Medicine and Health Sciences Commons^™

Alterations In Vasodilator-Stimulated Phosphoprotein (Vasp) Phosphorylation: Associations With Asthmatic Phenotype, Airway Inflammation And Β2-Agonist Use, Annette T. Hastie, Min Wu, Gayle C. Foster, Gregory A. Hawkins, Vikas Batra, Katherine A. Rybinski, Rosemary Cirelli, James G. Zangrilli, Stephen P. Peters

Department of Medicine Faculty Papers

Background

Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1) injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2) regular in vivo β₂-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion.

Methods

Bronchial epithelium was obtained from asthmatic …

Structural And Function Analyses Of The Global Regulatory Protein Sara From Staphylococcus Aureus, Yingfang Liu, Adhar C. Manna, Cheol-Ho Pan, Irina A. Kriksunov

Dartmouth Scholarship

The sarA locus in Staphylococcus aureus controls the expression of many virulence genes. The sarA regulatory molecule, SarA, is a 14.7-kDa protein (124 residues) that binds to the promoter region of target genes. Here we report the 2.6 Å-resolution x-ray crystal structure of the dimeric winged helix SarA protein, which differs from the published SarA structure dramatically. In the crystal packing, multiple dimers of SarA form a scaffold, possibly via divalent cations. Mutations of individual residues within the DNA-binding helix–turn–helix and the winged region as well as within the metal-binding pocket implicate basic residues R84 and R90 within the winged …

H2-M3-Restricted Cd8+ T Cells Are Not Required For Mhc Class Ib-Restricted Immunity Against Listeria Monocytogenes, Sarah E. F. D'Orazio, Christine A. Shaw, Michael N. Starnbach

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Studies using major histocompatibility complex (MHC)-Ia–deficient mice have shown that MHC-Ib–restricted CD8⁺ T cells can clear infections caused by intracellular pathogens such as Listeria monocytogenes. M3-restricted CD8⁺ T cells, which recognize short hydrophobic N-formylated peptides, appear to comprise a substantial portion of the MHC-Ib–restricted T cell response in the mouse model of L. monocytogenes infection. In this study, we isolated formyltransferase (fmt) mutant strains of L. monocytogenes that lacked the ability to add formyl groups to nascent polypeptides. These fmt mutant Listeria strains did not produce antigens that could be recognized by M3-restricted T …

Animal Carcinogenicity Studies: 1. Poor Human Predictivity, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Experimentation Collection

The regulation of human exposure to potentially carcinogenic chemicals constitutes society’s most important use of animal carcinogenicity data. Environmental contaminants of greatest concern within the USA are listed in the Environmental Protection Agency’s (EPA’s) Integrated Risk Information System (IRIS) chemicals database. However, of the 160 IRIS chemicals lacking even limited human exposure data but possessing animal data that had received a human carcinogenicity assessment by 1 January 2004, we found that in most cases (58.1%; 93/160), the EPA considered animal carcinogenicity data inadequate to support a classification of probable human carcinogen or non-carcinogen. For the 128 chemicals with human or …

Animal Carcinogenicity Studies: 2. Obstacles To Extrapolation Of Data To Humans, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Experimentation Collection

Due to limited human exposure data, risk classification and the consequent regulation of exposure to potential carcinogens has conventionally relied mainly upon animal tests. However, several investigations have revealed animal carcinogenicity data to be lacking in human predictivity. To investigate the reasons for this, we surveyed 160 chemicals possessing animal but not human exposure data within the US Environmental Protection Agency chemicals database, but which had received human carcinogenicity assessments by 1 January 2004. We discovered the use of a wide variety of species, with rodents predominating, and of a wide variety of routes of administration, and that there were …

Animal Carcinogenicity Studies: 3. Alternatives To The Bioassay, Andrew Knight, Jarrod Bailey, Jonathan Balcombe

