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Characterization Of Human Immunodeficiency Virus Type 1 Monomeric And Trimeric Gp120 Glycoproteins Stabilized In The Cd4-Bound State: Antigenicity, Biophysics, And Immunogenicity, Barna Dey, Marie Pancera, Krisha Svehla, Yuuei Shu, Shi-Hua Xiang, Jeffrey Vainshtein, Yuxing Li, Joseph Sodroski, Peter D. Kwong, John R. Mascola, Richard Wyatt

Nebraska Center for Virology: Faculty Publications

The human immunodeficiency virus type 1 exterior gp120 envelope glycoprotein is highly flexible, and this flexibility may contribute to the inability of monomeric gp120 immunogens to elicit broadly neutralizing antibodies. We previously showed that an S375W modification of a critical interfacial cavity central to the primary receptor binding site, the Phe43 cavity, stabilizes gp120 into the CD4-bound state. However, the immunological effects of this cavity-altering replacement were never tested. Subsequently, we screened other mutations that, along with the S375W alteration, might further stabilize the CD4-bound state. Here, we define a selected second cavity-altering replacement, T257S, and analyze the double mutations …

Georgeoral Immunization Of Rhesus Macaques With Adenoviral Hiv Vaccines Using Enteric-Coated Capsules, George T. Mercier, Pramod N. Nehete, Marco F. Passeri, Bharti N. Nehete, Eric A. Weaver, Nancy Smyth Templeton, Kimberly Schluns, Stephanie S. Buchl, K. Jagannadha Sastry, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Targeted delivery of vaccine candidates to the gastrointestinal (GI) tract holds potential for mucosal immunization, particularly against mucosal pathogens like the human immunodeficiency virus (HIV). Among the different strategies for achieving targeted release in the GI tract, namely the small intestine, pH sensitive enteric coating polymers have been shown to protect solid oral dosage forms from the harsh digestive environment of the stomach and dissolve relatively rapidly in the small intestine by taking advantage of the luminal pH gradient. We developed an enteric polymethacrylate formulation for coating hydroxy-propyl-methyl-cellulose (HPMC) capsules containing lyophilized Adenoviral type 5 (Ad5) vectors expressing HIV-1 gag …

Multiphoton Response Of Retinal Rod Photoreceptors, Vasilios Alexiades, Harihar Khanal

Publications

Phototransduction is the process by which light is converted into an electrical response in retinal photoreceptors. Rod photoreceptors contain a stack of (about 1000) disc membranes packed with photopigment rhodopsin molecules, which absorb the photons. We present computational experiments which show the profound effect on the response of the distances (how many discs apart) photons happen to be absorbed at. This photon-distribution effect alone can account for much of the observed variability in response.

The Quantitative Genetics Of Neurodevelopment: A Magnetic Resonance Imaging Study Of Childhood And Adolescence, James Eric Schmitt

Theses and Dissertations

Understanding the causes of individual differences in brain structure may give clues about the etiology of cognition, personality, and psychopathology, and also may identify endophenotypes for molecular genetic studies on brain development. We performed a comprehensive statistical genetic study of anatomic neuroimaging data from a large pediatric sample (N=600+) of twins and family members from the Child Psychiatry Branch at the NIMH. These analyses included variance decomposition of structural volumetric endophenotypes at several levels of resolution, voxel-level analysis of cortical thickness, assessment of gene by age interaction, several multivariate genetic analyses, and a search for genetically-mediated brain-behavioral relationships. These analyses …

The Endogenous Cannabinoid Anandamide Inhibits Cromakalim-Activated K+ Currents In Follicle-Enclosed Xenopus Oocytes, Murat Oz, Keun-Hang Susan Yang, Meral Dinc, Toni S. Shippenberg

