Medical Sciences Commons^™

A New Interpretation Of The Drug Levodopa In The Treatment Of Parkinson's Disease, Joanne T. Vannah

Graduate Masters Theses

An argument for levodopa induced dyskinesias (LID) as an expression of long term potentiation (LTP) in the striatum is presented. Normally, with an intact nigrostriatal dopamine (DA) input, long term depression (LTD) is expressed in the striatum, however, striatal LTD is lost following DA denervation and chronic levodopa treatment. It is possible that these changes in synaptic efficacy are due to two other chemical modulators, achetylcholine (ACh) and glutamate, which in turn leads to the induction of striatal LTP. ACh and glutamate may produce these changes in motor behavior by affecting the striosomal pathway in addition to their effect on …

Protection Against Ischemia And Reperfusion Injury, Peter R. Oeltgen, Paul D. Bishop, Mark S. Kindy, Juan A. Sanchez

Molecular and Cellular Biochemistry Faculty Patents

A compound and method for using the compound to reduce injury associated with ischemia and reperfusion of mammalian organs such as the heart. The compound, either Deltorphin A and/or Dermorphin H, may be administered as part of a preconditioning strategy which reduces the extent of injury and improves organ function following cessation and restoration of blood flow. The compound may be used in preparation for planned ischemia or in a prophylactic manner in anticipation of further ischemic events.

Endothelial Cell Pseudopods And Angiogenesis Of Breast Cancer Tumors, Ivan L. Cameron, Nicholas Short, Luzhe Sun, W. Elaine Hardman

Biochemistry and Microbiology

Background

A neoplastic tumor cannot grow beyond a millimeter or so in diameter without recruitment of endothelial cells and new blood vessels to supply nutrition and oxygen for tumor cell survival. This study was designed to investigate formation of new blood vessels within a human growing breast cancer tumor model (MDA MB231 in mammary fat pad of nude female mouse). Once the tumor grew to 35 mm³, it developed a well-vascularized capsule. Histological sections of tumors greater than 35 mm³were stained with PAS, with CD-31 antibody (an endothelial cell maker), or with hypoxia inducible factor 1α …

A Virtual Model Of The Human Cervical Spine For Physics-Based Simulation And Applications, Hyung Soo Ahn

Theses and Dissertations (ETD)

Utilizing recent advances in computer technology, Our Biomechanics Laboratory have made an effort to integrate computer animation and engineering analysis software into biomedical research, specifically towards simulation and animation of in vitro experimentation of the human cervical spine in the virtual world. The objectives of this study were to develop a virtual model of the human cervical spine for physics-based simulation and to apply the virtual model to studies of different surgical procedures and instrumentation.

A process for creating an accurate virtual model of the human cervical spine was developed. The model consisted of seven vertebrae (C2-T1) connected with soft …

Stim1, An Essential And Conserved Component Of Store-Operated Ca2+ Channel Function, Jack Roos, Paul J. Digregorio, Andriy V. Yeromin, Kari Ohlsen, Maria I. Lioudyno, Shenyuan L. Zhang, Olga Safrina, J. Ashot Kozak, Steven L. Wagner, Michael D. Cahalan, Gönül Veliçelebi, Kenneth A. Stauderman

Neuroscience, Cell Biology & Physiology Faculty Publications

Store-operated Ca²⁺ (SOC) channels regulate many cellular processes, but the underlying molecular components are not well defined. Using an RNA interference (RNAi)-based screen to identify genes that alter thapsigargin (TG)-dependent Ca²⁺ entry, we discovered a required and conserved role of Stim in SOC influx. RNAi-mediated knockdown of Stim in Drosophila S2 cells significantly reduced TG-dependent Ca²⁺ entry. Patch-clamp recording revealed nearly complete suppression of the Drosophila Ca²⁺ release-activated Ca²⁺(CRAC) current that has biophysical characteristics similar to CRAC current in human T cells. Similarly, knockdown of the human homologue STIM1 significantly reduced CRAC channel activity …