Experimentation Collection

Conventional animal carcinogenicity tests take around three years to design, conduct and interpret. Consequently, only a tiny fraction of the thousands of industrial chemicals currently in use have been tested for carcinogenicity. Despite the costs of hundreds of millions of dollars and millions of skilled personnel hours, as well as millions of animal lives, several investigations have revealed that animal carcinogenicity data lack human specificity (i.e. the ability to identify human non-carcinogens), which severely limits the human predictivity of the bioassay. This is due to the scientific inadequacies of many carcinogenicity bioassays, and numerous serious biological obstacles, which render profoundly …

Keeping Their Options Open: Acute Versus Persistent Infections, S. Furukawa, S. L. Kuchma, G. A. O'Toole

Dartmouth Scholarship

No abstract provided.

Transcriptome Signature Of Virulent And Attenuated Pseudorabies Virus-Infected Rodent Brain, Christina Paulus, Patricia J. Sollars, Gary E. Pickard, Lynn W. Enquist

School of Veterinary and Biomedical Sciences: Faculty Publications

Mammalian alphaherpesviruses normally establish latent infections in ganglia of the peripheral nervous system in their natural hosts. Occasionally, however, these viruses spread to the central nervous system (CNS), where they cause damaging, often fatal, infections. Attenuated alphaherpesvirus derivatives have been used extensively as neuronal circuit tracers in a variety of animal models. Their circuit-specific spread provides a unique paradigm to study the local and global CNS response to infection. Thus, we systematically analyzed the host gene expression profile after acute pseudorabies virus (PRV) infection of the CNS using Affymetrix GeneChip technology. Rats were injected intraocularly with one of three selected …

Dopamine-D1 And Δ-Opioid Receptors Co-Exist In Rat Striatal Neurons, L. M. Ambrose-Lanci, S. M. Gallagher, E. M. Unterwald, E. J. Van Bockstaele

Department of Neurosurgery Faculty Papers

Cocaine’s enhancement of dopaminergic neurotransmission in the mesolimbic pathway plays a critical role in the initial reinforcing properties of this drug. However, other neurotransmitter systems are also integral to the addiction process. A large body of data indicates that opioids and dopamine together mediate emotional and reinforced behaviors. In support of this, cocaine-mediated increases in activation of dopamine D1 receptors (D1R) results in a desensitization of δ-opioid receptor (DOR) signaling through adenylyl cyclase (AC) in striatal neurons. To further define cellular mechanisms underlying this effect, the subcellular distribution of DOR and D1R was examined in the rat dorsolateral striatum. Dual …

Treponema Denticola In Disseminating Endodontic Infections, F. Foschi, Jacques Izard, H. Sasaki, V. Sambri, C. Prati, R. Müller, P. Stashenko

Department of Food Science and Technology: Faculty Publications

Treponema denticola is a consensus periodontal pathogen that has recently been associated with endodontic pathology. In this study, the effect of mono-infection of the dental pulp with T. denticola and with polymicrobial “red-complex” organisms (RC) (Porphyromonas gingivalis, Tannerella forsythia, and T. denticola) in inducing disseminating infections in wild-type (WT) and severe-combined-immunodeficiency (SCID) mice was analyzed. After 21 days, a high incidence (5/10) of orofacial abscesses was observed in SCID mice mono-infected with T. denticola, whereas abscesses were rare in SCID mice infected with the red-complex organisms or in wild-type mice. Splenomegaly was …

Do Cd1-Restricted T Cells Contribute To Antibody-Mediated Immunity Against Mycobacterium Tuberculosis?, Mark L. Lang, Aharona Glatman-Freedman

Dartmouth Scholarship

No abstract provided.