Mathematics, Physics, and Computer Science Faculty Articles and Research

The effect of the endogenous cannabinoid anandamide on K+ currents activated by the ATP-sensitive potassium (KATP) channel opener cromakalim was investigated in follicle-enclosed Xenopus oocytes using the two-electrode voltage-clamp technique. Anandamide (1–90 μM) reversibly inhibited cromakalim-induced K+ currents, with an IC50 value of 8.1 ± 2 μM. Inhibition was noncompetitive and independent of membrane potential. Coapplication of anandamide with the cannabinoid type 1 (CB1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR 141716A) (1 μM), the CB2 receptor antagonist N-[(1S)endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) (1 μM), or pertussis toxin (5 μg/ml) did not alter the inhibitory effect of anandamide, suggesting that known cannabinoid receptors …

Molecular Mechanisms Of Olfactory Neurodegeneration, Radhika Anand Vaishnav

University of Kentucky Doctoral Dissertations

Olfactory sensory decline has been associated with normal aging as well as neurodegenerative disorders, yet the underlying mechanisms are unclear. The overall aim of this dissertation was to investigate the fundamental molecular and cellular mechanisms associated with olfactory neurodegeneration. This investigation uses an integrative approach, combining proteomics and gene expression analyses with cellular and tissuelevel characterization. Using these approaches, two model systems were investigated: 1) normally aging C57BL/6 mice of ages 1.5-, 6- and 20-months; and 2) a mouse model of elevated endogenous oxidative stress-associated neurodegeneration, namely, the Harlequin mutant mouse. The first specific aim was to test the hypothesis …

Clarification Of Basal Relationships In Rubus (Rosaceae) And The Origin Of Rubus Chamaemorus, Karen Michael

Masters Theses & Specialist Projects

Determination of phylogenetic relationships among ancestral species of Rubus has been elusive. Most Rubus species (including blackberries and raspberries), representing nine of the 12 subgenera, occur in a large, well supported clade named 'A' for reference). The remaining nine species are excluded from this group and represent three subgenera: subg. Anoplobatus (R. bartonianus, R. deliciosus, R. neomexicanus, R. odoratus, R. parviflorus, R. trilobus), subg. Chamaemorus (R. chamaemorus), and subg. Dalibarda (R. lasiococcus, R.pedatus). In addition, Rubus dalibarda L. is often treated in its own monotypic genus as Dalibarda repens L. Phylogenetic analyses of DNA sequence data from chloroplast regions and …

Narcotic Analgesics For Acute Migraine In The Emergency Room: Are We Meeting Headache Societies' Guidelines?, Mohammad Wasay, Khawaja Slaman Zaki, Saqib Uddin Khan, Rifat Rehmani

Department of Emergency Medicine

We analysed 161 patients with acute migraine in our emergency room (ER) to identify the use of narcotic analgesics as first-line treatment. Twenty-four percent of patients were treated with opioid analgesics and 76% patients were treated with non-opioid analgesics. Pain was completely relieved in 100 (62%) patients, partially relieved in 50 (31%) patients and was not relieved in 11 (7%) patients at the time of discharge. Pain relief was not related to the use of opioids vs. non-opioids. The treatment of acute migraine in our ER is in line with the guidelines of the Headache Societies and needs further improvement.

An In Vitro Model Of Ovarian Cancer: Studying The Effects Of Talc And Pycnogenol®, Amber Renée Buz'zard

Loma Linda University Electronic Theses, Dissertations & Projects

Ovarian cancer is the sixth most common cancer and accounts for more deaths than any other cancer of the female reproductive system. The American Cancer Society has suggested that poor diet, talc and industrial pollutants may increase the risk of developing ovarian cancer. Talc is ubiquitous and concern is raised about its safety, role as a possible carcinogen and known ability to cause irritation and inflammation. Due to the silent nature of ovarian cancer, chemoprevention is a high priority. The most useful chemopreventive compounds will inhibit, delay or reverse carcinogenesis, and can be taken for long periods of time with …

Chemoprevention Of Breast Cancer For Women At Hgh Risk, Kathryn Chan, Gloria J. Morris

Department of Medicine Faculty Papers

Breast cancer remains the second most common cause of cancer death in the United States. Several studies have identified cohorts of women at higher than average risk to develop this disease. These are women who are exposed to high levels of endogenous or exogenous estrogens, those with a family history of breast cancer, and those who harbor benign breast disease or genetic mutations that predispose to breast cancer. In this population group, adapting a chemoprevention strategy to decrease the risk of developing overt disease is a strong consideration. To this end, tamoxifen is the most accepted agent to date. This …

