Medicine and Health Sciences Commons^™

Prion Protein Glycosylation Is Not Required For Strain-Specific Neurotropism, Justin R. Piro, Brent T. Harris, Koren Nishina, Claudio Soto, Rodrigo Morales, Judy R. Rees, Surachai Supattapone

Dartmouth Scholarship

In this study, we tested the hypothesis that the glycosylation of the pathogenic isoform of the prion protein (PrP^Sc) might encode the selective neurotropism of prion strains. We prepared unglycosylated cellular prion protein (PrP^C) substrate molecules from normal mouse brain by treatment with PNGase F and used reconstituted serial protein cyclic misfolding amplification reactions to produce RML and 301C mouse prions containing unglycosylated PrP^Sc molecules. Both RML- and 301C-derived prions containing unglycosylated PrP^Sc molecules were infectious to wild-type mice, and neuropathological analysis showed that mice inoculated with these samples maintained strain-specific patterns of PrP …

Intravenous Inoculation Of A Bat-Associated Rabies Virus Causes Lethal Encephalopathy In Mice Through Invasion Of The Brain Via Neurosecretory Hypothalamic Fibers., Mirjam A R Preuss, Marie-Luise Faber, Gene S Tan, Michael Bette, Bernhard Dietzschold, Eberhard Weihe, Matthias J Schnell

Department of Microbiology and Immunology Faculty Papers

The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons via trans-synaptic spread. We speculate that in addition to the neuronal transport of the virus, hematogenous spread from the site of infection directly to the brain after accidental spill over into the vascular system might represent an alternative way for RV to invade the CNS. So far, it is unknown …

Single-Amino-Acid Alterations In A Highly Conserved Central Region Of Vesicular Stomatitis Virus N Protein Differentially Affect The Viral Nucleocapsid Template Functions, Debasis Nayak, Debasis Panda, Subash C. Das, Ming Lou, Asit K. Pattnaik

School of Veterinary and Biomedical Sciences: Faculty Publications

The nucleocapsid protein (N) of vesicular stomatitis virus and other rhabdoviruses plays a central role in the assembly and template functions of the viral N-RNA complex. The crystal structure of the viral N-RNA complex suggests that the central region of the N protein interacts with the viral RNA. Sequence alignment of rhabdovirus N proteins revealed several highly conserved regions, one of which spanned residues 282 to 291 (GLSSKSPYSS) in the central region of the molecule. Alanine-scanning mutagenesis of this region suggested that replacement of the tyrosine residue at position 289 (Y289) with alanine resulted in an N-RNA template that is …

Interaction With Lc8 Is Required For Pak1 Nuclear Import And Is Indispensable For Zebrafish Development., Christine M Lightcap, Gabor Kari, Luis E Arias-Romero, Jonathan Chernoff, Ulrich Rodeck, John C Williams

Department of Biochemistry and Molecular Biology Faculty Papers

Pak1 (p21 activated kinase 1) is a serine/threonine kinase implicated in regulation of cell motility and survival and in malignant transformation of mammary epithelial cells. In addition, the dynein light chain, LC8, has been described to cooperate with Pak1 in malignant transformation of breast cancer cells. Pak1 itself may aid breast cancer development by phosphorylating nuclear proteins, including estrogen receptor alpha. Recently, we showed that the LC8 binding site on Pak1 is adjacent to the nuclear localization sequence (NLS) required for Pak1 nuclear import. Here, we demonstrate that the LC8-Pak1 interaction is necessary for epidermal growth factor (EGF)-induced nuclear import …

Revisiting Histidine-Dependent Acid Phosphatases: A Distinct Group Of Tyrosine Phosphatases., Suresh Veeramani, Ming-Shyue Lee, Ming-Fong Lin