Effects Of A Small Mammalian Herbivore On A Grassland Undergoing Restoration, Margaret Murphy

Masters Theses & Specialist Projects

This thesis examines the effects of the prairie vole, Microtus ochrogaster, on a grassland undergoing restoration. The study addresses these effects with respect to treatment plots (vole-enhanced enclosures and vole-excluded exclosures) and control plots, which have not had the small mammal community manipulated. This study has also been accepted as a manuscript for publication in the "Proceedings of the 18th North American Prairie Conference."1 Two ancillary studies were also conducted. The first, reported in Appendix I, examines the composition and effects on plant community structure by the unmanipulated, small mammal community from the control plots within the area undergoing restoration …

Environmental Factors In Autoimmunity: Assessment Of Immunotoxicity Of Phthalates In The Induction Of Lupus-Type Anti-Dna Antibodies, So-Yon Lim

All-Inclusive List of Electronic Theses and Dissertations

Objectives: Little is known of the role of specific environmental factors in promoting autoimmune disorders such as systemic lupus erythematosus (SLE). The broad objective of this study was to address how exposure to phthalates, common environmental factors m foods, and biomedical devices could affect the immune functions of resistant and autoimmune-prone mice. Methods: The environmental chemical model used in this study is phthalates, which are widely used in various forms and readily occur during day-to-day human contacts. Groups of nonautoimmune-prone (BALB/c, DBA/2 and C57BL/6) and susceptible (NZB, NZB/W Fl) mice were immunized with phthalates ( ortho, meta and para) conjugated …

Modeling Of Immunoglobulin Uptake By N,N,N′,N′-Ethylenediaminetetramethylenephosphonic Acid-Modified Zirconia Particles Under Static And Dynamic Conditions, Sabyasachi Sarkar, Anuradha Subramanian

Papers in Biotechnology

A matrix developed from N,N,N′,N′-ethylenediaminetetramethylenephosphonic acid-modified zirconia beads (further referred to as r_PEZ); 25–38 μm in diameter and with a pore size of 22 ± 3 nm, was utilized for the separation of immunoglobulins (Igs). r_PEZ has been shown to bind to various Igs originating from a wide variety of species. To understand the mechanisms controlling the uptake of Igs by r_PEZ, static protein uptake experiments were carried out. The protein uptake profiles were further modeled with a kinetic rate constant model. Individual studies were undertaken for human immunoglobulin A, G and M (HIgA, HIgG and HIgM). The kinetic rate …

A Developmental Switch In The Response Of Drg Neurons To Ets Transcription Factor Signaling, Simon Hippenmeyer, Eline Vrieseling, Markus Sigrist, Thomas Portmann, Celia Laengle, David R. Ladle, Silvia Arber

Neuroscience, Cell Biology & Physiology Faculty Publications

Two ETS transcription factors of the Pea3 subfamily are induced in subpopulations of dorsal root ganglion (DRG) sensory and spinal motor neurons by target-derived factors. Their expression controls late aspects of neuronal differentiation such as target invasion and branching. Here, we show that the late onset of ETS gene expression is an essential requirement for normal sensory neuron differentiation. We provide genetic evidence in the mouse that precocious ETS expression in DRG sensory neurons perturbs axonal projections, the acquisition of terminal differentiation markers, and their dependence on neurotrophic support. Together, our findings indicate that DRG sensory neurons exhibit a temporal …

Requirements For Vibrio Cholerae Hapr Binding And Transcriptional Repression At The Hapr Promoter Are Distinct From Those At The Apha Promoter, Wei Lin, Gabriela Kovacikova, Karen Skorupski