Antisense Inhibition Of Cyclin D1 Expression Is Equivalent To Flavopiridol For Radiosensitization Of Zebrafish Embryos, Mary Frances Mcaleer, Kevin T. Duffy, William R. Davidson, Gabor Kari, Adam P. Dicker, Ulrich Rodeck, Eric Wickstrom

Department of Biochemistry and Molecular Biology Faculty Papers

Purpose: Flavopiridol, a small molecule pan-cyclin inhibitor, has been shown to enhance the radiation response of tumor cells both in vitro and in vivo. The clinical utility of flavopiridol, however, is limited by toxicity, previously attributed to pleiotropic inhibitory effects on several targets affecting multiple signal transduction pathways. Here we utilized zebrafish embryos to investigate radiosensitizing effects of flavopiridol in normal tissues.

Methods and Materials: Zebrafish embryos at the 1-4 cell stage were treated with 500 nM flavopiridol or injected with 0.5 pmol antisense hydroxylprolyl-phosphono nucleic acid oligomers to reduce cyclin D1 expression, then subjected to ionizing radiation (IR) or …

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

Faculty Scholarship

Bernstein (1967) hypothesized that preparation of the periphery was crucial for correct responses to motor output. To test this hypothesis in a behaving animal, we examined the roles of two identified motor neurons, B7 and B8, which contribute to feeding behavior in the marine mollusk Aplysia californica. Neuron B7 innervates a hinge muscle and has no overt behavioral effect during smaller-amplitude (type A) swallows, because the hinge muscle is too short to exert force. Neuron B8 activates a muscle (I4) that acts solely to grasp material during type A swallows. During larger-amplitude (type B) swallows, the behavioral actions of both …

A Domain-Oriented Approach To The Reduction Of Combinatorial Complexity In Signal Transduction Networks, Holger Conzelmann, Julio Saez-Rodriguez, Thomas Sauter, Boris N. Kholodenko Phd, Dsci, Ernst D. Gilles

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background:

Receptors and scaffold proteins possess a number of distinct domains and bind multiple partners. A common problem in modeling signaling systems arises from a combinatorial explosion of different states generated by feasible molecular species. The number of possible species grows exponentially with the number of different docking sites and can easily reach several millions. Models accounting for this combinatorial variety become impractical for many applications.

Results:

Our results show that under realistic assumptions on domain interactions, the dynamics of signaling pathways can be exactly described by reduced, hierarchically structured models. The method presented here provides a rigorous way to …

Clinical Perspectives Of Emerging Pathogens In Bleeding Disorders, Jamie Siegel

Department of Medicine Faculty Papers

As a result of immunological and nucleic-acid screening of plasma donations for transfusion-transmissible viruses, and the incorporation of viral reduction processes during plasma fractionation, coagulation-factor concentrates (CFC) are now judged safe in terms of many known infectious agents, including hepatitis B and C viruses, HIV, and human T-cell lymphotropic virus. However, emerging pathogens could pose future threats, particularly those with blood-borne stages that are resistant to viral-inactivation steps in the manufacturing process, such as non-lipid-coated viruses. As outlined in this Review, better understanding of infectious diseases allows challenges from newly described agents of potential concern in the future to be …

The Inflammatory And Normal Transcriptome Of Mouse Bladder Detrusor And Mucosa, Marcia R. Saban, Helen L. Hellmich, Mary Turner, Ngoc-Bich Nguyen, Rajanikanth Vadigepalli, David W. Dyer, Robert E. Hurst, Michael Centola, Ricardo Saban

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Background

An organ such as the bladder consists of complex, interacting set of tissues and cells. Inflammation has been implicated in every major disease of the bladder, including cancer, interstitial cystitis, and infection. However, scanty is the information about individual detrusor and urothelium transcriptomes in response to inflammation. Here, we used suppression subtractive hybridizations (SSH) to determine bladder tissue- and disease-specific genes and transcriptional regulatory elements (TRE)s. Unique TREs and genes were assembled into putative networks.

