are dystrophin, a-dys troglycan, b-dystroglycan, syntrophin, a-sarcoglycan, b-sarcoglycan, g-sarcoglycan, d-sarcoglycan, and sarcospan. Not al l of these are single protein species. The syntrophins consists of a group of three homologous proteins composed of acidic (a) and basic (b) components. Syntrophins are known to self-associate to form oligomers.

In this dissertation, syntrophin's oligomerization and its interactions with …

Direct And Indirect Excitation Of Laterodorsal Tegmental Neurons By Hypocretin/Orexin Peptides: Implications For Wakefulness And Narcolepsy, Sophie Burlet, Christopher Tyler, Christopher S. Leonard

NYMC Faculty Publications

Compelling evidence links the recently discovered hypothalamic peptides Hypocretin/Orexin (Hcrt/Orx) to rapid eye movement sleep (REM) control and the sleep disorder narcolepsy, yet how they influence sleep-related systems is not well understood. We investigated the action of Hcrt/Orx on mesopontine cholinergic (MPCh) neurons of the laterodorsal tegmental nucleus (LDT), a target group whose function is altered in canine narcolepsy and appears pivotal for normal REM and wakefulness. Extracellular recordings from mouse brainstem slices revealed that Hcrt/Orx evoked prolonged firing of LDT neurons. Whole-cell recordings revealed that Hcrt/Orx had actions on both presynaptic neurons and at postsynaptic sites. Hcrt/Orx produced an …

A Mechanistic Study Of Myoglobin Nephrotoxicity, Jennifer L. Minigh

Theses, Dissertations and Capstones

Myoglobin is an endogenous protein that can become nephrotoxic under certain conditions such as crush injuries, drug overdose, and seizures where prolonged contraction of muscle leads to cell death and leakage of myoglobin. The mechanism of myoglobin-induced nephrotoxicity is not fully understood. The purpose of this study was to characterize the sequence and mechanistic events associated with the in vitro toxicity of myoglobin in renal cortical slices. Renal tissue was isolated from Fischer 344 rats. Slices of renal cortex were prepared by freehand. These slices were then incubated for 60-180 minutes with myoglobin (0-12 mg/mL) pretreated with 4 mM ascorbic …

Effects Of A Serine 364 To Proline Mutation Of The Connexin43 Protein In Transgenic Mice, Chia-Ling Nhan-Chang

Loma Linda University Electronic Theses, Dissertations & Projects

[Abstract Not Included]