Biomolecular Tuning Of Electronic Transport Properties Of Carbon Nanotubes Via Antibody Functionalization, Kasif Teker, Dr. Eric Wickstrom, Balaji Panchapakesan

Department of Biochemistry and Molecular Biology Faculty Papers

Carbon nanotubes (CNTs) are remarkable solidstate nanomaterials due to their unique electrical and mechanical properties. The electronic properties of nanotubes combined with biological molecules such as proteins could make miniature devices for biological sensing applications. In this paper, the noncovalent interaction of single-wall CNTs with antibodies is presented for its potential applications for detecting overexpressed cell surface receptors in breast cancer cells. The degree of binding of antibodies on CNTs was found to be more than 80% for an extended sampling area by confocal microscopy. The key to achieve such high degree of functionalization is due to the separation of …

Combined Effects Of Aldehyde Dehydrogenase Variants And Maternal Mitochondrial Genes On Alcohol Consumption, Yedy Israel, Maria E. Quintanilla, Amalia Sapag, Lutske Tampier

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Two lines of rats bred to differ in their voluntary alcohol consumption — the alcohol-abstaining UChA rats and the alcohol-drinking UChB rats — differ in how effectively toxic acetaldehyde is removed during alcohol metabolism. UChB animals carry efficient variants of the aldehyde dehydrogenase 2 (ALDH2) genes and have active mitochondria, resulting in fast removal of acetaldehyde. UChA animals, in contrast, carry less efficient ALDH2 variants and less active mitochondria, which result in transient elevations of acetaldehyde levels after alcohol ingestion. Cross-breeding studies have demonstrated that the presence of active mitochondria inherited from UChB females can fully abolish the reduction of …

Multiple Domains In Siz Sumo Ligases Contribute To Substrate Selectivity., Alison Reindle, Irina Belichenko, Gwendolyn R Bylebyl, Xiaole L Chen, Nishant Gandhi, Erica S Johnson

Department of Biochemistry and Molecular Biology Faculty Papers

Saccharomyces cerevisiae contains two Siz/PIAS SUMO E3 ligases, Siz1 and Siz2/Nfi1, and one other known ligase, Mms21. Although ubiquitin ligases are highly substrate-specific, the degree to which SUMO ligases target distinct sets of substrates is unknown. Here we show that although Siz1 and Siz2 each have unique substrates in vivo, sumoylation of many substrates can be stimulated by either protein. Furthermore, in the absence of both Siz proteins, many of the same substrates are still sumoylated at low levels. Some of this residual sumoylation depends on MMS21. Siz1 targets its unique substrates through at least two distinct domains. Sumoylation of …

Soluble Amyloid Oligomers Increase Bilayer Conductance By Altering Dielectric Structure, Yuri Sokolov, J. Ashot Kozak, Rakez Kayed, Alexandr Chanturiya, Charles G. Glabe, James E. Hall

Neuroscience, Cell Biology & Physiology Faculty Publications

The amyloid hypothesis of Alzheimer's toxicity has undergone a resurgence with increasing evidence that it is not amyloid fibrils but a smaller oligomeric species that produces the deleterious results. In this paper we address the mechanism of this toxicity. Only oligomers increase the conductance of lipid bilayers and patch-clamped mammalian cells, producing almost identical current-voltage curves in both preparations. Oligomers increase the conductance of the bare bilayer, the cation conductance induced by nonactin, and the anion conductance induced by tetraphenyl borate. Negative charge reduces the sensitivity of the membrane to amyloid, but cholesterol has little effect. In contrast, the area …

Antimicrobial Effects Of Liquid Anesthetic Isoflurane On Candida Albicans, Viachaslau M. Barodka, Edward Acheampong, Garry Powell, Ludmilla Lobach, David A. Logan, Zahida Parveen, Valerie Armstead, Muhammad Mukhtar