Results

It was found that the control bladder mucosa presented regulatory elements driving genes such as myosin light chain phosphatase and calponin 1 that …

Task-Dependent Posterior Cingulate Activation In Mild Cognitive Impairment, Michele L. Ries, Taylor W. Schmitz, Tisha N. Kawahara, Britta M. Torgerson, Mehul A. Trivedi, Sterling C. Johnson

Brain and Mind Institute Researchers' Publications

Neuroimaging research has demonstrated that the posterior cingulate cortex (PCC) is functionally compromised in individuals diagnosed with amnestic mild cognitive impairment (MCI), a major risk factor for the development of Alzheimer's disease (AD). In functional MRI studies with healthy participants, this same region is active during self-appraisal (requiring retrieval of semantic knowledge about the self) as well as episodic recognition of previously learned information. Administering both types of tasks to people with MCI may reveal important information on the role of the PCC in recollection. This study investigated fMRI activation in the PCC in individuals with MCI and matched controls …

Reduced Hippocampal Activation During Episodic Encoding In Middle-Aged Individuals At Genetic Risk Of Alzheimer's Disease: A Cross-Sectional Study, Mehul A. Trivedi, Taylor W. Schmitz, Michele L. Ries, Britta M. Torgerson, Mark A. Sager, Bruce P. Hermann, Sanjay Asthana, Sterling C. Johnson

Brain and Mind Institute Researchers' Publications

Background: The presence of the apolipoprotein E (APOE) ε4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the ε4 allelle on hippocampal activation has not been firmly established. Methods: The present study examined the effects of APOE genotype on brain activation patterns in the media[ temporal lobe (MTL) during an episodic encoding task …

Competition Between The Dna Unwinding And Strand Pairing Activities Of The Werner And Bloom Syndrome Proteins, Amrita Machwe, Enerlyn M. Lozada, Liren Xiao, David K. Orren

Toxicology and Cancer Biology Faculty Publications

BACKGROUND: The premature aging and cancer-prone Werner and Bloom syndromes are caused by defects in the RecQ helicase enzymes WRN and BLM, respectively. Recently, both WRN and BLM (as well as several other RecQ members) have been shown to possess a strand annealing activity in addition to the requisite DNA unwinding activity. Since an annealing function would appear to directly oppose the action of a helicase, we have examined in this study the dynamic equilibrium between unwinding and annealing mediated by either WRN or BLM.

RESULTS: Our investigation into the competition between annealing and unwinding demonstrates that, under standard reaction …

A Mechanistic Study Of The Protective Effects Of S-Adenosyl-L-Methionine Against Hepatotoxicity Of Acetaminophen, Marcus V. Terneus Jr.

Theses, Dissertations and Capstones

Hepatic toxicity is known to be associated with excessive doses of the over-the-counter analgesic, acetaminophen (APAP). APAP overdose is the leading cause of drug-induced liver failure in the United States. APAP hepatotoxicity is dependent on the biotransformation of APAP by cytochrome P450 to the toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). APAP, when taken in excessive doses, can lead to severe liver damage with the potential to progress to liver failure. Despite substantial efforts in past studies, the mechanism by which APAP induces such damaging effects is not completely understood. Recent discoveries suggest that glutathione (GSH) depletion, protein alkylation and reactive metabolite …

Protein Kinase C Activity In Mouse Eggs Regulates Gamete Membrane Interaction, Hiroto Akabane

Theses, Dissertations and Capstones

Every mammalian life develops from one cell after fertilization of an egg by the sperm. The molecular pathways governing this event are still poorly understood. Numerous reports indicate that mammalian eggs highly express various protein kinase C (PKC) isoforms. Accordingly, we hypothesize that PKC activity in the egg plays an important role during egg-sperm membrane binding and fusion. In this study, we tested our hypothesis in mouse gametes using two types of PKC inhibitors (calphostin c and staurosporine) and the typical PKC activator, phorbol ester 12-tetradecanoylphorbol-13 acetate (PMA). After treatment with the individual drug, eggs were inseminated with sperm. The …