Dartmouth Scholarship

Virulence gene expression in certain strains of Vibrio cholerae is regulated in response to cell density by a quorum-sensing cascade that influences the levels of the LuxR homolog HapR through small regulatory RNAs that control the stability of its message. At high cell density, HapR represses the expression of the gene encoding the virulence gene activator AphA by binding to a site between −85 and −58 in the aphA promoter. We show here that a second binding site for HapR lies within the hapR promoter from which it functions to repress its own transcription. This site, as determined by gel …

Synthesis, Structural Studies And Desilylation Reactions Of Some N-2-(Trimethylsilyl)Ethyl-N-Nitrosocarbamates, Arpitha Thakkalapally, Vladimir Benin

Chemistry Faculty Publications

The present report describes the preparation and characterization of several N-2-(trimethylsilyl)ethyl-N-nitrosocarbamates, designed as precursors to thermally unstable secondary N-nitrosocarbamate anions via fluoride-assisted cleavage. X-ray structural studies demonstrate that the core N-nitrosocarbamate moiety has a nearly planar geometry, with an s-E orientation at the N–N bond. DFT calculations (B3LYP/6-31+G(d)) reproduce accurately the structural features of the title compounds and detailed conformational analysis at the same level of theory addresses the long-standing issue of preferred geometries for three classes of related structures: N-nitrosocarbamates, N-nitrosoureas and N-nitrosoamides. Desilylation studies demonstrate that both the …

Somatostatin Regulates Intracellular Signaling In Human Bronchial Smooth Muscle Cells, Michael J. Alfonzo

Seton Hall University Dissertations and Theses (ETDs)

Somatostatin (somatotropin release inhibitory factor; SRIF), is an endogenous peptide family that controls cellular secretion and proliferation. While SRIF's cognate receptors and associated actions have been clearly identified in a range of tissues, such as the endocrine, gastrointestinal and immune systems, a role in human lung physiology remains unknown. Using primary human bronchial smooth muscle cells (hBSMC) as a model for studying SRIF's actions, we have investigated whether SRIF receptors are present and functional in human bronchial smooth muscle. Reverse transcriptase- polymerase chain reaction (RT-PCR) analysis ofhBSMC total mRNA demonstrated the presence of the sst, receptor subtype, providing a molecular …

Dietary Omega-3 Fatty Acids And Ionizing Irradiation On Human Breast Cancer Xenograft Growth And Angiogenesis, W. Elaine Hardman, Luzhe Sun, Nicholas Short, Ivan L. Cameron

Biochemistry and Microbiology

Background

The effects of an omega-3 (n-3) fatty acid enriched diet alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA-MB231 breast cancer xenograft were tested. The cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into two diet groups: 1) mice with 10% corn oil (rich in omega 6 fatty acids) in their food, 2) mice consuming a 10% fat diet that was enriched in n-3 fatty acids. After two weeks on the diet, treatment with 200 cGy of IR every second …

Glutamate Receptors In Perirhinal Cortex Mediate Encoding, Retrieval, And Consolidation Of Object Recognition Memory., Boyer D Winters, Timothy J Bussey

Brain and Mind Institute Researchers' Publications

Object recognition is consistently impaired in human amnesia and animal models thereof. Results from subjects with permanent brain damage have revealed the importance of the perirhinal cortex to object recognition memory. Here, we report evidence from rats for interdependent but distinct stages in object recognition memory (encoding, retrieval, and consolidation), which require glutamate receptor activity within perirhinal cortex. Transient blockade of AMPA receptor-mediated synaptic transmission within perirhinal cortex disrupted encoding for short- and long-term memory as well as retrieval and consolidation. In contrast, transient NMDA receptor blockade during encoding affected only long-term object recognition memory; NMDA receptor activity was also …

Evaluation Of Glucocorticoid Sensitivity In 697 Pre-B Acute Lymphoblastic Leukemia Cells After Overexpression Or Silencing Of Map Kinase Phosphotase-1, Marc T. Abrams, Noreen Robertson, Gerald Litwack, Eric Wickstrom

Department of Biochemistry and Molecular Biology Faculty Papers

PURPOSE: To determine the effect of reducing MAP kinase phosphatase-1 (MKP-1) levels on cell death induced by glucocorticoid (GC) or hydroxyurea (HU) treatment in the human pre-B acute lymphoblastic leukemia cell line 697.

