Medicine and Health Sciences Commons^™

A Selective Gβγ-Linked Intracellular Mechanism For Modulation Of A Ligand-Gated Ion Channel By Ethanol, Gonzalo E. Yevenes, Gustavo Moraga-Cid, Robert W. Peoples, Günther Schmalzing, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

The current understanding about ethanol effects on the ligand-gated ion channel (LGIC) superfamily has been restricted to identify potential binding sites within transmembrane (TM) domains in the Cys-loop family. Here, we demonstrate a key role of the TM3–4 intracellular loop and Gβγ signaling for potentiation of glycine receptors (GlyRs) by ethanol. We discovered 2 motifs within the large intracellular loop of the GlyR α₁ subunit that are critical for the actions of pharmacological concentrations of ethanol. Significantly, the sites were ethanol-specific because they did not alter the sensitivity to general anesthetics, neurosteroids, or longer n-alcohols. Furthermore, Gβγ scavengers …

Kelly, Rita Helen Roberts (Fa 353), Manuscripts & Folklife Archives

FA Finding Aids

Finding aid and full-text scan of paper (Click on “Additional Files” below) for Folklife Archives Project 353. Paper: "Good Mothering through Breast Feeding: Observations of a Meeting of the La Leche League" written by Rita H. Kelly for a Western Kentucky University folk studies class.

Neural Substrates Of Sound–Touch Synesthesia After A Thalamic Lesion, Michael S. Beauchamp, Tony Ro

Publications and Research

Neural plasticity induced by stroke can mediate positive outcomes, such as recovery of function, but can also result in the formation of abnormal connections with negative consequences for perception and cognition. In three experiments using blood-oxygen level dependent (BOLD) functional magnetic resonance imaging, we examined the neural substrates of acquired auditory-tactile synesthesia, in which certain sounds can produce an intense somatosensory tingling sensation in a patient with a thalamic lesion. Compared with nine normal controls, the first experiment showed that the patient had a threefold greater BOLD response to sounds in the parietal operculum, the location of secondary somatosensory cortex. …

Scan-Rescan And Intra-Observer Variability Of Magnetic Resonance Imaging Of Carotid Atherosclerosis At 1.5 T And 3.0 T, Arvin Vidal, Yves Bureau, Trevor Wade, J David Spence, Brian K Rutt, Aaron Fenster, Grace Parraga

Medical Biophysics Publications

Carotid atherosclerosis measurements for eight subjects at baseline and 14 +/- 2 days later were examined using 1.5 T and 3.0 T magnetic resonance imaging (MRI). A single observer blinded to field strength, subject and timepoint manually segmented carotid artery wall and lumen boundaries in randomized images in five measurement trials. Mean increases in the signal-to-noise ratios (SNR) for T1-weighted images acquired at 3.0 T compared to 1.5 T were 90% (scan) and 80% (rescan). Despite significantly improved SNR and contrast-to-noise ratios (CNR) for images acquired at 3.0 T, vessel wall volume (VWV) intra-observer variability was not significantly different using …

Effects Of Shielding Adenoviral Vectors With Polyethylene Glycol On Vector-Specific And Vaccine-Mediated Immune Responses, Eric A. Weaver, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Many individuals have been previously exposed to human adenovirus serotype 5 (Ad5). This prior immunity has long been known to hinder its use for gene therapy and as a gene-based vaccine. Given these immunogenicity problems, we have tested whether polyethylene glycol (PEG) can blunt immune effects against Ad5 during systemic and mucosal vaccination. Ad5 vectors were covalently modified with 5-, 20-, and 35-kDa linear PEG polymers and evaluated for their ability to produce immune responses against transgene antigen products and the vector itself. We show that shielding Ad5 with different-sized PEGs generally reduces transduction and primary antibody responses by the …

Identification And Characterization Of Sigma(S), A Novel Component Of The Staphylococcus Aureus Stress And Virulence Responses, Lindsey N. Shaw, Catharina Lindholm, Tomasz K. Prajsnar, Halie K. Miller, Melanie C. Brown, Ewa Golonka, George C. Stewart, Andrej Tarkowski, Jan Potempa