Thimerosal-Induced Neuritoxicity: Apoptosis Occurs Through A Mitochondrial-Mediated Pathway Via The Jnk Signaling Pathway, Michelle L. Herdman

Theses, Dissertations and Capstones

Thimerosal is an organic mercurial containing an ethylmercury moiety attached to the sulfur atom of thiosalicylate. Since the 1930s, thimerosal has been used as an antiseptic and a preservative in a wide variety of products, including medicinal preparations administered to children and pregnant women. Past exposures to mercurials have indicated that mercury is a neurotoxin, and can also affect the kidney, skin, eyes, and immune system. Additionally, fetuses exposed to mercurials are more susceptible to toxicity because the nervous system is continuously developing. However, despite its widespread use, thimerosal was only studied on a limited basis until the end of …

Regulation Of Biofilm Formation Of Pseudomonas Aeruginosa, Nathaniel Edwards Head

Theses, Dissertations and Capstones

Cystic fibrosis (CF) is the most common, autosomal recessive lethal genetic disease in the Caucasian population, resulting from a malfunctioned cystic fibrosis transmembrane conductance regulator (CFTR) and leading to bacterial lung infections. P. aeruginosa, an opportunistic pathogen, establishes a chronic infection in CF with a phenotype of overproduction of an exopolysaccharide (alginate) due to host-directed mutagenesis. While free-floating planktonic bacteria can be properly cleared from the CF lung, P. aeruginosa, along with alginate production, establishes an infection in the form of a biofilm which supports its survival in nature and in vivo. As a result, genomic structure, …

Characterization Of The Dna-Binding Properties Of Silent Information Regulator 3 Protein, Cotteka Nichisha Johnson

Theses, Dissertations and Capstones

The eukaryotic genome is organized into distinct domains with discrete regulatory potential, influenced by the variation in local chromatin structure. An example of chromatin-mediated consequences on gene expression is mating type determination of yeast Saccharomyces cerevisiae, which depends on silencing of specific gene cassettes. Silencing in yeast involves key proteins, amongst which the Silent Information Regulator (Sir) proteins are essential. Sir1p, Sir2p, and Sir4p are recruited to nucleate silencing events, while Sir3p serves as the pivotal factor in spreading the silent state. This investigation characterizes the DNA binding properties of Sir3p using DNA fragments with varying degrees of inherent flexibility, …

Reversal Of Endotoxin-Induced Hypotension By Inhibition Of Inducible Nitric Oxide Synthase Activity Is Associated With Improved Oxidative Status In Rat Heart, Aorta And Mesenteric Artery, Bahar Tunçtan, Belma Korkmaz, Hati̇ce Yildirim, Lülüfer Tamer, Uğur Ati̇k, C. Kemal Buharalioğlu

Turkish Journal of Medical Sciences

Overproduction of reactive oxygen and nitrogen species leads to oxidative stress and decreased total antioxidant capacity, which is responsible for high mortality from several diseases such as endotoxic shock. Nitric oxide (NO) produced by inducible NO synthase (iNOS) during endotoxemia is the major cause of vascular hyporeactivity, hypotension and multiple organ failure. We investigated whether NO-mediated oxidative stress in rat heart, aorta and mesenteric artery is involved in the attenuation of endotoxin-induced hypotension by inhibition of iNOS. In conscious male Wistar rats, injection of endotoxin (10 mg/kg, i.p.) caused a gradual fall in mean arterial pressure (MAP) for 4 hours …

The Morphometric Measurements Of Humerus Segments, Ş. Deni̇z Akman, Pinar Karakaş, Memduha Gülhal Bozkir

Turkish Journal of Medical Sciences

The aim of the present study was to determine the lengths of humerus segments in the Turkish population and compare these with the data from other countries' population for use in forensic and archeological cases. For this purpose one hundred and twenty (56 left side and 64 right side) male adult dry Caucasians' humerus bones were taken to measure the morphometric properties of humerus segments. Six segments on the articular surface of the humerus (Maximum height of the humerus (MHH), and the distances between the articular segment of the humeral head and the greater tuberosity (H1), caput humeri and collum …