Journal Articles: Biochemistry & Molecular Biology

Although classical protein tyrosine phosphatase (PTP) superfamily members are cysteine-dependent, emerging evidence shows that many acid phosphatases (AcPs) function as histidine-dependent PTPs in vivo. These AcPs dephosphorylate phospho-tyrosine substrates intracellularly and could have roles in development and disease. In contrast to cysteine-dependent PTPs, they utilize histidine, rather than cysteine, for substrate dephosphorylation. Structural analyses reveal that active site histidine, but not cysteine, faces towards the substrate and functions as the phosphate acceptor. Nonetheless, during dephosphorylation, both histidine-dependent and cysteine-dependent PTPs use their active site arginine and aspartate for substrate binding and proton donation, respectively. Thus, we propose that they should …

Filtering Out The Noise: Evaluating The Impact Of Noise And Sound Reduction Strategies On Sleep Quality For Icu Patients, Karen J. Bosma, V. Marco Ranieri

Department of Medicine Publications

The review article by Xie and colleagues examines the impact of noise and noise reduction strategies on sleep quality for critically ill patients. Evaluating the impact of noise on sleep quality is challenging, as it must be measured relative to other factors that may be more or less disruptive to patients' sleep. Such factors may be difficult for patients, observers, and polysomnogram interpreters to identify, due to our limited understanding of the causes of sleep disruption in the critically ill, as well as the challenges in recording and quantifying sleep stages and sleep fragmentation in the intensive care unit. Furthermore, …

Cannabinoid Receptor Type 2 Activation Induces A Microglial Anti-Inflammatory Phenotype And Reduces Migration Via Mkp Induction And Erk Dephosphorylation, Edgar A. Romero-Sandoval, Ryan Horvath, Russell P. Landry, Joyce A. Deleo

Dartmouth Scholarship

Cannabinoid receptor type 2 (CBR2) inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting extracellular signal-regulated kinase (ERK) pathway, via mitogen-activated protein kinase-phosphatase (MKP) induction. MKPs regulate mitogen activated protein kinases, but their role in the modulation of microglial phenotype is not fully understood.

Neurite Outgrowth On Nanofiber Scaffolds With Different Orders, Structures, And Surface Properties, Jingwei Xie, Matthew R. Macewan, Xiaoran Li, Shelly E. Sakiyama-Elbert, Younan Xia

MIIR Faculty Research

Electrospun nanofibers can be readily assembled into various types of scaffolds for applications in neural tissue engineering. The objective of this study is to examine and understand the unique patterns of neurite outgrowth from primary dorsal root ganglia (DRG) cultured on scaffolds of electrospun nanofibers having different orders, structures, and surface properties. We found that the neurites extended radially outward from the DRG main body without specific directionality when cultured on a nonwoven mat of randomly oriented nanofibers. In contrast, the neurites preferentially extended along the long axis of fiber when cultured on a parallel array of aligned nanofibers. When …

Microarray-Based Cancer Prediction Using Soft Computing Approach., Xiaosheng Wang, Osamu Gotoh

Journal Articles: Genetics, Cell Biology & Anatomy

One of the difficulties in using gene expression profiles to predict cancer is how to effectively select a few informative genes to construct accurate prediction models from thousands or ten thousands of genes. We screen highly discriminative genes and gene pairs to create simple prediction models involved in single genes or gene pairs on the basis of soft computing approach and rough set theory. Accurate cancerous prediction is obtained when we apply the simple prediction models for four cancerous gene expression datasets: CNS tumor, colon tumor, lung cancer and DLBCL. Some genes closely correlated with the pathogenesis of specific or …

Decorin Is A Novel Antagonistic Ligand Of The Met Receptor., Silvia Goldoni, Ashley Humphries, Alexander Nyström, Sampurna Sattar, Rick T Owens, David J Mcquillan, Keith Ireton, Renato V Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, a member of the small leucine-rich proteoglycan gene family, impedes tumor cell growth by down-regulating the epidermal growth factor receptor. Decorin has a complex binding repertoire, thus, we predicted that decorin would modulate the bioactivity of other tyrosine kinase receptors. We discovered that decorin binds directly and with high affinity (K(d) = approximately 1.5 nM) to Met, the receptor for hepatocyte growth factor (HGF). Binding of decorin to Met is efficiently displaced by HGF and less efficiently by internalin B, a bacterial Met ligand. Interaction of decorin with Met induces transient receptor activation, recruitment of the E3 ubiquitin ligase …