Molecular Biosciences Faculty Publications

S. aureus is a highly successful pathogen that is speculated to be the most common cause of human disease. The progression of disease in S. aureus is subject to multi-factorial regulation, in response to the environments encountered during growth. This adaptive nature is thought to be central to pathogenesis, and is the result of multiple regulatory mechanisms employed in gene regulation. In this work we describe the existence of a novel S. aureus regulator, an as yet uncharacterized ECF-sigma factor (sigma(S)), that appears to be an important component of the stress and pathogenic responses of this organism. Using biochemical approaches …

Consistency Check Of Planned Adaptive Option On Helical Tomotherapy., M Schirm, S Yartsev, G Bauman, Jerry J. Battista Dr., Jacob Van Dyk

Oncology Publications

This study aims to evaluate a new Planned Adaptive software (TomoTherapy Inc., Madison, WI) of the helical tomotherapy system by retrospective verification and adaptive re-planning of radiation treatment. Four patients with different disease sites (brain, nasal cavity, lungs, prostate) were planned in duplicate using the diagnostic planning kVCT data set and MVCT studies of the first treatment fraction with the same optimization parameters for both plan types. The dosimetric characteristics of minimum, maximum, and mean dose to the targets as well as to organs at risk were compared. Both sets of plans were used for calculation of dose distributions in …

Role Of The Lpa2 Receptor In Protecting Against Apoptosis, Shuyu E

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) is a naturally occurring lipid mediator. It exists abundantly in biological fluids such as serum, saliva, follicular fluid, seminal fluid and malignant effusions and induces a vast array of biological responses affecting cell growth, survival, differentiation, migration and morphology. We recently identified lysophosphatidic acid (LPA) as a potent antiapoptotic agent for the intestinal epithelium. Based on computational modeling octadecenyl thiophosphate (OTP) was synthesized: a novel rationally designed, metabolically stabilized LPA mimic. OTP was more efficacious than LPA in reducing g-irradiation-, camptothecin-, or TNF-a/cycloheximide-induced apoptosis and caspase 3, 8 and 9 activity in the IEC-6 cell line. The …

Abcb6 Is A Porphyrin Transporter With A Novel Trafficking Signal That Is Conserved In Other Abc Transporters, Yu Fukuda

Theses and Dissertations (ETD)

The ATP-binding cassette (ABC) transporters play an important role as a barrier to protect cells from the accumulation of toxic xenobiotics and metabolites due to their ability to translocate a wide array of compounds across lipid bilayers. However, many ABC transporters, especially the ones localized in the intracellular organelles, are involved in critical biological processes such as antigen presentation. The core unit of ABC transporters contains two functional domains: the membrane spanning domain (MSD) and the nucleotide binding domain. The full transporters contain two of these units in tandem in a single polypeptide, whereas the half transporters only contain one …

Meta-Analysis: Prophylactic Drainage And Bleeding Complications In Thyroid Surgery, Steven A. Kennedy, Robert A. Irvine, Brian D. Westerberg, Hongbin Zhang

Publications and Research

Objective: To conduct a comprehensive systematic review and high-quality meta-analysis to determine whether prophylactic drain placement reduces adverse bleeding events in thyroid surgery.

Data Sources: MEDLINE (OVID and PubMed), CENTRAL, CDSR, ACP Journal Club, DARE, EMBASE, PREMEDUNE, OLDMEDLINE, CINAHL, BIOSIS Previews, LILACS, KOREAMED, SAMED, IndMED, SIGLE, ScienceDirect, and INGENTACONNECT.