Department of Medicine Faculty Papers

Candida albicans is a dimorphic fungus that can grow in yeast morphology or hyphal form depending on the surrounding environment. This ubiquitous fungus is present in skin and mucus membranes as a potential pathogen that under opportunistic conditions causes a series of systemic and superficial infections known as candidiasis, moniliasis or simply candidiasis. There has been a steady increase in the prevalence of candidiasis that is expressed in more virulent forms of infection. Although candidiasis is commonly manifested as mucocutaneous disease, life-threatening systemic invasion by this fungus can occur in every part of the body. The severity of candidal infections …

Foreign Body In The Esophagus: A Review, Omer Ashraf

Medical College Documents

Foreign body in the esophagus is a common emergency presentation. The approach towards a patient with a foreign body in the esophagus comprises a thorough history and systematic examination followed by relevant investigations. However, there is considerable debate over the most appropriate treatment option for such patients. This review aims to develop a comprehensive approach towards patients presenting with foreign body ingestion by developing clinical practice guidelines. These guidelines address not only the initial evaluation of the patient but also the various management alternatives and their advantages, limitations and applicability in various scenarios, based upon a review of the literature.

Bibliography Of Secondary Sources On The History Of Dermatology Iii. Books, Monographs, And Chapters In English Supplemented Through 2005., Lawrence Charles Parish, John Thorne Crissey, Jennifer L Parish, Daniel H Parish

Department of Dermatology and Cutaneous Biology Faculty Papers

Providing supplements to the history of dermatology bibliographic record has been a continuous project for the past four decades. When the endeavor was initiated, the original authors decided that only contributions in English and those directly related to dermatology, excluding sexually transmitted diseases as such, would be indexed.

There is the perennial question of whether such a manually created bibiliographic project has a need. The obvious answer remains yes. While Index Medicus has expanded the number of journals that are indexed, the number of dermatology publications currently included by Index Medicus is just over fifty. Granted, most of the papers …

The Role Of Mapks In B Cell Receptor-Induced Down-Regulation Of Egr-1 In Immature B Lymphoma Cells, Jiyuan Ke, Murali Gururajan, Anupam Kumar, Alan Simmons, Lilia Turcios, Ralph Lakshman Chelvarajan, David M. Cohen, David L. Wiest, John G. Monroe, Subbarao Bondada

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Cross-linking of the B cell receptor (BCR) on the immature B lymphoma cell line BKS-2 induces growth inhibition and apoptosis accompanied by rapid down-regulation of the immediate-early gene egr-1. In these lymphoma cells, egr-1 is expressed constitutively and has a prosurvival role, as Egr-1-specific antisense oligonucleotides or expression of a dominant-negative inhibitor of Egr-1 also prevented the growth of BKS-2 cells. Moreover, enhancement of Egr-1 protein with phorbol 12-myristate 13-acetate or an egr-1 expression vector rescued BKS-2 cells from BCR signal-induced growth inhibition. Nuclear run-on and mRNA stability assays indicated that BCR-derived signals act at the transcriptional level to …

Neuromechanics Of Multifunctionality During Rejection In Aplysia Californica, Hui Ye, Douglas W. Morton, Hillel J. Chiel

Faculty Scholarship

How are the same muscles and neurons used to generate qualitatively different behaviors? We studied this question by analyzing the biomechanical and neural mechanisms of rejection responses in the marine mollusk Aplysia californica and compared these mechanisms with those used to generate swallowing responses (Ye et al., 2006). During rejection, the central grasper of the feeding structure closes to push inedible food out of the buccal cavity. This contrasts with swallowing, during which the grasper is open as it moves toward the jaws (protracts). We examined how the shape change of the grasper during rejection mechanically reconfigured the surrounding musculature. …

Genetic Bases Of Executive Control In Preschool Children: Trails-P Performance Is Related To Drd2 Genotype, S. A. Wiebe, M. Y. Chang, J. Huggenvik, T. Jameson, K. A. Espy

Developmental Cognitive Neuroscience Laboratory: Faculty Publications

Several studies link the D2 dopamine receptor (DRD2) with executive control and the ability to adapt behavior to changing contextual contingencies in human adults (Roesch-Ely 2005; Rodriguez-Jimenez 2006) and in animal models (Kruzich 2004). The present study examined relations between DRD2 and executive control in human development. Recently, a version of the Trail-Making Task suitable for preschool children was developed, which does not require knowledge of letters or numbers (TRAILS-P; Espy 2004). The Trail-Making Test is a neuropsychological test sensitive to frontal or executive dysfunction (Reitan 1955) where subjects must connect stimuli on a page in sequence, connecting letters only …

Unlv Magazine, Cate Weeks, Shane Bevell, Erin O'Donnell, Eric Leake, Lori Bachand, David G. Schwartz, David Ashley

UNLV Magazine

No abstract provided.