Hiv Policy: The Path Forward--A Joint Position Paper Of The Hiv Medicine Association Of The Infectious Diseases Society Of America And The American College Of Physicians., Christine Lubinski, Judith Aberg, Arlene D Bardeguez, Richard Elion, Patricia Emmanuel, Daniel Kuritzkes, Michael Saag, Kathleen E Squires, Andrea Weddle, Jennifer Rainey, M Renee Zerehi, J Fred Ralston, David A Fleming, David Bronson, Molly Cooke, Charles Cutler, Yul Ejnes, Robert Gluckman, Mark Liebow, Kenneth Musana, Mark E Mayer, Mark W Purtle, P Preston Reynolds, Lavanya Viswanathan, Kevin B Weiss, Baligh Yehia

Department of Medicine Faculty Papers

Executive Summary

The American College of Physicians (ACP) and the Infectious Diseases Society of America (IDSA) have jointly published 3 policy statements on AIDS, the first in 1986 [1], the second in 1988 [2], and the third in 1994 [3]. In 2001, the IDSA created the HIV Medicine Association (HIVMA), and this updated policy paper is a collaboration between the ACP and the HIVMA of the IDSA. Since the last statement, many new developments call for the need to reexamine and update our policies relating to HIV infection. First, there have been major advances …

Effects Of Estrogen On Muscle Damage In Response To An Acute Resistance Exercise Protocol, Megan R. Wolf

Honors Scholar Theses

Creatine Kinase (CK) is used as a measure of exercise-induced muscle membrane damage. During acute eccentric (muscle lengthening) exercise, muscle sarcolemma, sarcoplasmic reticulum, and Z-lines are damaged, thus causing muscle proteins and enzymes to leak into the interstitial fluid.

Strenuous eccentric exercise produces an elevation of oxygen free radicals, which further increases muscle damage. Muscle soreness and fatigue can be attributed to this membrane damage. Estradiol, however, may preserve membrane stability post-exercise (Brancaccio, Maffulli, & Limongelli, 2007; Carter, Dobridge, & Hackney, 2001; Tiidus, 2001). Because estradiol has a similar structure to Vitamin E, which is known to have antioxidant properties, …

The Role Of Epha4 In Glial Scar Formation Following Injury, Krysti Todd

Honors Scholar Theses

Although many areas of the brain lose their regenerative capacity with age, stem cell niches have been identified in both the subventricular zone (SVZ) along the lateral walls of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (Gage, 2000; Alvarez-Buylla et al., 2001; Alvarez-Buylla and Lim, 2004). The SVZ niche utilizes many mechanisms to determine the migration patterns of neuroblasts along the RMS into the olfactory bulb, one being Eph/ephrin signaling (Conover et al., 2000; Holmberg et al., 2005). EphA4-mediated signaling is necessary for axon guidance during development, and its continued expression in the SVZ niche …

Myd88 Expression By Cns-Resident Cells Is Pivotal For Eliciting Protective Immunity In Brain Abscesses., Sarita Garg, Jessica R. Nichols, Nilufer Esen, Shuliang Liu, Nirmal K. Phulwani, Mohsin Md. Syed, William H. Wood, Yongqing Zhang, Kevin G. Becker, Amy Aldrich, Tammy Kielian

Journal Articles: Pathology and Microbiology

MyD88 KO (knockout) mice are exquisitely sensitive to CNS (central nervous system) infection with Staphylococcus aureus, a common aetiological agent of brain abscess, exhibiting global defects in innate immunity and exacerbated tissue damage. However, since brain abscesses are typified by the involvement of both activated CNS-resident and infiltrating immune cells, in our previous studies it has been impossible to determine the relative contribution of MyD88-dependent signalling in the CNS compared with the peripheral immune cell compartments. In the present study we addressed this by examining the course of S. aureus infection in MyD88 bone marrow chimaera mice. Interestingly, chimaeras where …

Genetic Variations In A Well Conserved 5-Untranslated Region Of Hepatitis C Virus Genome Isolated In Pakistan, Anila Yasmeen, Anwar Ali Siddiqui, Saeed Hamidb, Taranum Sultana, Wasim Jafri, Mats A.A. Perssonc