METHODS: Stable MKP-1 overexpressing transformants of the 697 pre-B ALL cell line were created and tested for sensitivity to the GC triamcinolone acetonide (TA) and HU, and compared to a control 697 cell line containing normal MKP-1 expression levels. Small interfering RNAs (siRNAs) were designed to inhibit MKP-1 expression and evaluated for their effect on GC-mediated cell death.

RESULTS: MKP-1 overexpression caused a phenotype of partial resistance …

The Cns Role Of Toll-Like Receptor 4 In Innate Neuroimmunity And Painful Neuropathy, Flobert Y. Tanga, Nancy Nutile-Mcmenemy, Joyce A. Deleo

Dartmouth Scholarship

Neuropathic pain remains a prevalent and persistent clinical problem because of our incomplete understanding of its pathogenesis. This study demonstrates for the first time, to our knowledge, a critical role for CNS innate immunity by means of microglial Toll-like receptor 4 (TLR4) in the induction phase of behavioral hypersensitivity in a mouse and rat model of neuropathy. We hypothesized that after L5 nerve transection, CNS neuroimmune activation and subsequent cytokine expression are triggered by the stimulation of microglial membrane-bound TLR4. To test this hypothesis, experiments were undertaken to assess tactile and thermal hypersensitivity in genetically altered (i.e., TLR4 knockout and …

Ocular Surface Epithelia Contain Abcg2-Dependent Side Population Cells Exhibiting Features Associated With Stem Cells., Murat T Budak, Onder S Alpdogan, Mingyuan Zhou, Robert M Lavker, M A Murat Akinci, J Mario Wolosin

Department of Medical Oncology Faculty Papers

When cell populations are incubated with the DNA-binding dye Hoechst 33342 and subjected to flow cytometry analysis for Hoechst 33342 emissions, active efflux of the dye by the ABCG2/BCRP1 transporter causes certain cells to appear as a segregated cohort, known as a side population (SP). Stem cells from several tissues have been shown to possess the SP phenotype. As the lack of specific surface markers has hindered the isolation and subsequent biochemical characterization of epithelial stem cells this study sought to determine the existence of SP cells and expression of ABCG2 in the epithelia of the ocular surface and evaluate …

Method For Treating Cytokine Mediated Hepatic Injury, Peter R. Oeltgen, Paul D. Bishop, Craig J. Mcclain, Shirish Barve

Graduate Center for Nutritional Sciences Faculty Patents

A method of modulating cytokine mediated hepatic injury by administering compound-D SEQ ID NO:1 to a mammal. A concentration of the compound in the range of about 0.5 mg/kg to about 20 mg/kg in a physiologically acceptable formulation blocks a cytokine cascade. A therapeutic method of modulating cytokine mediated acute inflammatory, trauma induced and toxin induced hepatic injury, particularly via tumor necrosis factor modulation, is thus disclosed.

Molecular And Clinical Analyses Of Greig Cephalopolysyndactyly And Pallister-Hall Syndromes: Robust Phenotype Prediction From The Type And Position Of Gli3 Mutations, Jennifer J. Johnston, Isabelle Olivos-Glander, Christina Killoran, David Tilstra Md

Articles

Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was …

26Al-Containing Acidic And Basic Sodium Aluminum Phosphate Preparation And Use In Studies Of Oral Aluminum Bioavailability From Foods Utilizing 26Al As An Aluminum Tracer, Robert A. Yokel, Aaron A. Urbas, Robert A. Lodder, John P. Selegue, Rebecca L. Florence