2004 Jeffress Research Grant Awards

Virginia Journal of Science

List of winners of the 2004 Jeffress Research Grant Awards.

Locus Ceruleus Regulates Sensory Encoding By Neurons And Networks In Waking Animals, David M. Devilbiss, Michelle E. Page, Barry D. Waterhouse

Department of Neurosurgery Faculty Papers

Substantial evidence indicates that the locus ceruleus (LC)–norepinephrine (NE) projection system regulates behavioral state and state-dependent processing of sensory information. Tonic LC discharge (0.1–5.0 Hz) is correlated with levels of arousal and demonstrates an optimal firing rate during good performance in a sustained attention task. In addition, studies have shown that locally applied NE or LC stimulation can modulate the responsiveness of neurons, including those in the thalamus, to nonmonoaminergic synaptic inputs. Many recent investigations further indicate that within sensory relay circuits of the thalamus both general and specific features of sensory information are represented within the collective firing patterns …

Paradoxical Facilitation Of Object Recognition Memory After Infusion Of Scopolamine Into Perirhinal Cortex: Implications For Cholinergic System Function., Boyer D Winters, Lisa M Saksida, Timothy J Bussey

Brain and Mind Institute Researchers' Publications

The cholinergic system has long been implicated in learning and memory, yet its specific function remains unclear. In the present study, we investigated the role of cortical acetylcholine in a rodent model of declarative memory by infusing the cholinergic muscarinic receptor antagonist scopolamine into the rat perirhinal cortex during different stages (encoding, storage/consolidation, and retrieval) of the spontaneous object recognition task. Presample infusions of scopolamine significantly impaired object recognition compared with performance of the same group of rats on saline trials; this result is consistent with previous reports supporting a role for perirhinal acetylcholine in object information acquisition. Scopolamine infusions …

Reduction In Urinary Arsenic With Bottled-Water Intervention, Arun B. Josyula, Hannah Mcclellen, Tracy A. Hysong, Margaret Kurzius-Spencer, Gerald S. Poplin, Stefan Stürup, Jefferey L. Burgess

Dartmouth Scholarship

The study was conducted to measure the effectiveness of providing bottled water in reducing arsenic exposure. Urine, tap-water and toenail samples were collected from non-smoking adults residing in Ajo (n=40) and Tucson (n=33), Arizona, USA. The Ajo subjects were provided bottled water for 12 months prior to re-sampling. The mean total arsenic (microg/L) in tap-water was 20.3+/-3.7 in Ajo and 4.0+/-2.3 in Tucson. Baseline urinary total inorganic arsenic (microg/L) was significantly higher among the Ajo subjects (n=40, 29.1+/-20.4) than among the Tucson subjects (n=32, 11.0+/-12.0, p<0.001), as was creatinine-adjusted urinary total inorganic arsenic (microg/g) (35.5+/-25.2 vs 13.2+/-9.3, p<0.001). Baseline concentrations of arsenic (microg/g) in toenails were also higher among the Ajo subjects (0.51+/-0.72) than among the Tucson subjects (0.17+/-0.21) (p<0.001). After the intervention, the mean urinary total inorganic arsenic in Ajo (n=36) dropped by 21%, from 29.4+/-21.1 to 23.2+/-23.2 (p=0.026). The creatinine-adjusted urinary total inorganic arsenic and toenail arsenic levels did not differ significantly with the intervention. Provision of arsenic-free bottled water resulted in a modest reduction in urinary total inorganic arsenic.