Department of Biological & Biomedical Sciences

The diversity and extent of sequence variations between hepatitis C virus (HCV) isolates from Pakistan were studied and the probable effects of these variations were assessed on secondary viral structures. Sequencing and phylogenetic analysis was performed on 33 samples, of which 25 were typed as genotype 3 by RFLP (restriction fragment length polymorphism) and 8 remained unresolved. Rooted neighbour-joining (NJ) tree revealed that 28 isolates were HCV type 3a and 5 isolates were typed as 3b. The majority of unresolved samples clustered in a different branch of genotype 3, supported by a bootstrap value of 71%. Another, cluster, cluster I, …

Distinct Dna Damage Signaling In The Brain Distinguishes Atld, Nbs, And Atr-Seckel Syndrome, Erin Renee Phillips Shull

Theses and Dissertations (ETD)

DNA double strand breaks create a situation of extreme stress under which a cell must either be capable of repairing the lesions in order to continue replication or succumb to death. Not surprisingly, deficiencies in DNA repair genes often lead to human diseases frequently associated with genomic instability, cancer proneness, and neuropathology. Neurological consequences of aberrant DNA repair mechanisms vary depending upon the affected gene and the pathway in which it operates. Ataxia-telangiectasia (A-T) is the prototypical disease associated with DNA double strand break (DSB) repair deficiency and is characterized by severe neural pathology. A-T results from homozygous mutations that …

Clinical Field-Strength Mri Of Amyloid Plaques Induced By Low-Level Cholesterol Feeding In Rabbits, John A. Ronald, Yuanxin Chen, Lisa Bernas, Hagen H. Kitzler, Kem A. Rogers, Robert A. Hegele, Brian K. Rutt

Robarts Imaging Publications

Two significant barriers have limited the development of effective treatment of Alzheimer’s disease. First, for many cases the aetiology is unknown and likely multi-factorial. Among these factors, hypercholesterolemia is a known risk predictor and has been linked to the formation of b-amyloid plaques, a pathological hallmark this disease. Second, standardized diagnostic tools are unable to definitively diagnose this disease prior to death; hence new diagnostic tools are urgently needed. Magnetic resonance imaging (MRI) using high field-strength scanners has shown promise for direct visualization of b-amyloid plaques, allowing in vivo longitudinal tracking of disease progression in mouse models. Here, we present …

Proceedings From The 1st Annual Boonshoft School Of Medicine Medical Student Research Symposium, Office Of Research Affairs, Boonshoft School Of Medicine

Medical Student Research Symposium Proceedings

The student abstract booklet contains a program and a list of students' poster presentations given at Wright State University's First Annual Boonshoft School of Medicine Medical Student Research Symposium held on May 1, 2009.

Altered Dendritic Cell Phenotype In Response To Leishmania Amazonensis Amastigote Infection Is Mediated By Map Kinase, Erk, Paola Mercedes Boggiatto, Fei Jie, Mousumi Ghosh, Katherine N. Gibson-Corley, Amanda E. Ramer-Tait, Douglas E. Jones, Christine A. Petersen

Amanda Ramer-Tait Publications

Initiation of productive immune responses against Leishmania depends on the successful transition of dendritic cells (DC) from an immature to a mature phenotype. This process is characterized by high CD₄₀ surface expression as well as interleukin-12 production, which are frequently seen in response to L. major infection. In vivo footpad infection of C₃HeB/FeJ mice for 7 days with L. amazonensis promoted an immature CD11c[1] DC phenotype characterized by both significantly low CD₄₀ surface expression and significantly decreased interleukin-12p40 production compared with L. major infection of these same mice. In vitro infection of bone marrow-derived dendritic cells …

Defining An Emerging Epidemic: Hcv Seroprevalence In A Large, Tertiary-Care Health Network In Pennsylvania, Margaret Hoffman-Terry Md, Facp, Joseph L. Yozviak Do, Facp, K Nadeem Ahmed Md, Sherrine Eid Mph, Timothy J. Friel Md, Kimberly A. Pacella, Luther Rhodes Iii Md

Department of Medicine

No abstract provided.