Pharmaceutical Sciences Faculty Publications

We synthesized ²⁶Al-containing acidic and basic (alkaline) sodium aluminum phosphates (SALPs) which are FDA-approved leavening and emulsifying agents, respectively, and used them to determine the oral bioavailability of aluminum incorporated in selected foods. We selected applicable methods from published syntheses (patents) and scaled them down (∼3000- and 850-fold) to prepare ∼300–400 mg of each SALP. The ²⁶Al was incorporated at the beginning of the syntheses to maximize ²⁶Al and ²⁷Al equilibration and incorporate the ²⁶Al in the naturally-occurring Al-containing chemical species of the products. Near infrared spectroscopy (NIR) and X-ray powder diffraction (XRD) were used …

Sara Is An Essential Positive Regulator Of Staphylococcus Epidermidis Biofilm Development, Maria A. Tormo, Miguel Marti, Jaione Valle, Adhar C. Manna

Dartmouth Scholarship

Staphylococcus epidermidis biofilm formation is associated with the production of the polysaccharide intercellular adhesin (PIA)--poly-N-acetylglucosamine polysaccharide (PNAG) by the products of the icaADBC operon. Recent evidence indicates that SarA, a central regulatory element that controls the production of Staphylococcus aureus virulence factors, is essential for the synthesis of PIA/PNAG and the ensuing biofilm development in this species. Based on the presence of a sarA homolog, we hypothesized that SarA could also be involved in the regulation of the biofilm formation process in S. epidermidis. To investigate this, we constructed nonpolar sarA deletions in two genetically unrelated S. epidermidis clinical strains, …

Identification Of A Tcpc-Tcpq Outer Membrane Complex Involved In The Biogenesis Of The Toxin-Coregulated Pilus Of Vibrio Cholerae, Niranjan Bose, Ronald K. Taylor

Dartmouth Scholarship

The toxin-coregulated pilus (TCP) of Vibrio cholerae and the soluble TcpF protein that is secreted via the TCP biogenesis apparatus are essential for intestinal colonization. The TCP biogenesis apparatus is composed of at least nine proteins but is largely uncharacterized. TcpC is an outer membrane lipoprotein required for TCP biogenesis that is a member of the secretin protein superfamily. In the present study, analysis of TcpC in a series of strains deficient in each of the TCP biogenesis proteins revealed that TcpC was absent specifically in a tcpQ mutant. TcpQ is a predicted periplasmic protein required for TCP biogenesis. Fractionation …

Learning To Like: A Role For Human Orbitofrontal Cortex In Conditioned Reward, Sylvia M L Cox, Alexandre Andrade, Ingrid Johnsrude

Brain and Mind Institute Researchers' Publications

A great deal of human behavior and motivation is based on the intrinsic emotional significance of rewarding or aversive events, as well as on the associations formed between such emotional events and concurrent environmental stimuli. Recent functional neuroimaging studies have implicated the ventral striatum, orbitofrontal cortex (OFC), and amygdala in the representation of reward values and/or in the anticipation of rewarding events. Here, we use functional magnetic resonance imaging to compare brain activation during the presentation of reward with that during presentation of (conditioned) stimuli that have been paired previously with reward. Specifically, we aimed to investigate conditioned reward in …

Automated Migration Analysis Based On Cell Texture: Method & Reliability, Jianfeng Qin, Thomas W. Chittenden, Ling Gao, Justin D D. Pearlman

Dartmouth Scholarship

Background: In this paper, we present and validate a way to measure automatically the extent of cell migration based on automated examination of a series of digital photographs. It was designed specifically to identify the impact of Second Hand Smoke (SHS) on endothelial cell migration but has broader applications. The analysis has two stages: (1) preprocessing of image texture, and (2) migration analysis.