The Status Of Oxidants And Antioxidants In The Neutrophils Of Patients With Recurrent Aphthous Stomatitis, Hi̇lmi̇ Cevdet Altinyazar, Ahmet Gürel, Rafet Koca, Ferah Armutçu, Murat Ünalacak

Turkish Journal of Medical Sciences

Recurrent aphthous stomatitis (RAS) is an inflammatory condition of unknown etiology. The exact role of the leukocytes in the pathogenesis of RAS is not known. The aim of this study was to evaluate the status of the oxidative system in neutophils of RAS patients. A total of 26 patients and 22 sex and age matched healthy control subjects were analyzed by measuring intracellular oxidant/antioxidant enzymes and related parameters; myeloperoxidase (MPO), xanthine oxidase (XO), catalase (CAT), superoxide dismutase (SOD), adenosine deaminase (AD), malondialdehyde (MDA) and nitric oxide (NO). Statistically significant increases in the activities of SOD, CAT and levels of MDA, …

Determination Of Nuclear Matrix Protein 22 Levels In Cystitis, Urothelial Dysplasia And Urothelial Carcinoma, Ahmet Gödekmerdan, Seyfetti̇n Yahşi̇, Ati̇lla Semerci̇öz, Fulya İlhan, Nusret Akpolat, Hayreddi̇n Yekeler

Turkish Journal of Medical Sciences

Urothelial carcinomas (UC) are the most common cancer type of the urinary system. The early diagnosis and treatment of UC are very important.The aim of this study was to evaluate the importance of the nuclear matrix protein 22 (NMP22) in early diagnosis of UC and to present its variation in cystitis and urothelial dysplasia (UD). Twenty patients with UC, 20 patients with UD and 20 patients with cystitis diagnosed by urinary cytological examination were enrolled in this study. In addition, 20 healthy people constituted the control group. Urine samples were collected from all patients and control subjects for NMP22 measurement …

Cytological And Clinical Features Of Hürthle Cell Neoplasia; Review Of The Literature Due To Three Cases, Nurper Onuk Fi̇li̇z, Reşi̇t Doğan Köseoğlu, İbrahi̇m Aladağ, Ahmet Eyi̇bi̇len, Mehmet Güven

Turkish Journal of Medical Sciences

NUK FİLİZ^1, Reşit Doğan KÖSEOĞLU^1, İbrahim ALADAĞ^2, Ahmet EYİBİLEN^2, Mehmet GÜVEN^2 ^1Department of Pathology, Faculty of Medicine, Gaziosmanpaşa University, Tokat - Turkey ^2 Department of Otorhinolaryngology, Faculty of Medicine, Gaziosmanpaşa University, Tokat - Turkey

Remifentanil Infusion And Paracervical Block Combination Versus Remifentanil Infusion Alone During In Vitro Fertilisation (Ivf), Ertan Öztürk, Berri̇n Günaydin, Onur Karabacak, Bi̇lge Tuncer, Mehmet Erdem, Ahmet Erdem, Bülent Tiraş, Kadi̇r Kaya

Turkish Journal of Medical Sciences

The aim of this study is to compare two accepted techniques; intravenous (IV) remifentanil infusion versus its combination with paracervical block (PCB) in patients undergoing transvaginal ultrasound guided oocyte retrieval (TUGOR). One hundred unpremedicated patients were divided into two groups to receive either IV remifentanil (Group R) or IV remifentanil plus PCB (Group R+PCB). After monitoring cardiopulmonary parameters, remifentanil infusion of 0.25 µg kg^{-1} min-1 was started in both in groups. Additionally, when the patient felt dizzy, PCB with 10 ml 1% lidocaine was performed only in Group R+PCB followed by remifentanil infusion reduction to 0.15 µg kg^{-1} min-1. Hemodynamic …