Investigation Of Magnetic Resonance Imaging And Spectroscopy For The Detection Of Breast Cancer, Robert Thomas Etnire

UNLV Theses, Dissertations, Professional Papers, and Capstones

Magnetic resonance imaging (MRI) of the breast offers an alternative to screening mammography which may benefit those women at high risk for breast cancer, women under the age of 40, and those with dense breast tissue. One concern with MRI is the number of high false positives. Coupling MRI with magnetic resonance spectroscopy(MRS) may lower the number of false positives, and thus improve the diagnostic capabilities of MRI for the clinician. MRS for breast imaging focuses on the total choline containing compounds in the spectra in the suspected breast lesion to analyze areas of concern. The results of the study …

An Evaluation Of Methicillin Resistant Staphylococcus Aureus Survival On Five Environmental Surfaces Under Two Different Humidities, With And Without The Addition Of Bovine Serum Albumin, Courtney Ann Coughenour

UNLV Theses, Dissertations, Professional Papers, and Capstones

The spread of antibiotic resistant bacteria is a major public health concern, as they result in greater healthcare costs and increased morbidity and mortality rates. Methicillin resistant Staphylococcus aureus (MRSA) is one organism of particular concern, with the number of infections increasing in epidemic proportion. Bacterial surface contamination with MRSA is significant, as it may serve as a reservoir for transmission and have negative health implications. The purpose of this study was to evaluate survival of MRSA on five environmental surface materials; glass, wood, vinyl, plastic, and cloth. The effect of relative humidity (RH) and bovine serum albumin (BSA) were …

An Evaluation Of Plastic Toys For Lead Contamination In Day Care Centers In The Las Vegas Valley, Joseph Alan Greenway

UNLV Theses, Dissertations, Professional Papers, and Capstones

The harmful effect of childhood exposure to environmental lead continues to be a major health concern. This study examined lead contamination within the plastic of children's toys. It was also hypothesized that the use of lead as a stabilizer would result in higher incidents of elevated lead (> 600 ppm) in polyvinyl chloride plastics (PVC) than non-PVC plastics. It was also hypothesized that, due to the use lead chromate, yellow toys would have higher incidents of elevated lead (> 600 ppm) than toys of other colors. Toy samples were limited to those found in day care centers in Las Vegas, …

The Combined Effect Of In-Situ Tumor And Irradiation On Peritumoral Brain Vasculature, Janice Ann Zawaski

Theses and Dissertations (ETD)

In the USA, 200,000 brain tumors are diagnosed each year with glioma representing 8.4% of the 200,000. The standard treatment for glioma consists of surgical resection, when possible, followed by radiation therapy (RT) and/or chemotherapy. Radiation therapy is one of the most effective treatments of brain tumors; however, the therapeutic ratio of RT is limited by damage to the normal tissue. We hypothesize that tumor growth has an adverse effect on the peritumoral tissue through the angiogenic/inflammatory environment it creates rendering it susceptible to further damage by RT which may be prevented by using anti-angiogenic/anti-inflammatory agents. We have developed a …

Genome Based Cell Population Heterogeneity Promotes Tumorigenicity: The Evolutionary Mechanism Of Cancer., Christine J. Ye, Joshua B. Stevens, Guo Liu, Steven W. Bremer, Aruna S. Jaiswal, Karen J. Ye, Ming-Fong Lin, Lesley Lawrenson, Wayne D. Lancaster, Markku Kurkinen, Joshua D. Liao, C. Gary Gairola, Malathy P. V. Shekhar, Satya Narayan, Fred R. Miller, Henry H. Q. Heng

Journal Articles: Biochemistry & Molecular Biology

Cancer progression represents an evolutionary process where overall genome level changes reflect system instability and serve as a driving force for evolving new systems. To illustrate this principle it must be demonstrated that karyotypic heterogeneity (population diversity) directly contributes to tumorigenicity. Five well characterized in vitro tumor progression models representing various types of cancers were selected for such an analysis. The tumorigenicity of each model has been linked to different molecular pathways, and there is no common molecular mechanism shared among them. According to our hypothesis that genome level heterogeneity is a key to cancer evolution, we expect to reveal …