Results: The output is a graphic overlay that indicates the front lines of cell migration superimposed on each original image, with automated reporting of the distance traversed vs. time. Expert preference compares to manual placement of leading …

A Contralateral Preference In The Lateral Occipital Area: Sensory And Attentional Mechanisms., Matthias Niemeier, Herbert C Goltz, Anil Kuchinad, Douglas B Tweed, Tutis Vilis

Brain and Mind Institute Researchers' Publications

Here we examined the level of the lateral occipital (LO) area within the processing stream of the ventral visual cortex. An important determinant of an area's level of processing is whether it codes visual elements on both sides of the visual field, as do higher visual areas, or prefers those in the contralateral visual field, as do early visual areas. The former would suggest that LO, on one side, combines bilateral visual elements into a whole, while the latter suggests that it codes only the parts of forms. We showed that LO has a relative preference for visual objects in …

Role For Akt3/Protein Kinase Bγ In Attainment Of Normal Brain Size, Rachel M. Easton, Han Cho, Kristin Roovers, Diana W. Shineman

Dartmouth Scholarship

Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1^−/− mice, which display a …

Rat/Mgra, A Regulator Of Autolysis, Is A Regulator Of Virulence Genes In Staphylococcus Aureus, Susham Ingavale, Willem Van Wamel, Thanh T. Luong, Chia Y. Lee, Ambrose L. Cheung

Dartmouth Scholarship

We have previously identified mgrA (rat) as a regulator of autolysis in Staphylococcus aureus. Besides its effect on autolytic activity, we recently found alterations in the expression of regulator and target virulence genes in the mgrA mutant. Northern analysis and transcription fusion assays showed that inactivation of mgrA has led to the downregulation of RNAIII of agr and hla and upregulation of sarS and spa. Although both SarA and agr are activators of α-hemolysin and a repressors of protein A synthesis, we found that the transcription of sarA was not affected in the mgrA mutant and …

An Analysis Of Biometric Technology As An Enabler To Information Assurance, Darren A. Deschaine

Theses and Dissertations

The use of and dependence on, Information technology (IT) has grown tremendously in the last two decades. Still, some believe the United States is only in the infancy of this growth. This explosive growth has opened the door to capabilities that were only dreamed of in the past. As easy as it is to see how advantageous this technology is, it also is clear that with its advantages come distinct responsibilities and new problems that must be addressed. For instance, the minute one begins using information processing systems, the world of information assurance (IA) becomes far more complex. As a …

Defective B Cell Responses In The Absence Of Sh2d1a, Massimo Morra, Robert A. Barrington, Ana C. Abadia-Molina, Susumo Okamoto, Aimee Julien, Charles A. Gullo Phd, Anuj Kalsy, Matthew J. Edwards, Gang Chen, Rosanne Spolski, Warren J. Leonard, Brigitte T. Huber, Persephone Borrow, Christine A. Biron A. Biron, Abhay R. Satoskar, Michael C. Carroll, Cox Terhorst

Biochemistry and Microbiology

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to Epstein-Barr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in SH2D1A-/- mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent in SH2D1A-/- mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, we examined whether SH2D1A-/- B cell functions were impaired. Using the adoptive …

5-Ht1b Receptor-Mediated Presynaptic Inhibition Of Gaba Release In The Suprachiasmatic Nucleus, Jayne R. Bramley, Patricia J. Sollars, Gary E. Pickard, F. Edward Dudek

School of Veterinary and Biomedical Sciences: Faculty Publications

The suprachiasmatic nucleus (SCN) receives a dense serotonergic innervation that modulates photic input to the SCN via serotonin 1B (5-HT_1B) presynaptic receptors on retinal glutamatergic terminals. However, the majority of 5-HT_1B binding sites in the SCN are located on nonretinal terminals and most axonal terminals in the SCN are GABAergic. We therefore tested the hypothesis that 5-HT_1B receptors might also be located on SCN GABAergic terminals by examining the effects of the highly selective 5-HT_1B receptor agonist CP-93,129 on SCN miniature inhibitory postsynaptic currents (mIPSCs). Whole cell patch-clamp recordings of mIPSCs were obtained from rat …