Review Methods: Studies for evaluation included all prospective trials assessing the use of drainage in thyroid surgery. We excluded case studies, retrospective studies, reviews, and studies that had a "selective" method of postoperative drainage that was not defined or was based on surgeon preference. Search strategies were broad and …

Borderline Personality Disorder: An Overview Of History, Diagnosis And Treatment In Adolescents, Linah Al-Alem, Hatim A. Omar

Pharmacology and Nutritional Sciences Faculty Publications

Borderline personality disorder (BPD) is a cluster B personality disorder. It is characterized by erratic behaviors, emotional instability and one of its hallmarks is self injurious behavior, which starts in adolescence. Patients with BPD are difficult to treat, most have a history of child sexual abuse, about a quarter present with sexual abuse from a caretaker. Although personality disorders are diagnosed only in adults, BPD manifests itself in adolescence in the form of uncontrollable anger, self mutilations, dissociation and other such behaviors. Hence, there is a growing number of scientists discussing the possibility of diagnosing BPD in adolescents. Here, we …

Studies To Characterize The Requirements For The Binding And Release Of Erdj3, A Mammalian Er Dnaj Homolog, From Substrates, Yi Jin

Theses and Dissertations (ETD)

Heat shock protein 70s (Hsp70s) and their DnaJ co-factors exist in all organisms and in all eukaryotic organelles. These highly conserved chaperone pairs facilitate a large number of cellular processes. ERdj3 was identified as a soluble, lumenal DnaJ family member that binds to unassembled immunoglobulin heavy chains (HC) along with the BiP chaperone complex in the endoplasmic reticulum of mammalian cells. Here we demonstrate that ERdj3 binds directly to two unfolded substrates: immunoglobulin γHC and denatured firefly luciferase. Using mutagenesis studies on ERdj3 in both in vivo and in vitro binding assays, we defined ERdj3’s critical amino acids in domain …

The Tetraspanin Cd9 Localizes To Platelet-Platelet Contacts And Regulates Thrombus Stability, Sarah Kathleen Hill

Theses and Dissertations (ETD)

CD9, a member of the tetraspanin family, is highly expressed on platelets (50,000-80,000 copies per platelet). Tetraspanins have been implicated in modulation of integrin function, and it is hypothesized that CD9 will modulate GPIIb-IIIa, the major platelet integrin.

The association between CD9 and GPIIb-IIIa was analyzed using immunoprecipitations and confocal microscopy. These two proteins were found to associate with each other, particularly at areas of platelet-platelet contact and at the periphery. Confocal analysis revealed CD9 localization was most intense at platelet-platelet contact, as well as in platelet filopodia and lamellipodia, but there is a lack of CD9 at areas of …

Interaction Of Bacteriophage Mu Middle Transcription Activator Protein Mor With Promoter Dna, Kartik Iyer

Theses and Dissertations (ETD)

Gene expression during lytic development of bacteriophage Mu is regulated by a

transcriptional cascade in three phases: early, middle and late. Transcription from the middle promoter Pm requires the 129-amino acid transcriptional activator Mor, a product of early transcription, and the Escherichia coli RNA polymerase. The Pm promoter has a recognizable -10 hexamer but lacks a -35 hexamer. Mor binds as a dimer to an imperfect dyad-symmetrical element containing two 6-bp inverted repeats and centered at -43.5 in Pm. The goals of this study were:

1. To test the prediction from the crystal structure of Mor that residues Y70 and …

Upregulation Of Heme Oxygenase-1 Combined With Increased Adiponectin Lowers Blood Pressure In Diabetic Spontaneously Hypertensive Rats Through A Reduction In Endothelial Cell Dysfunction, Apoptosis And Oxidative Stress, Jian Cao, George Drummond, Kazuyoshi Inoue, Komal Sodhi, Xiao Ying Li, Shinji Omura

Pharmaceutical Science and Research

This study was designed to investigate the effect of increased levels of HO-1 on hypertension exacerbated by diabetes. Diabetic spontaneously hypertensive rat (SHR) and WKY (control) animals were treated with streptozotocin (STZ) to induce diabetes and stannous chloride (SnCl2) to upregulate HO-1. Treatment with SnCl2 not only attenuated the increase of blood pressure (p<0.01), but also increased HO-1 protein content, HO activity and plasma adiponectin levels, decreased the levels of superoxide and 3-nitrotyrosine (NT), respectively. Reduction in oxidative stress resulted in the increased expression of Bcl-2 and AKT with a concomitant reduction in circulating endothelial cells (CEC) in the peripheral blood (p<0.005) and an improvement of femoral reactivity (response to acetylcholine). Thus induction of HO-1 accompanied with increased plasma adiponectin levels in diabetic hypertensive rats alters the phenotype through a reduction in oxidative stress, thereby permitting endothelial cells to maintain an anti-apoptotic environment and the restoration of endothelial responses thus preventing hypertension.