Survey Of Adult Cystic Fibrosis Patients And Parents Of Cystic Fibrosis Patients On Nutrition Education, Dixie Lea Durham

Boise State University Theses and Dissertations

Cystic fibrosis (CF) is an inherited disorder affecting more than 30,000 Americans, primarily Caucasians (CF Foundation, n.d.a). A defective gene on the seventh chromosome is inherited from the mother and the father. This gene causes the body to produce an abnormal protein that leads to thick, sticky mucus that is secreted by the lungs, pancreas, liver, sweat glands, and reproductive organs. The pancreas normally excretes enzymes that aid in the digestion of food, however this function is impaired in CF, and therefore CF patients must ingest replacement enzymes (CF Foundation, n.d.a). Despite advances in treatment, including replacement enzymes, under-nutrition and …

Basement Membrane Proteoglycans: Modulators Par Excellence Of Cancer Growth And Angiogenesis., Renato V. Iozzo, Jason J. Zoeller, Alexander Nyström

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Proteoglycans located in basement membranes, the nanostructures underling epithelial and endothelial layers, are unique in several respects. They are usually large, elongated molecules with a collage of domains that share structural and functional homology with numerous extracellular matrix proteins, growth factors and surface receptors. They mainly carry heparan sulfate side chains and these contribute not only to storing and preserving the biological activity of various heparan sulfate-binding cytokines and growth factors, but also in presenting them in a more "active configuration" to their cognate receptors. Abnormal expression or deregulated function of these proteoglycans affect cancer and angiogenesis, and are critical …

Contribution Of Organic Cation Transporter 2 (Oct2) To Cisplatin-Induced Nephrotoxicity, Kelly K. Filipski

Theses and Dissertations (ETD)

Cisplatin is the most widely used anticancer agent; however, the cellular pharmacokinetics are poorly understood. Cisplatin is predominantly eliminated through the urine via active secretion and is associated with nephrotoxicity. Currently, prehydration therapy is employed to prevent toxic renal side effects; however it has not been completely ameliorated. The studies described herein aim to determine the mechanism in which cisplatin enters the kidney cell from the blood and how it is subsequently secreted into the urine. Organic cation transporter 2 (OCT2) and ABCC2 are highly expressed in the kidney on the basolateral and apical membrane, respectively. We determined the contribution …

Generation And Characterization Of A Knock-In Allele Of Eklf: Probing The In Vivo Role Of The Chromatin Remodeling Domain In Definitive Hematopoietic Cells, Valerie Malyvanh Jansen

Theses and Dissertations (ETD)

The zinc finger-encoding transacting factor EKLF, or erythroid Krüppel-like factor, binds key regulatory elements of many erythroid-specific genes, and is essential for definitive erythropoiesis. Mice lacking this factor die of anemia by E15.5 of gestation, failing to activate β-globin gene transcription, and demonstrating a block in the erythroid differentiation program at the primitive erythroblast stage. In contrast, megakaryocytic progenitors are amplified in EKLF-null embryos, with increased Fli-1 gene expression, a marker of early megakaryocytic differentiation. These observations are consistent with the idea that EKLF modulates the megakaryocytic-erythroid (M-E) differentiation switch.

Our laboratory has previously demonstrated that an amino terminal sequence …

Studying The Specificity Of Hpxr Antagonists Using A Panel Of Cell-Based Assays, Fang Lei

Theses and Dissertations (ETD)

The pregnane X receptor (PXR or SXR; NR1I2) is a member of the nuclear receptor superfamily. It activates the transcription of a large network of genes including cytochrome P450 (CYP) and Mdr1 which play critical roles in chemicals metabolism and transportation. Induction of CYPs contributes to adverse drug-drug interactions. Non-toxic, PXR-specific antagonists will be valuable in attenuating the adverse drug-drug interaction which is the cause of many treatment failures in clinic. However, few hPXR antagonists were reported particularly the specific ones. In this thesis a reporter gene assay was used to study the specificity of hPXR antagonists from a panel …