Cd80 And Cd86 Control Antiviral Cd8+ T-Cell Function And Immune Surveillance Of Murine Gammaherpesvirus 68, Shinichiro Fuse, Joshua J. Obar, Sarah Bellfy, Erica K. Leung, Weijun Zhang, Edward J. Usherwood

Dartmouth Scholarship

The interactions between CD80 and CD86 on antigen-presenting cells and CD28 on T cells serve as an important costimulatory signal in the activation of T cells. Although the simplistic two-signal hypothesis has been challenged in recent years by the identification of different costimulators, this classical pathway has been shown to significantly impact antiviral humoral and cellular immune responses. How the CD80/CD86-CD28 pathway affects the control of chronic or latent infections has been less well characterized. In this study, we investigated its role in antiviral immune responses against murine gammaherpesvirus 68 (MHV-68) and immune surveillance using CD80/CD86^−/− mice. In the …

Gammaherpesvirus Persistence Alters Key Cd8 T-Cell Memory Characteristics And Enhances Antiviral Protection, Joshua J. Obar, Shinichiro Fuse, Erica K. Leung, Sarah C. Bellfy, Edward J. Usherwood

Dartmouth Scholarship

In herpesvirus infections, the virus persists for life but is contained through T-cell-mediated immune surveillance. How this immune surveillance operates is poorly understood. Recent studies of other persistent infections have indicated that virus persistence is associated with functional deficits in the CD8(+) T-cell response. To test whether this is the case in a herpesvirus infection, we used a mutant murine gammaherpesvirus that is defective in its ability to persist in the host. By comparing the immune response to this virus with a revertant virus that can persist, we were able to dissect the changes in the antiviral CD8(+) T-cell response …

Murine Monoclonal Anti-Idiotype Antibody 3h1 Sequences For Human Carcinoembryonic Antigen, Malaya Chatterjee, Heinz Köhler, Sunil K. Chatterjee, Kenneth A. Foon

Microbiology, Immunology and Molecular Genetics Faculty Patents

This invention provides compositions derived from the sequences encoding the variable light and/or variable heavy regions of monoclonal anti-idiotype antibody 3H1 and methods for using these compositions.

Salicylic Acid Activates Sigma Factor B By Rsbu-Dependent And -Independent Mechanisms, Marco Palma, Arnold Bayer, Leon I. Kupferwasser, Tammy Joska, Michael R. Yeaman, Ambrose Cheung

Dartmouth Scholarship

Salicylic acid (SAL) may impact Staphylococcus aureus virulence by activating the sigB operon (rsbU-V-W-sigB), thus leading to reductions in alpha-toxin production and decreased fibronectin binding (L. I. Kupferwasser et al., J. Clin. Investig. 112:222-233, 2003). As these prior studies were performed in strain RN6390 (an rsbU mutant) and its rsbU-repaired variant, SH1000, the current investigation was designed to determine if the SAL effect occurs via rsbU- and/or rsbV-dependent pathways in an rsbU-intact S. aureus strain (FDA486). We thus quantified the transcription from two sigB-dependent promoters (asp23 and sarA P3) in FDA486 in response to SAL exposure in vitro, using isogenic …

Alpha Interferon Potently Enhances The Anti-Human Immunodeficiency Virus Type 1 Activity Of Apobec3g In Resting Primary Cd4 T Cells, Keyang Chen, Jialing Huang, Chune Zhang, Sophia Huang, Guiseppe Nunnari, Feng-Xiang Wang, Xiangrong Tong, Ling Gao, Kristi Nikisher, Hui Zhang

Department of Medicine Faculty Papers

The interferon (IFN) system, including various IFNs and IFN-inducible gene products, is well known for its potent innate immunity against wide-range viruses. Recently, a family of cytidine deaminases, functioning as another innate immunity against retroviral infection, has been identified. However, its regulation remains largely unknown. In this report, we demonstrate that through a regular IFN-{alpha}/ß signal transduction pathway, IFN-{alpha} can significantly enhance the expression of apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) in human primary resting but not activated CD4 T cells and the amounts of APOBEC3G associated with a low molecular mass. Interestingly, short-time treatments of newly infected resting …