Retinoid X Receptor And Peroxisome Proliferator-Activated Receptor-Gamma Agonists Cooperate To Inhibit Matrix Metalloproteinase Gene Expression, Peter S. Burrage, Adam C. Schmucker, Yanqing Ren, Michael B. Sporn, Constance E. Brinckerhoff

Dartmouth Scholarship

We recently described the ability of retinoid X receptor (RXR) ligand LG100268 (LG268) to inhibit interleukin-1-beta (IL-1-β)-driven matrix metalloproteinase-1 (MMP-1) and MMP-13 gene expression in SW-1353 chondrosarcoma cells. Other investigators have demonstrated similar effects in chondrocytes treated with rosiglitazone, a ligand for peroxisome proliferator-activated receptor-gamma (PPARγ), for which RXR is an obligate dimerization partner. The goals of this study were to evaluate the inhibition of IL-1--induced expression of MMP-1andMMP-13 by combinatorial treatment with RXR and PPAR  ligands and to investigate the molecular mechanisms of this inhibition.

Characterization Of The Ompl1 Gene Of Pathogenic Leptospira Species In China And Cross-Immunogenicity Of The Ompl1 Protein, Haiyan Dong, Ye Hu, Feng Xue, Dexter Sun, David M. Ojcius, Yafei Mao, Jie Yan

All Dugoni School of Dentistry Faculty Articles

Background: The usefulness of available vaccine and serological tests for leptospirosis is limited by the low cross-reactivity of antigens from numerous serovars of pathogenic Leptospira spp. Identification of genus-specific protein antigens (GP-Ag) of Leptospira would be important for development of universal vaccines and serodiagnostic methods. OmpL1, a transmembrane porin of pathogenic leptospires, was identified as a possible GP-Ag, but its sequence diversity and immune cross-reactivity among different serovars of pathogenic leptospires remains largely unknown.

Results: PCR analysis demonstrated that the ompL1 gene existed in all 15 official Chinese standard strains as well as 163 clinical strains of pathogenic leptospires isolated …

Creation Of A Mouse With A Humanized Fpgs Gene Compatible With Normal Development, Linying Xie

Theses and Dissertations

Abstract: Folylpoly-γ-glutamate synthetase (FPGS) catalyzes the formation of polyglutamate forms of the reduced folates and antifolates such as methotrexate (MTX) and pemetrexed; this allows the retention of folates and antifolate cancer drugs inside the cell. The enzyme activity of FPGS is essential for cell proliferation and survival. The mouse fpgs gene contains two promoters spaced 10 kb apart which are activated in a tissue-specific manner. The upstream promoter (P1) and exons A1a and A1b are used in some differentiated tissues, mainly liver and kidney, whereas the downstream promoter (P2) and exon 1 are used in rapidly dividing cells. In contrast, …

The Role Of Gtp In Transient Splitting Of 70s Ribosomes By Rrf (Ribosome Recycling Factor) And Ef-G (Elongation Factor G)., Go Hirokawa, Nobuhiro Iwakura, Akira Kaji, Hideko Kaji

Department of Biochemistry and Molecular Biology Faculty Papers

Ribosome recycling factor (RRF), elongation factor G (EF-G) and GTP split 70S ribosomes into subunits. Here, we demonstrated that the splitting was transient and the exhaustion of GTP resulted in re-association of the split subunits into 70S ribosomes unless IF3 (initiation factor 3) was present. However, the splitting was observed with sucrose density gradient centrifugation (SDGC) without IF3 if RRF, EF-G and GTP were present in the SDGC buffer. The splitting of 70S ribosomes causes the decrease of light scattering by ribosomes. Kinetic constants obtained from the light scattering studies are sufficient to account for the splitting of 70S ribosomes …

Regulation Of The Human Parainfluenza Virus (Hpiv3) Fusion Protein, Amanda Ruth Chapman

Theses and Dissertations (ETD)

Paramyxoviruses include a number of important human pathogens, including measles virus, mumps virus, and the human parainfluenza viruses (hPIV) 1-4, as well as several animal pathogens, such as Sendai virus, Nipah virus and Hendra virus. The creation of effective drugs and vaccines against this family of viruses would play an important role in decreasing the prevalence of these viruses and contributing to the health of both humans and animals worldwide. The purpose of this work was to determine how the fusion (F) protein is regulated with a focus on the heptad repeat B (HRB) region of the F protein located …

The Role Of Fgf Signaling In Retinal Development, Abbie A. Hartge

Theses and Dissertations (ETD)

The development of the retina is a precise balance between intrinsic competence and extrinsic factors. This interplay is known to regulate the generation of cell types in the developing retina and similar mechanisms have been found in other regions of the CNS. In the developing retina, FGFs are a large family of secreted polypeptide growth factors. Fgf15 is the major Fgf expressed during retinal development in mice. Fgf15 is an example of an FGF that has been shown to control proliferation, cell fate specification, differentiation and migration during development. In this thesis I used analysis of specific genes throughout retinal …

Torsina And The Pathophysiology Of Dyt1 Dystonia, Yu Zhao

Theses and Dissertations (ETD)

The goal of my dissertation work was to examine the systems biology of torsinA, a DYT1 dystonia-associated protein, by using rodent model systems. TorsinA is a putative ATPase associated with a variety of cellular activities (AAA+). Deletion of glutamic acid residue 302/303 in TOR1A is causally associated with many cases of early-onset primary dystonia.

In our work, transient forebrain ischemia and sciatic nerve transection were used as central and peripheral neural perturbations, respectively, to gain insight into the in vivo role(s) of torsinA. Moreover, transgenic mouse models that overexpress either human mutant torsinA (hMT) or wild-type torsinA (hWT) were used …

The Differentiation Of Hepatocyte-Like Cells From Monkey Embryonic Stem Cells., Xiaocui Ma, Jian Wu, M Zern

jian duan wu

Embryonic stem cells (ESC) hold great potential for the treatment of liver diseases. Here, we report the differentiation of rhesus macaque ESC along a hepatocyte lineage. The undifferentiated monkey ESC line, ORMES-6, was cultured in an optimal culture condition in an effort to differentiate them into hepatocyte-like cells in vitro. The functional efficacy of the differentiated hepatic cells was evaluated using RT-PCR for the expression of hepatocyte specific genes, and Western blot analysis and immunocytochemistry for hepatic proteins such as alpha-fetoprotein (AFP), albumin and alpha1-antitrypsin (alpha1-AT). Functional assays were performed using the periodic acid schiff (PAS) reaction and ELISA. The …

Genetic Counselling And Testing For Inherited Gene Mutations In Newly Diagnosed Patients With Breast Cancer: A Review Of The Existing Literature And A Proposed Research Agenda, Bettina Meiser, Kathy Tucker, Michael Friedlander, Kristine Barlow-Stewart, Elizabeth Lobb, Christobel Saunders, Gillian Mitchell

Research outputs pre 2011

Many women newly diagnosed with breast cancer and with a strong family history of breast cancer are referred to a family cancer service for genetic counselling and for consideration of genetic testing for germline mutations in cancer predisposition genes following completion of their cancer treatment. However, there is growing evidence that mutation status may influence treatment recommendations, and that there may be benefits in having 'treatment-focused genetic counselling and testing' available shortly after cancer diagnosis. This article reviews the literature that could inform the development of treatment-focused genetic counselling and testing, including: the rationale for genetic testing to aid with …

Stromal Gene Signatures In Large-B-Cell Lymphomas., G Lenz, G Wright, S S Dave, W Xiao, J Powell, H Zhao, W Xu, B Tan, N Goldschmidt, Javeed Iqbal, Julie M. Vose, M Bast, Kai Fu, D D. Weisenburger, T C Greiner, James O. Armitage, A Kyle, L May, R D Gascoyne, J M Connors, G Troen, H Holte, S Kvaloy, D Dierickx, G Verhoef, J Delabie, E B Smeland, P Jares, A Martinez, A Lopez-Guillermo, E Montserrat, E Campo, R M Braziel, T P Miller, L M Rimsza, J R Cook, B Pohlman, J Sweetenham, R R Tubbs, R I Fisher, E Hartmann, A Rosenwald, G Ott, H-K Muller-Hermelink, D Wrench, T A Lister, E S Jaffe, W H Wilson, W C. Chan, L M Staudt

Journal Articles: Pathology and Microbiology

BACKGROUND: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear.

METHODS: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group.

RESULTS: A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted …

Androgen-Independent Prostate Cancer Cells Acquire The Complete Steroidogenic Potential Of Synthesizing Testosterone From Cholesterol., Paulette R. Dillard, Ming-Fong Lin, Shafiq A. Khan

Journal Articles: Biochemistry & Molecular Biology

The proliferation and differentiation of normal prostate epithelial cells depends upon the action of androgens produced by the testis. Prostate cancers retain the ability to respond to androgens in the initial stages of cancer development, but progressively become independent of exogenous androgens in advanced stages of the disease while maintaining the expression of functional androgen receptor (AR). In the present study, we have determined the potential of prostate cancer cells to synthesize androgens from cholesterol which may be involved in intracrine regulation of AR in advanced stages of the disease. Established androgen-independent prostate cancer cell lines, PC3 and DU145 cells, …

In Vivo Trafficking Of Endogenous Opioid Receptors, Yulin Wang, Elisabeth J. Van Bockstaele, Lee-Yuan Liu-Chen

Department of Neurosurgery Faculty Papers

Studies on trafficking of endogenous opioid receptors in vivo are subject of the present review. In many of the in vivo studies, the use of semi-quantitative immuno-electron microscopy is the approach of choice. Endogenous opioid receptors display differential subcellular distributions with μ opioid receptor (MOPR) being mostly present on the plasma membrane and δ- and κ-opioid receptors (DOPR and KOPR, respectively) having a significant intracellular pool. Etorphine and DAMGO cause endocytosis of the MOPR, but morphine does not, except in some dendrites. Interestingly, chronic inflammatory pain and morphine treatment promote trafficking of intracellular DOPR to the cell surface which may …

Fitness And Action Monitoring: Evidence For Improved Cognitive Flexibility In Young Adults, Jason R. Themanson, Matthew B. Pontifex, Charles H. Hillman

Jason R. Themanson, Ph.D

To improve behavior, one must detect errors and initiate subsequent corrective adaptations. This action monitoring process has been widely studied, but little is known about how one may improve this aspect of cognition. To examine the relationship between cardiorespiratory fitness and action monitoring, we recorded the error-related negativity (ERN), an event-related brain potential believed to index action monitoring, as well as post-error behavioral indices of action monitoring from healthy young adults (18–25 years) who varied in cardiorespiratory fitness. These measures were collected during the execution of flanker tasks emphasizing response accuracy or speed to better assess the specificity of any …

Finding Recurrent Regions Of Copy Number Variation: A Review, Oscar M. Rueda, Ramon Diaz-Uriarte

Ramon Diaz-Uriarte

Copy number alterations (CNA) in genomic DNA are linked to a variety of human diseases. Although many methods have been developed to analyze data from a single subject, disease-critical genes are more likely to be found in regions that are common or recurrent among diseased subjects. Unfortunately, finding recurrent CNA regions remains a challenge. We review existing methods for the identification of recurrent CNA regions. Methods differ in their working definition of ``recurrent region'', the type of input data, the statistical and computational methods used to identify recurrence, and the biological considerations they incorporate (which play a role in the …

Regressing Scalar Outcomes On Image Predictors Via Functional Principal Component Regression, Philip T. Reiss

Philip T. Reiss

No abstract provided.